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BackgroundThe migraine attack is classically divided into the prodromal, aura, headache and postdromal phase. Previous studies have highlighted non-headache symptoms associated with migraine occurring during the prodromal or postdromal phase. This study aimed to track the evolution of non-headache symptoms throughout all phases of the migraine attack. We also wished to delineate the phenotype of patients with more symptomatic migraine episodes and explore the association between non-painful symptoms and migraine disease activity and patients’ disability.MethodsTwo-hundred and twenty-five migraine patients were enrolled and were asked to recall retrospectively whether non-headache symptoms occurred during the prodromal, headache and postdromal phase of their attacks. The occurrence of symptoms during the different migraine phases was tested using the Cochran’s Q tests, Cohen’s and Fleiss’ kappa. Differences between groups according to the presence of non-headache symptoms through the entire migraine attack and correlations between the frequency of non-headache symptoms experienced during all phases and patients’ disease activity and disability were also assessed.ResultsNinety-nine percent of patients reported having at least one non-headache symptom in one phase of the migraine attack and 54% of patients had at least one non-headache symptom occurring during all phases of migraine. The occurrence of non-headache symptoms was different throughout the three phases of migraine, being higher during the headache phase than during the prodromal and postdromal phases. Symptoms with the highest co-occurrence throughout all migraine phases were neck stiffness, thirst and abdominal pain. Patients who experienced non-headache symptoms during all three phases of migraine were more frequently females, had a higher disability, were suffering from chronic migraine and had more frequently medication overuse headache.ConclusionMigraine is a complex neurological disorder with a wide constellation of non-headache symptoms that can affect the burden of the disease. A better characterization of the evolution of non-headache symptoms through the different phases of migraine can enrich our knowledge on migraine pathophysiology and improve the management of the disease.

Background and objectivesThe identification of predictors of response to antiCGRP mAbs could favor tailored therapies and personalized treatment plans. This study is aimed at investigating predictors of ≥ 50%, ≥ 75% and 100% response at 24 weeks in patients with high-frequency episodic (HFEM: 8–14 days/month) or chronic migraine (CM).MethodsThis is a large, multicenter, cohort, real-life study. We considered all consecutive adult patients affected by HFEM or CM who were prescribed antiCGRP mAbs for ≥ 24 weeks in 20 headache centers. Patients were interviewed face-to-face using a shared semi-structured questionnaire carefully exploring socio-demographic and clinical characteristics. Patients received subcutaneous erenumab (70 mg or140 mg, monthly), galcanezumab (120 mg monthly, following a 240 mg loading dose), or fremanezumab (225 mg, monthly or 675 mg, quarterly) according to drug market availability, physician’s choice, or patient’s preference. The primary endpoint of the study was the assessment of ≥ 50% response predictors at 24 weeks. Secondary endpoints included ≥ 75% and 100% response predictors at 24 weeks.ResultsEight hundred sixty-four migraine patients had been treated with antiCGRP mAbs for ≥ 24 weeks (erenumab: 639 pts; galcanezumab: 173 pts; fremanezumab: 55 pts). The ≥50% response (primary endpoint) in HFEM was positively associated with unilateral pain (UP) + unilateral cranial autonomic symptoms (UAs) (OR:4.23, 95%CI:1.57–11.4; p = 0.004), while in CM was positively associated with UAs (OR:1.49, 95%CI:1.05–2.11; p = 0.026), UP + UAs (OR:1.90, 95%CI:1.15–3.16; p = 0.012), UP + allodynia (OR:1.71, 95%CI:1.04–2.83; p = 0.034), and negatively associated with obesity (OR:0.21, 95%CI:0.07–0.64; p = 0.006). The 75% response (secondary endpoint) was positively associated with UP + UAs in HFEM (OR:3.44, 95%CI:1.42–8.31; p = 0.006) and with UP + UAs (OR:1.78, 95%CI:1.14–2.80; p = 0.012) and UP + allodynia (OR:1.92, 95%CI:1.22–3.06; p = 0.005) in CM. No predictor of 100% response emerged in patients with HFEM or CM.ConclusionsA critical evaluation of headache characteristics indicating peripheral or central sensitization may help in predicting responsiveness to antiCGRP mAbs in HFEM and CM. A more precise pain profiling may represent a steppingstone for a mechanism-based approach and personalized treatment of migraine with compounds targeting specific molecular mechanisms.

