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Background: Sex may impact clinical outcomes in patients with stroke treated with dual antiplatelet therapy (DAPT). We aimed to investigate the sex differences in the short-term outcomes of DAPT within a real-world population of patients with noncardioembolic mild-to-moderate ischemic stroke or high-risk transient ischemic attack., Methods: We performed a propensity score-matched analysis from a prospective multicentric cohort study (READAPT [Real-Life Study on Short-Term Dual Antiplatelet Treatment in Patients With Ischemic Stroke or Transient Ischemic Attack]) by including patients with noncardioembolic mild-to-moderate stroke (National Institutes of Health Stroke Scale score of 0-10) or high-risk transient ischemic attack (age, blood pressure, clinical features, duration of transient ischemic attack, presence of diabetes [ABCD 2 ] ≥4) who initiated DAPT within 48 hours of symptom onset. The primary effectiveness outcome was the 90-day risk of new ischemic stroke or other vascular events. The secondary effectiveness outcomes were the 90-day modified Rankin Scale score ordinal shift, vascular and all-cause mortality, and 24-hour early neurological improvement or deterioration. The safety outcomes included the 90-day risk of moderate-to-severe and any bleeding, symptomatic intracranial hemorrhage, and 24-hour hemorrhagic transformation. Outcomes were compared between sexes using Cox and generalized ordinal logistic regression analyses, along with calculating risk differences and ratios., Results: From 2278 patients in the READAPT study cohort, we included 1643 mild-to-moderate strokes or high-risk transient ischemic attacks treated with DAPT (mean age, 69.8±12.0 years; 34.3% women). We matched 531 women and men. The 90-day risk of new ischemic stroke or other vascular events was significantly lower among women than men (hazard ratio, 0.53 [95% CI, 0.28-0.99]; P =0.039). There were no significant differences in secondary effectiveness outcomes. The 90-day risk of safety outcomes was extremely low and did not differ between women and men (moderate-to-severe bleedings: 0.4% versus 0.8%; P =0.413; symptomatic intracranial hemorrhage: 0.2% versus 0.4%; P =0.563). Subgroup analysis for primary effectiveness outcome showed a lower 90-day risk of new ischemic stroke or other vascular events among women aged <50 years, baseline National Institutes of Health Stroke Scale score of 0 to 5, prestroke modified Rankin Scale score <2, large artery atherosclerosis cause, and no diabetes., Conclusions: Our findings suggest that women with noncardioembolic mild-to-moderate stroke or high-risk transient ischemic attack treated with DAPT may have lower short-term risk of recurrent ischemic events than men. Further research is needed to understand the mechanisms behind potential sex-based differences in outcomes after DAPT use., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05476081., Competing Interests: Dr Piscaglia reports grants from Sanofi Genzyme, Roche Health Solutions, Inc, Novartis Pharma, Biogen, and Merck Company Foundation. Dr Paciaroni reports compensation from Boehringer Ingelheim, PFIZER CANADA INC, Bristol-Myers Squibb; iRhythm Technologies; SANOFI-AVENTIS U.S. LLC, and Daiichi Sankyo Europe GmbH for other services. Dr Zini reports compensation from Bayer Healthcare for other services and Boehringer Ingelheim, Alexion Pharmaceuticals, and CSL Behring for consultant services. Dr Ornello reports grants from Novartis, Pfizer, and Allergan and compensation from Teva Pharmaceutical Industries, Eli Lilly and Company, Novartis, and H. Lundbeck A S for other services; AbbVie and Eli Lilly for data and safety monitoring services; Teva Pharmaceutical Industries for consultant services; and reports and travel support from Teva Pharmaceutical Industries. Dr Sacco reports compensation from Novartis for other services; compensation from Novo Nordisk, Boehringer Ingelheim, Teva Pharmaceutical Industries, Allergan, Novartis, PFIZER CANADA INC, Abbott Canada, H. Lundbeck A S, AstraZeneca, and Eli Lilly and Company for consultant services; and employment by Università degli Studi dell’Aquila. The other authors report no conflicts.

Background: Patients with ischemic stroke (IS) or TIA face an elevated cardiovascular risk, warranting intensive lipid-lowering therapy. Despite recommendations, adherence to guidelines is suboptimal, leading to frequent undertreatment. This study aims to evaluate the statin use after IS and TIA., Methods: LIPYDS is a multicenter, observational, retrospective study including ≥ 18-year-old patients discharged after IS/TIA from 19 Italian centers in 2021. Multivariable logistic regression analysis was used to determine (1) the association between statin prescription (Any-statin versus No-statin), type (High-Intensity-statin versus Other-statin [Moderate/Low-Intensity]) with stroke etiology (TOAST), (2) clinical variables independently associated with statin prescription in the entire cohort and within TOAST categories., Results: We included 3,740 patients (median age 75 [IQR 64-82]; median LDL-C 104 [IQR 79-131]). At discharge, 1,971 (52.7%) received a High-intensity-statin, 800 (21.4%) Other-statin, 969 (25.9%) No-statin therapy. Among patients not on statin therapy before the event (N = 2686 [71.8%]), 50.1% initiated High-intensity-statin (78.2% of those with Large-Artery-Atherosclerosis, 60.8% Small-Vessel-Disease, 34.7% Cardioembolic, 47.4% Undetermined etiology); in 33% the decision to abstain from initiating statin therapy persisted. Large-Artery-Atherosclerosis showed the strongest association with Any-statin (aOR 3.07 [95%CI 2.39-3.95], p < 0.001) and High-intensity-statin (aOR 4.51 [95%CI 3.39-6.00], p < 0.001), while Cardioembolic stroke showed an inverse association (respectively, aOR 0.36 [95%CI 0.31-0.43], p < 0.001 and aOR 0.52 [95%CI 0.44-0.62], p < 0.001). Stepwise regression highlighted LDL-C and previous statin therapy as consistent predictors of statin at discharge. Older patients and women were less likely to be on a high-intensity formulation., Conclusion: Statins, especially at high-intensity, are under-prescribed after IS and TIA, with older patients, women and those with non-atherosclerotic strokes being the most affected., Competing Interests: Declarations. Conflict of interest: Andrea Zini received funding for speaker honoraria and consulting fees from Daiichi-Sankyo, Bayer, CSL Behring, Angels Initiative, Alexion-AstraZeneca, for scientific advisory board from Alexion-AstraZeneca and Bayer. Manuel Cappellari received consultancy or advisory board fees or speaker’s honoraria from Pfizer/Bristol-Meyer-Squibb, and Daiichi-Sankyo. All other co-authors have no relevant competing interests related to this study. Ethical statement: This study was approved by the local Ethical Committee (Comitato Etico Milano Area 3, n. 290-20042022)., (© 2024. Fondazione Società Italiana di Neurologia.)

