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Patent foramen ovale (PFO) may be an underlying factor in the pathogenesis of migraine, vasospastic angina, and Takotsubo cardiomyopathy. This article reviews the role that PFO may play in each of these clinical entities and discusses potential interventions. It also proposes a novel clinical syndrome wherein PFO may be the unifying link among migraine, coronary vasospasm, and Takotsubo cardiomyopathy in predisposed individuals.

Introduction: Acute confusional migraine (ACM) is a rare variant of migraine that is benign and self-resolving but difficult to diagnose. Without known causative pathophysiology and a lack of recognition in the International Classification of Headache Disorders (ICHD-3), ACM offers a puzzling clinical presentation. There currently is no standardized treatment for ACM, but with a growing anecdotal dataset there is the opportunity to formally recognize and establish protocols to improve patient care and outcomes.Case Report: A 14-year-old female presented to the emergency department (ED) with acute onset of confusion, vision changes, right-sided weakness, and dysarthria one hour prior to arrival. A stroke workup at the initial ED offered no pertinent findings. The patient was transferred to a pediatric specialty ED where all symptoms, aside from numbness and a mild headache, resolved during transfer. After administration of a migraine cocktail at the pediatric specialty ED, all remaining symptoms completely resolved. The patient was discharged home from the ED the same evening with outpatient follow-up.Conclusion: This case presents the difficulty of diagnosing and treating ACM prior to its self-resolution. It highlights the need for formal recognition of the condition by the ICHD-3. In doing so, greater recognition will promote more research, awareness, and establishment of a standardized treatment for ACM.

Background: Migraine is a prevalent episodic brain disorder known for recurrent attacks of unilateral headaches, accompanied by complaints of photophobia, phonophobia, nausea, and vomiting. Two main categories of migraine are migraine with aura (MA) and migraine without aura (MO). Main body: Early twin and population studies have shown a genetic basis for these disorders, and efforts have been invested since to discern the genes involved. Many techniques, including candidate-gene association studies, loci linkage studies, genome-wide association, and transcription studies, have been used for this goal. As a result, several genes were pinned with concurrent and conflicting data among studies. It is important to understand the evolution of techniques and their findings. Conclusions: This review provides a chronological understanding of the different techniques used from the dawn of migraine genetic investigations and the genes linked with the migraine subtypes.

BackgroundVestibular migraine (VM) is one of the most common causes of recurrent vertigo and presents with a history of spontaneous or positional vertigo with a history of migraine headaches. While research has identified a high prevalence of migraine headaches and vestibular deficits among fragile X premutation carriers, there has been no discussion about VM within this population.ObjectiveThis case series and review seeks to describe the clinical characteristics and pathophysiology of VM among individuals with the fragile X premutation. We also seek to discuss treatment and future steps in addressing VM in this population.MethodsA review of the literature regarding vestibular migraine and presentation of migraine headaches and vestibular deficits among premutation carriers was performed. A detailed clinical history of migraine headaches and vertigo was obtained from three patients with the fragile X premutation seen by the senior author (RJH).ResultsAll three cases first developed symptoms of migraine headaches earlier in life, with the development of VM near menopause. Two of the three cases developed progressive balance issues following the development of VM. All three cases found that their VM episodes were improved or resolved with pharmacological and/or lifestyle interventions.ConclusionsIt is important to recognize VM among premutation carriers because beneficial treatments are available. Future studies are needed regarding the prevalence of VM and the relationship to subsequent FXTAS. The pathophysiology of VM remains uncertain but possibilities include mitochondrial abnormalities, cranial nerve VIII toxicity secondary to neurotoxic protein accumulation, and calcitonin gene-related peptide (CGRP) signaling dysfunction due to altered levels of fragile X messenger ribonucleoprotein (FMRP).

Background: In recent years, miRNAs found in biological fluids have gained interest as biomarkers of numerous conditions, including migraine. This study aimed to identify differences in the levels of circulating miRNAs in the serum of migraineurs as compared to healthy controls, as well as between patients with different types of migraine and during the ictal and nonictal phases of the condition. Methods: The screening phase of the study included serum from 13 migraine patients and 13 sex and age matched controls. A panel of 179 miRNAs was analysed using locked nucleic acid SYBR based qPCR. Based on statistical analysis (U Mann-Whitney test) and data from existing literature, nine miRNAs were selected for validation by TaqMan qPCR in an independent cohort of 26 migraineurs and eleven healthy controls. For comparison between the study and control group, U Mann-Whitney test was performed. The differences between patients with chronic and episodic migraine, migraine with and without aura and in ictal and nonictal phases were analysed with Kruskal-Wallis test. The results were corrected for multiple comparisons using Benjamini-Hochberg method. In all analysis p value ≤ 0,05 was considered as significant. Results: Two miRNAs, miR-145-5p and miR-26a-5p were significantly upregulated in serum of migraineurs compared to healthy controls. MiRNA-19a-3p was downregulated in patients currently experiencing migraine headache compared to those in the interictal period. No differences were found between patients with different migraine types. Conclusion: The results of our study add to the growing body of evidence for dysregulation of the circulating miRNA profile by migraine. They are further supported by previous reports on differential expression of miR-145-5p, miR-26a-5p and miR-19a-3p in migraineurs. However, more research on larger populations is needed to validate these findings, as well as elucidate the role of circulating miRNAs in the condition. Moreover, to wholly explore the biomarker potential of miRNAs, migraine patients should not only be compared to healthy controls but also to populations with different headache disorders. [ABSTRACT FROM AUTHOR]

Autonomic symptoms may be local and general clinical manifestations of both epilepsy and migraine caused by the dysfunction of brain areas best known as the central autonomic network. Despite their prevalence, autonomic signs are often misdiagnosed and their treatment is undervalued. This review aims to describe the autonomic manifestations reported during seizures and migraineur attacks according to their presentation, focusing on the role of the central autonomic network (CAN) and on the parasympathetic outflow that often-induced cranial autonomic symptoms (CAS) during migraineur attacks. Further, our purpose is to analyze the pathophysiological meanings and whether their presence influences the prognosis and therapy of these disorders. [ABSTRACT FROM AUTHOR]

Migraine is a common chronic neurological disorder that lacks objective imaging biomarkers, while resting-state functional magnetic resonance imaging (rs-fMRI) can be used to extract potential biomarkers. Recently, graph neural networks (GNNs) have gained significant popularity in the classification of brain disorders because of their powerful ability to model brains. Hypergraph neural networks (HGNNs), a branch of GNNs, are particularly effective in capturing high-order neighborhood information. In this paper, we proposed a hypergraph neural network model, incorporating hypergraph dual attention mechanism and hypergraph pooling strategy (APHGNN), for migraine classification derived from the preprocessed rs-fMRI data. First, we constructed hypergraphs from functional connectivity matrices based on the preprocessed rs-fMRI data. Then, we designed three network layers: in the hypergraph dual attention layer, we introduced attention mechanism in both the hyperedge feature aggregation phase and the node feature aggregation phase, making full use of both node and hyperedge information to update node features; in the hypergraph pooling layer, we employed a node selection-based pooling strategy to score and filter nodes, retaining key node features; in the readout layer, we calculated the average and maximum values of the key node features, concatenated and aggregated them, and used the resulting vectors for classification. The experimental results demonstrate that our model outperforms other baseline methods in classification performance and exhibits good generalization. Additionally, the key brain regions extracted through the hypergraph pooling strategy can serve as potential biomarkers for migraine, providing valuable insights for migraine diagnosis. [ABSTRACT FROM AUTHOR]

Background: Patients with migraine often experience not only headache pain but also cognitive dysfunction, particularly in attention, which is frequently overlooked in both diagnosis and treatment. The influence of these attentional deficits on the pain-related clinical characteristics of migraine remains poorly understood, and clarifying this relationship could improve care strategies. Methods: This study included 52 patients with migraine and 34 healthy controls. We employed the Attentional Network Test for Interactions and Vigilance–Executive and Arousal Components paradigm, combined with electroencephalography, to assess attentional deficits in patients with migraine, with an emphasis on phasic alerting, orienting, executive control, executive vigilance, and arousal vigilance. An extreme gradient boosting binary classifier was trained on features showing group differences to distinguish patients with migraine from healthy controls. Moreover, an extreme gradient boosting regression model was developed to predict clinical characteristics of patients with migraine using their attentional deficit features. Results: For general performance, patients with migraine presented a larger inverse efficiency score, a higher prestimulus beta-band power spectral density and a lower gamma-band event-related synchronization at Cz electrode, and stronger high alpha-band activity at the primary visual cortex, compared to healthy controls. Although no behavior differences in three basic attentional networks were found, patients showed magnified N1 amplitude and prolonged latency of P2 for phasic alerting-trials as well as an increased orienting evoked-P1 amplitude. For vigilance function, improvements in the hit rate of executive vigilance-trials were exhibited in controls but not in patients. Besides, patients with migraine exhibited longer reaction time as well as larger variability in arousal vigilance-trials than controls. The binary classifier developed by such attentional deficit features achieved an F1 score of 0.762 and an accuracy of 0.779 in distinguishing patients with migraine from healthy controls. Crucially, the predicted value available from the regression model involving attentional deficit features significantly correlated with the real value for the frequency of headache. Conclusions: Patients with migraine demonstrated significant attentional deficits, which can be used to differentiate migraine patients from healthy populations and to predict clinical characteristics. These findings highlight the need to address cognitive dysfunction, particularly attentional deficits, in the clinical management of migraine. [ABSTRACT FROM AUTHOR]

• Neuroinflammation significantly contributes to the pathophysiology and chronicity of migraines. • Microglia and astrocytes are central to neuroinflammatory responses in migraine development. • Cytokines and chemokines are important in glia-neuron crosstalk during migraine pathogenesis. • [11C] PBR28-targeted imaging and single-cell sequencing advance understanding of neuroinflammation mechanisms in migraine. • Estrogen and TRPM8 emerge as promising personalized therapeutic targets. Migraine is a complex neurological disorder with neuroinflammation playing a crucial role in its pathogenesis. This review provides an overview of the neuroinflammation mechanisms in migraine, focusing on both cellular and molecular aspects. At the cellular level, we examine the role of glial cells, including astrocytes, microglia, oligodendrocytes in the central nervous system, and Schwann cells and satellite glial cells in the peripheral nervous system. On the molecular level, we explore the signaling pathways, including IL-1β, TNF-α, IL-6, and non-coding RNAs, that mediate cell interactions or independent actions. Some of the molecular signaling pathways mentioned, such as TNF-α and IL-1β, have been investigated as druggable targets. Recent advancements, such as [11C] PBR28-targeted imaging for visualizing astrocyte activation and single-cell sequencing for exploring cellular heterogeneity, represent breakthroughs in understanding the mechanisms of neuroinflammation in migraine. By considering factors for personalized treatments, estrogen and TRPM8 emerge as promising therapeutic targets regarding sexual dimorphism. These advancements may help bridge the gap between preclinical findings and clinical applications, ultimately leading to more precise and personalized options for migraine patients. [ABSTRACT FROM AUTHOR]

