Search

Abstract Introduction Migraine is under-diagnosed and under-treated. Many people with migraine do not seek medical care, and those who do may initially receive a different diagnosis and/or be dissatisfied with provided care on their journey before treatment with a CGRP-mAb (calcitonin-gene-related-peptide monoclonal antibody). Methods This is a cross-sectional, self-reported, online survey of subjects in Lilly’s Emgality® Patient Support Program in 2022. Questionnaires collected insights into subjects’ prior experiences with migraine and interactions with healthcare professionals before receiving CGRP-mAbs. Results Of the 250 participants with episodic and 250 with chronic migraine, 90% were female and white with a mean age of 26.2 years (± 11.9) at diagnosis and 40.6 (± 12.0) years at survey enrollment. Many participants (71%) suspected they had migraine before diagnosis, with 31% reluctant to seek help. Of these, approximately one-third were unaware of treatment, did not think that a physician could do anything more for migraine, would not take them seriously, or were reluctant due to a previous unhelpful experience. Participants mainly received information from friends/family (47%) or the internet (28%). Participants initially sought treatment due to an increase in migraine frequency (77%), attacks interfering with work or school (75%), or increased pain intensity (74%). Subjects saw a mean of 4.1 (± 4.3) healthcare providers before migraine diagnosis, and 20% of participants previously received a different diagnosis. Participants reported migraine causes included stress/anxiety/depression (42%), hormonal changes (30%), nutrition (20%), and weather (16%). Acute treatment of migraine included prescription (82%) and over-the-counter (50%) medications, changes in nutrition (62%), adjusting fluid intake (56%), and relaxation techniques (55%). Preventive medications included anticonvulsants (61%), antidepressants (44%), blood pressure-lowering medications (43%), and botulinum toxin A injections (17%). Most discontinuations were due to lack of efficacy or side effects. Conclusion People with migraine describe reluctance in seeking health care, and misunderstandings seem common especially in the beginning of their migraine journey. Graphical abstract available for this article. Graphical Abstract

Abstract Objective The aim of this paper is to critically re-appraise the published trials assessing propranolol for migraine prophylaxis. Methods We report 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 propranolol with placebo for migraine prophylaxis in adults. The outcomes of interest were informed by the Core 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 monthly migraine days, the reduction of monthly migraine days, and the number of adverse events leading to discontinuation. We assessed risk of bias by using a modified Cochrane RoB (risk of bias) 2.0 tool and the certainty of evidence by using the GRADE approach. Results Our search yielded twenty trials (n = 1291 patients) eligible for data synthesis and analysis. The analysis revealed a moderate certainty evidence that propranolol leads to a reduction in monthly migraine days versus placebo (-1.27; 95% CI: -2.25 to -0.3). We found moderate certainty evidence that propranolol increases the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo with a relative risk of 1.65 (95% CI 1.41 to 1.93); absolute risk difference: 179 more per 1,000 (95% CI 113 to 256). We found high certainty evidence that propranolol increases the proportion of patients who discontinue due to adverse events compared to placebo with a risk difference of 0.02 (95% CI 0.00 to 0.03); absolute risk difference: 20 more per 1,000 (95% CI 0 to 30). Conclusions The present meta-analysis shows that propranolol has a prophylactic role in migraine, with an overall acceptable tolerability profile. Combining these results with its long-standing use and its global availability at a low cost confirms its role as a first line agent in the prophylaxis of migraine.

Abstract Glymphatic system is an emerging pathway of removing metabolic waste products and toxic solutes from the brain tissue. It is made of a network of perivascular spaces, filled in cerebrospinal and interstitial fluid, encompassing penetrating and pial vessels and communicating with the subarachnoid space. It is separated from vessels by the blood brain barrier and from brain tissue by the endfeet of the astrocytes rich in aquaporin 4, a membrane protein which controls the water flow along the perivascular space. Animal models and magnetic resonance (MR) studies allowed to characterize the glymphatic system function and determine how its impairment could lead to numerous neurological disorders (e.g. Alzheimer’s disease, stroke, sleep disturbances, migraine, idiopathic normal pressure hydrocephalus). This review aims to summarize the role of the glymphatic system in the pathophysiology of migraine in order to provide new ways of approaching to this disease and to its therapy.