Background: According to the literature, about one third of patients with brain ischemic symptoms lasting <24 h, which are classified as Transient ischemic attacks (TIAs) according to the traditional "time-based" definition, show the presence of acute ischemic lesions at neuroimaging. Recent evidence has shown that the presence of acute ischemic lesions at neuroimaging may impact on the outcome of patients with transient ischemic symptoms treated with dual antiplatelet treatment (DAPT). This uncertainty is even more compelling in recent years as short-term DAPT has become the standard treatment for any non-cardioembolic TIA or minor ischemic stroke., Methods: This is a pre-specified subgroup analysis from a prospective multicenter real-world study (READAPT). The analysis included patients with time-based TIA-that is, those with ischemic symptoms lasting <24 h-who started DAPT. In the whole population, we assessed the presence of acute brain ischemic lesions at neuroimaging and their association with the ABCD 2 score. To assess the impact of acute brain ischemic lesions on 90-day prognosis, we performed a propensity score matching of patients with and without those lesions. We adopted a primary effectiveness outcome which was a composite of new stroke/TIA events and death due to vascular causes at 90 days., Results: We included 517 patients-324 (62.7%) male-with a median (interquartile range-IQR) age of 74 (IQR = 65-81) years; 144 patients (27.9%) had acute brain ischemic lesions at neuroimaging. The proportion of patients with brain ischemic lesions did not vary according to the ABCD 2 score. At follow-up, 4 patients with brain ischemic lesions (2.8%) and 21 patients without lesions (5.6%) reported the primary effectiveness outcome, which was similar between the groups before ( p  = 0.178) and after matching ( p  = 0.518)., Conclusions: In our population, patients with transient ischemic symptoms and acute ischemic lesions at brain magnetic resonance imaging (MRI) had a risk of recurrent ischemic events similar to those without lesions. The risk of recurrent ischemic events was low in both groups., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.Z. reports compensation from Angels Initiative, Boehringer-Ingelheim, and Daiichi Sankyo for consultant services; from Angels Initiative, Boehringer-Ingelheim, and CSL Behring for speaking honoraria or other education services; from Daiichi Sankyo for meeting; from Bayer and Astra Zeneca for participation on a Data Safety, Monitoring Board or Advisory Board; and he is member of ESO guidelines, ISA-AII guidelines, and IRETAS steering committee. R.O. reports grants from Novartis and Allergan; compensation from Teva Pharmaceutical Industries, Eli Lilly and Company, and Novartis for other services; and travel support from Teva Pharmaceutical Industries. S.S. reports compensation from Novartis, NovoNordisk, Allergan, AstraZeneca, Pfizer Canada, Inc., Eli Lilly and Company, Teva Pharmaceutical Industries, H. Lundbeck A/S, and Abbott Canada for consultant services; employment by Università degli Studi dell’Aquila; and compensation from Novartis for other services. MP reports compensation from Daiichi Sankyo Company, Bristol Myers Squibb, Bayer, and Pfizer Canada, Inc., for consultant services. DT reports compensation from Alexion, Astra Zeneca, Medtronic, and Pfizer for consultant services and participation on a Data Safety, Monitoring Board or Advisory Board. The other authors report no conflicts.

Background: Short-term dual antiplatelet treatment (DAPT) is superior to single antiplatelet treatment (SAPT) for secondary prevention in non-cardioembolic minor ischemic stroke and high-risk transient ischemic attack (TIA). As the real-world use of DAPT is broader than in trials, it is important to clarify its benefit/risk profile in a diverse population., Methods: Post hoc analysis of prospectively collected data from the READAPT cohort and three prospective stroke registries including patients with mild-to-moderate (National Institute of Health Stroke Scale (NIHSS) score 0-10) ischemic stroke receiving early DAPT or SAPT. The primary effectiveness outcome was 90-day return to pre-stroke neurological functioning using modified Rankin Scale (mRS) score. Secondary effectiveness outcomes were 90-day mRS shift, new ischemic stroke/TIA, vascular and all-cause death, 24 h early neurological improvement or deterioration. The safety outcome was 90-day intracranial hemorrhage., Results: We matched 1008 patients treated with DAPT and 1008 treated with SAPT. Compared to SAPT, patients treated with DAPT showed higher likelihood of 90-day primary effectiveness outcome (87.5% vs. 84.4%, risk difference 3.1% (95% confidence interval (CI): 0.1%-6.1%); p = 0.047, risk ratio 1.03 (95% CI: 1.01-1.07); p = 0.043) and higher rate of 24-h early neurological improvement (25.3% vs. 15.4%, risk difference 9.9% (95% CI: 6.4%-13.4%); p < 0.001, risk ratio 1.65 (95% CI: 1.37-1.97); p < 0.001). No differences were observed for other study outcomes. Subgroup analysis confirmed benefit of DAPT over SAPT for primary effectiveness outcome in patients with moderate stroke, those treated with intravenous thrombolysis, and those who received antiplatelet loading dose., Conclusion: Our findings suggest that DAPT use might be safe and more effective than SAPT even in the real world and in patients who do not strictly fulfill the criteria of landmark large clinical trials., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AZ reports compensation from Angels Initiative, Boehringer-Ingelheim, Daiichi Sankyo for consultant services; from Angels Initiative, Boehringer-Ingelheim, CSL Behring for speaking honoraria or other education services; from Daiichi Sankyo for meeting; from Bayer, and Astra Zeneca for participation on a Data Safety, Monitoring or Advisory Board; he is member of ESO guidelines, ISA-AII guidelines, and IRETAS steering committee. RO reports grants from Novartis and Allergan; compensation from Teva Pharmaceutical Industries, Eli Lilly and Company, and Novartis for other services; and travel support from Teva Pharmaceutical Industries. SS reports compensation from Novartis, NovoNordisk, Allergan, AstraZeneca, Pfizer Canada, Inc, Eli Lilly and Company, Teva Pharmaceutical Industries, H. Lundbeck A/S, and Abbott Canada for consultant services; compensation from Novartis for other services. MP reports compensation from Daiichi Sankyo Company, Bristol Myers Squibb, Bayer, and Pfizer Canada, Inc., for consultant services. The other authors report no conflicts.

