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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Clinical Neurology".

Deadline for manuscript submissions: 25 August 2026 | Viewed by 5133

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Editors

Prof. Dr. Hartmut Göbel

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Guest Editor

Kiel Migraine and Headache Center, 24149 Kiel, Germany
Interests: migraine; headache; neurology; pain management; diagnosis; comorbidity
Special Issues, Collections and Topics in MDPI journals

Dr. Carl H. Göbel

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Guest Editor

1. Department of Neurology, University Hospital Schleswig-Holstein, Campus Kiel, 24149 Kiel, Germany
2. Kiel Migraine and Headache Center, 24149 Kiel, Germany
Interests: migraine; headache; neurology

Special Issue Information

Dear Colleagues,

Migraine is the most prominent headache disorder and ranks third among all diseases worldwide, affecting nearly 15% of the global population annually. It is most prevalent in women aged 30 to 40 and is more common than diabetes, asthma, and epilepsy combined. Chronic migraine alone impacts approximately 2% of the world’s population. The WHO lists migraine as the leading cause of disability under the age of 50, especially in women. Headache disorders account for over 75% of all years lived with disability due to neurological diseases—surpassing stroke, dementia, Parkinson’s disease, multiple sclerosis, and epilepsy. Despite this immense burden, headache disorders are still underdiagnosed and undertreated. Comorbidities such as depression, anxiety, cardiovascular disease, and stroke—especially in young women—underline the urgent need for improved care structures.

This Special Issue aims to highlight cutting-edge advances in migraine research, diagnosis, and treatment. We welcome contributions addressing novel pathophysiological insights, genetic risk factors, precision medicine approaches, and innovations in acute and preventive therapies, including CGRP-antibodies, gepants, ditans, and neuromodulation. By bringing together clinical and translational research, this Special Issue seeks to catalyze change and mobilize the scientific community to reduce the individual and societal burden of migraine and headache disorders.

Prof. Dr. Hartmut Göbel
Dr. Carl H. Göbel
Guest Editors

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Keywords

migraine
chronic migraine
headache disorders
CGRP antibodies
gepants
ditans
triptans
precision medicine
neuromodulation
comorbidities
disability burden
pediatric migraine
ICHD-3 classification
neurotransmitters
preventive therapy
translational headache research

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Published Papers (6 papers)

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Research

13 pages, 568 KB

Open AccessArticle

Angiotensin-Converting Enzyme (ACE) Insertion/Deletion (I/D) Polymorphism and Migraine Susceptibility and Phenotypes: A Clinical-Genetic Study in a United Arab Emirates (UAE) Cohort

by Eslam ElNebrisi, Mohamed Elshafei, Sarah Safwat, Lamia Ibrahim, Mariam A. L. Younan, Shyam Babu Chandran, Mohamed Hussein and Nadia M. ElRouby

J. Clin. Med. 2026, 15(14), 5748; https://doi.org/10.3390/jcm15145748 - 22 Jul 2026

Viewed by 365

Abstract

Background/Objectives: Migraine is a complex neurovascular disorder with a multifactorial genetic basis and remains a leading cause of neurological disability worldwide. The angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism has been implicated in vascular regulation and neurovascular reactivity; however, its role in migraine susceptibility and clinical expression remains unclear. This study aimed to evaluate the association between ACE I/D polymorphism and migraine susceptibility and clinical phenotypes in a diverse clinical cohort. Methods: A case–control study was conducted including 183 participants, comprising clinically diagnosed migraine patients (n = 82) and age- and sex-matched controls (n = 101). Genomic DNA was extracted from peripheral blood samples, and ACE I/D genotyping was performed using polymerase chain reaction. Genotype distribution was compared using chi-square tests, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results: Overall genotype frequencies were Deletion/Deletion (DD) 43.7%, ID 38.8%, and Insertion/Insertion (II) 17.5%. Genotype distributions were comparable between migraine patients and controls (χ² ≈ 0.92, p = 0.632). No statistically significant associations were identified between ACE I/D polymorphism and migraine susceptibility, genotype models, or migraine subtypes. However, the II genotype was associated with higher Migraine Disability Assessment (MIDAS) scores among migraine patients. Conclusions: The ACE I/D polymorphism was not associated with migraine susceptibility or clinical phenotypes in this cohort. These findings suggest that ACE I/D polymorphism does not appear to be a major determinant of migraine susceptibility in this cohort. The results highlight the need to investigate broader genetic and molecular mechanisms and support the application of integrative genomic approaches to better understand migraine heterogeneity and inform precision medicine strategies. Full article