Abstract Background Migraine and epilepsy are two paroxysmal chronic neurological disorders affecting a high number of individuals and being responsible for a high individual and socioeconomic burden. The link between these disorders has been of interest for decades and innovations concerning diagnosing and treatment enable new insights into their relationship. Findings Although appearing to be distinct at first glance, both diseases exhibit a noteworthy comorbidity, shared pathophysiological pathways, and significant overlaps in characteristics like clinical manifestation or prophylactic treatment. This review aims to explore the intricate relationship between these two conditions, shedding light on shared pathophysiological foundations, genetic interdependencies, common and distinct clinical features, clinically overlapping syndromes, and therapeutic similarities. There are several shared pathophysiological mechanisms, like CSD, the likely underlying cause of migraine aura, or neurotransmitters, mainly Glutamate and GABA, which represent important roles in triggering migraine attacks and seizures. The genetic interrelations between the two disorders can be observed by taking a closer look at the group of familial hemiplegic migraines, which are caused by mutations in genes like CACNA1A, ATP1A2, or SCN1A. The intricate relationship is further underlined by the high number of shared clinical features, which can be observed over the entire course of migraine attacks and epileptic seizures. While the variety of the clinical manifestation of an epileptic seizure is naturally higher than that of a migraine attack, a distinction can indeed be difficult in some cases, e.g. in occipital lobe epilepsy. Moreover, triggering factors like sleep deprivation or alcohol consumption play an important role in both diseases. In the period after the seizure or migraine attack, symptoms like speech difficulties, tiredness, and yawning occur. While the actual attack of the disease usually lasts for a limited time, research indicates that individuals suffering from migraine and/or epilepsy are highly affected in their daily life, especially regarding cognitive and social aspects, a burden that is even worsened using antiseizure medication. This medication allows us to reveal further connections, as certain antiepileptics are proven to have beneficial effects on the frequency and severity of migraine and have been used as a preventive drug for both diseases over many years. Conclusion Migraine and epilepsy show a high number of similarities in their mechanisms and clinical presentation. A deeper understanding of the intricate relationship will positively advance patient–oriented research and clinical work.

Abstract The 2030 Agenda for Sustainable Development sets out, through 17 Sustainable Development Goals (SDGs), a path for the prosperity of people and the planet. SDG 3 in particular aims to ensure healthy lives and promote well-being for all at all ages and includes several targets to enhance health. This review presents a “headache-tailored” perspective on how to achieve SDG 3 by focusing on six specific actions: targeting chronic headaches; reducing the overuse of acute pain-relieving medications; promoting the education of healthcare professionals; granting access to medication in low- and middle-income countries (LMIC); implementing training and educational opportunities for healthcare professionals in low and middle income countries; building a global alliance against headache disorders. Addressing the burden of headache disorders directly impacts on populations’ health, as well as on the possibility to improve the productivity of people aged below 50, women in particular. Our analysis pointed out several elements, and included: moving forward from frequency-based parameters to define headache severity; recognizing and managing comorbid diseases and risk factors; implementing a disease management multi-modal management model that incorporates pharmacological and non-pharmacological treatments; early recognizing and managing the overuse of acute pain-relieving medications; promoting undergraduate, postgraduate, and continuing medical education of healthcare professionals with specific training on headache; and promoting a culture that favors the recognition of headaches as diseases with a neurobiological basis, where this is not yet recognized. Making headache care more sustainable is an achievable objective, which will require multi-stakeholder collaborations across all sectors of society, both health-related and not health-related. Robust investments will be needed; however, considering the high prevalence of headache disorders and the associated disability, these investments will surely improve multiple health outcomes and lift development and well-being globally.

Abstract Objective Topiramate is a repurposed first-line treatment for migraine prophylaxis. The aim of this systematic review and meta-analysis is to critically re-appraise the existing evidence supporting the efficacy and tolerability of topiramate. Methods A systematic search in MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov was performed for trials of pharmacological treatment in migraine prophylaxis as of August 13, 2022, following the Preferred Reporting Items for Systematic Reviews (PRISMA). Randomized controlled trials in adult patients that used topiramate for the prophylactic treatment of migraine, with placebo as active comparator, were included. Two reviewers independently screened the retrieved studies and extracted all data. Outcomes of interest were the 50% responder rates, the reduction in monthly migraine days, and adverse events leading to treatment discontinuation. Results were pooled and meta-analyzed, with sensitivity analysis based on the risk of bias of the studies, the monthly migraine days at baseline, and the previous use of other prophylactic treatments. Certainty evidence was judged according to the GRADE framework. Results Eight out of 10,826 studies fulfilled the inclusion/exclusion criteria, accounting for 2,610 randomized patients. Six studies included patients with episodic migraine and two with chronic migraine. Topiramate dose ranged from 50 to 200 mg/day, and all studies included a placebo arm. There was a high certainty that topiramate: 1) increased the proportion of patients who achieved a 50% responder rate in monthly migraine days, compared to placebo [relative risk: 1.61 (95% confidence interval (CI): 1.29–2.01); absolute risk difference: 168 more per 1,000 (95% CI: 80 to 278 more)]; 2) was associated with 0.99 (95% CI: 1.41–0.58) fewer migraine days than placebo; 3) and had a higher proportion of patients with adverse events leading to treatment discontinuation [absolute risk difference 80 patients more per 1,000 (95% CI: 20 to 140 more patients)]. Conclusions There is high-quality evidence of the efficacy of topiramate in the prophylaxis of migraine, albeit its use poses a risk of adverse events that may lead to treatment discontinuation, with a negative effect on patient satisfaction and adherence to care.