Background and Purpose: Randomized controlled trials (RCTs) proved the efficacy of short-term dual antiplatelet therapy (DAPT) in secondary prevention of minor ischemic stroke or high-risk transient ischemic attack (TIA). We aimed at evaluating effectiveness and safety of short-term DAPT in real-world, where treatment use is broader than in RCTs., Methods: READAPT (REAl-life study on short-term Dual Antiplatelet treatment in Patients with ischemic stroke or Transient ischemic attack) (NCT05476081) was an observational multicenter real-world study with a 90-day follow-up. We included patients aged 18+ receiving short-term DAPT soon after ischemic stroke or TIA. No stringent NIHSS and ABCD 2 score cut-offs were applied but adherence to guidelines was recommended. Primary effectiveness outcome was stroke (ischemic or hemorrhagic) or death due to vascular causes, primary safety outcome was moderate-to-severe bleeding. Secondary outcomes were the type of ischemic and hemorrhagic events, disability, cause of death, and compliance to treatment., Results: We included 1920 patients; 69.9% started DAPT after an ischemic stroke; only 8.9% strictly followed entry criteria or procedures of RCTs. Primary effectiveness outcome occurred in 3.9% and primary safety outcome in 0.6% of cases. In total, 3.3% cerebrovascular ischemic recurrences occurred, 0.2% intracerebral hemorrhages, and 2.7% bleedings; 0.2% of patients died due to vascular causes. Patients with NIHSS score ⩽5 and those without acute lesions at neuroimaging had significantly higher primary effectiveness outcomes than their counterparts. Additionally, DAPT start >24 h after symptom onset was associated with a lower likelihood of bleeding., Conclusions: In real-world, most of the patients who receive DAPT after an ischemic stroke or a TIA do not follow RCTs entry criteria and procedures. Nevertheless, short-term DAPT remains effective and safe in this population. No safety concerns are raised in patients with low-risk TIA, more severe stroke, and delayed treatment start., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AZ reports compensation from Angels Initiative, Boehringer-Ingelheim, Daiichi Sankyo, CSL Behring, Bayer, and Astra Zeneca; and he is member of ESO guidelines, ISA-AII guidelines, and IRETAS steering committee. RO reports compensations from Novartis and Allergan, Teva Pharmaceutical Industries, Eli Lilly and Company, SS reports compensations from Novartis, NovoNordisk, Allergan, AstraZeneca, Pfizer Canada, Inc, Eli Lilly and Company, Teva Pharmaceutical Industries, H. Lundbeck A/S, and Abbott Canada; employment by Università degli Studi dell’Aquila. MPa reports compensation from Daiichi Sankyo Company, Bristol Myers Squibb, Bayer, and Pfizer Canada, Inc. DT reports compensation from Alexion, AstraZeneca, Medtronic, and Pfizer. The other authors report no conflicts.

