Lucas Hendrik Overeem

Introduction: Migraine is a debilitating neurological disease with a multifaceted pathophysiology. Pre‐existing comorbidities may influence the risk of developing migraine. This review and meta‐analysis aim to present a comprehensive overview of the known comorbidities predisposing individuals to new migraine onset, thereby improving our understanding of the respective diseases' interactions.Methods: A systematic search of PubMed and EMBASE identified studies on pre‐existing comorbidities as risk factors for new migraine onset. We performed three‐level meta‐analyses employing restricted maximum likelihood estimation to calculate pooled risk ratios (pRR). Subgroup and sensitivity analyses were conducted to assess the robustness of the data. Risk of bias (RoB) was assessed with the Quality in Prognostic Studies Tool. This review was pre‐registered on Prospero (CRD42024501140).Results: From a total of 17,330 records, we identified 38 studies, encompassing 124 effect sizes from 58 exposures. Most studies (n = 28, 74%) had a low RoB. Heterogeneity was high (>90%), primarily due to within‐study differences (>50%), and was not significantly impacted by moderator tests or the exclusion of outliers. We found significantly increased risks for migraine onset associated with prior atopic conditions [pRR = 1.53 (1.15, 2.03)], psychiatric or psychological disorders [pRR = 2.63 (1.79, 3.85)], sleep disorders [pRR = 1.89 (1.26, 2.85)], and cardiovascular conditions [pRR = 1.72 (1.07, 2.76)].Conclusions: Pre‐existing atopic, psychiatric, sleep, and cardiovascular conditions are significantly associated with new migraine onset, likely due to shared genetic predisposition and mediating factors like stress and inflammation. Future research should focus on these associations to advance targeted prevention and treatment strategies.

Background: Diagnosing headache disorders poses significant challenges, particularly in primary and secondary levels of care (PSLC), potentially leading to misdiagnosis and underdiagnosis. This study evaluates diagnostic agreement for migraine, tension-type headache (TTH), and cluster headache (CH) between PSLC and tertiary care (TLC) and assesses adherence to the International Classification of Headache Disorders 3rd edition (ICHD-3) guidelines. Methods: A retrospective, cross-sectional analysis was conducted at Charité - Universitätsmedizin Berlin’s tertiary headache center. The patients’ self-reported diagnoses from the PSLC were compared with those in TLC and with ICHD-3 criteria. Cohen’s kappa (κ) and R² were used to assess diagnostic agreement. Results: Among 1,468 patients (43.4 ± 14.4 years; 74.5% women), 69.5% reported a diagnosis in PSLC, and 99.5% were diagnosed at their first TLC visit. Overall agreement between PSLC and TLC was 80% (κ = 0.55; R²=30%). Agreement between the PSLC and ICHD-3 was 77% for migraine, 82% for TTH, and 96% for CH (κ = 0.65; R²=41%). TLC diagnoses aligned with ICHD-3 in over 90%. Conclusion: Our findings indicate a significant degree of diagnostic agreement across different levels of care according to the ICHD-3 guidelines. However, there remains insufficient reliability in clinical diagnostics, highlighting the need for continued efforts to improve the early recognition and diagnostic accuracy and consistency of primary headaches to optimize patient care and treatment outcomes in Germany.

Aim: Cluster headache (CH) is often underdiagnosed and improperly treated. We explored the characteristics of CH patients referred to our tertiary headache center and compared them to patients with migraine and tension-type headache (TTH). Methods: This cross-sectional study was conducted at the Headache Center of the Charité – Universitätsmedizin Berlin from December 2015 to January 2023. We collected data on headache characteristics, comorbidities, prior treatments, and treatment recommendations from the doctor's letter generated after their first consultation. Patient-Reported Outcome Measures were assessed using the Headache Impact Test, the Depression, Anxiety and Stress Scale 21, and the Short Form 12. We compared characteristics of patients diagnosed with CH to those with migraine and TTH, matched for age, sex, and body mass index. Results: From the overall cohort of 1468 patients (mean age 43 ± 14 years; 75% women), 56 patients (mean age 44 ± 9 years; 23% women) were diagnosed with CH. Among these 56 patients, 54% ( n = 30) were diagnosed with chronic CH. Although 84% were correctly diagnosed before referral, 34% lacked first-line acute treatment, and 55% had not received guideline-recommended preventive medication. Compared to patients with migraine, patients with CH had a shorter disease duration from onset to referral (5.5 [7.3] years vs. 20.0 [21.0] years, p < 0.001). Smoking and illicit drug use were significantly more frequent among patients with CH ( p < 0.001 and p < 0.05 for the comparison with migraine and TTH, respectively), but not the rate of manifest cardiovascular diseases. Patient-Reported Outcome Measures scores did not differ significantly. Conclusion: Both acute and preventive treatment in patients with CH remains inadequate at primary and secondary care levels. The high prevalence of chronic CH suggests a high threshold for referral to specialized centers.