Abstract 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.

Abstract Migraine is a debilitating disorder, and while the introduction of monoclonal antibodies (mAbs) has led to efficacious and tolerable responses, a substantial number of patients are so-called “non-responders”. We introduce reasons for this insufficient response, including insufficient blockade of Calcitonin Gene-Related Peptide (CGRP) or its receptor. We present a clinical case, i.e. a female migraine patient who mistakenly administered supratherapeutic (three-fold higher) doses of erenumab leading to more efficacious clinical responses without any side-effects. This example illustrates that the initial dosages might have been too low, resulting in a remaining undesired increased effect of CGRP. While a capsaicin forearm model has repeatedly been used to evaluate the pharmacokinetic-pharmacodynamic relationship of mAbs, we provide directions to revisit or reconsider dose-finding and dose-ranging of these drugs. These directions include (i) refinement and application of a capsaicin forehead model (instead of a forearm model) to study trigeminovascular activity and improve dosing, and (ii) reconsideration of trial populations. Indeed, the dose-finding studies were mainly performed in relatively young and normal-weight males, while most phase III/IV trials are marked by a high female-to-male ratio, mainly consisting of overweight to obese females. Considering these aspects in future trials could optimize healthcare for a larger proportion of migraine patients.

Abstract Most individuals with access to the internet use social media platforms. These platforms represent an excellent opportunity to disseminate knowledge about management and treatment to the benefit of patients. The International Headache Society, The European Headache Federation, and The American Headache Society have electronic media committees to promote and highlight the organizations’ expertise and disseminate research findings. A growing mistrust in science has made dealing with infodemics (i.e., sudden access to excessive unvetted information) an increasing part of clinical management. An increasing role of these committees will be to address this challenge. As an example, recent studies have demonstrated that the most popular online content on migraine management is not evidence-based and is disseminated by for-profit organizations. As healthcare professionals and members of professional headache organizations, we are obliged to prioritize knowledge dissemination. A progressive social media strategy is associated not only with increased online visibility and outreach, but also with a higher scientific interest. To identify gaps and barriers, future research should assess the range of available information on headache disorders in electronic media, characterize direct and indirect consequences on clinical management, and recognize best practice and strategies to improve our communication on internet-based communication platforms. In turn, these efforts will reduce the burden of headache disorders by facilitating improved education of both patients and providers.

Abstract Objective While there are several trials that support the efficacy of various drugs for migraine prophylaxis against placebo, there is limited evidence addressing the comparative safety and efficacy of these drugs. We conducted a systematic review and network meta-analysis to facilitate comparison between drugs for migraine prophylaxis. Methods We searched MEDLINE, EMBASE, CENTRAL, and clinicaltrials.gov from inception to August 13, 2022, for randomized trials of pharmacological treatments for migraine prophylaxis in adults. Reviewers worked independently and in duplicate to screen references, extract data, and assess risk of bias. We performed a frequentist random-effects network meta-analysis and rated the certainty (quality) of evidence as either high, moderate, low, or very low using the GRADE approach. Results We identified 74 eligible trials, reporting on 32,990 patients. We found high certainty evidence that monoclonal antibodies acting on the calcitonin gene related peptide or its receptor (CGRP(r)mAbs), gepants, and topiramate increase the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo. We found moderate certainty evidence that beta-blockers, valproate, and amitriptyline increase the proportion of patients who experience a 50% or more reduction in monthly migraine days, and low certainty evidence that gabapentin may not be different from placebo. We found high certainty evidence that, compared to placebo, valproate and amitriptyline lead to substantial adverse events leading to discontinuation, moderate certainty evidence that topiramate, beta-blockers, and gabapentin increase adverse events leading to discontinuation, and moderate to high certainty evidence that (CGRP(r)mAbs) and gepants do not increase adverse events. Conclusions (CGRP(r)mAbs) have the best safety and efficacy profile of all drugs for migraine prophylaxis, followed closely by gepants.

Abstract 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.