Background: The outcomes of minor ischemic stroke resulting from small artery occlusion (SAO-MIS) have not yet been characterized after dual antiplatelet treatment (DAPT) has become the standard of care. We provided updated figures on the short-term prognosis of SAO-MIS treated with early short-term DAPT and compared the outcomes of SAO-MIS versus non-SAO-MIS patients., Methods: This is a prespecified sub-analysis from a prospective multicentric real-world study (READAPT, NCT05476081) including patients with minor (NIHSS≤5) non-cardioembolic ischemic stroke treated with DAPT. The primary outcome was a composite of 90-day symptomatic ischemic stroke or major cardiovascular events. Secondary outcomes were the 90-day ordinal distribution of modified Rankin Scale (mRS) scores, 90-day excellent functional outcome (mRS of 0 to 1), and 24-h early neurological deterioration (END). Safety outcomes were 90-day intracerebral hemorrhage, moderate-to-severe and any bleedings. All outcomes were compared between SAO-MIS and non-SAO-MIS patients., Results: We included 678 MIS, of whom 253 (37.3 %) were SAO-related. At 90 days, 3 patients with SAO-MIS had primary outcome (1.2 % [95 % CI 0.2 %-3.5 %]), which were all SAO-related ischemic strokes. For the secondary outcomes, most SAO-MIS patients (n = 191, 75.5 %) had 90-day excellent functional outcome and 12 had 24-h END (4.7 % [95 % CI 2.5 %-8.3 %]). Referring to safety outcomes, 90-day intracerebral hemorrhage occurred only in one patient with SAO-MIS (0.4 % [95 % CI 0.0 %- 2.2 %]). Compared to non-SAO-MIS, the 90-day risk of recurrent vascular events was significantly lower among SAO-MIS (aHR 0.24 [95 % CI 0.08-0.68]; p = 0.007), while there were not significant differences in other secondary outcomes, nor in the risk of safety events., Conclusions: Our findings show overall favorable short-term prognosis after SAO-MIS treated with DAPT. Future studies should investigate factors associated with residual stroke risk and long-term outcomes of SAO-MIS., Competing Interests: Declaration of competing interest Andrea Zini reports compensation from Angels Initiative, Boehringer-Ingelheim, Daiichi Sankyo for consultant services; from Angels Initiative, Boehringer-Ingelheim, CSL Behring for speaking honoraria or other education services; from Daiichi Sankyo for meeting; from Bayer, and Astra Zeneca for participation on a Data Safety, Monitoring Board or Advisory Board; and he is member of ESO guidelines, ISA-AII guidelines, and IRETAS steering committee. Raffaele Ornello reports grants from Novartis and Allergan; compensation from Teva Pharmaceutical Industries, Eli Lilly and Company, and Novartis for other services; and travel support from Teva Pharmaceutical Industries. Simona Sacco reports compensation from Novartis, NovoNordisk, Allergan, AstraZeneca, Pfizer Canada, Inc., Eli Lilly and Company, Teva Pharmaceutical Industries, H. Lundbeck A/S, and Abbott Canada for consultant services; employment by University of L'Aquila; and compensation from Novartis for other services. Maurizio Paciaroni reports compensation from Daiichi Sankyo Company, Bristol Myers Squibb, Bayer, and Pfizer Canada, Inc., for consultant services. Danilo Toni reports compensation from Alexion, Astra Zeneca, Medtronic, and Pfizer for consultant services and participation on a Data Safety, Monitoring Board or Advisory Board. The other authors report no conflicts., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The optimal treatment for acute minor ischemic stroke is still undefined. and options include dual antiplatelet treatment (DAPT), intravenous thrombolysis (IVT), or their combination. We aimed to investigate benefits and risks of combining IVT and DAPT versus DAPT alone in patients with MIS., Methods and Results: This is a prespecified propensity score-matched analysis from a prospective multicentric real-world study (READAPT [Real-Life Study on Short-Term Dual Antiplatelet Treatment in Patients With Ischemic Stroke or Transient Ischemic Attack]). We included patients with MIS (National Institutes of Health Stroke Scale score at admission ≤5), without prestroke disability (modified Rankin scale [mRS] score ≤2). The primary outcomes were 90-day mRS score of 0 to 2 and ordinal mRS distribution. The secondary outcomes included 90-day risk of stroke and other vascular events and 24-hour early neurological improvement or deterioration (≥2-point National Institutes of Health Stroke Scale score decrease or increase from the baseline, respectively). From 1373 patients with MIS, 240 patients treated with IVT plus DAPT were matched with 427 patients treated with DAPT alone. At 90 days, IVT plus DAPT versus DAPT alone showed similar frequency of mRS 0 to 2 (risk difference, 2.3% [95% CI -2.0% to 6.7%]; P =0.295; risk ratio, 1.03 [95% CI 0.98-1.08]; P =0.312) but more favorable ordinal mRS scores distribution (odds ratio, 0.57 [95% CI 0.41-0.79]; P <0.001). Compared with patients treated with DAPT alone, those combining IVT and DAPT had higher 24-hour early neurological improvement (risk difference, 20.9% [95% CI 13.1%-28.6%]; risk ratio, 1.59 [95% CI 1.34-1.89]; both P <0.001) and lower 90-day risk of stroke and other vascular events (hazard ratio, 0.27 [95% CI 0.08-0.90]; P =0.034). There were no differences in safety outcomes., Conclusions: According to findings from this observational study, patients with MIS may benefit in terms of better functional outcome and lower risk of recurrent events from combining IVT and DAPT versus DAPT alone without safety concerns., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05476081.

The implications of neurogenic inflammation and neuroinflammation in the pathophysiology of migraine have been clearly demonstrated in preclinical migraine models involving several sites relevant in the trigemino-vascular system, including dural vessels and trigeminal endings, the trigeminal ganglion, the trigeminal nucleus caudalis as well as central trigeminal pain processing structures. In this context, a relevant role has been attributed over the years to some sensory and parasympathetic neuropeptides, in particular calcitonin gene neuropeptide, vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Several preclinical and clinical lines of evidence also support the implication of the potent vasodilator and messenger molecule nitric oxide in migraine pathophysiology. All these molecules are involved in vasodilation of the intracranial vasculature, as well as in the peripheral and central sensitization of the trigeminal system. At meningeal level, the engagement of some immune cells of innate immunity, including mast-cells and dendritic cells, and their mediators, has been observed in preclinical migraine models of neurogenic inflammation in response to sensory neuropeptides release due to trigemino-vascular system activation. In the context of neuroinflammatory events implicated in migraine pathogenesis, also activated glial cells in the peripheral and central structures processing trigeminal nociceptive signals seem to play a relevant role. Finally, cortical spreading depression, the pathophysiological substrate of migraine aura, has been reported to be associated with inflammatory mechanisms such as pro-inflammatory cytokine upregulation and intracellular signalling. Reactive astrocytosis consequent to cortical spreading depression is linked to an upregulation of these inflammatory markers. The present review summarizes current findings on the roles of immune cells and inflammatory responses in the pathophysiology of migraine and their possible exploitation in the view of innovative disease-modifying strategies., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

Giacomo Balla, a famous Italian Futurist painter, was a great observer of both human motion and emotion. He showed a profound interest toward neurophysiological and neurological sciences. During his search of his personal artistic style, he attended the lessons of Cesare Lombroso, a criminal anthropologist, who at the time was also professor of neurology at the University of Turin. Some years later, he became a close friend of Doctor Francesco Ghilarducci, who had spent a few years in Paris at Jean-Martin Charcot's "School." Balla spent most of his career studying the dynamics of movement and speed. Some of his most famous paintings were inspired by photographic studies on the locomotor system, such as those of the French physiologist Étienne-Jules Marey. His personal painting style reveals his deep interest in neurosciences. We hereby illustrate the role of some of Giacomo Balla's paintings as historical records of the neuroscience environment at the turn of the 20th century.

