Prevalence and characteristics of rapid eye movement sleep behaviour disorder in adults with migraine: a cross-sectional screening study.

BACKGROUND AND PURPOSE: Migraine and sleep disorders share a bidirectional relationship, but little is known about the specific association between migraine and rapid eye movement (REM) sleep behaviour disorder (RBD). The aim was to assess the prevalence of RBD and associated clinical characteristics in adults with migraine. METHODS: This analysis is part of a cross-sectional survey study conducted at the Headache Centre of the Charité-Universitätsmedizin Berlin between August 2020 and March 2023. At the end of their regular medical consultation, patients with migraine filled out (1) the validated RBD Screening Questionnaire (RBDSQ), (2) a questionnaire on REM sleep intrusions and (3) the Depression, Anxiety and Stress Scale 21. The primary endpoint was the percentage of patients with a positive RBD screening. A multivariate analysis was performed to identify characteristics independently associated with features of RBD. RESULTS: A total of 751 patients (44.1 ± 13.2 years; 87.4% female) with complete RBDSQ were included in this analysis, of which 443 (58.9%) screened positive for RBD. In multivariate analysis, a positive screening for RBD was associated with younger age (odds ratio [OR] 0.9, 95% confidence interval [CI] 0.8-0.9 per 10-year increase; p = 0.005) and with features suggestive of REM sleep intrusions (OR 4.3, 95% CI 1.8-10.4; p = 0.001). Migraine aura remained in the model without reaching statistical significance (OR 1.3, 95% CI 0.9-1.8; p = 0.079). DISCUSSION: Symptoms of RBD are frequent in adults with migraine. Further studies including polysomnography are required to confirm this association, and to explore potential common pathophysiological mechanisms.

PACAP-38 and sex hormones in women with migraine: exploratory analysis of a cross-sectional, matched cohort study.

BACKGROUND: Endogeneous and exogeneous sex hormones can impact the frequency and severity of migraine attacks, but the underlying mechanisms are poorly understood. In this study, we investigate the relationship between female sex hormones and Pituitary Adenylate Cyclase-Activating Polypeptide-38 (PACAP-38) concentrations in plasma of women with migraine and healthy controls, aiming to elucidate potential hormonal influences on PACAP dynamics and their relevance to migraine pathophysiology. METHODS: This analysis is part of a cross-sectional, matched-cohort study. We recruited two groups of women with episodic migraine: one with a regular menstrual cycle (M-RMC) and another undergoing combined oral contraceptive treatment (M-COC). Additionally, we included corresponding age-matched control groups without migraine for both categories (C-RMC and C-COC). For participants with a RMC, the study visits were scheduled during the perimenstrual period (menstrual cycle day 2 ± 2) and periovulatory period (day 13 ± 2). Participants using COC were examined at day 4 ± 2 of the hormone-free interval and between day 7-14 of the hormone intake phase. During these visits, PACAP-38 concentrations in plasma were measured using a commercial Enzyme-linked-immunosorbent assay (ELISA) kit. RESULTS: The study included 120 women, with 30 participants in each group. Women with migraine and a RMC had significantly higher PACAP-38 plasma concentrations compared to healthy controls at both study visits [day 2 ± 2: M-RMC: 2547.41 pg/ml (IQR 814.27 - 4473.48) vs. C-RMC: 1129.49 pg/ml (IQR 257.34 - 2684.88), p = 0.025; day 13 ± 2: M-RMC: 3098.89 pg/ml (IQR 1186.29 - 4379.47) vs. C-RMC: 1626.89 (IQR 383.83 - 3038.36), p = 0.028]. In contrast, PACAP-38 levels were comparable between migraine and control groups receiving COC. Women with migraine and a RMC exhibited higher PACAP-38 concentrations during menstruation compared to those using COC during the hormone-free interval. CONCLUSION: Systemic PACAP-38 concentrations in women vary based on the presence of migraine diagnosis and their hormonal status.

Alice in Wonderland Syndrome (AIWS): prevalence and characteristics in adults with migraine.

OBJECTIVE: Alice in Wonderland Syndrome (AIWS) is a sensory disorder characterized by a distorted somatosensory and/or visual perception. Additionally, distortion of time perception and symptoms of derealization/depersonalization may occur. AIWS is frequently associated with migraine. However, its prevalence, and clinical characteristics remain poorly understood. Here, we investigated the prevalence and features of AIWS in individuals with migraine. We hypothesized AIWS is more frequent in migraine patients with aura than in those without aura. METHODS: This was a prospective cross-sectional cohort study, conducted at a tertiary headache center. Participants with migraine filled out questionnaires, providing details on demographics, headache, AIWS characteristics and the occurrence of transient visual phenomena such as fragmented vision. RESULTS: Of 808 migraine patients, 133 individuals (16.5%, mean age 44.4 ± 13.3 years, 87% women) reported AIWS symptoms throughout their lives. Micro- and/or telopsia (72.9%) were most frequent, followed by micro- and/or macrosomatognosia (49.6%), and macro- and/or pelopsia (38.3%), lasting on average half an hour. AIWS symptoms occurred in association with headache in 65.1% of individuals, and 53.7% had their first AIWS episode at the age of 18 years or earlier. Migraine patients with aura were more likely to report AIWS symptoms than those without aura (19.5% vs. 14.1%, p = 0.04). Participants with AIWS reported a higher incidence of 17 out of the 22 investigated visual phenomena. CONCLUSION: AIWS symptoms appear to be a common lifetime phenomenon in migraine patients. The correlation and clinical parallels between AIWS and migraine aura could indicate shared underlying pathomechanisms.