Abstract Background Triptans are migraine-specific acute treatments. A well-accepted definition of triptan failure is needed in clinical practice and for research. The primary aim of the present Consensus was to provide a definition of triptan failure. To develop this definition, we deemed necessary to develop as first a consensus definition of effective treatment of an acute migraine attack and of triptan-responder. Main body The Consensus process included a preliminary literature review, a Delphi round and a subsequent open discussion. According to the Consensus Panel, effective treatment of a migraine attack is to be defined on patient well-being featured by a) improvement of headache, b) relief of non-pain symptoms and c) absence of adverse events. An attack is considered effectively treated if patient’s well-being, as defined above, is restored within 2 hours and for at least 24 hours. An individual with migraine is considered as triptan-responder when the given triptan leads to effective acute attack treatment in at least three out of four migraine attacks. On the other hand, an individual with migraine is considered triptan non-responder in the presence of failure of a single triptan (not matching the definition of triptan-responder). The Consensus Panel defined an individual with migraine as triptan-resistant in the presence of failure of at least 2 triptans; triptan refractory, in the presence of failure to at least 3 triptans, including subcutaneous formulation; triptan ineligibile in the presence of an acknowledged contraindication to triptan use, as specified in the summary of product characteristics. Conclusions The novel definitions can be useful in clinical practice for the assessment of acute attack treatments patients with migraine. They may be helpful in identifying people not responding to triptans and in need for novel acute migraine treatments. The definitions will also be of help in standardizing research on migraine acute care.

Abstract Background Erenumab, a fully human monoclonal antibody that targets the calcitonin gene-related peptide receptor, has demonstrated efficacy and safety in the prevention of episodic and chronic migraine. There exists an unmet need to establish the safety of erenumab in older individuals, in view of existing multiple comorbidities, polypharmacy, and age-related physiological changes. This pooled analysis of five large migraine-prevention studies examined the safety of erenumab stratified across age groups, particularly in older populations. Methods Pooled and age-stratified analysis of safety data from the 12-week double-blind treatment phase (DBTP) of five randomized, placebo-controlled Phase 2 and 3 studies of erenumab in participants with episodic or chronic migraine across the age groups

Abstract Introduction Chronic headache due to the overuse of medication for the treatment of migraine attacks has a prevalence of 0.5–2.0%. This guideline provides guidance for the management of medication overuse (MO) and medication overuse headache (MOH). Recommendations Treatment of headache due to overuse of analgesics or specific migraine medications involves several stages. Patients with medication overuse (MO) or medication overuse headache (MOH) should be educated about the relationship between frequent use of symptomatic headache medication and the transition from episodic to chronic migraine (chronification), with the aim of reducing and limiting the use of acute medication. In a second step, migraine prophylaxis should be initiated in patients with migraine and overuse of analgesics or specific migraine drugs. Topiramate, onabotulinumtoxinA and the monoclonal antibodies against CGRP or the CGRP-receptor are effective in patients with chronic migraine and medication overuse. In patients with tension-type headache, prophylaxis is performed with amitriptyline. Drug prophylaxis should be supplemented by non-drug interventions. For patients in whom education and prophylactic medication are not effective, pausing acute medication is recommended. This treatment can be performed in an outpatient, day hospital or inpatient setting. Patients with headache due to overuse of opioids should undergo inpatient withdrawal. The success rate of the stepped treatment approach is 50–70% after 6 to 12 months. A high relapse rate is observed in patients with opioid overuse. Tricyclic antidepressants, neuroleptics (antiemetics) and the administration of steroids are recommended for the treatment of withdrawal symptoms or headaches during the medication pause. Consistent patient education and further close monitoring reduce the risk of relapse.

Abstract Background A previous European Headache Federation (EHF) guideline addressed the use of monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway to prevent migraine. Since then, randomized controlled trials (RCTs) and real-world evidence have expanded the evidence and knowledge for those treatments. Therefore, the EHF panel decided to provide an updated guideline on the use of those treatments. Methods The guideline was developed following the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. The working group identified relevant questions, performed a systematic review and an analysis of the literature, assessed the quality of the available evidence, and wrote recommendations. Where the GRADE approach was not applicable, expert opinion was provided. Results We found moderate to high quality of evidence to recommend eptinezumab, erenumab, fremanezumab, and galcanezumab in individuals with episodic and chronic migraine. For several important clinical questions, we found not enough evidence to provide evidence-based recommendations and guidance relied on experts’ opinion. Nevertheless, we provided updated suggestions regarding the long-term management of those treatments and their place with respect to the other migraine preventatives. Conclusion Monoclonal antibodies targeting the CGRP pathway are recommended for migraine prevention as they are effective and safe also in the long-term.

Abstract In this editorial we aim to provide an overview of Narrative-based Medicine (NBM) and highlight what it may offer to the care of individuals with headache disorders.