The diagnostic criteria of menstrual migraine (MM), migraine related to menstruation and pure menstrual migraine, are placed in the appendix of the International Classification of Headache Disorders and are still primarily considered as research criteria that need validation. Although there is a great wealth of knowledge about the neurobiological processes underlying MM and its symptoms, the mechanisms by which an attack starts during the menstrual cycle remain baffling, and the disease is still undertreated. In this narrative review, we aim to summarize recent data on pathophysiology, epidemiology, burden of disease and treatment of MM. The vast majority of the literature focuses on the relationship between MM and hormonal factors. The role of falling in estrogen levels is believed to increase the susceptibility of blood vessels to prostaglandins, which have been implicated in neurogenic inflammation. Moreover, fluctuations of ovarian steroid hormone levels modulate calcitonin gene-related peptide in the trigeminovascular system. In addition, it has been observed that gonadal hormones modulate cortical spreading depression susceptibility in animal models. Sex hormone influences on MM affect not only the frequency and severity of headache attack but also its treatment. Understanding the mechanisms that contribute to neuroendocrine vulnerability in some women and some menstrual cycles may yield possible marker of the disease opening treatment options specifically targeting MM. An increased interest for future research on the subject will further elucidate how to manage this debilitating type of migraine.

Introduction: Since closure has restrictive eligibility criteria, the vast majority of patients with cryptogenic stroke and patent foramen ovale (PFO) receive medical treatment. However, the optimal antithrombotic strategy is still unclear. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to define risk/benefit profile of anticoagulation compared with antiplatelet treatment in PFO-related stroke., Methods: Systematic review protocol was registered in PROSPERO (CRD42019117559). Following PRISMA guidelines, we searched MEDLINE, EMBASE, and Cochrane CENTRAL database (2000-2019) for RCTs randomly allocating patients with cryptogenic stroke and PFO to medical treatment. Risk of bias was assessed with Cochrane RoB tool. Main outcomes were stroke recurrence and major bleeding. RoPE score-dependent analysis was implemented to define a possible role for patient selection., Results: Five RCTs met inclusion criteria (3 high-, 1 fair-, 1 poor-quality RCTs). Overall, meta-analysis included 1565 patients (mean age 55.5 years), 753 (48.1%) receiving anticoagulation. Compared with antiplatelet treatment, anticoagulation conveyed no net benefit in prevention of recurrent stroke (OR = 0.66, 95% CI 0.41-1.07, p heterogeneity  = 0.46), and associated with a non-significant higher risk of major bleeding (OR = 1.64, 95% CI 0.79-3.43, p heterogeneity  = 0.57). In patients with high RoPE score, anticoagulation significantly reduced the risk of recurrent stroke (OR = 0.22, 95% CI 0.06-0.8, p heterogeneity  = 0.88)., Conclusion: Our meta-analysis shows that anticoagulation confers no net benefit in recurrent stroke prevention over antiplatelets in patients with PFO-related stroke. RoPE score might help in selecting patients benefiting from anticoagulation, but further trials are needed to delineate risk/benefit profile of anticoagulation.

Background: Dural arteriovenous fistulas are intracranial vascular malformations, fed by dural arteries and draining venous sinuses or meningeal veins. Clinical course varies widely and ranges from benign with spontaneous remission to fatal, due to cerebral hemorrhage. In a 10-year single institution experience, clinical presentation of dural arteriovenous fistulas, and in particular headache and angiographic features, as well as long-term outcome were analyzed., Methods: Data of 42 intracranial dural arteriovenous fistulas of 40 patients concerning demographic characteristics, medical history and risk factors, clinical presentation and headache features, location and neuroimaging findings, as well as treatment and outcome, were collected. Furthermore, we used the modified-Rankin Scale to assess the long-term outcome, by telephone contact with patients and/or their relatives., Results: Patients aged between 25 and 89 years (mean age 55.8 ± 15.5). According to different clinical presentation and evolution, related to their unique drainage pattern into the cavernous sinus, we examined the carotid-cavernous fistulas separately from other dural arteriovenous fistulas. Interestingly, we found that the migraine-like headache was the major onset symptom of dural arteriovenous fistulas different from carotid-cavernous fistulas (p = 0.036). On the other hand, non-migraine-like headache was a typical characteristic of carotid-cavernous fistulas (p = 0.003). Moreover, ocular symptoms were more frequently observed in carotid-cavernous fistulas (92.9% p < 0.001). Seventy percent of patients did not report any impact on quality of life (mRS 0 or 1) at follow-up., Conclusions: These findings suggest a link between the site of lesion and clinical features of the headache, a symptom that usually leads to hospitalization. In particular, ocular symptoms accompanying non-migraine-like headache should be promptly recognized and raise the suspicion of a carotid-cavernous fistula, while migraine-like headache may suggests other dural arteriovenous fistulas. This study provides new significant insights on headache and its characteristics as a presentation symptom in dural arteriovenous fistulas.

Background and Purpose: Educational intervention has proved to be effective in reducing drug abuse in uncomplicated medication-overuse headache (MOH). This ancillary of the SAMOHA multicentre study aimed to assess any differences in phenotypic characteristics, type and amount of drugs overused, and comorbidities between patients with MOH who responded to simple advice and those who did not., Methods: Demographic and clinical headache data of the last 3 months before enrollment of patients were collected and patients were then asked to fill out a daily headache diary for 4 weeks. Patients were then divided into two subgroups, i.e. those with confirmed MOH continued in the study [randomized (R) group], whereas those who did not still show any features of MOH dropped out of the study., Results: A total of 88 (67.7%) patients still met the inclusion criteria after the baseline 4 weeks (R group). Conversely, 42 (32.3%) patients dropped out of the study. A detailed analysis of those who dropped out revealed that only 34 were not randomized at visit 2 because they no longer satisfied the inclusion criteria for MOH [screening failures (SF) group]. The SF group was significantly younger and had fewer years of migraine history than the R group. Moreover, the SF group had a significantly shorter history of chronicity compared with the R group., Conclusions: Our findings suggest that in MOH trials, after an educational session, an observational period is needed in order to confirm the diagnosis of MOH and to avoid overestimation of the effect of other treatments used to manage MOH. Future research should focus mainly on those patients with MOH who do not respond to simple advice and with unsuccessful withdrawal., (© 2018 EAN.)