Influence of metabolic state and body composition on the action of pharmacological treatment of migraine.

Migraine is a disabling neurovascular disorder among people of all ages, with the highest prevalence in the fertile years, and in women. Migraine impacts the quality of life of affected individuals tremendously and, in addition, it is associated with highly prevalent metabolic diseases, such as obesity, diabetes mellitus and thyroid dysfunction. Also, the clinical response to drugs might be affected in patients with metabolic disease due to body composition and metabolic change. Therefore, the efficacy of antimigraine drugs could be altered in patients with both migraine and metabolic disease. However, knowledge of the pharmacology and the related clinical effects of antimigraine drugs in patients with metabolic disease are limited. Therefore, and given the clinical relevance, this article provides a comprehensive overview of the current research and hypotheses related to the influence of metabolic state and body composition on the action of antimigraine drugs. In addition, the influence of antimigraine drugs on metabolic functioning and, vice versa, the influence of metabolic diseases and its hormonal modulating medication on migraine activity is outlined. Future exploration on personalizing migraine treatment to individual characteristics is necessary to enhance therapeutic strategies, especially given its increasing significance in recent decades.

Impact of a reimbursement policy change on treatment with erenumab in migraine - a real-world experience from Germany.

BACKGROUND: Monoclonal antibodies (mAbs) targeting the Calcitonin Gene-Related Peptide (CGRP) pathway are safe and effective treatments for migraine prevention. However, the high cost of these novel therapies has led to reimbursement policies requiring patients to try multiple traditional preventives before access. In Germany, a recent change in insurance policy significantly expanded coverage for the CGRP receptor mAb erenumab, enabling migraine patients who failed just one prior prophylactic medication to receive this mAb. Here, we compare the clinical response to treatment with erenumab in migraine patients treated using the old and new coverage policy. METHODS: In this retrospective cohort study, we included CGRP-mAb naïve patients with episodic or chronic migraine, who started erenumab at our headache center according to either the old or the new insurance policy and received at least 3 consecutive injections. Headache diaries and electronic documentation were used to evaluate reductions in monthly headache and migraine days (MHD and MMD) and ≥ 50% and ≥ 30% responder rates at month 3 (weeks 9-12) of treatment. RESULTS: We included 146 patients who received erenumab according to the old policy and 63 patients that were treated using the new policy. At weeks 9-12 of treatment, 37.7% of the old policy group had a 50% or greater reduction in MHD, compared to 63.5% of the new policy group (P < 0.001). Mean reduction in MHD was 5.02 days (SD = 5.46) and 6.67 days (SD = 5.32, P = 0.045) in the old and new policy cohort, respectively. After propensity score matching, the marginal effect of the new policy on treatment outcome was 2.29 days (standard error, SE: 0.715, P = 0.001) more reduction in MHD, and 30.1% (SE: 10.6%, P = 0.005) increase in ≥ 50% response rate for MHD. CONCLUSIONS: Starting erenumab earlier in the course of migraine progression in a real-world setting may lead to a better response than starting after multiple failed prophylactic attempts. Continually gathering real-world evidence may help policymakers in deciding how readily to cover CGRP-targeted therapies in migraine prevention.

Near-death experiences are associated with rapid eye movement (REM) sleep intrusions in migraine patients, independent of migraine aura.

BACKGROUND AND PURPOSE: Migraine aura, near-death experiences (NDEs), and rapid eye movement (REM) sleep intrusions might share common mechanisms. Here, we investigated the prevalence of NDEs and REM sleep intrusions in people with migraine. We hypothesized that NDEs and REM sleep intrusions are more prevalent in migraine patients with aura than in those without. METHODS: We conducted a prospective cross-sectional cohort study at a tertiary headache center, based on a prespecified sample size (n = 808). Migraine patients completed a series of questionnaires, including questions about demographic and headache characteristics, the 16-item Greyson NDE scale, four questions about REM sleep intrusions, and the Depression, Anxiety, and Stress Scale 21 (DASS-21). RESULTS: Of 808 migraine patients (mean age 44.4 ± 13.3 years, 87.0% women), 353 (43.7%) had a current or previous history of migraine aura. Prevalence of NDE was 2.7% and not different in patients with and without aura (2.8% vs. 2.6%; p > 0.999). REM sleep intrusions were reported by 5.4% of participants and in a similar proportion of patients with and without aura (6.3% vs. 4.9%; p = 0.43). However, participants with REM sleep intrusions had had an NDE more often than participants without REM sleep intrusions (n = 5/44, 11.4% vs. n = 17/754, 2.2%; p = 0.005). Higher DASS-21 scores were associated with REM sleep intrusions (p < 0.001). CONCLUSIONS: In this tertiary center cohort study, the prevalence of NDE and REM sleep intrusions was not influenced by migraine aura status. However, we identified an association between NDE and REM sleep intrusions, which corroborates the notion that they might share pathophysiological mechanisms.