The Internet Addiction Test (IAT) by Kimberly Young is one of the most utilized diagnostic instruments for Internet addiction. Although many studies have documented psychometric properties of the IAT, consensus on the optimal overall structure of the instrument has yet to emerge since previous analyses yielded markedly different factor analytic results. The objective of this study was to evaluate the psychometric properties of the Italian version of the IAT, specifically testing the factor structure stability across cultures. In order to determine the dimensional structure underlying the questionnaire, both exploratory and confirmatory factor analyses were performed. The reliability of the questionnaire was computed by the Cronbach alpha coefficient. Data analyses were conducted on a sample of 485 college students (32.3%, 157/485 males and 67.7%, 328/485 females) with a mean age of 24.05 years (SD 7.3, range 17-47). Results showed 176/485 (36.3%) participants with IAT score from 40 to 69, revealing excessive Internet use, and 11/485 (1.9%) participants with IAT score from 70 to 100, suggesting significant problems because of Internet use. The IAT Italian version showed good psychometric properties, in terms of internal consistency and factorial validity. Alpha values were satisfactory for both the one-factor solution (Cronbach alpha=.91), and the two-factor solution (Cronbach alpha=.88 and Cronbach alpha=.79). The one-factor solution comprised 20 items, explaining 36.18% of the variance. The two-factor solution, accounting for 42.15% of the variance, showed 11 items loading on Factor 1 (Emotional and Cognitive Preoccupation with the Internet) and 7 items on Factor 2 (Loss of Control and Interference with Daily Life). Goodness-of-fit indexes (NNFI: Non-Normed Fit Index; CFI: Comparative Fit Index; RMSEA: Root Mean Square Error of Approximation; SRMR: Standardized Root Mean Square Residual) from confirmatory factor analyses conducted on a random half subsample of participants (n=243) were satisfactory in both factorial solutions: two-factor model (χ²₁₃₂= 354.17, P<.001, χ²/df=2.68, NNFI=.99, CFI=.99, RMSEA=.02 [90% CI 0.000-0.038], and SRMR=.07), and one-factor model (χ²₁₆₉=483.79, P<.001, χ²/df=2.86, NNFI=.98, CFI=.99, RMSEA=.02 [90% CI 0.000-0.039], and SRMR=.07). Our study was aimed at determining the most parsimonious and veridical representation of the structure of Internet addiction as measured by the IAT. Based on our findings, support was provided for both single and two-factor models, with slightly strong support for the bidimensionality of the instrument. Given the inconsistency of the factor analytic literature of the IAT, researchers should exercise caution when using the instrument, dividing the scale into factors or subscales. Additional research examining the cross-cultural stability of factor solutions is still needed.

BackgroundHeadache disorders are a global public health concern affecting diverse populations. This review examines headache service organizations in low-, middle-, and high-income countries. It addresses global challenges in pharmacological headache treatment, with a focus on safety, tolerability, reproductive and child health, and outlines disparities in accessing innovative treatments worldwide.Main bodyOrganized headache services are essential due to the wide prevalence and varying severity of headache disorders. The tiered headache service model is globally recognized, although its implementation varies based on financial and workforce considerations. Headache burden affects well-being, causing disability, economic challenges, and work limitations, irrespective of location or income. All nations still require improved diagnosis and treatment, and the majority of countries face obstacles including limited access, awareness, economic barriers, and inadequate health policies. Provided adequate internet availability, telemedicine could help improve health equity by expanding access to headache care, since it can offer patients access to services without lengthy waiting times or extensive travel and can provide healthcare unavailable in underserved areas due to staff shortages.Numerous health disparities restrict global access to many headache medications, especially impacting individuals historically excluded from randomized controlled trials, such as those with cardiovascular and cerebrovascular conditions, as well as pregnant women. Furthermore, despite advancements in researching migraine treatments for young patients, the options for treatment remain limited.Access to headache treatment relies on factors like medication availability, approval, financial coverage, and healthcare provider expertise. Inadequate public awareness leads to neglect by policymakers and undertreatment by patients and healthcare providers. Global access discrepancies are exacerbated by the introduction of novel disease-specific medications, particularly impacting Asian, African, and Latin American nations excluded from clinical trials. While North America and Europe experience broad availability of migraine treatments, the majority of countries worldwide lack access to these therapies.ConclusionsHealthcare disparities, treatment access, and medication availability are concerning issues in headache medicine. Variations in national healthcare systems impact headache management, and costly innovative drugs are widening these gaps. Healthcare practitioners and experts should acknowledge these challenges and work towards minimizing access barriers for equitable global headache care in the future.