Objective We performed a systematic review on the comorbidities of familial/sporadic hemiplegic migraine (F/SHM) with seizure/epilepsy in patients with CACNA1A, ATP1A2 or SCN1A mutations, to identify the genotypes associated and investigate for the presence of mutational hot spots. Methods We performed a search in MEDLINE and in the Human Gene Mutation and Leiden Open Variation Databases for mutations in the CACNA1A, ATP1A2 and SCN1A genes. After having examined the clinical characteristics of the patients, we selected those having HM and seizures, febrile seizures or epilepsy. For each gene, we determined both the frequency and the positions at protein levels of these mutations, as well as the penetrance of epilepsy within families. Results Concerning F/SHM-Epilepsy1 (F/SHME1) and F/SHME2 endophenotypes, we observed a prevalent involvement of the transmembrane domains, and a strong correlation in F/SHME1 when the positively charged amino acids were involved. The penetrance of epilepsy within the families was highest for patients carrying mutation in the CACNA1A gene (60%), and lower in those having SCN1A (33.3%) and ATP1A2 (30.9%) mutations. Conclusion Among the HM cases with seizure/epilepsy, we observed mutational hot spots in the transmembrane domains of CACNA1A and ATP1A2 proteins. These findings could lead to a better understanding of the pathological mechanisms underlying migraine and epilepsy, therein guaranteeing the most appropriate therapeutic approach.

Background The impact of adverse events (AEs) of antiepileptic drugs (AEDs) have an impact on compliance and dropouts. We compared tolerability of AEs of AEDs among patients with migraine, epilepsy, or both. Methods Overall, 335 patients (epilepsy (n = 142), migraine (n = 131), and both (n = 62)), were evaluated with the Liverpool Adverse Events Profile (LAEP) to assess the magnitude, profile and occurrence rate of the AEs of valproate, topiramate, and lamotrigine. Results AEs were significantly more common with topiramate treatment (71.0%) and among migraineurs (69.5%), the latter being more prone to discontinue AEDs (46.6%). The profile of AEs with topiramate and valproate differed among groups. Moreover, treatment with both topiramate and valproate was associated, for all groups, with a worse tolerability profile compared to lamotrigine. Conclusion Our data suggest a specific drug and disease AE profile of AEDs. Specifically, migraineurs are the most affected by AEs, even though they receive very low dosages of AEDs. This finding might be considered a clinical implication of central sensitization mechanisms. Both the profile and tolerability of AEs, highly influencing quality of life, depended on the underlying conditions, and deeply impacted on treatment dropout. Therefore, before starting, switching or stopping AED treatment, all options need to be considered.

Background and Purpose: In medication-overuse headache (MOH) patients, the presence of psychopathological disturbances may be a predictor of relapse and poor response to treatment. This multicentre study aimed to assess the occurrence of psychopathological disorders in MOH patients by comparing the incidence of psychopathological disturbances with episodic migraine (EM) patients and healthy controls (HC)., Methods: The psychopathological assessment of patients and HC involved the administrations of the Beck Depression Inventory, the Beck Anxiety Inventory, the Modified Mini International Neuropsychiatric Interview (M-MINI), the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Leeds Dependence Questionnaire., Results: The MOH, EM and HC groups (88, 129 and 102 subjects, respectively) differed significantly from each other for the presence of moderate/severe anxiety, whereas mood disorder and depression were revealed in similar proportions for both MOH and EM patients. By stratifying the M-MINI questionnaire results according to the number of psychiatric disorders, it was found that MOH patients had a more complex profile of psychiatric comorbidity. Furthermore, clinically relevant obsessive-compulsive disturbances for abused drugs assessed by Y-BOCS appeared to be more represented in the MOH group, whilst the prevalence of this trait in the EM group was comparable to that of HC (12.5%, 0.8% and 0%, respectively)., Conclusions: Our study indicates the multiple presence of psychopathological comorbidities in patients with MOH. In light of this, it is recommended that the assessment of the psychopathological profile be included in an evaluation of MOH patients, allowing the clinician to more rapidly start an appropriate behavioural treatment, which would greatly improve MOH management., (© 2015 EAN.)

Background: Medication overuse headache (MOH) is a common and debilitating disorder characterized by generation, perpetuation, and persistence of intense chronic migraine, caused by overuse of analgesics, triptans, or other acute headache compounds. It has been suggested that MOH could share some pathogenetic mechanisms with other kinds of drug addiction. In this regard, histone deacetylases 3 (HDAC3) seems to have a role in the memory processes involved in extinction of drug-seeking behavior in animal models. HDAC3 is inhibited by sodium valproate, a drug with proven efficacy in MOH. Recent evidence suggests an involvement of genetic factors in predisposition to medication overuse., Results: In this association study, we sequenced all exons, intron/exon junctions, and 3'-5'UTR regions of HDAC3 in 23 MOH patients to investigate its role in medication overuse. Associations between genotypes with continuous and dichotomous clinical characteristics were tested by multivariate analysis and Fisher's exact test, respectively. Sequencing of HDAC3 revealed six single-nucleotide polymorphisms. The G allele of rs2530223 was significantly associated with the number of acute medications/month used and with the number of days/month in which medications were used (p = 0.006 and p = 0.007, respectively), but neither with headache frequency or intensity. None of the single-nucleotide polymorphisms (SNPs) was associated with clinical characteristics or response to sodium valproate., Conclusions: HDAC3 could be implicated in excessive medication consumption in MOH patients. Our preliminary findings provide support for the need of further investigation on larger independent samples to confirm and extend the role of HDAC3 in medication overuse headache.