(This article belongs to the Special Issue Advances and Updates in Migraine)

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14 pages, 1503 KB

Open AccessArticle

Comparative Real-World Outcomes of OnabotulinumtoxinA and CGRP Monoclonal Antibodies in Chronic Migraine

by Chun-Fu Lin, Chen-Chih Chung, Jia-Hung Chen, Nai-Fang Chi, Chaur-Jong Hu, Hung-En Huang, Chih-Chung Chen, Tu-Hsueh Yeh, James Cheng-Chung Wei and Hsun-Hua Lee

J. Clin. Med. 2026, 15(13), 4963; https://doi.org/10.3390/jcm15134963 - 25 Jun 2026

Viewed by 354

Abstract

Background: OnabotulinumtoxinA and calcitonin gene-related peptide (CGRP) monoclonal antibodies are widely used for chronic migraine prevention, but comparative real-world evidence on healthcare utilization remains limited. This study aimed to compare the association of onabotulinumtoxinA versus CGRP monoclonal antibodies with acute triptan prescription and migraine-related return visits in patients with chronic migraine. Methods: We conducted a retrospective cohort study using the TriNetX global federated electronic health record database from 2018 to 2024. Adults with chronic migraine who initiated onabotulinumtoxinA or a CGRP monoclonal antibody were matched 1:1 by propensity score. The primary outcomes were time to acute triptan prescription and time to first migraine-related return visit during follow-up. Results: After propensity score matching, 10,140 patients were included in each treatment group. OnabotulinumtoxinA was associated with a lower hazard of acute triptan prescription than CGRP monoclonal antibodies (hazard ratio 0.513, 95% confidence interval 0.481–0.546; p < 0.001), whereas migraine-related return visits were similar between groups (hazard ratio 1.008, 95% confidence interval 0.977–1.039; p = 0.69). Conclusions: In this multicenter real-world analysis, onabotulinumtoxinA was associated with a lower hazard of acute triptan prescription than CGRP monoclonal antibodies, while migraine-related return visits were comparable. These findings reflect treatment-related healthcare utilization patterns in routine practice and should be interpreted considering the limitations of retrospective electronic health record data. Full article

(This article belongs to the Special Issue Advances and Updates in Migraine)

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16 pages, 905 KB

Open AccessArticle

Evaluation of Atrial and Ventricular Myocardial Repolarization Markers During Acute Migraine Attack

by Yavuz Katırcı, Emine Emektar, Meral Yıldırım, Özge Güler, Osman Korucu, Yücel Yüzbaşıoğlu, Mesher Ensarioğlu, Süleyman Mehmetcan Ceritoğlu, Onur Küçük and Semih Aydemir

J. Clin. Med. 2026, 15(10), 3952; https://doi.org/10.3390/jcm15103952 - 20 May 2026

Viewed by 411

Abstract

Background: Migraine is a neurological disorder affecting approximately 15% of the general population, and autonomic nervous system (ANS) dysfunction is a well-characterized feature of the condition. Sympathovagal imbalance during acute migraine attacks has been linked to cardiac electrical instability. This study aimed to evaluate atrial and ventricular myocardial repolarization markers in migraine patients at three serial electrocardiography (ECG) time points. Methods: A prospective observational cross-sectional study was conducted in a tertiary emergency department (ED), enrolling 70 migraine patients and 70 age- and sex-matched healthy controls. Three 12-lead ECGs were obtained per patient: during the migraine attack (within 60 min of ED admission), after analgesic treatment (verbal pain relief or Numeric Rating Scale [NRS] decrease greater than 4 points), and in the pain-free period (at least 24 h after the attack, within 7 days). Measured parameters included P-wave duration, P-wave dispersion, QT interval, QT dispersion, corrected QT (QTc) duration (Bazett formula), QTc dispersion, Tpeak–Tend (Tp-e) interval, Tp-e dispersion, and Tp-e/QTc ratio. ECGs were evaluated by two blinded emergency medicine specialists. Results: All repolarization markers were significantly higher in migraine patients than in controls (p < 0.05 for all). Comparing the first (ictal) with the second (post-treatment) measurements, all markers except P-wave dispersion decreased significantly (p < 0.05). All markers were significantly higher during the attack than in the pain-free period (p < 0.05 for all). Tp-e interval and Tp-e/QTc ratio showed a further significant reduction between the second and third measurements (p = 0.016 and p = 0.004, respectively). P-wave dispersion was significant only for the first-to-second comparison (p = 0.034) and did not differ significantly between the first and third (p = 0.137) or second and third (p = 0.725) measurements. Pulse rate was significantly higher in the migraine group than in controls (p = 0.012). Conclusions: Acute migraine attacks were associated with significant elevation of both atrial and ventricular repolarization markers, with near-normalization during pain-free periods. These findings are consistent with a proposed mechanism of ANS-mediated cardiac electrical instability during acute attacks, although direct confirmation in future studies is required. Clinicians managing acute migraine in the ED should consider ECG monitoring in patients with cardiovascular risk factors. For anesthesiologists and intensivists, the elevated Tp-e and Tp-e/QTc observed ictally indicate that preoperative ECG assessment in migraine patients may be warranted to guide anesthetic planning. Full article