Despite that it is commonly accepted that migraine is a disorder of the nervous system with a prominent genetic basis, it is comorbid with a plethora of medical conditions. Several studies have found bidirectional comorbidity between migraine and different disorders including neurological, psychiatric, cardio- and cerebrovascular, gastrointestinal, metaboloendocrine, and immunological conditions. Each of these has its own genetic load and shares some common characteristics with migraine. The bidirectional mechanisms that are likely to underlie this extensive comorbidity between migraine and other diseases are manifold. Comorbid pathologies can induce and promote thalamocortical network dysexcitability, multi-organ transient or persistent pro-inflammatory state, and disproportionate energetic needs in a variable combination, which in turn may be causative mechanisms of the activation of an ample defensive system with includes the trigeminovascular system in conjunction with the neuroendocrine hypothalamic system. This strategy is designed to maintain brain homeostasis by regulating homeostatic needs, such as normal subcortico-cortical excitability, energy balance, osmoregulation, and emotional response. In this light, the treatment of migraine should always involves a multidisciplinary approach, aimed at identifying and, if necessary, eliminating possible risk and comorbidity factors.

Artificial intelligence (AI) is revolutionizing the field of biomedical research and treatment, leveraging machine learning (ML) and advanced algorithms to analyze extensive health and medical data more efficiently. In headache disorders, particularly migraine, AI has shown promising potential in various applications, such as understanding disease mechanisms and predicting patient responses to therapies. Implementing next-generation AI in headache research and treatment could transform the field by providing precision treatments and augmenting clinical practice, thereby improving patient and public health outcomes and reducing clinician workload. AI-powered tools, such as large language models, could facilitate automated clinical notes and faster identification of effective drug combinations in headache patients, reducing cognitive burdens and physician burnout. AI diagnostic models also could enhance diagnostic accuracy for non-headache specialists, making headache management more accessible in general medical practice. Furthermore, virtual health assistants, digital applications, and wearable devices are pivotal in migraine management, enabling symptom tracking, trigger identification, and preventive measures. AI tools also could offer stress management and pain relief solutions to headache patients through digital applications. However, considerations such as technology literacy, compatibility, privacy, and regulatory standards must be adequately addressed. Overall, AI-driven advancements in headache management hold significant potential for enhancing patient care, clinical practice and research, which should encourage the headache community to adopt AI innovations. Graphical Abstract

In an fMRI study, Baksa et al. found that different circadian peaks of migraine attack onset are associated with different interictal brain activity in response to threatening fearful stimuli. [...]considering the plethora of pathologies with which migraine, especially when it evolves into a chronic form, is comorbid (see Altamura et al.), we think it is time to move from the original definition of migraine as a “disease” to the definition of a “migraine syndrome,” which incorporates both the pain manifestation and the parade of central and systemic symptoms and pathologies with which it shares comorbidity. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Combination treatments for migraine prophylaxis present a promising approach to addressing the diverse and complex mechanisms underlying migraine. This review explores the potential of combining oral conventional prophylactics, onabotulinumtoxin A, monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway, and small molecule CGRP receptor antagonists (gepants). Among the most promising strategies, dual CGRP inhibition through mAbs and gepants may enhance efficacy by targeting both the CGRP peptide and its receptor, while the combination of onabotulinumtoxin A with CGRP treatments offers synergistic pain relief. Oral non-CGRP treatments, which are accessible and often prescribed for patients with comorbid conditions, provide an affordable and practical option in combination regimens. Despite the potential of these combinations, there is a lack of evidence to support their widespread inclusion in clinical guidelines. The high cost of certain combinations, such as onabotulinumtoxin A with a CGRP mAb or dual anti-CGRP mAbs, presents feasibility challenges. Further large-scale trials are needed to establish safe and effective combination protocols and solidify their role in clinical practice, particularly for treatment-resistant patients. Graphical Abstract