Background: The pervasive integration of digital devices into daily life has raised concerns about their potential health impacts. This study aimed to explore the causal relationships between digital device use and the risk of migraine using Mendelian randomization (MR). Methods: Genetic data on digital device use and migraines were sourced from large-scale genome-wide association studies conducted by the UK Biobank, the FinnGen study, and the International Headache Genetics Consortium. Univariable MR (UVMR), meta-analysis, and multivariable MR (MVMR) approaches were conducted to explore and verify the causal effects of digital device use (including mobile phone use, computer use, playing computer games, and watching television) on migraine risk. Sensitivity analyses were conducted using Cochran's Q, MR-Egger intercept test, MR pleiotropy residual sum and outlier, MR Radial, MR Steiger, and leave-one-out methods. Results: UVMR analyses revealed that genetically predicted mobile phone use was significantly associated with an increased risk of overall migraine (odds ratio [OR] = 2.39, p = 9.78e-5) and migraine without aura (MO) (OR = 2.25, p = 0.024). Additionally, there were significant positive associations between genetically predicted television watching and the risk of overall migraine (OR = 1.63, p = 2.12e-5) and MO (OR = 2.10, p = 4.98e-5). These results were further supported by the meta-analysis and MVMR analysis. Sensitivity analysis indicated no heterogeneity or pleiotropy. Conclusion: This comprehensive MR study provides preliminary evidence for the causal impact of mobile phone use and television watching on the risk of migraines. Further studies are needed to explore these associations across different populations. [ABSTRACT FROM AUTHOR]

Background: Migraine patients have an increased long-term risk of cardio and cerebrovascular events. However, whether these patients are more susceptible to white matter lesions (WMLs) remains debated. To explore this question, our study assessed the proportion of RLS in migraine patients and explored the association between right-to-left shunt (RLS) and WMLs. Methods: In this study, we included 998 migraine patients. Contrast transcranial doppler (c-TCD) was used to diagnose RLS and assess the extent of the shunt in RLS patients. Of the 998 patients, 505 underwent cranial magnetic resonance imaging (MRI) assessments. WMLs were classified into periventricular white matter lesions (pvWMLs) and deep white matter lesions (dWMLs). Results: Among the 998 migraine patients, 946 had migraine without aura (MO; mean age 36.68 ± 10.46 years; 80.5% female), and 52 had migraine with aura (MA; mean age 29.85 ± 8.59 years; 71.2% female). Compared with MO patients, MA patients had an earlier onset age (23.1 ± 7.97 vs. 28.44 ± 10.38 years, p < 0. 001) and a shorter disease duration (6.76 vs. 8.34 years, p = 0.024). The overall proportion of RLS patients was 41.9%, with a greater proportion of RLS patients in the MA group than in the MO group (55.8% vs. 41. 1%, p = 0.037). The percentage of RLS-positive patients with no/small shunt was greater in the MO group than in the MA group (81.5% vs. 65.4%, p = 0.004), whereas the percentage of RLS-positive patients with moderate/large shunt was greater in the MA group (34.6% vs. 18.5%, p = 0.024). The proportion of RLS patients was lower in the WML-positive group (n = 173) than in the WML-negative group (n = 332), but the difference was not significant (40.5% vs. 45.8%, p = 0.253). Conclusion: This study revealed that 41.9% of migraine patients had RLS, and the proportion of RLS patients was 41. 1% in the MO group and 55.8% in the MA group. The rate of RLS positivity in migraine patients may not be related to the incidence of WMLs. [ABSTRACT FROM AUTHOR]

Background: Novel abortive treatments for migraine, ditans and gepants, have promising implications in triptan-insufficient responders with minimal existing comparative data. Our study aims to synthesize evidence through a systematic review and network meta-analysis to assess the comparative efficacy of lasmiditan, rimegepant and ubrogepant in triptan-insufficient responders. Method: We searched PubMed, Embase, CENTRAL, and EBSCO Open Dissertations up to May 2024. We included randomized controlled trials (RCTs) that compared novel abortive treatments, including lasmiditan, rimegepant, and ubrogepant, in migraine patients who self-reported insufficient response to triptans. Outcomes are represented using relative risks with corresponding 95% confidence intervals (CI). The surface under the cumulative ranking curve (SUCRA) was used to rank each medication. Results: A total of five phase 3 RCTs involving 3,004 patients were included in the analysis. All three agents were significantly superior to placebo for two-hour pain freedom (RR = 1.93, 95% CI [1.52, 2.46]), freedom from the most bothersome symptoms at two hours (RR = 1.55, 95% CI [1.37, 1.75]), and pain relief at two hours (RR = 1.46, 95% CI [1.35, 1.58]). No statistically significant differences in efficacy outcomes were observed among the three agents. However, lasmiditan 200 mg had the highest cumulative probability for two-hour pain freedom and relief (SUCRA 0.9, 0.8, respective), while rimegepant led in relieving the most bothersome symptoms (SUCRA 0.7). Conclusion: Lasmiditan, rimegepant, and ubrogepant are effective for acute treatment of migraine in triptan-insufficient responders, with high-dose lasmiditan showing the highest efficacy for pain control. [ABSTRACT FROM AUTHOR]

Objective: Chronic migraine (CM) patients with medication overuse headache (MOH) were recently shown to be associated with leaky gut and inflammation. We aimed to investigate gut microbiota profiles of CM patients with MOH, and their correlations with inflammatory serum parameters, migraine food triggers, and comorbid anxiety and depression. Materials and methods: The study included women participants (32 CM patients with NSAID overuse headache, and 16 healthy non-headache sufferers). Migraine duration, monthly migraine headache days, presence of irritable bowel syndrome symptoms, and HADS-D and HADS-A scores were recorded. Serum samples were collected to measure circulating LPS, HMGB1, HIF-1α, and IL-6. The gut microbiota profiles of the patients were evaluated using fecal samples. Results: Serum LPS, HMGB1, HIF-1α, and IL-6 levels were significantly higher in the CM + MOH group compared to the healthy controls. HADS-A and HADS-D scores were considerably higher in the CM + MOH group compared to the healthy controls. In the microbiota analysis, alpha and beta diversities were similar between the two groups. The class Clostridia, the order Eubacteriales, and the genus Ruminococcus were less abundant in the CM + NSAID overuse headache group compared to the control group. At the genus level Desulfovibrio, Gemmiger, and Dialister and at the species level, Clostridium fessum, Blautia luti, Dorea longicatena, Eubacterium coprostanoligenes, and Gemmiger formicilis were more abundant in the CM + NSAID overuse headache group compared to the control group. Desulfovibrio, Gemmiger, Dialister, Ethanoligenens harbinense, Eubacterium coprostanoligenes, Dorea longicatena, and Thermoclostridium stercorarium showed positive correlations and Clostridia bacteria showed negative correlations with migraine food triggers. Positive correlations were found between LPS and Hapalosiphonaceae, HMGB1 and Melghirimyces, HIF1-α and Rouxeilla and Blautia luti, IL-6 and Melghirimyces and Ruminococcus. Conclusion: In CM patients with MOH, we have revealed the presence of dysbiosis towards an inflammatory state, and positive correlations were shown between altered gut microbiota and inflammatory serum parameters and migraine food triggers. [ABSTRACT FROM AUTHOR]

Background: Calcitonin gene-related peptide (CGRP) is part of the calcitonin peptide family, which includes calcitonin (CT), amylin (AMY), and adrenomedullin (ADM). CGRP and its receptor are highly present in the trigeminovascular system (TVS). Recent research suggests that other members of the calcitonin family could be feasible therapeutic targets in the treatment of migraine. The present study aims to elucidate the distribution of ADM, AMY, CT, and their receptors in the rat TVS, and to explore potential sex differences in their expression. Methods: Trigeminal ganglia (TG) were dissected from male and female adult rats. Protein and gene expression were assessed through immunohistochemistry and RT-qPCR. Additionally, the dura mater was isolated for further investigation of protein expression and fiber localization using immunohistochemistry. Results: Quantitative gene expression analysis revealed the presence of all genes in male and female TGs, except for calcitonin receptor (CTR). Notably, CGRP mRNA levels in TG were several folds higher than those of other genes. The receptor activity-modifying protein-1 (RAMP1) mRNA levels were significantly higher in female compared to male. No AMY or CT immunoreactivity was observed in the TVS. In contrast, immunoreactivity for ADM, CGRP, RAMP1, CTR, and calcitonin-like receptor (CLR) were observed in the cytoplasm of TG neurons. Immunoreactive Aδ-fibers storing RAMP1, ADM and CLR were also identified. RAMP2 and RAMP3 were expressed in nucleus of TG neurons and in satellite glial cells. Furthermore, RAMP1 and CLR were co-localized with CASPR in the nodes of Ranvier located in Aδ-fibers. Conclusions: This study provides valuable insights into the distribution of the CGRP family of peptides and their receptors in the TVS. CGRP mRNA levels in the TG were markedly higher than those of other genes, demonstrating the key role of CGRP. The co-localization of CLR and RAMP1 on Aδ-fibers with CASPR suggests a potential role for this receptor in modulating trigeminal nerve function and neuronal excitability, with implications for migraine pathophysiology. Additionally, RAMP1 mRNA levels were significantly higher in female TG compared to males, indicating sex-specific differences in gene expression. These findings underscore the need for further research into the functional significance of gender-related variations. [ABSTRACT FROM AUTHOR]

