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Background and aimMonoclonal antibodies acting on the calcitonin gene-related peptide or on its receptor are new drugs to prevent migraine. Four monoclonal antibodies have been developed: one targeting the calcitonin gene-related peptide receptor (erenumab) and three targeting the calcitonin gene-related peptide (eptinezumab, fremanezumab, and galcanezumab). The aim of this document by the European Headache Federation (EHF) is to provide an evidence-based and expert-based guideline on the use of the monoclonal antibodies acting on the calcitonin gene-related peptide for migraine prevention.MethodsThe guideline was developed following the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. The working group identified relevant questions, performed systematic review and analysis of the literature, assessed the quality of available evidence, and wrote recommendations. Where the GRADE approach was not applicable, expert opinion was provided.ResultsWe found low to high quality of evidence to recommend eptinezumab, erenumab, fremanezumab, and galcanezumab in patients with episodic migraine and medium to high quality of evidence to recommend erenumab, fremanezumab, and galcanezumab in patients with chronic migraine. For several clinical questions, there was not enough evidence to provide recommendations using the GRADE approach and recommendations relied on experts’ opinion.ConclusionMonoclonal antibodies acting on the calcitonin gene-related peptide are new drugs which can be recommended for migraine prevention. Real life data will be useful to improve the use of those drugs in clinical practice.

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.

The debate on the clinical definition of refractory Chronic Migraine (rCM) is still far to be concluded. The importance to create a clinical framing of these rCM patients resides in the complete disability they show, in the high risk of serious adverse events from acute and preventative drugs and in the uncontrolled application of therapeutic techniques not yet validated.The European Headache Federation Expert Group on rCM presents hereby the updated definition criteria for this harmful subset of headache disorders. This attempt wants to be the first impulse towards the correct identification of these patients, the correct application of innovative therapeutic techniques and lastly aim to be acknowledged as clinical entity in the next definitive version of the International Classification of Headache Disorders 3 (ICHD-3 beta).

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.

The TNF/TNFR system exerts multiple proinflammatory and immunosuppressive functions in the pathogenesis of chronic inflammation and autoimmunity. In EAE, the experimental model of Multiple Sclerosis (MS), genetic ablation of TNFR2, results in exacerbated immune reactivity and chronic disease course. The underlying mechanism driving this immunosuppressive function of TNFR2 remains unclear. We show here that chronic exacerbated EAE in TNFR2 KO mice is associated with increased Th17-cell responses and reduced numbers of Foxp3 1 Treg cells both in the spinal cord and peripheral lymphoid organs. Treg cells from TNFR2-deficient animals developing EAE show decreased proliferative and suppressive functions, both ex vivo and in vivo, and appear responsible for the exacerbated non-remitting disease, as evidenced by phenotypic rescue following adoptive transfer of Treg cells from WT but not TNFR2 À/À donors. Reciprocal BM transplantation experiments between WT and TNFR2-deficient mice demonstrated that the capacity of TNFR2 to support Treg-cell expansion and function during EAE is non-intrinsic to Treg or other haematopoietic cells but requires expression of TNFR2 in radiation-resistant cells of the host. These results reveal a previously unsuspected role for non-haematopoietic TNFR2 in modulating Treg-cell expansion and immune suppression during development of autoimmunity and suggest that a similar mechanism may affect chronicity and relapses characterizing human autoimmune disease, including MS.Key words: Animal models . Autoimmunity . Cellular immunology . Multiple sclerosis . TNFRZ Supporting Information available online IntroductionMultiple sclerosis (MS) is a chronic neuroimmunological disease characterized by disseminated foci of inflammatory demyelination in the brain and spinal cord (SC), commonly affecting young adults between the age of 20 and 40. Typically, MS has a relapsing and remitting course followed by the development of irreversible neurological disability due to persistent axonal dysfunction and neuronal loss. CNS demyelination, the pathological hallmark of MS is brought about by autoreactive à These authors contributed equally to this work. , which produces T-cell-driven demyelination with components from cellular and humoral immunity leading to axonal injury associated with disability ranging from mild weakness to severe paralysis [3,4]. Dysfunctional immune suppressive/tolerogenic mechanisms causing aggressive autoimmune behavior and demyelination are thought to play a dominant pathogenic role both in EAE and MS [1,3]. Chronicity and relapses in autoimmune diseases including MS seem to involve defective integration of inflammatory and antiinflammatory cues. Numerous studies have dissected the multiple and opposing roles of cytokine-producing cells in the autoimmune pathogenesis of MS and EAE. IL-17-(Th17) [5,6] and IFN-g-(Th1) [7][8][9][10] producing cells are considered the effector T (Teff) cells that have been detected in SC lesions at different stages of the disease progression and are thought t...

Our analysis indicates a significant dropout rate related to nocebo in trials for PD treatment. Adherence and efficacy may be adversely affected with additional implications for clinical practice.

This paper presents the evolution of ideas on headache symptoms from antiquity through the 19th century. A thorough study of texts, medical books and reports along with a review of the available literature in PubMed was undertaken: observations on headaches date back nearly 4,000 years to the ritual texts of Mesopotamia. Nicolaes Tulp, Thomas Willis and Gerhard van Swieten also made important contributions on various forms of headaches in the 17th and 18th centuries. Edward Liveing and William Gowers made the major contributions to the field in the late 19th century. Overall, observations on headaches span a timeline of nearly 9,000 years. The work of the physicians during the 18th and 19th century, however, set the basis for scientific research.