Background: The management of Medication overuse headache (MOH) represents a difficult challenge for clinicians and headache experts, particularly for the responder rate after a successful withdrawal treatment. The purpose of this study was to investigate the role of demographic and clinical characteristics as well as the score of Migraine-Specific Quality of Life Questionnaire (MSQ), Migraine Disability Questionnaire and Leeds Dependence Questionnaire in predicting a response after a successful withdrawal treatment in patients with MOH., Methods: This ancillary study is part of a randomized trial that demonstrated the safety and the efficacy of a 3-month treatment with sodium valproate (VPA) (800 mg/day vs placebo) in MOH. Demographic and clinical characteristics and questionnaire results were obtained from the entire sample., Results: A significant correlation was found only between MOH relapse and the total MSQ score, the Role Preventive sub-scale and the Emotional Function sub-scale, suggesting a poorer quality of life in non responders., Conclusion: A high MSQ score could be associated with a poor short-term outcome in MOH patients after a successful treatment with detoxification followed by a new treatment.

Objective: To assess the efficacy, safety and tolerability of sodium valproate (800mg/die) compared with placebo in medication-overuse headache patients with a history of migraine without aura., Methods: This is a multicenter, randomized, double-blind, placebo-controlled study enrolled medication-overuse headache patients for a 3-month treatment period with sodium valproate (800mg/day) or placebo after a 6 day outpatient detoxification regimen, followed by a 3-month follow-up. Primary outcome was defined by the proportion of patients achieving ≥50% reduction in the number of days with headache per month (responders) from the baseline to the last 4 weeks of the 3-month treatment. Multivariate logistic regression models were used on the primary endpoint, adjusting for age, sex, disease duration, comorbidity and surgery. The last-observation-carried-forward method was used to adjust for missing values., Results: Nine sites enrolled 130 patients and, after a 6-day detoxification phase, randomized 88 eligible patients. The 3-month responder rate was higher in the sodium valproate (45.0%) than in the placebo arm (23.8%) with an absolute difference of about 20% (p=0.0431). Sodium valproate had safety and tolerability profiles comparable to placebo., Conclusions: The present study supports the efficacy and safety of sodium valproate in the treatment of medication overuse headache with history of migraine after detoxification., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Objective: To evaluate seizures as first clinical manifestation of brain arteriovenous malformations (AVMs), in relation to angioarchitectural features of these vascular anomalies., Methods: We performed a prospective observational study, collecting records of patients with AVMs consecutively admitted to the Neurological and Neurosurgery Units of Perugia University and to the Neurosurgery Unit of Terni Hospital, during a 10-year period (1 January 2002 to 1 June 2012). Two groups of patients, with or without seizures as AVM first presentation, were analysed to identify differences in demographic and angiographic features. A multivariate logistic regression model was also developed., Results: We examined 101 patients with AVMs, 55 male and 46 female. Seizures were the initial clinical manifestation in 31 (30.7%) patients. We found a significant difference (p<0.05) between two groups of patients, with or without seizures as AVM first presentation concerning location, side, topography and venous drainage. A multivariate logistic regression model showed that clinical presentation with seizures was correlated with a location in the temporal and frontal lobes, and with a superficial topography. The strongest association (OR 3.48; 95% CI 1.77 to 6.85) was observed between seizures and AVM location in the temporal lobe., Conclusions: Vascular remodelling and haemodynamic changes of AVMs might create conditions for epileptogenesis. However, here we show that malformations with specific angiographic characteristics are more likely to be associated with seizures as first clinical presentation. Location is the most important feature related to epilepsy and in particular the temporal lobe might play a crucial role in the occurrence of seizure.

Background: Familial hemiplegic migraine (FHM) is a rare autosomal dominant migraine subtype, characterized by fully reversible motor weakness as a specific symptom of aura. Mutations in the ion transportation coding genes CACNA1A , ATP1A2 and SCN1A are responsible for the FHM phenotype. Moreover, some mutations in ATP1A2 or SCN1A also may lead to epilepsy., Case: Here we report on a three-generation family with five patients having a novel ATP1A2 mutation on exon 19, causing guanine-to-adenine substitution (c.2620G>A, p.Gly874Ser) that co-segregated in the five living relatives with migraine, four of whom had hemiplegic migraine. Moreover, three patients presented with epilepsy, one of whom had generalized epilepsy with febrile seizures plus (GEFS+)., Conclusions: The present study provides further evidence on the involvement of ATP1A2 mutations in both migraine and epilepsy, underlying the relevance of genetic analysis in families with a comorbidity of both disorders.

Background: Medication overuse headache (MOH) is a very heterogeneous disorder for which a recommended treatment is not yet available. The purpose of this study was to investigate any possible roles of demographic and clinical characteristics of MOH patients that might predict a response to detoxification and advice with or without preventive treatment., Findings: This ancillary study is part of the Sodium vAlproate in the treatment of Medication Overuse HeadAche (SAMOHA) study that randomized 88 MOH patients for 3-month treatment period with sodium valproate (VPA) (800 mg/day) or placebo after a 6-day outpatient detoxification regimen. Demographic and clinical characteristics obtained on patients from both study arms were analyzed to point out an association with the response to the treatment. While for patients from VPA arm no significant results were obtained, comparing responders to non-responders to detoxification and advice to withdraw from MOH, a significant difference in headache duration was observed. Specifically, the efficacy of such treatment resulted ineffective in headache lasting longer than 30 years., Conclusions: Our findings suggest that the benefit from detoxification and advice can be excluded in MOH of long duration. Therefore, a preventive treatment is suggested particularly for these patients.