AbstractObjectiveMethodsResultsConclusion\nPLAIN LANGUAGE SUMMARYTo evaluate quality of life, migraine disability, and work productivity and activity impairment in patients with migraine who received preventive treatment by comparing standard of care preventive medications and calcitonin gene-related monoclonal antibodies (CGRP mAbs), including galcanezumab alone.This cross-sectional study conducted across the United States (US) and Europe used data from the Adelphi Migraine Disease Specific Programme. Physicians completed record forms for consecutive patients, who then completed self-report forms assessing patient-reported outcomes (PROs) such as quality of life, migraine disability, and work productivity and activity impairment. T-tests, Fisher’s exact test, and Mann–Whitney U test were used for analysis.From May 2022 to June 2023, 557 physicians submitted data for 6723 patients. A total of 4036 patients (US 956; Europe 3080) with a history of preventive treatment were included (>60% female, >80% White, mean [standard deviation] age range, 38.7 [12.8] to 46.3 [12.1]). Patients who received 3+ lines of preventive therapy and were receiving CGRP mAbs (including galcanezumab alone) had enhanced health-related quality of life (HRQoL) compared to those who received standard of care. Similar findings were observed across Europe; however, in the US, there was no significant difference in any PROs.Patients with migraine in the overall population and Europe who received 3+ lines of preventive migraine therapy and were receiving CGRP mAbs/galcanezumab demonstrated enhanced HRQoL compared to those who received standard of care.This study evaluated quality of life, migraine disability, and work productivity in patients with migraine who were treated with standard of care preventive medications or calcitonin gene-related monoclonal antibodies (CGRP mAbs), including galcanezumab alone. The study was conducted across the United States and Europe and included data from 557 physicians and 6723 patients. Results showed that patients with migraine who received 3+ lines of preventive therapy and were receiving CGRP mAbs in overall population and Europe demonstrated enhanced health-related quality of life (HRQoL) compared with those who received standard of care. However, in the US, there was no significant difference in HRQoL and migraine disability. The study concludes that CGRP mAb treatments, especially in patients requiring multiple lines of preventive therapy, are a viable approach for optimal migraine management. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusions While headache disorders are linked to low physical activity levels, the impact of depression on this relationship is unclear.To assess how single and comorbid diagnoses of migraine and tension‐type headache (TTH) interact with depression and leisure‐time physical activity (LTPA) levels in The Brazilian Longitudinal Study of Adult Health (ELSA‐Brasil).In this cross‐sectional analysis based on the ELSA‐Brasil baseline data, the relationship of migraine, TTH (both assessed with the International Classification of Headache Disorders, Second Edition), and depression (assessed with the Clinical Interview Schedule–Revised) with LTPA levels (International Physical Activity Questionnaire) was investigated by employing linear regression models. Models were adjusted for sociodemographic, lifestyle, and clinical covariates, and interaction terms were created to examine additive effects of comorbid conditions.Among 14,088 participants, 54.4% (7668/14,088) were female, prevalence rates were: TTH = 39.6% (5573/14,088), migraine = 27.0% (3806/14,088), depression = 0.7% (94/14,088), depression + TTH = 1.1% (148/14,088), and depression + migraine = 2.5% (356/14,088). The mean (standard deviation) LTPA levels across the groups were: no headache + no depression = 148.7 (183.0) min/week, TTH = 133.5 (170.1) min/week, migraine = 110.3 (154.8) min/week, depression = 76.5 (146.3) min/week, depression + TTH = 84.5 (127.7) min/week, and depression + migraine = 64.3 (123.2) min/week. Negative associations were found for depression (β = −55.1, 95% confidence interval [CI] −93.6 to −17.0; p = 0.005), migraine (β = −24.7, 95% CI −33.2 to −15.4; p < 0.001), and TTH (β = −15.5, 95% CI −23.1 to −7.6; p < 0.001) with LTPA. No interaction effect was observed for depression + TTH (β = 36.0, 95% CI −12.6 to 84.6; p = 0.147) and depression + migraine (β = 31.7, 95% CI −11.3 to 74.7; p = 0.149), indicating no additive effect of comorbid conditions on LTPA levels. After adjusting for headache attack frequency, only depression + migraine remained negatively associated with LTPA (β = −38.7, 95% CI −71.6 to −5.8; p = 0.021).Headache disorders and depression were independently and inversely associated with LTPA, with the strongest effects seen in depression alone or comorbid with migraine. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion Understanding the neural mechanisms underlying migraine and other primary headache disorders is critical for the development of long‐term cures. Magnetoencephalography (MEG), an imaging modality that measures neuronal currents and cortical excitability with high temporal and superior spatial resolution, has been increasingly used in neurological research. Initial MEG studies showed promise in directly recording cortical spreading depression—a cortical correlate of migraine with aura. However, lately MEG technology has highly evolved with greater potential to reveal underlying pathophysiology of migraine and primary headache disorders, and aid in the identification of biomarkers.To systematically review the use of MEG in migraine and other primary headache disorders and summarize findings.We conducted a systematic search and selection of MEG studies in migraine and primary headache disorders from inception until June 8, 2023, in Medline, Embase, Cochrane, and Scopus databases. Peer‐reviewed English articles reporting the use of MEG for clinical or research purposes in migraine and primary headache disorders were selected.We found 560 articles and included 38 in this review after screening. Twelve studies investigated resting‐state, while others investigated a sensory modality using an evoked or event‐related paradigm with a total of 35 cohort and 3 case studies. Thirty‐two studies focused exclusively on migraine, while the rest reported other primary headache disorders.The findings show an evolution of MEG from a 7‐ to a 306‐channel system and analysis evolving from sensor‐level evoked responses to more advanced source‐level connectivity measures. A relatively few MEG studies portrayed migraine and primary headache disorders as a sensory abnormality, especially of the visual system. We found heterogeneity in the datasets, data reporting standards (due to constantly evolving MEG technology and analysis methods), and patient characteristics. Studies were inadequately powered and there was no evidence of blinding procedures to avoid selection bias in case–control studies, which could have led to false‐positive findings. More studies are needed to investigate the affective–cognitive aspects that exacerbate pain and disability in migraine and primary headache disorders. [ABSTRACT FROM AUTHOR]

Rodent migraine models have been developed to study the underlying molecular mechanisms of migraine, but these need further development and validation to stay relevant. The glyceryl trinitrate (GTN) mouse model with tactile hypersensitivity as the primary readout, has been highly used to understand the pathophysiology of migraine. Nevertheless, this readout has questionable translatability to the experience of spontaneous pain and additional readouts are needed to improve this model. We explored the applicability of several spontaneous behaviours and burrowing activity as additional markers to detect effects of repeated GTN injections in mice. We used the Laboratory Animal Behaviour Observation Registration and Analysis System (LABORAS) test system to understand the potential effect of GTN on locomotion and other behavioral parameters in two different experiments. Burrowing was used to investigate the potential effect on GTN on a voluntary innate behavior of mice. We found no clear effect of GTN on either locomotion or burrowing in these experiments. With our experimental design, there was no significant difference between GTN and vehicle and neither locomotion nor burrowing activity will readily supplement the von Frey test. The search for additional none-evoked markers of pain in rodent migraine models will continue. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion Observational studies have reported inconsistent relationships between migraine and the risk of intracranial aneurysm and subarachnoid hemorrhage (SAH).To determine whether genetic liability to migraine is associated with risk of intracranial aneurysm and aneurysmal SAH.This study was designed as a two‐sample Mendelian randomization (MR) analysis. Genetic associations with migraine were obtained from a large‐scale meta‐analysis of five population and clinic‐based genome‐wide association studies of migraine (102,084 cases and 771,257 controls of European ancestry). Genetic associations with intracranial aneurysm and SAH were obtained from a meta‐analysis of 22 population‐based genome‐wide association studies (7495 cases and 71,934 controls of European ancestry). Findings were corroborated by sensitivity analyses and replicated in an independent sample of combined cases of intracranial aneurysm and SAH (3529 cases and 234,948 controls of Asian ancestry from the Biobank Japan and China Kadoorie Biobanks). In secondary analyses, we investigated the outcomes of extracranial aneurysm in the FinnGen and UK Biobank cohorts (up to 7466 combined cases of thoracic and abdominal aortic aneurysm).Genetic liability to migraine was associated with increased risk of the combined outcome of unruptured intracranial aneurysm and SAH (odds ratio [OR] of outcome per doubling in migraine liability 1.19, 95% confidence interval [CI] 1.06–1.35; p = 0.005). This finding was replicated in an independent sample (OR 1.15, 95% CI 1.02–1.30; p = 0.027), and there were similar associations across the component outcomes of unruptured intracranial aneurysm (OR 1.20, 95% CI 1.01–1.42; p = 0.035) and SAH (OR 1.18, 95% 1.04–1.33; p = 0.008). These findings were consistent in sensitivity analyses robust to violations of the MR assumptions. In reverse MR analyses, genetic liability to intracranial aneurysm was not associated with migraine (OR 1.03, 95% CI 0.99–1.07; p = 0.141). In a secondary analysis, there were similar associations of genetic liability to migraine with all forms of aortic aneurysm (OR for combined thoracic and aortic aneurysm 1.18, 95% CI 1.10–1.27; p = 8.49 × 10−6).Genetic liability to migraine was associated with increased risk of intracranial and extracranial aneurysms, supporting a causal relationship between liability to migraine and these traits. Further work is needed to identify the biological mechanisms and clinical relevance of these findings. [ABSTRACT FROM AUTHOR]

Objective Background Methods Results Conclusion To compare the rate and extent of absorption of zavegepant 10 mg (therapeutic dose) or 20 mg (supratherapeutic dose) nasal spray during a migraine attack versus non‐migraine period, assess safety, and explore efficacy and the relationship between zavegepant concentration and therapeutic response.Physiologic changes occurring during a migraine attack could affect the pharmacokinetics of treatments for migraine.This was a Phase 1, multicenter, open‐label, randomized, single‐dose, two‐period, fixed‐sequence, comparative bioavailability study. Participants with a history of 2–8 migraine attacks per month of moderate or severe pain intensity were randomized to a single dose of zavegepant 10 or 20 mg, administered intranasally during a migraine attack (Period 1) and in a non‐migraine period (Period 2). Blood samples were collected pre‐dose and at pre‐specified intervals up to 24 h post‐dose for plasma zavegepant concentration measurement. Safety was monitored throughout, and efficacy (migraine pain intensity score, nausea, photophobia, phonophobia, aura, and functional disability) assessed during Period 1. Plasma zavegepant pharmacokinetic parameters were calculated by standard noncompartmental methods, including maximum plasma concentration (Cmax), area under plasma concentration–time curve from time zero to infinity (AUC0–inf), and time of Cmax (Tmax).A total of 37 participants were evaluable for pharmacokinetics. Following administration of zavegepant 10 mg, geometric mean ratios for Period 1/Period 2 were 82.8% (90% confidence interval [CI] 60.5–113.2) for Cmax and 90.1% (90% CI 70.2–115.5) for AUC0–inf. Following administration of zavegepant 20 mg, geometric mean ratios for Period 1/Period 2 were 72.5% (90% CI 57.9–90.8) for Cmax and 73.4% (90% CI 58.8–91.7) for AUC0–inf. Averaging over the study period, geometric mean ratios for zavegepant 20 mg/10 mg were 142.5% (90% CI 118.6–171.4) for Cmax and 157.0% (90% CI 133.6–184.5) for AUC0–inf. Median Tmax was 0.5 h for both doses regardless of Period. Zavegepant was well tolerated in both study periods and effective during Period 1 at both dose levels. There was no apparent correlation between concentration at 0.5 h or 2 h post‐dose and efficacy outcomes.Zavegepant exposure was comparable during a migraine attack and a non‐migraine period, particularly at the therapeutic dose of 10 mg. When averaging over migraine and non‐migraine periods, there was a less‐than‐dose proportional increase in zavegepant exposure when the dose was doubled from 10 to 20 mg. The median Tmax was 0.5 h regardless of migraine attack or dose. Zavegepant 10 and 20 mg exhibited favorable safety profiles during migraine attacks and non‐migraine periods, and were effective to relieve pain, associated symptoms, and functional disability during migraine attacks, with no apparent correlation between zavegepant concentration and efficacy outcomes. [ABSTRACT FROM AUTHOR]

Background: Studies on post-stroke anxiety (PSA) following the lifting of COVID-19 restriction measures are currently lacking. We investigated the factors affecting PSA after full release of COVID-19 epidemic in China. Methods: Patients with stroke admitted to the First People's Hospital of Changde City from March 2023 to September 2023 participated in a questionnaire survey comprising a general demographic questionnaire, the Generalized Anxiety Scale-7. Additionally, data on the National Institutes of Health Stroke Scale, modified Rankin Scale, C-reactive protein (CRP), thyroid-stimulating hormone (TSH), homocysteine, TOAST classification, and the stroke site were collected, and the correlations between these indices and the mental health conditions of the patients were evaluated. Results: Among 947 patients, the incidence of PSA was 14.57%.PSA was not linked to prior COVID-19 infection. This study found that Sleep duration (P=0.01), hyperlipidemia (P=0.01), migraine (P=0.02), and family history of stroke (P=0.01) were associated with PSA. Conclusions: Our study found that the prevalence of PSA was 14.57%. In addition, sleep duration, hyperlipidemia, migraine and family history of stroke were independent risk factors for PSA following the lifting of COVID-19 restrictions. [ABSTRACT FROM AUTHOR]

Introduction: Migraine is a prevalent neurological disorder characterized by recurrent attacks, leading to a substantial global disease burden. Recent observational studies have reported the onset and worsening of migraine following COVID-19 infection and vaccination. However, traditional observational study designs have limitations in controlling for confounding factors, potentially resulting in biased and inconsistent conclusions. To address this, we applied Mendelian randomization (MR) to investigate the causal relationship between COVID-19 infection and vaccination with migraine. Methods: This study utilized summary-level genome-wide association study (GWAS) data from the GWAS catalog and FinnGen database to evaluate the effects of varying degrees of COVID-19 infection and vaccination on migraine. We employed inverse variance weighted (IVW) fixed-effect and random-effect models as the primary methods for MR analysis, with MR-Egger and other approaches as complementary methods. Sensitivity analyses, including Cochran's Q test, MR-Egger intercept regression, and MR-PRESSO, were conducted to ensure robustness of the results. Results: Our MR analysis revealed no significant causal association between COVID-19 infection and migraine. However, a significant causal association was found between COVID-19 vaccination and migraine (beta = 0.071, P = 0.034). The results were confirmed through a series of sensitivity tests, demonstrating the robustness of the findings. Discussion: This study provides novel evidence of a significant causal link between COVID-19 vaccination and migraine, while no such association was observed with COVID-19 infection. These findings may have important implications for clinical practice, particularly in planning treatment adjustments and optimizing patient care for individuals with migraines in the context of COVID-19 vaccination. [ABSTRACT FROM AUTHOR]