(This article belongs to the Special Issue Advances and Updates in Migraine)

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12 pages, 1853 KB

Open AccessArticle

Neurologic Symptoms and Cerebrovascular Events During Atogepant Therapy: A Case Series with Contextual Comparison with a Non-Gepant–Treated Migraine Cohort

by Carl H. Göbel, Axel Heinze, Katja Heinze-Kuhn, Anna Cirkel and Hartmut Göbel

J. Clin. Med. 2026, 15(5), 1930; https://doi.org/10.3390/jcm15051930 - 3 Mar 2026

Viewed by 1089

Abstract

Background: CGRP contributes to cerebrovascular regulation, mainly based on experimental and translational data; human evidence remains limited. Gepants, including atogepant, are effective migraine preventives and achieve partial penetration across the blood–brain barrier. However, their neurologic and cerebrovascular safety in heterogeneous patient populations remains incompletely characterized. Objective: To describe acute neurologic events observed during atogepant therapy, provide contextual information regarding their baseline occurrence, and explore potential mechanisms by which CGRP receptor blockade may influence neurovascular resilience. Methods: We report five adults treated with atogepant (30–60 mg/day) who developed acute neurologic symptoms prompting emergency hospital admission. All patients underwent comprehensive diagnostic assessment including neuroimaging, vascular studies, cardiac evaluation, and laboratory testing. To provide context, a retrospective comparison cohort of migraine patients not treated with gepants during a similar period was analyzed. Baseline characteristics were summarized, and event occurrence was compared using Fisher’s exact test. Results: Among 575 individuals treated with atogepant, five experienced acute neurologic events, including one cerebellar infarction and several transient focal syndromes without structural correlates. No cerebrovascular events requiring hospitalization were identified in the non-gepant cohort (n = 610). In an unadjusted analysis, this difference was statistically significant (p = 0.027). The events were clinically heterogeneous, and several lacked radiologic confirmation of ischemia. Conventional vascular risk factors were present in some patients. Conclusions: These findings do not imply causality but raise the possibility that CGRP receptor blockade may reduce cerebrovascular adaptability in susceptible individuals. Clinicians should remain vigilant for ischemia or microvascular dysfunction when patients receiving atogepant present with acute vertigo, diplopia, ptosis, or hemisensory symptoms—even when CT and CTA are normal—and obtain timely MRI and vascular assessment. The absence of comparable events in a retrospective non-gepant cohort provides contextual information but does not permit inference regarding increased risk due to potential confounding and unmeasured factors. The findings are exploratory and hypothesis-generating, underscoring the need for prospective controlled studies to clarify the cerebrovascular safety of CGRP receptor antagonists in routine clinical practice. Full article

(This article belongs to the Special Issue Advances and Updates in Migraine)

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15 pages, 978 KB

Open AccessArticle

Clinical and Genetic Factors Associated with Non-Response to Erenumab

by Giulia Mallucci, Salvatore Terrazzino, Martina Giacon, Alberto Cordella, Sarah Cargnin, Christoph Schankin, Claudio Gobbi and Chiara Zecca

