Background Clinical trials and real-world studies revealed a spectrum of response to CGRP(-receptor) monoclonal antibodies (mAbs) in migraine prophylaxis, ranging from no effect at all to total migraine freedom. In this study, we aimed to compare clinical characteristics between super-responders (SR) and non-responders (NR) to CGRP(-receptor) mAbs. Methods We performed a retrospective cohort study at the Headache Center, Charité – Universitätsmedizin Berlin. The definition of super-response was a ≥ 75% reduction in monthly headache days (MHD) in the third month after treatment initiation compared to the month prior to treatment begin (baseline). Non-response was defined as ≤ 25% reduction in MHD after three months of treatment with a CGRP-receptor mAb and subsequent three months of treatment with CGRP mAb, or vice versa. We collected demographic data, migraine disease characteristics, migraine symptoms during the attacks in both study groups (SR/NR) as well as the general medical history. SR and NR were compared using Chi-square test for categorical variables, and t-test for continuous variables. Results Between November 2018 and June 2022, n = 260 patients with migraine received preventive treatment with CGRP(-receptor) mAbs and provided complete headache documentation for the baseline phase and the third treatment month. Among those, we identified n = 29 SR (11%) and n = 26 NR (10%). SR reported more often especially vomiting (SR n = 12/25, 48% vs. NR n = 4/22, 18%; p = 0.031) and typical migraine characteristics such as unilateral localization, pulsating character, photophobia and nausea. A subjective good response to triptans was significantly higher in SR (n = 26/29, 90%) than in NR (n = 15/25, 60%, p = 0.010). NR suffered more frequently from chronic migraine (NR n = 24/26, 92% vs. SR n = 15/29, 52%; p = 0.001), medication overuse headache (NR n = 14/24, 58% versus SR n = 8/29, 28%; p = 0.024), and concomitant depression (NR n = 17/26, 65% vs. SR n = 8/29, 28%; p = 0.005). Conclusion Several clinical parameters differ between SR and NR to prophylactic CGRP(-R) mAbs. A thorough clinical evaluation prior to treatment initiation might help to achieve a more personalized management in patients with migraine.

Background and Objectives:Sex hormones may modulate CGRP release in the trigeminovascular system. We studied CGRP concentrations in plasma and tear fluid in female participants with episodic migraine (EM) and a regular menstrual cycle (RMC), female participants with EM and combined oral contraception (COC), and female participants with EM in the postmenopause. For control, we analyzed three corresponding groups of age-matched female participants without EM.Methods:Participants with a RMC had two visits: during menstruation on menstrual cycle day 2 ± 2 and in the periovulatory period on day 13 ± 2. Participants with COC were examined at day 4 ± 2 of the hormone-free interval (HFI) and between days 7-14 of hormone intake (HI). Postmenopausal participants were assessed once at a random time point. Plasma and tear fluid samples were collected at each visit for determination of CGRP levels with an enzyme-linked immunosorbent assay.Results:A total of 180 female participants (n=30 per group) completed the study. Participants with migraine and a RMC showed statistically significantly higher CGRP concentrations in plasma and tear fluid during menstruation compared to female participants without migraine [plasma: 5.95 pg/ml (IQR 4.37 – 10.44) vs. 4.61 pg/ml (IQR 2.83 – 6.92), p=0.020 (Mann-Whitney U test); tear fluid: 1.20 ng/ml (IQR 0.36 – 2.52) vs. 0.4 ng/ml (IQR 0.14 – 1.22), p=0.005 (Mann-Whitney U test)]. In contrast, female participants with COC and in the postmenopause had similar CGRP levels in the migraine and the control groups. In migraine participants with a RMC, tear fluid but not plasma CGRP concentrations during menstruation were statistically significantly higher compared to migraine participants under COC (p=0.015 vs. HFI and p=0.029 vs. HI, Mann-Whitney U test).Discussion:Different sex hormone profiles may influence CGRP concentrations in people, with current or past capacity to menstruate, with migraine. Measurement of CGRP in tear fluid was feasible and warrants further investigation.