Background: Environmental contaminants may play a significant role in the development of migraine. Perchlorate, nitrate, and thiocyanate were selected for this study due to their known impact on thyroid function, which is closely linked to neurological processes. Disruptions in thyroid function have been associated with various neurological disorders, including migraines. However, there is currently no evidence linking exposure to these specific chemicals to migraine. The study aims to evaluate the association between urinary concentrations of perchlorate, nitrate, and thiocyanate with the prevalence of severe headache or migraine in U.S. adults. Methods: A cross-sectional study was conducted using data from the National Health and Nutrition Examination Survey (NHANES) 2001–2004. Utilizing electrospray tandem mass spectrometry in conjunction with ion chromatography, urinary concentrations of perchlorate, nitrate, and thiocyanate urine were measured. Multiple logistic regression models were employed to evaluate the linear correlation between perchlorate, nitrate, and thiocyanate exposure and severe headache or migraine. The non-linear relationship is described analytically using a fitted smoothing curve and a two-piecewise regression model. Subgroup analyses were used to further clarify the stability of this relationship across different populations. Results: There were 1,446 participants in this population-based study, ranging in age from 20 to 85. After adjusting for potential confounding variables, the multiple logistic regression findings demonstrated that thiocyanate was significantly positively associated with the prevalence of migraine (odds ratio [OR] = 1.18; [1.06, 1.30]; p < 0.001). There was consistency in this connection across different subgroups (p for interaction >0.05). Furthermore, there was a non-linear correlation between urinary thiocyanate and migraine. Using a fitted smoothing curve and a two-piecewise regression model, it was found that the correlation between urinary thiocyanate and migraine was U-shaped (p for Log-likelihood ratio = 0.002). According to the findings of the multiple regression analysis, there was no significant correlation between urinary perchlorate and nitrate and migraine (both p > 0.05). Conclusion: We should limit our exposure to thiocyanate by keeping it within a reasonable range, as indicated by the U-shaped correlation between urinary thiocyanate and migraine. [ABSTRACT FROM AUTHOR]

Background: Migraine is a widespread, recurrent primary headache disorder primarily characterized by severe pulsatile headache, typically on one or both sides. It is often accompanied by nausea, vomiting, and hypersensitivity to sound and light. Despite the availability of multiple drugs for migraine management, the condition often becomes chronic due to untimely or irrational drug use, significantly distressing patients and increasing the burden on families and society. Over the past two decades, numerous clinical studies on migraine have been published. This study aimed to provide a comprehensive summary of the current status and trends of migraine clinical trials through bibliometric analysis. Methods: We used visual network tools such as CiteSpace and VOSviewer to perform a knowledge graph analysis of publications related to migraine clinical trials extracted from the WoSCC. Results: This study analyzed 1,129 articles published in 389 journals from 61 countries. The number of publications on migraine clinical trials has steadily increased from 2004 to 2023. The United States and Albert Einstein College of Medicine are the leading countries and institutions in this field, respectively. Richard B. Lipton is the most prolific author, making significant contributions to the research. The journal Headache has the highest number of publications and citations in this area. Keywords such as "efficacy," "RCT," "CGRP," "prophylaxis," "disability," "depression," "questionnaire," and "real-world effectiveness" received significant attention. Conclusion: This study identified reliable research hotspots and provided directions for clinicians. The treatment of migraine continues to be challenging. Future trends may include continued growth in migraine classification, risk factor analysis, and comorbidity studies. Research on CGRP and epigenetics will advance the progress of precision medicine in the migraine field. [ABSTRACT FROM AUTHOR]

Background: Migraine is a neurological condition marked by frequent headaches, which tends to be accompanied by nausea and vomiting in severe instances. Injectable therapies for migraine, such as monoclonal antibodies that target calcitonin gene-related peptide (CGRP), have proven to be effective and safe. While various oral drugs are available, none have been developed for migraines. Patients prefer oral therapies because they are easier to use, making atogepant, an orally accessible small-molecule CGRP receptor antagonist, a possible alternative. Objectives: This systematic review and meta-analysis compared the safety and effectiveness of atogepant with placebo in treating migraine. Methods: Adhering to the PRISMA guidelines, we meticulously gathered randomized controlled trials (RCTs) from databases including the Cochrane Library, PubMed, Science Direct, and ClinicalTrials.gov. Studies comparing atogepant with placebo and reporting monthly migraine days (MMDs) as the primary outcome along with secondary outcomes such as monthly headache days and acute medication use days were included. Two independent reviewers conducted the data extraction and quality assessment. Statistical analyses were carried out using RevMan, utilizing risk ratios for dichotomous outcomes and mean differences for continuous outcomes, and a random-effects model. Results: Our primary outcome was the change in MMDs over 12 weeks, which showed a significant reduction with atogepant at dosages of 10, 30, and 60 mg. Secondary outcomes, such as monthly headache days, proportion of patients achieving a ≥ 50% reduction in MMDs, acute medication use days, and patient-reported outcomes, consistently showed that atogepant outperformed placebo, highlighting its effectiveness in reducing the migraine burden. Conclusion: Higher doses of atogepant are more effective in lowering migraine and headache-related days and increasing quality of life metrics. However, this is accompanied by an increased incidence of adverse events, suggesting the need for careful dose optimization to balance the benefits and risks. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display%5frecord.php?RecordID=563395. Unique Identifier: CRD42024563395. [ABSTRACT FROM AUTHOR]

Background: Neck pain and primary headache disorders are highly prevalent in populations and clinical cohorts. Medication-overuse headache (MOH) is a treatable secondary headache, mainly developing in migraine sufferers, that accounts for the majority of patients presenting to headache clinics. Nevertheless, the association between neck pain and MOH has not been reported. This study evaluated the prevalence and clinical course of neck pain in patients with MOH before and after MOH treatment. Methods: We analyzed 635 MOH patients enrolled in a nationwide, prospective, multicenter MOH registry. Demographics and clinical data were collected at baseline and 3 months to evaluate changes in the status and severity of neck pain and headache. Severity of neck pain was graded into 4 groups, and severe neck pain was defined as grade 3 or 4. Results: Among 635 patients with MOH, 366 (57.6%) reported neck pain at baseline. MOH patients with neck pain had an earlier onset of their primary headache disorder (23.4 ± 12.7 vs. 26.2 ± 13.3 years, p = 0.007). Although monthly headache days were comparable between the patients with neck pain and those without neck pain, the neck pain group had higher levels of anxiety (7.4 ± 5.8 vs. 6.4 ± 5.4, p = 0.017), more severe cutaneous allodynia (2.4 ± 3.3 vs. 1.8 ± 3.0, p = 0.038), and poorer quality of life (171.7 ± 70.4 vs. 184.0 ± 68.9, p = 0.029). At 3 months, 456 (71.8%) were followed-up, and 257 (56.4%) were recovered from MOH. Compared to the baseline, the proportion of severe neck pain (40.4% vs. 19.4%, p < 0.001) was decreased. The proportion of severe neck pain was much lower in patients with recovery from MOH compared to those without (4.7% vs. 15.1%, p < 0.001). Conclusions: Neck pain in MOH patients was associated with earlier onset of headache, higher levels of anxiety and allodynia, and poorer quality of life. Improvement in neck pain improvement was linked to recovery from MOH. These findings suggest the potential importance of integrating and management of neck pain into clinical practice for MOH. [ABSTRACT FROM AUTHOR]

Objective Background Methods Results Conclusions To evaluate long‐term reductions in acute headache medication (AHM) use with eptinezumab versus placebo in patients with prior preventive migraine treatment failures and medication overuse (MO).Preventive migraine treatment is recommended for patients for whom AHMs have failed and for those who are using excessive amounts of AHM. MO may worsen headache and migraine symptoms in people with migraine; it is a risk factor for disease chronification and/or MO headache.DELIVER was a multicenter, parallel‐group, double‐blind, randomized, placebo‐controlled, phase 3b clinical trial that randomized adults with migraine and two to four prior preventive failures to eptinezumab 100 mg, 300 mg, or placebo infusion every 12 weeks; patients initially given placebo received eptinezumab 100 mg or 300 mg in the extension period. MO was defined according to diagnostic criteria for MO headache in the baseline diary reports. This post hoc analysis of the DELIVER study included change from baseline in AHM days/month of use (ergotamines, triptans, simple or combination analgesics, and opioids; total and select class‐specific use) in the MO population.A total of 890 patients were included in the total population, and 438/890 (49.2%) had MO at baseline. In both the total population and MO population, eptinezumab resulted in greater reductions in total AHM days/month of use during weeks 1–24 than placebo, with triptans showing the largest reduction among AHM classes. Patients switching from placebo to eptinezumab experienced reductions in AHM days/month similar to that of initial eptinezumab treatment. In the extension population, mean (standard error [SE]) changes from baseline in AHM days/month were −4.6 (0.32; 100 mg) and −4.8 (0.32; 300 mg) across weeks 1–4 in patients who received eptinezumab for the entire treatment period and were −4.8 (0.44; placebo–100 mg) and −5.5 (0.44; placebo–300 mg) across weeks 25–28 in patients who switched from placebo to eptinezumab. Mean (SE) changes from baseline in AHM days/month in the extension MO population were −6.5 (0.59; 100 mg) and −6.6 (0.57; 300 mg) across weeks 1–4 in patients who received eptinezumab for the entire treatment period and were −7.1 (0.81; 100 mg) and −8.0 (0.80; 300 mg) across weeks 25–28 in patients who were switched from placebo to eptinezumab. All treatment arms sustained or further reduced AHM use across 18 months of trial participation. Across weeks 1–4, in patients fulfilling criteria for MO at baseline, 68.0% (102/150) of patients treated with eptinezumab 100 mg and 74.7% (109/146) of patients treated with eptinezumab 300 mg reported AHM use below MO thresholds compared to 43.3% (61/141) of patients receiving placebo. In patients with MO at baseline, the proportion of patients without MO remained above 60.0% for all treatment groups during the extension period.Eptinezumab reduced total AHM use more than placebo in patients with prior preventive failures and in patients with MO at baseline; largest reductions were observed for triptans. Robust reductions in AHM use after eptinezumab were sustained or further reduced with up to 18 months of treatment, and most patients no longer met thresholds for MO. [ABSTRACT FROM AUTHOR]