J. Clin. Med. 2025, 14(24), 8922; https://doi.org/10.3390/jcm14248922 - 17 Dec 2025

Viewed by 933

Abstract

Background: Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, such as erenumab (ERE), are effective migraine-preventive therapies for many patients. Identifying clinical and genetic factors associated with treatment failure is crucial for optimizing patient management. Methods: This multicenter, prospective observational study included patients with episodic or chronic migraine treated with ERE for 12 months. Demographics, migraine history, comorbidities, treatment outcomes, and genetic variants in CGRP receptor-related genes (CALCRL and RAMP1) were evaluated for associations with non-response to ERE, defined as a <50% reduction in monthly migraine days. Results: Of the 140 patients starting ERE, 11 were lost to follow up, 12 stopped ERE due to side effects; 18 patients were non-responders and were compared to 99 responders. Arterial hypertension [adjusted OR (aOR): 7.77, p = 0.007], smoking (aOR: 4.98, p = 0.014), and insomnia requiring medication (aOR: 4.51, p = 0.027) were associated with non-responder status. Genetic analysis revealed a nominal association between the RAMP1 rs6431564 polymorphism and non-responder status (nominal p = 0.025), which did not survive Bonferroni correction. The G allele was linked to a reduced risk (aOR per G allele: 0.28, p = 0.025) and caused the increased expression of RAMP1 in an allele-dose manner. Conclusions: Hypertension, smoking, insomnia requiring medication, and, nominally, the RAMP1 rs6431564 polymorphism were associated with non-responder status to ERE in migraine patients. Further validation of the present results in larger cohorts is needed. Full article

(This article belongs to the Special Issue Advances and Updates in Migraine)

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16 pages, 1737 KB

Open AccessArticle

miR-197, miR-101, and miR-143 and Pro-Inflammatory Cytokines in Migraine

by Roberto Carlos Rosales-Gómez, Beatriz Teresita Martín-Márquez, Alvaro Jovanny Tovar-Cuevas, Omar Cárdenas-Saenz, Patricia Orozco-Puga, Milton Omar Guzmán-Ornelas, Nathan Alejandro Peña-Dueñas, Flavio Sandoval-García, Daniela Ortiz-Ríos, Mariana Chávez-Tostado, Diana Mercedes Hernández-Corona, Miriam Méndez-del Villar and Fernanda-Isadora Corona-Meraz

J. Clin. Med. 2025, 14(18), 6410; https://doi.org/10.3390/jcm14186410 - 11 Sep 2025

Cited by 1 | Viewed by 1324

Abstract

Background: Migraine is a disabling neurological disorder where the release of neuropeptides and a local and systemic proinflammatory state prevail. MicroRNAs (miRs) are epigenetic regulators that control the expression of genes involved in inflammation, neovascularization, and pain-related processes. Cytokines mediate the inflammatory state, while miRs can modulate their expression. Methods: This is an analytical and observational study in which subjects with a diagnosis of chronic and episodic migraine and healthy controls were recruited, and the migraine patients were classified by episodic or chronic migraine, as well as with or without aura. Cytokines were measured using the ELISA technique, and the microRNAs hsa-miR-197-3p, hsa-miR-101-3p, and hsa-miR-143-3p were evaluated using qPCR methodology. We also utilized bioinformatic tools, such as miRBase, TargetScan, miRNet, and miRPath, to analyze the interactions and pathways involved. Results: Our findings revealed that hsa-miR-197-3p is elevated in patients without aura (29.91 ± 11.14 with aura vs. 81.10 ± 53.85 without aura, RU; p = 0.021), whereas hsa-miR-143-3p is elevated in episodic migraine (0.0639 ± 0.0227 in EM vs. 0.0308 ± 0.0174, RU p = 0.011). Furthermore, we found higher levels of IL-17 (9.46 ± 1.06 in CM vs. 7.61 ± 2.12 in EM, p = 0.030), IL-6 (4.95 ± 2.84 in CM vs. 1.52 ± 0.98 non-migraine subjects, p = 0.016), and TNFα in chronic migraine patients (0.46 ± 0.24 in CM vs. 0.20 ± 0.05 in non-migraine, p = 0.011 and vs. 0.20 ± 0.13 in EM, p = 0.016). Conclusions: Inflammation is present in migraine regardless of the clinical characteristics of the patients, although it may be accentuated in chronic migraine. Our preliminary findings suggest a potential role for peripheral inflammatory markers, including specific microRNAs (miR-197, miR-101, and miR-143) and cytokines (TNF-α, IL-6, and IL-17A), in the pathophysiology of migraine. These results, although limited by sample size and cross-sectional design, highlight molecular pathways that warrant further investigation. Full article

(This article belongs to the Special Issue Advances and Updates in Migraine)

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