Abstract Background Although migraine is less common in older people, preventive treatment of migraine in these individuals may be more challenging due to the presence of multiple comorbidities and polypharmacy. Additionally, evidence for migraine treatment efficacy, safety, and tolerability is limited in this population. We evaluated efficacy, safety, and tolerability of fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene–related peptide (CGRP), in clinical trial participants aged ≥60 years with episodic migraine (EM) or chronic migraine (CM). Methods This analysis included data from 3 randomized, double-blind, placebo-controlled phase 3 studies: the HALO EM study, HALO CM study, and FOCUS study in participants with EM or CM and prior inadequate response to 2–4 migraine preventive medication classes. Participants in all studies were randomized 1:1:1 to receive 12 weeks of subcutaneous treatment with quarterly fremanezumab (Months 1/2/3: EM/CM, 675 mg/placebo/placebo), monthly fremanezumab (Months 1/2/3: EM, 225 mg/225 mg/225 mg; CM, 675 mg/225 mg/225 mg), or matched monthly placebo. Results These pooled analyses included 246 participants aged ≥60 years. Reductions in monthly migraine days from baseline over 12 weeks were significantly greater with fremanezumab (least-squares mean change from baseline [standard error]: quarterly fremanezumab, − 4.3 [0.59]; monthly fremanezumab, − 4.6 [0.54]) versus placebo (placebo, − 2.3 [0.57]; both P

Abstract Background New treatments are currently offering new opportunities and challenges in clinical management and research in the migraine field. There is the need of homogenous criteria to identify candidates for treatment escalation as well as of reliable criteria to identify refractoriness to treatment. To overcome those issues, the European Headache Federation (EHF) issued a Consensus document to propose criteria to approach difficult-to-treat migraine patients in a standardized way. The Consensus proposed well-defined criteria for resistant migraine (i.e., patients who do not respond to some treatment but who have residual therapeutic opportunities) and refractory migraine (i.e., patients who still have debilitating migraine despite maximal treatment efforts). The aim of this study was to better understand the perceived impact of resistant and refractory migraine and the attitude of physicians involved in migraine care toward those conditions. Methods We conducted a web-questionnaire-based cross-sectional international study involving physicians with interest in headache care. Results There were 277 questionnaires available for analysis. A relevant proportion of participants reported that patients with resistant and refractory migraine were frequently seen in their clinical practice (49.5% for resistant and 28.9% for refractory migraine); percentages were higher when considering only those working in specialized headache centers (75% and 46% respectively). However, many physicians reported low or moderate confidence in managing resistant (8.1% and 43.3%, respectively) and refractory (20.7% and 48.4%, respectively) migraine patients; confidence in treating resistant and refractory migraine patients was different according to the level of care and to the number of patients visited per week. Patients with resistant and refractory migraine were infrequently referred to more specialized centers (12% and 19%, respectively); also in this case, figures were different according to the level of care. Conclusions This report highlights the clinical relevance of difficult-to-treat migraine and the presence of unmet needs in this field. There is the need of more evidence regarding the management of those patients and clear guidance referring to the organization of care and available opportunities.

Abstract Introduction Despite advances in the management of headache disorders, some patients with migraine do not experience adequate pain relief with acute and preventive treatments. It is the aim of the present document to provide a definition of those migraines which are difficult-to-treat, to create awareness of existence of this group of patients, to help Healthcare Authorities in understanding the implications, and to create a basis to develop a better pathophysiological understanding and to support further therapeutic advances. Main body Definitions were established with a consensus process using the Delphi method. Patients with migraine with or without aura or with chronic migraine can be defined as having resistant migraine and refractory migraine according to previous preventative failures. Resistant migraine is defined by having failed at least 3 classes of migraine preventatives and suffer from at least 8 debilitating headache days per month for at least 3 consecutive months without improvement; definition can be based on review of medical charts. Refractory migraine is defined by having failed all of the available preventatives and suffer from at least 8 debilitating headache days per month for at least 6 consecutive months. Drug failure may include lack of efficacy or lack of tolerability. Debilitating headache is defined as headache causing serious impairment to conduct activities of daily living despite the use of pain-relief drugs with established efficacy at the recommended dose and taken early during the attack; failure of at least two different triptans is required. Conclusions We hope, that the updated EHF definition will be able to solve the conflicts that have limited the use of definitions which have been put forward in the past. Only with a widely accepted definition, progresses in difficult-to-treat migraine can be achieved. This new definition has also the aim to increase the understanding of the impact of the migraine as a disease with all of its social, legal and healthcare implications. It is the hope of the EHF Expert Consensus Group that the proposed criteria will stimulate further clinical, scientific and social attention to patients who suffer from migraine which is difficult-to-treat.

Abstract Monoclonal antibodies against the calcitonin gene-related peptide (CGRP) receptor (Erenumab) or against CGRP (Eptinezumab, Fremanezumab, Galcanezumab) are new substances for the preventive treatment of migraine. They represent an extension of the therapeutic options, which already exist in migraine prevention. In randomized, placebo-controlled studies, the efficacy and good tolerability of these specific substances have been demonstrated in patients with episodic and chronic migraine. The following treatment recommendation presents a summary of the pivotal studies. Recommendations are provided for the targeted selection of patients as well as for the evaluation of therapeutic success and the duration of treatment. Finally, possible restrictions on the use of this new substance group are discussed. This guideline is an abridged and translated version of the guideline published by Diener H-C, May A et al., Prevention of migraine with monoclonal antibodies against CGRP or the CGRP receptor, Supplement to S1 Guideline Therapy of Migraine Attack and Prevention of Migraine, 2019, Deutsche Gesellschaft für Neurologie (eds.), Guidelines for Diagnostics and Therapy in Neurology. A complete version of this guideline can be found on the website of the Deutsche Gesellschaft für Neurologie ( www.dgn.org/leitlinien ) and the AWMF (Arbeitsgemeinschaft wissenschaftlicher Medizinischer Gesellschaften). This guideline has been approved by the German Neurological Society (DGN) and the German Migraine and Headache Society (GMHS) and was reviewed by the two societies.

