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.

BackgroundTherapeutic options for migraine prevention in non-responders to monoclonal antibodies (mAbs) targeting Calcitonin Gene-Related Peptide (CGRP) and its receptor are often limited. Real-world data have shown that non-responders to the CGRP-receptor mAb erenumab may benefit from switching to a CGRP ligand mAb. However, it remains unclear whether, vice versa, erenumab is effective in non-responders to CGRP ligand mAbs. In this study, we aim to assess the efficacy of erenumab in patients who have previously failed a CGRP ligand mAb.MethodsThis monocentric retrospective cohort study included patients with episodic or chronic migraine in whom a non-response (< 30% reduction of monthly headache days during month 3 of treatment compared to baseline) to the CGRP ligand mAbs galcanezumab or fremanezumab led to a switch to erenumab, and who had received at least 3 administrations of erenumab. Monthly headache days were retrieved from headache diaries to assess the ≥30% responder rates and the absolute reduction of monthly headache days at 3 and 6 months of treatment with erenumab in this cohort.ResultsFrom May 2019 to July 2022, we identified 20 patients who completed 3 months of treatment with erenumab after non-response to a CGRP ligand mAb. Fourteen patients continued treatment for ≥6 months. The ≥30% responder rate was 35% at 3 months, and 45% at 6 months of treatment with erenumab, respectively. Monthly headache days were reduced from 18.6 ± 5.9 during baseline by 4.1 ± 3.1 days during month 3, and by 7.0 ± 4.8 days during month 6 compared to the month before treatment with erenumab (p < 0.001, respectively). Responders and non-responders to erenumab did not differ with respect to demographic or headache characteristics.ConclusionSwitching to erenumab in non-responders to a CGRP ligand mAb might be beneficial in a subgroup of resistant patients, with increasing responder rates after 6 months of treatment. Larger prospective studies should aim to predict which subgroup of patients benefit from a switch.

Olfactory epithelium (OE) is capable of lifelong regeneration due to presence of basal progenitor cells that respond to injury or neuronal loss with increased activity. However, this capability diminishes with advancing age and a decrease in odor perception in older individuals is well established. To characterize changes associated with age in the peripheral olfactory system, an in-depth analysis of the OE and its neuronal projections onto the olfactory bulb (OB) as a function of age was performed. Human olfactory tissue autopsy samples from 36 subjects with an average age of 74.1 years were analyzed.Established cell type-specific antibodies were used to identify OE component cells in whole mucosal sheets and epithelial sections as well as glomeruli and periglomerular structures in OB sections. With age, a reduction in OE area occurs across the mucosa progressing in a posterior-dorsal direction. Deterioration of the olfactory system is accompanied with diminution of neuron-containing OE, mature olfactory sensory neurons (OSNs) and OB innervation. On an individual level, the neuronal density within the epithelium appears to predict synapse density within the OB. The innervation of the OB is uneven with higher density at the ventral half that decreases with age as opposed to stable innervation at the dorsal half. Respiratory metaplasia, submucosal cysts, and neuromata, were commonly identified in aged OE. The finding of respiratory metaplasia and aneuronal epithelium with reduction in global basal cells suggests a progression of stem cell quiescence as an underlying pathophysiology of age-related smell loss in humans.

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