Background:Methods:Results:Conclusions:The field of dietary therapies for migraine has grown in popularity. Less research has been conducted to establish the relationship between migraine and the composite dietary antioxidant index (CDAI), a crucial indicator for evaluating the overall combined effects of multiple dietary antioxidants. Therefore, this study addressed this gap based on the National Health and Nutrition Examination Survey (NHANES) database.Multivariate logistic regression equations were used to investigate the relationship between CDAI and migraine, and smoothed-fitted curves were plotted. After a nonlinear relationship was discovered, the recursive algorithm and a two-stage linear regression model were employed to calculate the turning point. Additional stratified analyses were performed to explore differences between populations.This study included a total of 9,190 participants aged 20 years old or older. A U-shaped association was observed between the CDAI and migraine, with an inflection point of 0.2. They were negatively correlated before the inflection point with OR of 0.93 (95% CI = 0.88–0.97) and positively correlated after the inflection point with OR of 1.04 (95% CI = 1.01–1.07). This U-shaped relationship persisted among people aged <60 and ≥60 years, women, and people with BMI <30 and ≥30.We identified a U-shaped association between CDAI and migraine in the U.S. adult population. Further case–control studies and experimental research are needed to explore the underlying mechanisms of action. [ABSTRACT FROM AUTHOR]

Objective: To assess tablet utilization patterns and describe pre-treatment characteristics among new users of rimegepant. Background: Rimegepant is the only oral calcitonin gene-related peptide antagonist approved in the United States for both the acute and preventive treatment of migraine. Methods: We conducted a retrospective cohort study of people with migraine who initiated treatment with rimegepant using two US commercial claims databases (MarketScan and Optum). Patients (≥18 years old) with migraine who newly initiated rimegepant were included. Patients were stratified into two groups representing acute (quantity = 8) and prevention (quantity = 15 or 16) use cohorts. Baseline characteristics and medication use history were assessed on index and during the 365-day pre-index period. Rimegepant utilization periods were calculated based on days supplied and varying approaches to define use periods. Tablet quantity per 30 days was reported separately for both acute and prevention cohorts. Results: In MarketScan, a total of 14,037 rimegepant users were identified; 11,195 (79.8%) in the acute group and 1,880 (13.4%) in the prevention group. Rimegepant utilization for acute use was 4.9 ± 2.1 tablets per 30 days and for preventive use was 13.1 ± 7.7 tablets per 30 days. There was high baseline prevalence of triptan contraindications, warnings, and high cardiovascular risk, with a combined 46.2% meeting one or more of these criteria. Acute medication overuse was also common (25.1%) prior to rimegepant initiation. Results were consistent in the Optum database. Conclusion: Our analysis provides the first real-world data available on tablet utilization and characteristics of new users of rimegepant. PLAIN LANGUAGE SUMMARY: There is little information available on the characteristics of people with migraine who start to use rimegepant, which is the only medicine approved for both the prevention of migraine attacks and the acute treatment of migraine attacks after they have started. Information on new users of rimegepant at least 18 years of age was obtained from two commercial databases of US healthcare claims (MarketScan and Optum). The researchers used this information to evaluate people's age, sex, pre-existing illnesses, and prior use of migraine medications at the time they started using rimegepant, and they also used several different methods to estimate how often people used rimegepant after treatment was started. The MarketScan database contained information on 14,037 people with migraine who started using rimegepant, with this group having an average age of 43 years and being comprised mostly of females (88%). Prior to starting rimegepant, almost half (46%) of the people were considered to have high cardiovascular risk and 25% considered at risk of overusing acute migraine medications. Most of the 14,037 people (80%) who started rimegepant used it to treat migraine attacks after they started and this group used approximately 5 tablets every month. The smaller number of people who used rimegepant to prevent migraine attacks used approximately 13 tablets every month. The information obtained from the Optum database was similar to that obtained from the MarketScan database. The researchers' analysis is the first to describe the characteristics of people with migraine who start to use rimegepant outside the setting of a controlled clinical trial. Their results show that new users of rimegepant represent a complex population with a significant profile of pre-existing illness and a diverse treatment history. [ABSTRACT FROM AUTHOR]

Background: Telemedicine offers a promising solution to enhance the delivery and personalization of headache care. Integrating electronic (e-)tools enables the objective monitoring of migraine. Objectives: This study aims to demonstrate the relevance of e-tools for personalized headache care, assess patient and caregiver compliance and satisfaction, and present their use in enhancing care. Methods: Firstly, a systematic review was performed to validate the diagnostic accuracy of e-diaries for diagnosing migraine. Secondly, we collected e-diary data prospectively from diagnosed adult migraine patients at the Leiden Headache Center. Finally, questionnaires were sent to evaluate satisfaction of patients and health care providers with the Leiden e-headache diary and video consultations. Results: In the systematic review, the Leiden Headache Center's e-diary was the only validated tool. Patients (n = 1,009) were followed for a median of 181 days (interquartile range [IQR] 84–240). Compliance was 96.4% (IQR 85.2 − 99.1%), with 10.8% of days missing. Factors positively associated with compliance were older age (p < 0.001), female sex (p < 0.001), higher e-diary grade (p < 0.001), and clinical use (p = 0.04). The e-diary received a median score of 8/10 and was well-liked by patients (n = 535) and providers (n = 23). Video consultations were a good alternative for physical visits according to 76.9% of patients and 84.6% of providers. Conclusion: Validated e-headache diaries and video consultations in telemedicine enhance headache care accessibility, providing convenient care at preferred times and locations. [ABSTRACT FROM AUTHOR]

Background/Objective: Genome-wide association studies (GWASs) demonstrate a complex genetic landscape for migraine risk. Migraine polygenic risk scores (PRSs) developed from GWAS data may have utility for predicting disease course. We analyzed the strength of association between an integrative migraine PRS and age at onset and chronification. Methods: In this retrospective clinical/genetic case–control study, PGS004799 was calculated for adults with European ancestry from two real-world community cohorts. In the DodoNA cohort, 1653 treated, deeply phenotyped migraine cases, diagnosed using International Classification of Headache Disorders 3rd edition criteria, were followed for a mean (range) of 2.3 (1–10) years and compared to 3460 controls (without migraine diagnosis). In the GHI cohort, 2443 cases were identified using the first migraine ICD code as a proxy for migraine onset and compared to 8576 controls (without migraine ICD codes). PRS associations with age at onset (DodoNA) or first migraine ICD code (GHI) and chronification (DodoNA) were evaluated. Results: In both cohorts, PRS was higher in cases (DodoNA mean (range) cases: 0.82 (0.07–1.76), controls: 0.78 (0.04–1.56); t (5111) = −6.1, p = 1.4 × 10−9, GHI: cases: 0.79 (0.003–1.68), controls: 0.75 (−0.06–1.53); t (11,017) = −7.69, p = 1.6 × 10−14), and a higher PRS was associated with earlier onset in females (HR [95% CI] DodoNA: 2.1 [1.6–2.6, p < 0.001; GHI: 1.8 [1.4–2.1], p < 0.001) and in males (DodoNA: 2.5 [1.3–4.7], p = 0.005; GHI: 1.6 [1.1–2.6], p = 0.027). PRS was not different in cases with or without chronification (t (1651) = −1.67, p = 0.094) and was not associated with earlier chronification (1.2 [0.8–1.6], p = 0.424). Conclusions: Higher genetic risk was associated with earlier onset and increased risk of migraine well into adulthood, but not with chronification. This suggests that the PRS quantifies genetic susceptibility that is distinct from factors influencing disease course. [ABSTRACT FROM AUTHOR]

Introduction: The term 'refractory migraine' (RM) is commonly used in clinical settings; however, it is not recognized in the International Classification of Headache Disorders, third edition. A growing need for a shared definition of refractoriness has been highlighted by a multidisciplinary expert group. Although definitions for RM currently exist, the key parameters for the definition of refractoriness (e.g., unresponsiveness to treatment, high frequency, severe disability, or all of these features) remain contentious. Thus, a consensus on the definition of RM is crucial. Methods: Calcitonin gene‐related peptide (CGRP) is a neuropeptide that plays an important role in migraine pathophysiology and is a target for migraine preventive therapies. Monoclonal antibodies targeting the CGRP (i.e., galcanezumab, fremanezumab, and eptinezumab) and its receptor (erenumab) have shown consistent efficacy for migraine prophylaxis with excellent safety profiles. Their effect on refractory cases has also been reported, offering promise to the many patients who have not found relief with existing treatments. Therefore, we anticipate a paradigm shift in migraine treatment. Results: Following the widespread use of monoclonal antibodies targeting the CGRP and its receptor, the European Headache Federation proposed a definition for two subsets of difficult‐to‐treat migraine—resistant and refractory migraine—that considers both the frequency and disability caused by single and frequent attacks. Conclusion: We expect that this definition will help resolve previous conflicts that have limited the use of earlier definitions. [ABSTRACT FROM AUTHOR]

Migraine and stroke are neurological disorders with significant global prevalence and impact. Recent advances in migraine therapy have focused on the calcitonin gene-related peptide (CGRP) pathway. This review examines the shared pathomechanisms between migraine and stroke, with emphasis on the role of CGRP. We analyze the current literature on CGRP's functions in cerebrovascular regulation, edema formation, neuroinflammation, and neuroprotection. CGRP acts as a potent vasodilator and plays a crucial role in trigeminovascular activation during migraine attacks. In stroke, CGRP has demonstrated neuroprotective effects by improving collateral circulation and reducing ischemia-reperfusion injury. Concerns have been raised about the potential impact of CGRP inhibitors on stroke risk and outcomes. Studies in animals suggest that CGRP receptor antagonists may worsen cerebral ischemia by impairing collateral flow. We discuss the implications of these findings for the use of CGRP-targeting therapies in migraine patients, especially those at increased risk of stroke. Additionally, we explore the complex interplay between CGRP, endothelial function, and platelet activity in both conditions. This review highlights the need for further research to elucidate the long-term cerebrovascular safety of CGRP pathway inhibitors and to identify potential subgroups of migraine patients who may be at higher risk of adverse cerebrovascular events with these novel therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer continues to be a leading cause of death globally. Advances in effective treatment have been hindered by difficulties in personalized therapy, especially among patients with comorbid conditions. The use of artificial intelligence (AI) in patient profiling presents a promising strategy for enhancing individualized cancer therapy. AI technologies, such as machine learning (ML), deep learning (DL), and natural language processing (NLP), have become crucial in identifying genetic and molecular biomarkers for cancer and migraine. These technologies facilitate predictive analytics to evaluate the impact of migraine on cancer treatment in patients with comorbidities, helping to forecast outcomes and supporting clinical decision-making through real-time treatment adjustments. AI has considerable potential to enhance the precision and efficacy of managing cancer patients with comorbid migraine. However, challenges related to data integration, clinical validation, and ethical considerations must be addressed. Background: Cancer remains a leading cause of death worldwide. Progress in its effective treatment has been hampered by challenges in personalized therapy, particularly in patients with comorbid conditions. The integration of artificial intelligence (AI) into patient profiling offers a promising approach to enhancing individualized anticancer therapy. Objective: This narrative review explores the role of AI in refining anticancer therapy through personalized profiling, with a specific focus on cancer patients with comorbid migraine. Methods: A comprehensive literature search was conducted across multiple databases, including PubMed, Scopus, and Google Scholar. Studies were selected based on their relevance to AI applications in oncology and migraine management, with a focus on personalized medicine and predictive modeling. Key themes were synthesized to provide an overview of recent developments, challenges, and emerging directions. Results: AI technologies, such as machine learning (ML), deep learning (DL), and natural language processing (NLP), have become instrumental in the discovery of genetic and molecular biomarkers of cancer and migraine. These technologies also enable predictive analytics for assessing the impact of migraine on cancer therapy in comorbid cases, predicting outcomes and provide clinical decision support systems (CDSS) for real-time treatment adjustments. Conclusions: AI holds significant potential to improve the precision and effectiveness of the management and therapy of cancer patients with comorbid migraine. Nevertheless, challenges remain over data integration, clinical validation, and ethical consideration, which must be addressed to appreciate the full potential for the approach outlined herein. [ABSTRACT FROM AUTHOR]