Abstract The global prevalence of migraine as a primary headache has been estimated as 14.4% in both sexes. Migraine headache has been ranked as the highest contributor to disability in under 50 years old population in the world. Extensive research has been conducted in order to clarify the pathological mechanisms of migraine. Although uncertainties remains, it has been indicated that vascular dysfunction, cortical spreading depression (CSD), activation of the trigeminovascular pathway, pro-inflammatory and oxidative state may play a putative role in migraine pain generation. Knowledge about pathophysiological mechanisms of migraine should be integrated into a multimodal treatment approach to increase quality of life in patients. With respect to this, within the integrative health studies growing interest pertains to dietary interventions. Although the number of studies concerning effects of diet on headache/migraine is not yet very large, the current article will review the available evidence in this area. All publications on headache/migraine and dietary interventions up to May 2019 were included in the present review through a PubMed/MEDLINE and ScienceDirect database search. According to the current findings, Ketogenic diet and modified Atkins diet are thought to play a role in neuroprotection, improving mitochondrial function and energy metabolism, compensating serotoninergic dysfunction, decreasing calcitonin gene-related peptide (CGRP) level and suppressing neuro-inflammation. It can also be speculated that prescription of low glycemic diet may be promising in headache/migraine control through attenuating the inflammatory state. Moreover, obesity and headaches including migraine could be attributed to each other through mechanisms like inflammation, and irregular hypothalamic function. Thereby, applying dietary strategies for weight loss may also ameliorate headache/migraine. Another important dietary intervention that might be effective in headache/migraine improvement is related to balance between the intake of essential fatty acids, omega-6 and omega-3 which also affect inflammatory responses, platelet function and regulation of vascular tone. Regarding elimination diets, it appears that targeted these diets in migraine patients with food sensitivities could be effective in headache/migraine prevention. Taken together, dietary approaches that could be considered as effective strategies in headache/migraine prophylaxis include weight loss diets in obese headache patients, ketogenic and low-calorie diets, reducing omega-6 and increasing omega-3 fatty acid intakes.

Abstract Background and aim Headache is very often the cause for seeking an emergency department (ED). However, less is known about the different diagnosis of headache disorders in the ED, their management and treatment. The aim of this survey is to analyse the management of headache patients in two different ED in Europe. Methods This retrospective survey was performed from September 2018 until January 2019. Patients were collected from the San Luca Hospital, Milan, Italy and the Ordensklinikum Barmherzige Schwestern, Linz, Austria. Only patients with a non-traumatic headache, as the primary reason for medical clarification, were included. Patients were analysed for their complexity and range of examination, their diagnoses, acute treatment and overall efficacy rate. Results The survey consists of 415 patients, with a mean age of 43.32 (SD ±17.72); 65% were female. Technical investigation was performed in 57.8% of patients. For acute treatment non-steroidal-anti-inflammatory drugs (NSAIDs) were the most used, whereas triptans were not given. A primary headache disorder was diagnosed in 45.3% of patients, being migraine the most common, but in 32% of cases the diagnosis was not further specified. Life-threatening secondary headaches accounted for less than 2% of cases. Conclusions The vast majority of patients attending an ED because of headache are suffering from a primary headache disorder. Life-threatening secondary headaches are rare but seek attention. NSAIDs are by far the most common drugs for treating headaches in the ED, but not triptans.

Abstract Background and aim Migraine headache and vestibular-type vertigo co-occur in the general population about three times more often than expected by chance. Attacks of episodic vertigo (eV) are currently not recognized as migraine equivalents or variants in the International Classification of Headache Disorders, 3rd edition (ICHD III). No strong data exist about the prevalence of eV during the phases of a migraine attack. The aim of this study is to analyze the timing association between migraine-related episodic vertigo and the phases of migraine. Methods The “Migraine and Neck Pain Study” gathered data from nearly 500 adult participants in a questionnaire-based survey. In this prospective, follow-up study we re-analyzed patients with episodic migraine with and without aura who experienced eV anytime around their migraine attacks. For this we defined 3 different time periods. Results 146/487 (30%) reported eV anytime during the migraine attack; 79/487 (16%) that noticed eV with the start of the headache, 51/487 (10%) within 2 h before the headache and 16/487 (3%) experienced eV 2–48 h before the headache, as a premonitory symptom. 130/487 (26.7%) of our patients can be diagnosed with vestibular or probable vestibular migraine supporting the clinical association of migraine and vertigo. Conclusions Our results seem to further support the concept that vertigo in migraine is best thought of as an integral manifestation of migraine, rather than a prodromal or aura symptom.

