The glymphatic system in migraine and other headaches.

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.

Headaches and facial pain attributed to SARS-CoV-2 infection and vaccination: a systematic review.

BACKGROUND AND PURPOSE: The aim was to provide insights to the characteristics of headache in the context of COVID-19 on behalf of the Headache Scientific Panel and the Neuro-COVID-19 Task Force of the European Academy of Neurology (EAN) and the European Headache Federation (EHF). METHODS: Following the Delphi method the Task Force identified six relevant questions and then conducted a systematic literature review to provide evidence-based answers and suggest specific diagnostic criteria. RESULTS: No data for facial pain were identified in the literature search. (1) Headache incidence during acute COVID-19 varies considerably, with higher prevalence rates in prospective compared to retrospective studies (28.9%-74.6% vs. 6.5%-34.0%). (2) Acute COVID-19 headache is usually bilateral or holocranial and often moderate to severe with throbbing pain quality lasting 2-14 days after first signs of COVID-19; photo-phonophobia, nausea, anosmia and ageusia are common associated features; persistent headache shares similar clinical characteristics. (3) Acute COVID-19 headache is presumably caused by immune-mediated mechanisms that activate the trigeminovascular system. (4) Headache occurs in 13.3%-76.9% following SARS-CoV-2 vaccination and occurs more often amongst women with a pre-existing primary headache; the risk of developing headache is higher with the adenoviral-vector-type vaccines than with other preparations. (5) Headache related to SARS-CoV-2 vaccination is mostly bilateral, and throbbing, pressing, jolting or stabbing. (6) No studies have been conducted investigating the underlying mechanism of headache attributed to SARS-CoV-2 vaccines. CONCLUSION: The results of this joint EAN/EHF initiative provide a framework for a better understanding of headache in the context of SARS-CoV-2 infection and vaccination.

Migraine - a borderland disease to epilepsy: near it but not of it.

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.

Considerations for hormonal therapy in migraine patients: a critical review of current practice.

INTRODUCTION: Migraine, a neurovascular headache disorder, is a leading cause of disability worldwide. Within the multifaceted pathophysiology of migraine, hormonal fluctuations play an evident triggering and exacerbating role, pointing toward the need for identification and proper usage of both existing and new hormonal targets in migraine treatment. AREAS COVERED: With a threefold higher incidence of migraine in women than in men, the authors delve into sex hormone-related events in migraine patients. A comprehensive overview is given of existing hormonal therapies, including oral contraceptives, intrauterine devices, transdermal and subcutaneous estradiol patches, gnRH-agonists, oral testosterone, and 5α reductase inhibitors. The authors discuss their effectiveness and risks, noting their suitability for different patient profiles. Next, novel evolving hormonal treatments, such as oxytocin and prolactin, are explored. Lastly, the authors cover hormonal conditions associated with migraine, such as polycystic ovary syndrome, endometriosis, and transgender persons receiving gender affirming hormone therapy, aiming to provide more personalized and effective solutions for migraine management. EXPERT OPINION: Rigorous research into both existing and new hormonal targets, as well as the underlying pathophysiology, is needed to support a tailored approach in migraine treatment, in an ongoing effort to alleviate the impact of migraine on individuals and society.

Rethinking headache as a global public health case model for reaching the SDG 3 HEALTH by 2030.

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.

European Headache Federation (EHF) critical reappraisal and meta-analysis of oral drugs in migraine prevention - part 3: topiramate.

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.

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

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

Revisiting dose-finding of monoclonal antibodies in migraine.

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.

The increasing role of electronic media in headache.

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.

The comparative effectiveness of migraine preventive drugs: a systematic review and network meta-analysis.

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.

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

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

New Migraine Drugs for Older Adults.

Migraine is one of the most widespread and burdensome diseases, affecting one in every seven individuals in the world, for an estimated global prevalence of 14%. Until recently, therapeutic choices for older migraineurs have been limited by safety concerns and such patients have typically been excluded from clinical trials. However, randomized controlled trials (RCTs) of new migraine drugs have begun to include participants aged over 65 years, offering clinicians relevant safety and efficacy data to be able to treat older patients with the newest drug classes, including monoclonal antibodies for CGRP (r), CGRP antagonists, and drugs targeting the serotonin 5-HT1F receptor. RCT inclusion criteria nonetheless select the most appropriate older patients, usually excluding polymorbid participants. In a real-life setting, older patients may have several comorbidities, and this reduces the clinical applicability of the new drugs to these patients. Two main points should be addressed to solve this barrier: the inclusion of a sufficient number of migraineurs aged over 65 years in RCTs and the publication of appropriate guidelines for a tailored treatment that considers the existence of multimorbid pathologies in this population of individuals.