Background: Migraine patients unresponsive to calcitonin gene-related peptide (CGRP)(-receptor, -R) monoclonal antibodies (mAbs) may benefit from switching between CGRP(-R) mAbs. However, some patients do not tolerate or respond to any subcutaneous mAbs. This study evaluates the efficacy of the intravenous CGRP mAb eptinezumab in these therapy-refractory patients. Methods: In this retrospective cohort study, patients with migraine who previously failed erenumab and at least one CGRP mAb (fremanezumab and/or galcanezumab) received eptinezumab 100 mg, followed by a second dose of 100 mg or 300 mg after 12 weeks. Monthly headache days, monthly migraine days, acute medication days, and migraine pain intensity were recorded from standardized headache diaries during the four weeks before the first infusion (baseline), and during weeks 9–12 and 21–24 of treatment. Patient-reported outcomes were analyzed at baseline, weeks 12, and 24. Results: From January 2023 to February 2024, 41 patients received eptinezumab 100 mg. Of these, 38 (93%) received a second infusion after 12 weeks, with 29 (71%) increasing the dose to 300 mg. The percentage of patients with a ≥30% reduction rate in monthly migraine days was 23.1% at week 12 and 29.7% at week 24. Monthly migraine days decreased from 16.3 ± 8.0 at baseline to 15.4 ± 8.1 days during weeks 9–12 and 14.4 ± 8.0 days during weeks 21–24 ( p = 0.07). During weeks 21–24, 38.5% reported a clinically meaningful reduction in HIT-6 scores and 52.4% in MIDAS scores. No adverse events were reported. Conclusions: Eptinezumab may be an effective and well-tolerated option for some treatment-refractory migraine patients unresponsive to subcutaneous CGRP-(R) mAbs.

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.

The medial portrayal of migraine is often stereotypical and inaccurate but reflects how society perceives migraine. The discrepancy between others’ views and the reality of affected individuals may negatively affect access to treatment and the disease course of patients with migraine. This study aimed to investigate whether images presented in the media as typical migraine attacks are perceived as realistic and representative by migraine patients in Rostock, a smaller town in rural Germany, and compare the results to those from Berlin, a large metropolis. We performed an online survey in Rostock. Migraine patients were shown ten images of migraine attacks, which were among the most downloaded stock pictures on the internet under the search term "migraine". They rated on a scale of 0–100 to what extent the pictures were realistic for migraine attacks (realism score), representative of their own migraine (representation score), or the society’s view of migraine (society score). In addition, we compared our results with a recently published study from the metropolitan region of Berlin. A total of 174 migraine patients completed our survey. Mean (SD) realism, representation, and society scores were 59.9 (17.5), 56.7 (18.3), and 58.4 (17.1) respectively. Images of older patients were perceived as significantly more realistic and representative than those of younger patients (P < .001). Patients in Rostock (rural region) rated the images as significantly more realistic and representative than survey participants in Berlin (metropolis). Migraine patients in a rural region found typical migraine images only moderately realistic and representative but to a higher degree than their counterparts from a metropolis.

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.

Calcitonin gene-related peptide-targeted monoclonal antibodies (CGRP mAbs) are increasingly being used as preventive treatments for migraine. Their effectiveness and safety were established through numerous randomized placebo-controlled trials and real-world studies, yet a significant proportion of patients do not respond to this treatment, and currently, there is a lack of accepted predictors of response to guide expectations, as data from studies so far are lacking and inconsistent. We searched Embase and MEDLINE databases for studies reporting on predictors of response to CGRP and/or CGRP-receptor (CGRP-R) mAbs, defined as a 30% or 50% reduction in monthly headache or migraine days at varying durations of follow-up. Quantitative synthesis was performed where applicable. We found 38 real-world studies that investigated the association between various predictors and response rates. Based on these studies, good response to triptans and unilateral pain with or without unilateral autonomic symptoms are predictors of a good response to CGRP(-R) mAbs. Conversely, obesity, interictal allodynia, the presence of daily headaches, a higher number of non-successful previous prophylactic medications, and psychiatric comorbidities including depression are predictive of a poor response to CGRP(-R) mAbs. Future studies should confirm these results and help to generate more tailored treatment strategies in patients with migraine.

Background and Objective OnabotulinumtoxinA (BoNTA) is a relatively safe and effective treatment for chronic migraine. The local mode of action of BoNTA favors the combination of oral treatments with systemic action. However, little is known about the possible interactions with other preventive treatments. The objective of the study was to describe the use of oral preventive treatments in patients with chronic migraine treated with BoNTA in routine clinical care and discuss the tolerability and efficacy according to the presence or absence of concomitant oral treatments. Methods In this multicenter, observational, retrospective, cohort study, we collected data from patients with chronic migraine receiving prophylactic treatment with BoNTA. Patients were eligible if aged ≥18 years, diagnosed with chronic migraine according to the International Classification of Headache Disorders, Third Edition criteria, and treated with BoNTA according to the PREEMPT paradigm. We documented the proportion of patients with at least one concomitant treatment prescribed specifically for migraine (CT+M) and their side effects during four BoNTA treatment cycles. Additionally, we collected monthly headache days and monthly acute medication days from the patients’ headache diaries. Patients with CT+M were compared to those without concomitant treatment (CT−) using a nonparametric approach. Results Our cohort included 181 patients taking BoNTA, of whom 77 (42.5%) received a CT+M. The most frequently prescribed concomitant treatments were antidepressants and antihypertensive drugs. Side effects in the CT+M group occurred in 14 patients (18.2%). Only in three of them (3.9%), the side effects had a significant interference with the patient’s functioning (all in topiramate 200-mg/day users). Both CT+M and CT− groups had a significant reduction in monthly headache days of respectively − 6 (95% confidence interval − 9, − 3; p < 0.001; w = 0.200) during cycle 4 compared with baseline versus − 9 (95% confidence interval − 13, −6; p < 0.001; w = 0.469). However, the reduction in monthly headache days was significantly smaller in patients with CT+M after the fourth treatment cycle compared with patients with CT− (p = 0.004). Conclusions Prescription of oral concomitant preventive treatment is common in patients with chronic migraine receiving BoNTA. We did not identify any unexpected safety or tolerability issues in patients receiving BoNTA and a CT+M. However, patients with a CT+M experienced a smaller reduction in monthly headache days when compared with those with CT−, which might be associated with a higher resistance to treatment in that subgroup of patients.

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.