Abstract Background Idiopathic Intracranial Hypertension (IIH) is characterized by an elevation of intracranial pressure (ICP no identifiable cause. The aetiology remains largely unknown, however observations made in a number of recent clinical studies are increasing the understanding of the disease and now provide the basis for evidence-based treatment strategies. Methods The Embase, CDSR, CENTRAL, DARE and MEDLINE databases were searched up to 1st June 2018. We analyzed randomized controlled trials and systematic reviews that investigate IIH. Results Diagnostic uncertainty, headache morbidity and visual loss are among the highest concerns of clinicians and patients in this disease area. Research in this field is infrequent due to the rarity of the disease and the lack of understanding of the underlying pathology. Conclusions This European Headache Federation consensus paper provides evidence-based recommendations and practical advice on the investigation and management of IIH.

Abstract Although clinically distinguishable, migraine and cluster headache share prominent features such as unilateral pain, common pharmacological triggers such glyceryl trinitrate, histamine, calcitonin gene-related peptide (CGRP) and response to triptans and neuromodulation. Recent data also suggest efficacy of anti CGRP monoclonal antibodies in both migraine and cluster headache. While exact mechanisms behind both disorders remain to be fully understood, the trigeminovascular system represents one possible common pathophysiological pathway and network of both disorders. Here, we review past and current literature shedding light on similarities and differences in phenotype, heritability, pathophysiology, imaging findings and treatment options of migraine and cluster headache. A continued focus on their shared pathophysiological pathways may be important in paving future treatment avenues that could benefit both migraine and cluster headache patients.

Abstract We systematically reviewed data about the effect of exogenous estrogens and progestogens on the course of migraine during reproductive age. Thereafter a consensus procedure among international experts was undertaken to develop statements to support clinical decision making, in terms of possible effects on migraine course of exogenous estrogens and progestogens and on possible treatment of headache associated with the use or with the withdrawal of hormones. Overall, quality of current evidence is low. Recommendations are provided for all the compounds with available evidence including the conventional 21/7 combined hormonal contraception, the desogestrel only oral pill, combined oral contraceptives with shortened pill-free interval, combined oral contraceptives with estradiol supplementation during the pill-free interval, extended regimen of combined hormonal contraceptive with pill or patch, combined hormonal contraceptive vaginal ring, transdermal estradiol supplementation with gel, transdermal estradiol supplementation with patch, subcutaneous estrogen implant with cyclical oral progestogen. As the quality of available data is poor, further research is needed on this topic to improve the knowledge about the use of estrogens and progestogens in women with migraine. There is a need for better management of headaches related to the use of hormones or their withdrawal.

Abstract Background Cluster headache (CH) is a clinically well-defined primary headache disorder, approximately 20% of cluster headache sufferers experience recurrent attacks without periods of significant remission. For the treatment of chronic cluster headache (CCH) only limited therapeutic options are available. Methods A potential refractory CCH patient group was identified according to the clinical definition of rCCH based on the consensus statement of the European Headache Federation (EHF). Treatment with OnabotulinumtoxinA (BoNT-A; Botox®, 150 Allergan IU) was done according to the PREEMPT study protocol. A standardized headache diary was used for recording frequency, duration of attacks and pain intensity. To assess personal burden the HIT-6 and the Hospital Anxiety and Depression scale was used. Primary outcome measure was a > 50% reduction in headache minutes. Results Seventeen male patients suffering from rCCH, aged 32 ± 11 (mean ± SD) years, presenting a mean disease duration of 6.6 years completed the study of 28 weeks. The cut-off point of > 50% reduction in headache minutes as positive result was reached in 58.8%, 29.4% experienced an improvement of 30–50%. Mean frequency of headache days dropped from 28.2 to 11.8 days at week 24 (p = 0.0001; 95% CI -21.33 to − 11.61;). Intensity of remaining attacks was also reduced significantly. Headache disability scores showed a trend to improvement after BoNT-A. Conclusions Encouraging results for the treatment with BoNT-A in rCCH patients were observed in our study population.