Objective: To conduct a retrospective cross‐sectional multicenter study to validate the relationships between migraine‐associated symptoms. Background: Symptoms associated with headache—photophobia and phonophobia, nausea, and/or vomiting—are required criteria for migraine diagnosis based on the International Classification of Headache Disorders‐Third Edition (ICHD‐3). However, individuals with migraine report high rates of other symptoms (e.g., lightheadedness, difficulty thinking). We recently completed a single‐center study assessing the relationships between an expanded set of migraine‐associated symptoms. Methods: A pre‐registered cross‐sectional multicenter retrospective analysis was conducted on standardized questionnaire data of youth ages 6–17 years from two headache registries at pediatric tertiary care centers. Cluster Analysis of Migraine‐associated Symptoms (CAMS) was implemented to assess associations between 11 migraine‐associated symptoms. We explored differences between the two centers, and how CAMS was associated with demographics, including sex and age, and headache burden. Results: There were 10,721 participants who were 66.5% female and had a median (interquartile range) age of 13 (10–15) years. The first three CAMS dimensions accounted for 46.5% of the variance and were consistent across sites. The first dimension indicated those reporting any migraine‐associated symptoms were likely to report multiple. The second dimension separated symptoms into those included in ICHD‐3 migraine diagnostic criteria and non‐ICHD symptoms (e.g., lightheadedness, difficulty thinking). The third dimension separated sensory hypersensitivity and vestibular symptoms. An abundance of migraine‐associated symptoms correlated with greater headache severity (Spearman's ρ = 0.18, 95% confidence interval [CI] 0.17–0.20; small effect size) and disability (ρ = 0.26, 95% CI 0.25–0.28; small effect size). We also observed differences in associated symptoms across age and sex. Discussion: Associations between an expanded set of migraine‐associated symptoms are informative for headache burden and reveal intriguing changes across child development and sex. We were able to replicate findings across two centers, indicating that these symptom clusters are inherent to migraine. Plain Language Summary: The presence of symptoms such as light or sound sensitivity, nausea, and vomiting can help clinicians differentiate between migraine and other headache disorders, such as tension‐type headache. However, people with migraine commonly experience symptoms that are not part of migraine diagnostic criteria per the International Classification for Headache Disorders‐Third Edition criteria, including lightheadedness, vision changes, and vertigo. In this study, we found that by considering these other associated symptoms, we were able to better understand the burden of headache in children and adolescents; e.g., we found that having more associated symptoms was associated with more headache severity and greater headache impact in children and teenagers. [ABSTRACT FROM AUTHOR]

Objectives: We used Cluster Analysis of Migraine‐associated Symptoms (CAMS) to critically evaluate current International Classification of Headache Disorders‐Third Edition (ICHD‐3) migraine‐associated symptoms criteria. Background: Diagnostic criteria play a central role in guiding clinical trial inclusion, and therefore available treatments. Migraine and tension‐type headaches (TTH) are differentiated in ICHD‐3 by many headache characteristics, including associated symptoms. A diagnosis of probable migraine indicates some but not all features of migraine are met. Photophobia and phonophobia, or nausea and/or vomiting, are required to meet a diagnosis of migraine; however, CAMS—a model that describes associated symptoms across youth with headache—indicates that a broader range of symptoms contain information about migraine burden. Methods: In this multisite retrospective cross‐sectional study, we evaluated ICHD‐3 migraine criteria. Youth aged 6–17 years with migraine (including probable migraine) or TTH were included in the analysis. We used CAMS to evaluate the migraine‐associated symptom criterion. With CAMS as a guide, we evaluated how changes to the migraine‐associated symptom criterion altered who met the diagnosis of migraine. Results: Of the 9017 participants included in this study, 66.7% were female and had a median (interquartile range) age of 13 (10–15) years. Most participants had migraine or probable migraine (99.0%), and the remainder had TTH (1.0%). A sizable percentage (10.1%) of youth under the umbrella diagnosis of migraine were diagnosed with probable migraine because they did not meet migraine‐associated symptom criterion D; however, many in this group reported several non‐ICHD migraine‐associated symptoms. We explored alterations to criterion D based on CAMS. Allowing for photophobia or phonophobia re‐categorized 55.6% of youth as having migraine, though some only had one symptom. Including lightheadedness or lightheadedness and spinning re‐categorized 19.7% and 25.8% of youth with migraine, respectively, but all of those who were re‐categorized had at least two migraine‐associated symptoms. Conclusion: The ICHD‐3 captures the most prevalent migraine‐associated symptoms; however, many youths with probable migraine who do not meet full criteria due to insufficient associated symptoms nonetheless experience multiple non‐ICHD migraine‐associated symptoms. Changes to criterion D should be considered for the ICHD‐4. Plain Language Summary: For clinicians to make a diagnosis of migraine based on International Classification of Headache Disorders‐Third Edition (ICHD‐3) criteria, patients must have headache‐associated nausea, vomiting, or light and sound sensitivity (criterion D). However, migraine can also be associated with other symptoms like lightheadedness, difficulties with thinking, and vertigo. In this study of youth aged 6–17 years with migraine, probable migraine, or tension‐type headache, we looked at how altering the ICHD‐3 criterion D changed participants' diagnosis based on their symptoms; overall, our results suggest that the next version of ICHD should account for the fact that many youth who do not experience nausea, vomiting, or light and sound sensitivities still experience manyx other migraine associated symptoms. [ABSTRACT FROM AUTHOR]

Objective: Describe the epidemiology of cluster headache (CH) using Veterans Health Administration (VHA) Electronic Health Record (EHR) data. Background: Epidemiologic studies of CH at the population level are difficult because it has a prevalence of ~0.1%. Hospital system‐wide studies are an attractive alternative as they have large numbers of patients and broader populations than headache or neurology clinic‐based studies. The VHA is an ideal hospital‐based system in which to study CH because it is nationwide, predominantly male, has a strong focus on mood disorders and suicidality, and has accessible individual medical records. Here, we report the first headache study based on an ongoing longitudinal cohort of patients with CH using VHA EHR data. Methods: The VHA EHR data were accessed from Fiscal Year 2008 to 2019. Patients with CH consisted of all patients with at least one outpatient visit containing a CH diagnosis code from the International Classification of Diseases (ICD)‐9 or ‐10. We extracted data on demographic features, incidence, and prevalence, as well as pain and psychiatric comorbidities. Results: Of the 1,524,960 distinct patients who presented for headache treatment in the VHA between Fiscal Year 2008–2019, 24,131 had at least one visit with a CH diagnosis. The 1‐year period prevalence of a CH diagnosis in the VHA ranges from 0.08% to 0.10% for women and 0.10% to 0.18% for men. A larger proportion of women versus men received a diagnosis of unspecified CH (59.6% [1412/2368] vs. 53.6% [11,663/21,763], p < 0.001). Most patients with CH had both comorbid headache and non‐headache pain diagnoses. Headache not‐otherwise‐specified was the most common comorbid headache disorder at 70.0% (16,885/24,131) and was more common in women (76.1%, 1801/2368) compared to men (69.3%, 15,084/21,763). Other common comorbidities included migraine, depression, tobacco use, and obstructive sleep apnea. Rates of suicidal ideation or attempt were almost 50% higher in women (5‐year proportion 9.4%, 222/2368) with CH compared to men (6.6%, 1433/21,763). Conclusions: To our knowledge this is the largest hospital system study of CH to date and reinforces several previous studies. Pain, mental health, and sleep disorders comorbidities are particularly prevalent in this group and were often more common in women compared to men with CH. Future work should examine gender and race stratified prevalence estimates within the VHA and other healthcare systems. Plain Language Summary: This study describes the epidemiology of cluster headache among all Veterans Health Administration (VHA) enrollees using electronic medical record data from the VHA. We found that during any given 1‐year period, between 0.08–0.10% of women and 0.10–0.18% of men in the VHA were treated for cluster headache. Many of these patients also had co‐occurring disorders including other headache disorders and depression, so more research is needed to find the best ways to treat these patients. [ABSTRACT FROM AUTHOR]

Objectives: To compare the effectiveness of parenteral agents to reduce relapse in patients with acute migraine and identify factors that predict relapse. Background: Following discharge from emergency settings, many patients with acute migraine will experience a relapse in pain; severe relapses may result in re‐visits to emergency settings. Methods: A comprehensive literature search, updated to 2023, was conducted to identify randomized controlled trials assessing the effectiveness of parenteral agents on relapse outcomes in patients with acute migraine discharged from emergency settings. Two independent reviewers completed study selection, quality assessment, and data extraction. A traditional meta‐analysis compared parenteral corticosteroids to placebo; a frequentist network analysis assessed direct and indirect comparisons. Results are reported as risk ratios (RRs) and 95% confidence intervals (CIs). The review protocol was registered with the International Prospective Register of Systematic Reviews (identifier: CRD42018099493). Results: From 8949 citations, a total of 53 unique studies were included involving 6167 patients. Most studies had a high or unclear risk of bias. Corticosteroids significantly reduced relapses compared to placebo (RR 0.67, 95% CI 0.52–0.88; I2 = 0%). Patients receiving lidocaine (RR 0.10, 95% CI 0.01–0.82), sedatives/hypnotics (RR 0.33, 95% CI 0.14–0.75), ergot agents (RR 0.44, 95% CI 0.25–0.75), neuroleptics (RR 0.47, 95% CI 0.31–0.71), opioids (RR 0.58; 95% CI 0.35–0.94), or corticosteroids (RR 0.64, 95% CI 0.47–0.86) were significantly less likely to relapse. Lidocaine (RR 0.09, 95% CI 0.01–0.71), combination therapy (RR 0.12, 95% CI 0.02–0.74), or adding corticosteroids (RR 0.61, 95% CI 0.44–0.84) were more likely to reduce severe relapses. Longer duration of headache and residual pain at discharge were significantly associated with higher relapses. Discussion: Corticosteroids remain the recommended first‐line option to reduce relapse outcomes. Some parenteral agents typically provided for pain relief including ergot agents, neuroleptics, or combination therapy may effectively reduce relapse; however, opioids are not recommended due to safety concerns. Additional research is needed for some lesser studied, albeit promising, agents including lidocaine and propofol. Effective pain control in emergency settings prior to discharge and duration of headache may play a role in the success of such treatments and further investigations could provide further insight regarding how and why some parenteral agents are effective in mitigating relapse events. Plain Language Summary: After leaving the hospital, some patients will have a relapse of migraine pain and may return to the emergency department, but we do not always know why this is or how to best help these patients. While corticosteroids can reduce relapse, we systematically reviewed the direct and indirect evidence for injectable medications to reduce relapse in patients with migraine. The results of our review indicated that (1) the duration of migraine pain and having pain at discharge were associated with relapse, and (2) routinely used medicines besides corticosteroids (e.g., neuroleptics and ergot agents) may be effective in reducing relapse. [ABSTRACT FROM AUTHOR]