European Headache Federation (EHF) consensus on the definition of effective treatment of a migraine attack and of triptan failure.

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.

Safety and tolerability of erenumab in individuals with episodic or chronic migraine across age groups: a pooled analysis of placebo-controlled trials.

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 < 40 years, 40-49 years, 50-59 years, and ≥ 60 years was completed. The safety of erenumab across age groups was determined by assessing safety endpoints including treatment-emergent adverse events (AEs), serious AEs, and events leading to study drug discontinuation. RESULTS: Overall, 3345 participants across five studies were randomized to receive either placebo (n = 1359), erenumab 70 mg (n = 1132) or erenumab 140 mg (n = 854); 3176 (94.9%) completed the DBTP, and 169 (5.1%) discontinued, mainly due to participant decision (110; 3.3%). Overall, 1349 (40.6%), 1122 (33.8%), and 850 (25.6%) participants received at least one dose of placebo, erenumab 70 mg, and erenumab 140 mg, respectively. Incidence of treatment-emergent AEs was similar across all age groups for both doses of erenumab (70 mg or 140 mg) and placebo (< 40 years, 44.0% vs 44.4%; 40-49 years, 42.5% vs 49.2%; 50-59 years, 46.5% vs 41.6%; ≥ 60 years, 43.8% vs 59.4%). Incidence of treatment-emergent serious AEs overall, and stratified by age groups for both doses and placebo was low (< 40 years, 0.9% vs 1.2%; 40-49 years, 1.7% vs 1.9%; and 50-59 years, 1.6% vs 1.1%), with no serious AEs reported in participants aged ≥ 60 years. No deaths were reported. CONCLUSIONS: Erenumab (70 mg or 140 mg) exhibited a similar safety profile compared with placebo across age groups in individuals with episodic or chronic migraine, with no increased emergence of events due to age. Erenumab was well tolerated in older participants with multiple comorbidities, polypharmacy, and age-related physiological changes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifiers: NCT02066415, NCT02456740, NCT02483585, NCT03096834, NCT03333109.

Management of medication overuse (MO) and medication overuse headache (MOH) S1 guideline.

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.

European Headache Federation guideline on the use of monoclonal antibodies targeting the calcitonin gene related peptide pathway for migraine prevention - 2022 update.

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.

Narrative-based medicine in headache disorders.

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.

Efficacy and quality-of-life improvements with fremanezumab treatment in patients with difficult-to-treat migraine with associated neurological dysfunction.

BACKGROUND AND PURPOSE: Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin-gene-related peptide, has demonstrated efficacy as a preventive treatment for adults with episodic migraine or chronic migraine and inadequate response to two to four prior preventive treatment classes in the phase 3b FOCUS study. In this post hoc analysis, efficacy and effects on quality-of-life outcomes for fremanezumab were evaluated in subgroups of patients with and without aura or similar neurological symptoms, here referred to as migraine with or without associated neurological dysfunction. METHODS: In the FOCUS study, 838 patients were randomized (1:1:1) to quarterly fremanezumab, monthly fremanezumab or matched placebo for 12 weeks of double-blind treatment. For this post hoc analysis, subgroups of patients with migraine with and without associated neurological dysfunction at baseline were identified based on patient response to questions about symptoms. RESULTS: In patients with migraine with associated neurological dysfunction at baseline, fremanezumab significantly reduced monthly average days with neurological symptoms (quarterly, -1.7 days; monthly, -1.8 days) compared to placebo (-0.5 days; both p ≤ 0.01). In comparison with placebo, both dosing regimens of fremanezumab yielded greater reductions in monthly migraine days over 12 weeks (p < 0.0001) and improvements in Headache Impact Test 6 and Migraine-Specific Quality of Life scores over the last 4 weeks (p < 0.05), regardless of neurological dysfunction at baseline. CONCLUSIONS: Fremanezumab reduced days with neurological symptoms, effectively prevented migraine, and improved quality of life in patients with migraine with associated neurological dysfunction, including those with previous inadequate response to two to four migraine preventive medication classes.