Spreading depression (SD) is a slowly propagating wave of neuronal and glial depolarization lasting a few minutes, that can develop within the cerebral cortex or other brain areas after electrical, mechanical or chemical depolarizing stimulations. Cortical SD (CSD) is considered the neurophysiological correlate of migraine aura. It is characterized by massive increases in both extracellular K⁺ and glutamate, as well as rises in intracellular Na⁺ and Ca²⁺. These ionic shifts produce slow direct current (DC) potential shifts that can be recorded extracellularly. Moreover, CSD is associated with changes in cortical parenchymal blood flow. CSD has been shown to be a common therapeutic target for currently prescribed migraine prophylactic drugs. Yet, no effects have been observed for the antiepileptic drugs carbamazepine and oxcarbazepine, consistent with their lack of efficacy on migraine. Some molecules of interest for migraine have been tested for their effect on CSD. Specifically, blocking CSD may play an enabling role for novel benzopyran derivative tonabersat in preventing migraine with aura. Additionally, calcitonin gene-related peptide (CGRP) antagonists have been recently reported to inhibit CSD, suggesting the contribution of CGRP receptor activation to the initiation and maintenance of CSD not only at the classic vascular sites, but also at a central neuronal level. Understanding what may be lying behind this contribution, would add further insights into the mechanisms of actions for "gepants", which may be pivotal for the effectiveness of these drugs as anti-migraine agents. CSD models are useful tools for testing current and novel prophylactic drugs, providing knowledge on mechanisms of action relevant for migraine.

Cortical spreading depression (CSD) is a key pathogenetic step in migraine with aura. Dysfunctions of voltage-dependent and receptor-operated channels have been implicated in the generation of CSD and in the pathophysiology of migraine. Although a known correlation exists between migraine and release of the calcitonin gene-related peptide (CGRP), the possibility that CGRP is involved in CSD has not been examined in detail. We analyzed the pharmacological mechanisms underlying CSD and investigated the possibility that endogenous CGRP contributes to this phenomenon. CSD was analyzed in rat neocortical slices by imaging of the intrinsic optical signal. CSD was measured as the percentage of the maximal surface of a cortical slice covered by the propagation of intrinsic optical signal changes during an induction episode. Reproducible CSD episodes were induced through repetitive elevations of extracellular potassium concentration. AMPA glutamate receptor antagonism did not inhibit CSD, whereas NMDA receptor antagonism did inhibit CSD. Blockade of voltage-dependent sodium channels by TTX also reduced CSD. CSD was also decreased by the antiepileptic drug topiramate, but not by carbamazepine. Interestingly, endogenous CGRP was released in the cortical tissue in a calcium-dependent manner during CSD, and three different CGRP receptor antagonists had a dose-dependent inhibitory effect on CSD, suggesting a critical role of CGRP in this phenomenon. Our findings show that both glutamate NMDA receptors and voltage-dependent sodium channels play roles in CSD. They also demonstrate that CGRP antagonism reduces CSD, supporting the possible use of drugs targeting central CGRP receptors as antimigraine agents.

Background: Headache has been reported to be the first clinical presentation in several patients with cerebral arteriovenous malformations (AVMs). Headache associated with AVMs often shows characteristics of migraine with and without aura. Angiographic characteristics of AVMs, such as their location, could determine the 'migraine-like' features of attacks., Methods: We performed an observational study of the clinical and angiographic characteristics of a cohort of 40 consecutive patients with AVMs who had been admitted to our institute for endovascular embolization over a 4-year period. Headache was characterized according to ICHD-II criteria. The relationship between headaches and the angioarchitectural features of AVMs was also analysed., Results: Migraine-like headache was the first clinical manifestation in 22.5% of patients. The location of the malformation was significantly associated with migraine-like presentation (p=0.03) and the occipital lobe was the predominant site., Conclusions: An occipital location may be linked with spreading depression, a pathogenic mechanism of migraine. Headache associated with arteriovenous malformations in the occipital lobe, although secondary in nature, could have clinical features similar to migraine.

Objectives: This study was aimed at investigating the frequency of the visual phenomenon of palinopsia (visual perseveration) in patients with migraine., Methods: We interviewed 63 patients with migraine with aura (MwA), 137 patients with migraine without aura (MwoA) and 226 sex-age-matched healthy control subjects using an ad hoc structured interview/questionnaire. The interview was divided into four classes of variables for statistical testing., Results: Palinopsia occurred in 19/200 patients (9.5%); of them 10/63 had MwA and 9/137 MwoA (14.2% vs 6.6%, chi = 9.7, degrees of freedom = 1, p = 0.002). Patients with palinopsia had a significantly lower migraine attack frequency than those without this visual phenomenon (4.3 ± 0.3 vs 14.4 ± 0.2, z = 7.1, p < 0.0001). No healthy control subjects complained of palinopsia according to the structured interview/questionnaire., Discussion: Palinopsia is probably under-diagnosed in patients with migraine. Further investigations are needed to assess whether migraineurs are particularly susceptible to the development of recurrent episodes of visual perseveration.

Several cellular and molecular mechanisms have been implicated in migraine pathophysiology including abnormal neuronal excitability and vascular events. Drugs from different pharmacological classes are used for migraine prophylaxis. These agents may normalize neuronal excitability by modulating distinct ionic channels and various neurotransmitter systems. They can also block cortical spreading depression, prevent peripheral and/or central pain sensitization, and normalize brainstem function. Most of the drugs recently used in migraine prophylaxis have been identified by serendipidy and they have been originally approved for other indications. Subsequently, their use has been extended to migraine prevention, according to their putative mechanisms of action. More recently, trials on adequate samples of migraine patients have been conducted for several drugs. In the present review, we will present and discuss the pathophysiological bases for the use of antidepressants, beta-adrenergic blockers, calcium channel blockers and antiepileptic drugs in migraine prevention. Currently, the major classes of conventional migraine preventive drugs include the antidepressant amitriptyline, the beta-adrenergic blocker propranolol, and the antiepileptic drugs topiramate and valproic acid. Promising results have recently been obtained for angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor blockers. Some limited clinical findings have also been reported for atypical antipsychotic agents, nutritional supplements and also botulinum toxin. Targets of migraine preventive treatment are to reduce frequency and intensity of attacks and to decrease disability related to chronic headache.