Objective: To assess the real‐world effectiveness of ubrogepant by evaluating self‐reported satisfaction with pain relief, ability to think clearly, and return to normal function in individuals who had used ubrogepant to treat a migraine episode within the preceding 14 days. Background: Ubrogepant is an oral calcitonin gene–related peptide receptor antagonist approved for the acute treatment of migraine in adults. Few studies have evaluated the real‐world effectiveness of ubrogepant. Methods: The UNIVERSE study was an observational, cross‐sectional survey conducted between February 2021 and April 2021 in US adult Migraine Buddy application (app) users currently treated with ubrogepant. Individuals who were 18 years of age or older and reported at least one dose of ubrogepant in the previous 14 days completed a 30‐question survey in the app. The survey assessed respondent demographics, migraine history, acute treatment patterns, and treatment satisfaction with ubrogepant. Respondents also reported prior acute medication use and reasons for switching to ubrogepant. Results: Of the 1303 ubrogepant users contacted, 302 (23.2%; 50 mg, 120 participants; 100 mg, 182 participants) were included in this study. The mean (standard deviation) age was 41.9 (11.2) years, and 90.1% (272/302) were female. Satisfaction with migraine relief at 2, 4, and 24 h post‐dose was reported by 75.8% (229/302), 83.4% (252/302), and 78.5% (237/302) of participants, respectively. Satisfaction with the ability to think clearly after taking ubrogepant was reported by 85.1% (257/302) of participants, and 83.8% (253/302) were satisfied with their ability to return to normal function. Furthermore, 90.7% (274/302) of participants reported that they were likely to continue using ubrogepant to treat their migraine. Most participants (n = 264 [87%]) reported switching to ubrogepant due to inadequate treatment response with their previous treatment. In this subgroup, comparable outcomes were observed with respect to satisfaction with migraine relief, ability to think clearly, and return to normal function. Conclusions: Ubrogepant demonstrated real‐world effectiveness in the acute treatment of migraine, as evidenced by high levels of treatment satisfaction and a strong indication of their intent to continue using the medication. Plain Language Summary: Ubrogepant is approved for the acute treatment of migraine in adults. In this study, adults who had used ubrogepant to treat a migraine attack in the previous 14 days responded to survey questions regarding their satisfaction with pain relief, ability to think clearly, and return to normal function. Results indicated that the majority of participants experienced high levels of satisfaction with ubrogepant because most of them said that these areas of their life improved after treatment. [ABSTRACT FROM AUTHOR]

Objective: To study if galcanezumab is effective for vestibular migraine (VM). Background: There are currently no placebo‐controlled trials showing that treatment is effective for VM. Therefore, we performed the first placebo controlled, randomized clinical trial of a calcitonin gene–related peptide–targeted monoclonal antibody for VM. Methods: This was a single site, prospective, double‐blind placebo controlled randomized clinical trial. Key inclusion criteria were as follows: participants aged 18–75 years with a diagnosis of VM or probable VM per Barany Society criteria. The primary outcome was change in VM‐PATHI (Vestibular Migraine Patient Assessment Tool and Handicap Inventory) score, and secondary outcomes included change in DHI (Dizziness Handicap Inventory) score, and count of definite dizzy days (DDDs). Participants were randomized 1:1 to 3 months of treatment with galcanezumab or placebo via subcutaneous injection with a pre‐filled syringe, 240 mg the first month, and 120 mg for the second and third months. Results: Forty participants were randomized, and 38 participants were in the modified intent to treat analysis. VM‐PATHI score was reduced 5.1 points (95% confidence interval [CI] −13.0 to 2.7) for placebo (N = 21), and 14.8 points (95% CI −23.0 to −6.5) for galcanezumab (N = 17), a difference of −9.6 (95% CI −20.7 to 1.5, p = 0.044). DHI dropped 8.3 points in the placebo arm (95% CI −15.0 to 1.6), and 22.0 points in the galcanezumab arm (95% CI −31.9 to −12.1), a difference of −13.7 (95% CI −20.4 to −8.5, p = 0.018). The count of DDDs per month dropped from 18 days (standard deviation [SD] 7.6) in the baseline month to 12.5 days (SD 11.2) in month 4 for those in the placebo arm, and from 17.9 days (SD 7.9) in the baseline month to 6.6 days (SD 7.3) in month 4 for those in the galcanezumab arm, a difference of −5.7 days (95% CI −10.7 to −0.7, p = 0.026). No serious adverse events were observed. Conclusions: In this pilot study, galcanezumab was effective in treating VM. Plain Language Summary: Vestibular migraine is a common cause of dizziness. In this study, we investigated whether treatment with a drug called galcanezumab worked better than placebo for treating dizziness. We found that galcanezumab reduced dizziness more than placebo in patients with vestibular migraine. [ABSTRACT FROM AUTHOR]

Background: Fasting headaches frequently occur during the first few days of Ramadan, and treatment is challenging because of fasting. Objective: This study aimed to evaluate the effect of extended‐release paracetamol on preventing fasting headaches. Methods: A randomized, open‐label clinical trial investigated the efficacy of extended‐release paracetamol at a daily dose of 1330 mg in preventing fasting headache. Adults aged 18 years and older were recruited through the Clinical Trial Unit at the King Saud University Medical City. The eligible participants in the study fasted 13.5 h daily during the first week of Ramadan. Participants in the treatment and control arms were followed up to investigate the occurrence, severity, and timing of headache symptoms via self‐reporting using a standardized headache diary scale with a daily online link or phone call. The primary outcome was the frequency of headache episodes while fasting during the first week of Ramadan. Results: A total of 238 participants were enrolled and randomized. Of these, 173 followed the protocol (80 treated, 93 control) for at least the first day and were included in the analysis. Most participants were young and healthy, with a mean age of 32.2 ± 10.2 years. More men were included in the study (102/173; 59.0%), a small proportion of participants were smokers (31/173; 17.9%), and almost all participants reported being coffee drinkers (165/173; 95.4%); nonetheless, these characteristics were evenly distributed between the two groups in the study. The overall incidence of headache episodes was 33.0% (57/173) on day 1 and decreased to 11.3% (18/159) on day 7. On average over the 7 days, no significant effect was observed for the treatment on the incidence of headache, as the findings from the generalized estimating equation model indicated (β = −0.398, p = 0.084; odds ratio = 0.67, 95% confidence interval [CI] 0.42–1.06). Moreover, there was initially no significant difference in the incidence of headache episodes between the treatment and control groups. However, the treatment group had significantly fewer headache episodes during fasting than the control group on day 3 (4/72 [5.6%] vs. 15/91 [16.5%], p = 0.031; relative risk [RR] = 0.34, 95% CI 0.12–0.97) and day 6 (5/69 [7.2%] vs. 20/90 [22.2%], p = 0.010; RR = 0.33, 95% CI 0.13–0.82). No adverse effects were observed during the study period. Conclusion: No significant differences were observed in the occurrence of fasting headaches between the two groups on most days during the study period. Additional studies are required to address fasting headaches during the first week of Ramadan. Plain Language Summary: Ramadan is a month in which millions of Muslims fast from dawn to dusk; however, fasting during the day (e.g., for 13 hours) may cause headache and discourage individuals from this spiritual practice and can impact normal productivity, especially during the first week as the body adapts. We tested whether taking extended‐release paracetamol before fasting in the morning could avert fasting‐induced headache. Extended‐release paracetamol can be partially beneficial in delaying, but not necessarily preventing, fasting‐induced headache. [Correction added on 12th September 2024, after the first online publication: The Plain Language Summary has been updated.] [ABSTRACT FROM AUTHOR]

Objective: To estimate the number needed to treat and cost per additional responder for atogepant and rimegepant versus placebo for the preventive treatment of episodic migraine (EM) in the United States. Background: Migraine has an enormous impact on a person's daily activities and quality of life, and results in significant clinical and economic burden to both individuals and society. It is important to understand the comparative efficacy and economic value of oral calcitonin gene–related peptide receptor antagonists (gepants) for preventive treatment of EM. Currently, atogepant and rimegepant are US Food and Drug Administration approved for preventive treatment of migraine (rimegepant for EM and atogepant for EM and for chronic migraine). In the absence of head‐to‐head trials, we utilized an indirect treatment comparison on efficacy data from clinical trials conducted for the preventive treatment of EM. We estimated number needed to treat, a valuable metric used in clinical practice to compare treatment efficacy, and cost per additional responder, which can be used to establish the cost effectiveness of a treatment. Methods: An indirect treatment comparison was conducted to compare the efficacy of atogepant 60 mg once daily and rimegepant 75 mg once every other day as preventive treatments for EM using published data from the registrational trials of atogepant (ADVANCE) and rimegepant (BHV3000‐305). The efficacy outcome of interest was ≥50% reduction from baseline in mean monthly migraine/headache days (≥50% responder rate), which was variably defined for a base case and two scenario analyses. Number needed to treat and cost per additional responder versus placebo were calculated and compared between both treatments (weeks 9–12 in the base case analysis; weeks 1–12 and 9–12 for atogepant and during weeks 9–12 for rimegepant in the scenario analyses). Results: In the base case analysis, ≥50% responder rates were 64.9% (95% confidence interval [CI], 53.9–74.5) for atogepant and 51.8% (95% CI, 42.9–60.6) for rimegepant, compared to 44.1% (95% CI, 39.4–49.0) for placebo. The median number needed to treat versus placebo in the base case scenario was 4.8 (95% CI, 3.1–9.0) for atogepant compared to 13.0 (95% CI, 5.9–75.1) for rimegepant. The cost per additional responder versus placebo in the base case scenario was estimated to be $15,823 (95% CI, $11,079–$29,516) for atogepant compared to $73,029 (95% CI, $32,901–$422,104) for rimegepant. Results of the two scenario analyses were consistent with the base case analysis. Conclusions: Atogepant had substantially lower numbers needed to treat and costs per additional responder versus placebo than rimegepant for the preventive treatment of EM across all evaluated scenarios. These analyses suggest that atogepant may be more cost effective than rimegepant for the preventive treatment of EM. Limitations include differences in inclusion/exclusion criteria and in reporting of the ≥50% responder rates between trials. Plain Language Summary: No trials have directly compared atogepant to rimegepant for prevention of episodic migraine, so we used data from published clinical trials to conduct an indirect treatment comparison of these two medicines, estimate the number of patients needed to achieve at least a 50% migraine day reduction, and determine the cost of treatment per additional responder. Our results suggested that 5 patients would need to be treated with atogepant to achieve at least a 50% migraine day reduction, compared to 13 with rimegepant. We also estimated that treatment with rimegepant would cost approximately $60,000 more than treatment with atogepant to achieve a ≥50% reduction in migraine days for one patient. [ABSTRACT FROM AUTHOR]