Introduction Migraine prophylactic therapy has changed over recent years with the development and approval of monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway. As new therapies emerged, leading headache societies have been providing guidelines on the initiation and escalation of such therapies. However, there is a lack of robust evidence looking at the duration of successful prophylaxis and the effects of therapy discontinuation. In this narrative review we explore both the biological and clinical rationale for prophylactic therapy discontinuation to provide a basis for clinical decision-making. Methods Three different literature search strategies were conducted for this narrative review. These include i) stopping rules in comorbidities of migraine in which overlapping preventives are prescribed, notably depression and epilepsy; ii) stopping rules of oral treatment and botox; iii) stopping rules of antibodies targeting the CGRP (receptor). Keywords were utilized in the following databases: Embase, Medline ALL, Web of Science Core collection, Cochran Central Register of Controlled Trials, and Google Scholar. Discussion Reasons to guide decision-making in stopping prophylactic migraine therapies include adverse events, efficacy failure, drug holiday following long-term administration, and patient-specific reasons. Certain guidelines contain both positive and negative stopping rules. Following withdrawal of migraine prophylaxis, migraine burden may return to pre-treatment level, remain unchanged, or lie somewhere in-between. The current suggestion to discontinue CGRP(-receptor) targeted mAbs after 6 to 12 months is based on expert opinion, as opposed to robust scientific evidence. Current guidelines advise the clinician to assess the success of CGRP(-receptor) targeted mAbs after three months. Based on excellent tolerability data and the absence of scientific data, we propose if no other reasons apply, to stop the use of mAbs when the number of migraine days decreases to four or fewer migraine days per month. There is a higher likelihood of developing side effects with oral migraine preventatives, and so we suggest stopping these drugs according to the national guidelines if they are well tolerated. Conclusion Translational and basic studies are warranted to investigate the long-term effects of a preventive drug after its discontinuation, starting from what is known about the biology of migraine. In addition, observational studies and, eventually, clinical trials focusing on the effect of discontinuation of migraine prophylactic therapies, are essential to substantiate evidence-based recommendations on stopping rules for both oral preventives and CGRP(-receptor) targeted therapies in migraine. Graphical Abstract

Background The representation of migraine in the media is stereotypical. Standard images of migraine attacks display stylish young women holding their head in a pain pose. This representation may contribute to the social stigmatization of patients with migraine. Objective We aimed to analyze how patients with migraine and health care workers perceive online images of migraine. Methods The study consisted of an anonymous web-based survey of patients with migraine at the Headache Center of Charité – Universitätsmedizin Berlin (migraine group) and employees and students at our university (health care group). A total of 10 frequently used Adobe Stock photos of migraine attacks were presented to the participants. Each photo was rated on a scale of 0% to 100% based on how closely it resembled a realistic migraine attack (realism score). Patients with migraine also indicated how much each photo corresponded to their own experience of migraine as a percentage (representation score). We calculated the mean realism and representation scores for all photos and conducted further analyses using the categories male or female models, younger or older models, and unilateral or bilateral pain pose. Results A total of 367 patients with migraine and 331 health care employees and students completed the survey. In both groups, the mean realism score was <50% (migraine group: 47.8%, SD 18.3%; health care group: 46.0%, SD 16.2%). Patients with migraine identified their own migraine experience in these photos to a lesser degree (mean representation score 44.4%, SD 19.8%; P<.001 when compared to the realism score). Patients and health care workers considered photos with male models to be more realistic than photos with females (P<.001) and photos with older models to be more realistic than those with younger people (P<.001). In the health care group only, a bilateral pain posture was deemed more realistic than a unilateral pose (P<.001). Conclusions Standard images of migraine attacks are considered only slightly or moderately realistic by patients and health care workers. Some characteristics perceived as more realistic such as male sex or older age are in contrast with migraine epidemiology. A more accurate representation of migraine in the media could help to raise awareness for migraine and reduce the associated stigma.

Discontinuation of treatment with monoclonal antibodies (mAb) targeting the Calcitonin Gene-Related Peptide (CGRP) pathway leads to an increase in migraine frequency. We aimed to assess changes in free and total CGRP plasma concentrations after the discontinuation of CGRP(-receptor) mAbs. This prospective analysis included 59 patients with migraine (n = 25 erenumab, n = 25 galcanezumab, n = 9 fremanezumab) who discontinued mAbs after ≥8 months of treatment. Patients were visited at the time of the last mAb injection (V1) and 16 weeks later (V2). For control, 30 migraine patients without preventive drug therapy were included. We measured free CGRP plasma concentrations in the erenumab and fremanezumab group and total CGRP concentrations in the galcanezumab group. Free CGRP plasma concentrations did not change after treatment discontinuation [erenumab: V1 31.2 pg/mL (IQR 25.8–45.6), V2 30.3 pg/mL (IQR 22.9–47.6), p = 0.65; fremanezumab V1 29.4 pg/mL (IQR 16.4–61.9), V2 34.4 (19.2–62.0), p = 0.86]. Controls had similar CGRP values of 32.6 pg/mL (IQR 21.3–44.6). Total CGRP concentrations in the galcanezumab group were 5439.3 pg/mL (2412.7–6338.1) at V1, and decreased to 1853.2 pg/mL (1136.5–3297.0) at V2 (p < 0.001). Cessation of treatment with CGRP(-R) mAbs did not have an impact on the free-circulating CGRP concentrations. Total CGRP decreased significantly after three months of treatment discontinuation.