BackgroundMonoclonal antibodies anti-calcitonin gene-related peptide (mAbs anti-CGRP) pathway are effective and safe on migraine prevention. However, some drug agencies limited these treatments to one year due to their high costs. This study aimed at evaluating the effect of discontinuing mAbs anti-CGRP on monthly migraine days (MMDs) and disability in high-frequency episodic (HFEM) and chronic migraine (CM) patients.MethodsThis observational longitudinal cohort study was conducted at 10 Italian headache centres. Consecutive adult patients were followed-up for three months (F-UP1–3) after discontinuation of a one-year erenumab/galcanezumab treatment. The primary endpoint was the change in F-UP MMDs. Secondary endpoints included variation in pain intensity (Numerical Rating Scale, NRS), monthly acute medication intake (MAMI), and HIT-6 scores. We also assessed from F-UP1 to 3 the ≥50% response rate, relapse rate to CM, and recurrence of Medication Overuse (MO).ResultsWe enrolled 154 patients (72.1% female, 48.2 ± 11.1 years, 107 CM, 47 HFEM); 91 were treated with erenumab, 63 with galcanezumab. From F-UP1 to F-UP3, MMDs, MAMI, NRS, and HIT-6 progressively increased but were still lower at F-UP3 than baseline (Friedman’s analysis of rank, p < .001). In the F-UP1–3 visits, ≥50% response rate frequency did not differ significantly between CM and HFEM patients. However, the median reduction in response rate at F-UP3 was higher in HFEM (− 47.7% [25th, − 79.5; 75th,-17.0]) than in CM patients (− 25.5% [25th, − 47.1; 75th, − 3.3]; Mann-Whitney U test; p = .032). Of the 84 baseline CM patients who had reverted to episodic migraine, 28 (33.3%) relapsed to CM at F-UP1, 35 (41.7%) at F-UP2, 39 (46.4%) at F-UP3. Of the 64 baseline patients suffering of medication overuse headache ceasing MO, 15 (18.3%) relapsed to MO at F-UP1, 26 (31.6%) at F-UP2, and 30 (42.3%, 11 missing data) at F-UP3. Lower MMDs, MAMI, NRS, and HIT-6 and higher response rate in the last month of therapy characterized patients with ≥50% response rate at F-UP1 and F-UP3 (Mann-Whitney U test; consistently p < .01).ConclusionMigraine frequency and disability gradually increased after mAbs anti-CGRP interruption. Most patients did not relapse to MO or CM despite the increase in MMDs. Our data suggest to reconsider mAbs anti-CGRP discontinuation.

Background and aim “Other primary headaches” is a group of heterogeneous headache disorders described in Chapter 4 of the third edition of the International Classification of Headache Disorders (ICHD-III). Due to the limited number of cases, most of these disorders are considered rare and represent a diagnostic and therapeutic challenge for clinicians and headache specialists. To increase knowledge, improve their recognition, and foster research on these rare headache disorders, this review provides a comprehensive up-to-date description of their hallmarks, including epidemiologic data, key clinical characteristics, proposed pathophysiological mechanisms, and suggested treatments. Principal findings Diagnosing rare headache disorders is challenging. A few key clinical features can help improve their recognition and distinction. These include identifying a specific trigger or stimulus for headache development such as cough, exercise, or sexual activity, a particular pattern of onset or recurrence, like for hypnic headache, primary thunderclap headache, or new daily persistent headache, or a unique scalp location for the pain such as for nummular headache or epicrania fugax. These clinical details are crucial for narrowing the differential diagnosis and making the correct diagnosis. However, regardless of the specificity of the clinical presentation, secondary causes must be ruled out when facing patients with these rare clinical presentations. Limited evidence on the pathophysiology and treatment of these disorders is available, and high-quality studies are lacking. Conclusions Accurate diagnosis and additional research on these rare headache disorders are needed. Multicenter and international collaborations within the framework of international headache societies and among tertiary headache centers are key to developing efficient and high-quality registries and databases. Additionally, clinical trials are needed to develop evidence supporting the treatments current in use and to address the unmet needs of these rare diseases. Only through these efforts it will be possible to design specific studies to increase our understanding of these rare disorders and improve the quality of life of individuals living with these conditions.