Abstract Background Migraine is prevalent everywhere, and disabling. It is also neglected: consequently, it is under-diagnosed and undertreated. We analysed data from the Eurolight study on consultations and utilization of migraine-specific medications as indicators of adequacy of medical care in Europe. Methods Eurolight was a cross-sectional questionnaire-based survey in 10 European countries. Sampling was population-based in six (Germany, Italy, Lithuania, Luxembourg, Netherlands, Spain) and from consecutive patients attending general practitioners (GPs) for any reason in three (Austria, France, UK). Additional samples in Netherlands and Spain, and the only sample from Ireland, were recruited by lay headache organisations. We recorded migraine prevalence and frequency, and utilization of medical services and medications (acute and preventative). Results Among 9247 participants (mean age 43.9 ± 13.9 years, M/F ratio 1:1.4), 3466 (37.6%) were diagnosed with migraine (definite or probable). Of these, 1175 (33.8%) reported frequent migraine (> 5 days/month) and might clearly expect benefit from, and therefore had need of, preventative medication. In population-based samples, minorities of participants with migraine had seen a GP (9.5–18.0%) or specialist (3.1–15.0%), and smaller minorities received adequate treatment: triptans 3.4–11.0%, with Spain outlying at 22.4%; preventative medication (1.6–6.4% of those eligible, with Spain again outlying at 13.7%). Proportions were greater in GP-based samples (13.6–24.5% using triptans, 4.4–9.1% on preventative medication) and among those from lay organisations (46.2–68.2% and 16.0–41.7%). Participants with migraine who had consulted specialists (3.1–33.8%) were receiving the best care by these indicators; those treated by GPs (9.5–29.6%) fared less well, and those dependent on self-medication (48.0–84.2%) were, apparently, inadequately treated. Conclusion In wealthy European countries, too few people with migraine consult physicians, with proportionately too many of these seeing specialists, and migraine-specific medications are used inadequately even among those who do. These findings represent yet another call for action in Europe to improve care for people with headache. Education of both health-care providers and the public should be central to this action.

Abstract Several data indicate that migraine, especially migraine with aura, is associated with an increased risk of ischemic stroke and other vascular events. Of concern is whether the risk of ischemic stroke in migraineurs is magnified by the use of hormonal contraceptives. As migraine prevalence is high in women of reproductive age, it is common to face the issue of migraine and hormonal contraceptive use in clinical practice. In this document, we systematically reviewed data about the association between migraine, ischemic stroke and hormonal contraceptive use. Thereafter a consensus procedure among international experts was done to develop statements to support clinical decision making, in terms of cardiovascular safety, for prescription of hormonal contraceptives to women with migraine. Overall, quality of current evidence regarding the risk of ischemic stroke in migraineurs associated with the use of hormonal contraceptives is low. Available data suggest that combined hormonal contraceptive may further increase the risk of ischemic stroke in those who have migraine, specifically migraine with aura. Thus, our current statements privilege safety and provide several suggestions to try to avoid possible risks. As the quality of available data is poor further research is needed on this topic to increase safe use of hormonal contraceptives in women with migraine.

Abstract The trigeminovascular system plays a key role in the pathophysiology of migraine. The activation of the trigeminovascular system causes release of various neurotransmitters and neuropeptides, including serotonin and calcitonin gene-related peptide (CGRP), which modulate pain transmission and vascular tone. Thirty years after discovery of agonists for serotonin 5-HT1B and 5-HT1D receptors (triptans) and less than fifteen after the proof of concept of the gepant class of CGRP receptor antagonists, we are still a long way from understanding their precise site and mode of action in migraine. The effect on cranial vasculature is relevant, because all specific anti-migraine drugs and migraine pharmacological triggers may act in perivascular space. This review reports the effects of triptans and CGRP blocking molecules on cranial vasculature in humans, focusing on their specific relevance to migraine treatment.

Following the publication of this article [1], the authors noticed that they incorrectly reported the Absolute risk of ischemic stroke in women aged 20 to 44 years in relation to the use of hormonal contraception and migraine status due to a miscalculation. They apologize for this misreported result.

BackgroundTo evaluate if plasma levels of midregional pro-adrenomedullin (MR-proADM) improve prediction of functional outcome in ischemic stroke.MethodsIn 168 consecutive ischemic stroke patients, plasma levels of MR-proADM were measured within 24 hours from symptom onset. Functional outcome was assessed by the modified Rankin Scale (mRS) at 90 days following stroke. Logistic regression, receiver operating characteristics (ROC) curve analysis, net reclassification improvement (NRI), and Kaplan-Meier survival analysis were applied.ResultsPlasma MR-proADM levels were found significantly higher in patients with unfavourable (mRS 3-6) compared to favourable (mRS 0-2) outcomes. MR-proADM levels were entered into a predictive model including the patients' age, National Institutes of Health Stroke Scale (NIHSS), and the use of recanalization therapy. The area under the ROC curve did not increase significantly. However, category-free NRI of 0.577 (pConclusionsPlasma MR-proADM levels improve prediction of functional outcome in ischemic stroke when added to the patients' age, NIHSS on admission, and the use of recanalization therapy. Levels of MR-proADM in peripheral blood improve reclassification of patients when the SPAN-100 is used to predict the patients' functional outcome.