Effect of switching to erenumab in non-responders to a CGRP ligand antibody treatment in migraine: A real-world cohort study.

Background: Therapeutic 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. Methods: This 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. Results: From 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. Conclusion: Switching 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.

Clinical evaluation of super-responders vs. non-responders to CGRP(-receptor) monoclonal antibodies: a real-world experience.

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.

Sex Hormones and Calcitonin Gene-Related Peptide in Women With Migraine: A Cross-sectional, Matched Cohort Study.

BACKGROUND AND OBJECTIVES: Sex hormones may modulate calcitonin gene-related peptide (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 3 corresponding groups of age-matched female participants without EM. METHODS: Participants with an RMC had 2 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 and 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 ELISA. RESULTS: A total of 180 female participants (n = 30 per group) completed the study. Participants with migraine and an RMC showed statistically significantly higher CGRP concentrations in plasma and tear fluid during menstruation compared with 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 an RMC, tear fluid but not plasma CGRP concentrations during menstruation were statistically significantly higher compared with 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.

Migraine and Hormonal Contraception in Gynecological Outpatient Care-Cross-Sectional Study among Practicing Gynecologists in Germany.

Hormonal contraception (HC) can influence the migraine burden and should be considered in the comprehensive management of women with migraine. In this study, we aim to investigate the influence of migraine and migraine aura on the prescribing behavior of combined oral contraception (COC) and progestogen monotherapy (PM) in gynecological outpatient care. From October 2021 to March 2022, we performed an observational, cross-sectional study using a self-administered online-based survey. The questionnaire was distributed by mail and e-mail among 11,834 practicing gynecologists in Germany using the publicly available contact information. A total of 851 gynecologists responded to the questionnaire, of whom 12% never prescribe COC in the presence of migraine. Further 75% prescribe COC depending on the presence of limiting factors such as cardiovascular risk factors and comorbidities. When deciding to start PM, migraine appears to be less relevant, as 82% prescribe PM without restrictions. In the presence of aura, 90% of gynecologists do not prescribe COC at all, while PM is prescribed in 53% without restrictions. Almost all gynecologists reported to be actively involved in migraine therapy by having already initiated (80%), discontinued (96%), or changed (99%) HC due to migraine. Our results reveal that participating gynecologists actively consider migraine and migraine aura before and while prescribing HC. Gynecologists appear cautious in prescribing HC in patients with migraine aura.

Change of CGRP Plasma Concentrations in Migraine after Discontinuation of CGRP-(Receptor) Monoclonal Antibodies.

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.

Advances in pharmacotherapy for the prophylactic treatment of resistant and refractory migraine.

INTRODUCTION: Refractory migraine is associated with low quality of life and great socioeconomic burden. Despite high need for effective, tolerable preventive therapies, there has been little research on potential therapeutic options. Monoclonal antibodies (mAbs) against Calcitonin Gene-Related Peptide (CGRP) are the first preventive therapeutic approach for migraine based on the underlying pathophysiology. AREAS COVERED: Following a brief introduction into the term 'refractory migraine,' the authors reviewavailable treatment options, focusing on current phase III trials of substances acting on the CGRP pathway. EXPERT OPINION: No uniform definition for refractory migraine is available. The vast majority of proposals recommend treatment failure of 2-4 drug classes as a key diagnostic criterion. Phase III studies on CGRP-(receptor) mAbs demonstrated excellent efficacy and tolerability in patients with chronic and episodic migraine including subjects with multiple unsuccessful conventional therapy attempts. However, more comparator trials showing superiority of mAbs versus oral preventatives, such as the HER-MEs study are needed. In summary, with the CGRP antibodies, a group of drugs has entered the market which will most likely not only significantly improve the quality of life of many individual migraine patients but could also reduce indirect health-care costs associated with migraine by reducing recurrent medical consultations.

Integrated age-related immunohistological changes occur in human olfactory epithelium and olfactory bulb.

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. KEY POINTS: A gradual loss of olfactory sensory neurons with age in human olfactory epithelium is also reflected in a reduction in glomeruli within the olfactory bulb. This gradual loss of neurons and synaptic connections with age occurs in a specific, spatially inhomogeneous manner. Decreasing mitotically active olfactory epithelium basal cells may contribute to age-related neuronal decline and smell loss in humans.