Objective: To qualitatively and quantitatively summarize the evidence for the use of onabotulinumtoxinA injections in children and adolescents with migraine. Background: There are limited evidence‐based treatment options for youth with migraine, especially youth with chronic migraine (CM). OnabotulinumtoxinA injections are an established evidence‐based treatment for adults with CM. While several studies have assessed their safety and efficacy among adolescents with CM, there are no published systematic reviews summarizing the pediatric evidence. Methods: We carried out a systematic review, reported according to the Preferred Reporting Items for Systematic Review and Meta‐Analysis, aiming to identify studies that included five or more children and adolescents aged ≤18 years with a diagnosis of migraine, who were treated with ≥50 units (U) of onabotulinumtoxinA and had outcomes assessed ≥4 weeks after one or more injection cycle. Both observational studies and randomized controlled trials (RCTs) were eligible for inclusion. Two investigators independently carried out the first (titles and abstracts) and second (full text) screening stages, as well as data extraction and quality appraisal. The American Academy of Neurology risk of bias grading scheme was used to assess study risk of bias. Studies with adequate data were pooled using random effects meta‐analyses, and Hedge's g standardized mean differences with 95% confidence intervals (CIs) were generated to estimate the effect sizes of the continuous outcomes included. Studies lacking data required for meta‐analysis were summarized qualitatively. Results: We screened 634 studies and included 14 studies comprising 491 participants, of whom 489 had CM. Two studies were RCTs, 12 were observational uncontrolled studies, and all but one study included only youth with CM. Five Class IV observational uncontrolled studies were amenable to pooling in meta‐analyses. After a mean of 2–2.6 injection cycles, headache frequency was shown to decrease significantly after treatment with onabotulinumtoxinA (Hedge's g = 0.97, 95% CI 0.58–1.35; p < 0.0001), as did severity (Hedge's g = 1.24, 95% CI 0.55–1.94; p = 0.0005), with both estimates having a large effect size magnitude. A Class I parallel‐group RCT of one injection series (155 U, 74 U, or placebo), powered to detect a change in 4 headache days per month, did not find outcome differences between the active and placebo treatment arms. A Class IV crossover RCT showed superiority of active (155 U) versus placebo injections. The remaining Class IV observational studies that were excluded from the meta‐analyses all showed improved outcomes with onabotulinumtoxinA injections over time. No serious adverse events related to treatment occurred. Conclusion: OnabotulinumtoxinA injections have established safety for use in children and adolescents with CM and are likely effective in reducing headache frequency and severity over time. However, in the absence of an adequately powered parallel‐group RCT assessing the efficacy of multiple injection cycles, it remains unclear if this intervention is superior to placebo. Plain Language Summary: The results of our review suggest that onabotulinumtoxinA injections are safe and that they are likely effective for children and adolescents with chronic migraine. However, the available research is generally biased because of study design issues, and it is still uncertain if onabotulinumtoxinA injections have benefits above and beyond the benefits of placebo injections for children and adolescents. Better‐designed research is required to understand if onabotulinumtoxinA injections are more effective than placebo injections in treating children and adolescents with chronic migraine. [ABSTRACT FROM AUTHOR]

Objective: To apply the 2019 joint American Academy of Neurology (AAN) and American Headache Society (AHS) quality measures for headache management to a cohort of neurology resident physicians and then assess outcomes related to guideline adherence. Background: The optimization of headache management is essential to reduce both the individual and systemic impact of these disorders. In 2014, the AAN developed 10 quality measures for evidence‐based management of patients with headache. A workgroup updated and condensed its headache quality measures in 2019, narrowing the set to six measurements, four of which would primarily focus on the management of migraine and two of which would address the management of cluster headache. Methods: This quality improvement study was conducted using a pretest‐posttest study design. A pre‐intervention survey based on retrospective analysis of five clinic notes for adherence to the measures was designed and distributed to all neurology residents (n = 32) at a large, academic tertiary referral center. The intervention included the creation of an electronic medical record template to aid residents in following the measures during clinical encounters, as well as the provision of direct feedback based on pre‐intervention results. Finally, a post‐intervention survey was distributed for completion based on notes written during the intervention period. Analysis was limited to migraine, given the low percentage of cluster headache seen in clinic. Results: An increase in adherence was seen in three of the four migraine‐related quality measures, with the Use of Abortive Medications for Migraine and Documentation of Counseling on Modifiable Lifestyle and Chronification Factors demonstrating statistically significant improvements (75.8% to 88.0% [p = 0.013] and 83.9% to 94.0% [p = 0.029] adherence, respectively). For secondary outcomes, the increase in the utilization of appropriate diagnostic criteria (82.6% to 93.2%, p = 0.018) was significant, and the self‐assessed confidence rating for adherence to guidelines was significant (p < 0.001). Conclusions: This study provides evidence that the quality improvement intervention led to increased adherence to the AAN and AHS migraine‐related measures. It is anticipated that increased adherence may lead to improved patient outcomes. Plain Language Summary: In 2019, the American Academy of Neurology and the American Headache Society worked together to create a set of quality measures to guide clinicians in the care of patients with headache; however, we do not know if these guidelines are being followed. This study aimed to see if resident neurologists at a large academic medical center would better follow these guidelines if they were part of a standardized electronic medical record template. Overall, this study showed that applying the headache quality measures in a real clinical setting is feasible and can improve best‐care practices. [ABSTRACT FROM AUTHOR]

Rosai-Dorfman disease (RDD) with craniocervical junction involvement is a rare clinical entity. We present herein a case of a pediatric patient with craniocervical junction RDD which was surgically treated. A 10-year-old female with a history of B-cell acute lymphoblastic leukemia (B-ALL) in remission and RDD presented with frontal migraine headaches. She previously had a right posterior chest wall lesion which was biopsy-proven RDD. She was found on imaging to have a dural-based right craniocervical junction lesion. Given her history of B-ALL, after a multidisciplinary discussion, the decision was made to proceed with resection with possible initiation of cobimetinib or clofarabine. The patient underwent a suboccipital craniotomy, C1 laminectomy, and resection of the dural-based lesion. Gross total resection was achieved, and histopathology confirmed the diagnosis of RDD. She was discharged home on postoperative day 4. No recurrence was seen on follow-up imaging at 3 months. We conducted a systematic literature review examining all cases of pediatric intracranial RDD and all cases of craniocervical junction RDD. This represents, to the best of our knowledge, only the second case of pediatric craniocervical junction RDD. Although RDD is often self-limiting, medical treatment is often considered for intracranial disease, but tissue confirmation is necessary. Surgical resection provides histopathologic diagnosis and can sometimes serve as definitive treatment for a particular lesion. [ABSTRACT FROM AUTHOR]

Persistent activation and increased mechanical responsiveness of nociceptive neurons that innervate the cranial meninges are considered to be the key processes underlying migraine pain genesis. Meningeal neurogenic inflammation involving neuropeptide-driven neurovascular and neuroimmune interactions likely drives meningeal nociceptors in migraine. Meningeal arteries may directly activate sensitized meningeal nociceptors during vasodilatation or indirectly via local elaboration of pro-nociceptive mediators. In migraine with aura, nociceptive molecules generated in the cortex in response to cortical spreading depolarization (CSD) could activate and sensitize meningeal nociceptors directly or indirectly via an axon reflex and neurogenic inflammation. Migraine treatments target sensory neuropeptides and receptors located in meningeal vascular, immune, neuronal, and glial cells. Migraine is a highly prevalent and disabling pain disorder that affects >1 billion people worldwide. One central hypothesis points to the cranial meninges as a key site underlying migraine headache genesis through complex interplay between meningeal sensory nerves, blood vessels, and adjacent immune cells. How these interactions might generate migraine headaches remains incompletely understood and a subject of much debate. In this review we discuss clinical and preclinical evidence supporting the concept that meningeal sterile inflammation, involving neurovascular and neuroimmune interactions, underlies migraine headache genesis. We examine downstream signaling pathways implicated in the development of migraine pain in response to exogenous events such as infusing migraine-triggering chemical substances. We further discuss cortex-to-meninges signaling pathways that could underlie migraine pain in response to endogenous events, such as cortical spreading depolarization (CSD), and explore future directions for the field. [ABSTRACT FROM AUTHOR]

Atogepant, an oral calcitonin gene‐related peptide receptor antagonist, is approved for the preventive treatment of migraine. A phase 1, open‐label, single‐dose, 2‐period crossover study evaluated the effect of a high‐fat meal on the pharmacokinetics and safety of atogepant in 20 healthy adults. Administration of atogepant 60 mg immediate‐release (IR) tablets under fed conditions reduced the area under the plasma concentration‐time curve (AUC) from 0 to time t and from 0 to time infinity by approximately 18% and reduced the maximum plasma concentration (Cmax) by 22%. The 90% confidence intervals for the geometric mean ratios of Cmax and AUC were not contained within the bioequivalence limits of 80%‐125%. There was no change in the median time to maximum plasma concentration in the fed versus fasted state. The incidence of treatment‐emergent adverse events (TEAEs) was similar between fed and fasted conditions. Four TEAEs were considered related to study intervention and were reported after participants received atogepant under fasted conditions (3 participants). A single‐dose atogepant 60 mg IR tablet was safe and tolerated under both fed and fasted states. Due to the wide effective dose range of 10‐60 mg/day for atogepant for the preventive treatment of migraine, the food effect on its pharmacokinetics is not considered clinically relevant. [ABSTRACT FROM AUTHOR]

Aims: In this study, we aimed to evaluate the relationship between the dietary inflammatory index (DII) and mental health outcomes among patients with migraine headaches. Methods: In this cross-sectional study, 262 subjects were included. The dietary intakes were collected using a validated 168-item semi-quantitative food frequency questionnaire. Items were scored according to their inflammatory potential, so a higher DII indicated a more pro-inflammatory diet. The association between DII and the mental health of participants was investigated using multinomial logistic regression and odds ratio (OR) with a corresponding 95% confidence interval (CI) was reported. Results: Overall, 224 women and 38 men, with a mean (standard error) DII of −2.96 (0.06), age of 36.1 (0.53) years, and BMI of 25.55 (0.21) kg/m2, comprised our study population. DII was positively associated with a higher risk of depression in patients with the highest adherence to a pro-inflammatory diet compared to those with the lowest adherence (OR = 1.76; 95%CI: 1.04, 3.00; Ptrend = 0.035). Adjustments for age, sex, marital status, smoking status, migraine headache index score, number of family members, mean arterial pressure, medication, physical activity, and BMI intensified the association in a way that the risk of depression was 2.03 times higher in patients with the highest adherence to a pro-inflammatory diet compared to those with the lowest adherence to a pro-inflammatory diet (OR = 2.03; 95%CI: 1.18, 3.49; Ptrend = 0.011). Conclusion: Our findings suggest that depression was positively associated with adherence to a pro-inflammatory diet. However, no significant association was observed between anxiety and stress with DII. [ABSTRACT FROM AUTHOR]

Migraine is a disabling neurological disorder that affects more than one billion people worldwide. The clinical presentation is characterized by recurrent headache attacks, which are often accompanied by photophobia, phonophobia, nausea and vomiting. Although the pathogenesis of migraine remains incompletely understood, mounting evidence suggests that specific signalling molecules are involved in the initiation and modulation of migraine attacks. These signalling molecules include pituitary adenylate cyclase-activating polypeptide (PACAP), a vasoactive peptide that is known to induce migraine attacks when administered by intravenous infusion to people with migraine. Discoveries linking PACAP to migraine pathogenesis have led to the development of drugs that target PACAP signalling, and a phase II trial has provided evidence that a monoclonal antibody against PACAP is effective for migraine prevention. In this Review, we explore the molecular and cellular mechanisms of PACAP signalling, shedding light on its role in the trigeminovascular system and migraine pathogenesis. We then discuss emerging therapeutic strategies that target PACAP signalling for the treatment of migraine and consider the research needed to translate the current knowledge into a treatment for migraine in the clinic. Pituitary adenylate cyclase-activating polypeptide signalling has been linked to migraine pathogenesis. In this Review, Ashina and co-workers explore the molecular and cellular mechanisms of pituitary adenylate cyclase-activating polypeptide signalling and discuss emerging therapeutic strategies to target this pathway for migraine treatment. Key points: Pituitary adenylate cyclase-activating polypeptide (PACAP) signalling has been identified as an important pathogenic contributor to migraine, supported by evidence from both animal and human studies. PACAP causes vasodilation and influences immune cell recruitment and activation, which are processes implicated in the pathophysiology of migraine. Intravenous infusion of PACAP can induce migraine attacks in humans, highlighting its direct role in migraine pathogenesis. A monoclonal antibody against PACAP signalling has shown promise in a phase II trial for migraine prevention, indicating potential therapeutic benefits. The complexity of the role that PACAP has in migraine is underscored by its interaction with multiple receptors and the trigeminovascular system; further research is needed to fully understand the therapeutic potential of targeting PACAP signalling. [ABSTRACT FROM AUTHOR]