INTRODUCTION:Migraine is a disabling neurological disorder often mismanaged, with only a minority of individuals receiving a timely correct diagnosis and appropriate treatment. The aim of this work was to establish consensus-based indications for improving the management of individuals with migraine and optimizing their journey from general practice to specialist care. METHODS:A panel of 17 Italian experts, including neurologists, pharmacologists, and general practitioners (GPs) assessed a total of 36 statements addressing migraine diagnosis and management in primary care, referral pathways, and long-term care through the Delphi methodology. RESULTS:The panel endorsed the role of GPs in the early identification and management of migraine, emphasizing the use of validated screening tools and headache diaries as well as the adoption of structured care pathways, where available, to ensure consistent and effective management. Specialist referral was emphasized for chronic migraine, medication overuse, or for individuals with inadequate response to preventive therapies. The panel advocated for a shared, long-term care model grounded in dynamic, bidirectional collaboration across healthcare levels to reduce the burden on tertiary headache centers. CONCLUSION:This consensus provides practical, context-specific guidance to facilitate care of migraine across primary and specialist care. Proper implementation of this model may streamline the management of individuals with migraine, reduce diagnostic delays, prevent unnecessary costs, and ultimately guide the development of a coordinated migraine care model in Italy.

Medication-overuse headache (MOH) is a prevalent and disabling secondary headache disorder that arises in individuals with a pre-existing primary headache as a consequence of regular overuse of acute medications. Increasing evidence suggests that MOH shares fundamental pathophysiological and behavioural features with nociplastic pain conditions, supporting the view that it cannot be explained solely as a pharmacological complication. Rather, MOH appears to reflect complex interactions between neurobiological vulnerability, maladaptive neuroplasticity, and behavioural factors. In this review, we reappraise MOH through the lens of nociplastic pain to provide a unifying framework for its pathophysiology and management. Evidence from neuroimaging, neurophysiological, genetic, and experimental studies consistently indicates that MOH is associated with central sensitization, impaired descending pain modulation, and dysfunction of reward and cognitive control networks, particularly involving fronto-striatal and brainstem circuits. These alterations closely resemble those observed in other nociplastic pain conditions and appear largely reversible following successful withdrawal and preventive treatment. Behavioural features such as craving, impulsivity, catastrophizing, and cephalalgiophobia play a pivotal role in maintaining medication overuse and predicting poor outcomes, reinforcing the conceptualization of MOH as a biobehavioural syndrome. Management strategies have evolved from detoxification-centered approaches toward integrated, patient-centered care. While withdrawal remains a cornerstone of treatment, growing evidence supports flexible strategies in which preventive therapies, especially CGRP-targeting monoclonal antibodies and gepants, can be initiated before or alongside withdrawal, reducing headache burden and facilitating disengagement from acute medication overuse. Behavioural and psychological interventions, including cognitive behavioural therapy and mindfulness-based approaches, are essential to address emotional drivers, enhance adherence, and modulate nociplastic mechanisms. Current guidelines increasingly endorse multimodal and multidisciplinary management, although evidence quality remains heterogeneous. Reframing MOH within a nociplastic pain framework supports a shift from rigid detoxification models toward personalized, mechanism-based, and multidisciplinary care. Future research integrating clinical, imaging, neurobiological, and behavioural markers, potentially supported by artificial intelligence–based predictive models, may further refine patient stratification and optimize long-term outcomes in MOH.

Long-term (> 24 weeks) real-world evidence of eptinezumab’s effectiveness is limited. We evaluated ≥ 50

Background: Migraine in older adults represents an increasingly relevant yet underrecognized clinical challenge in aging societies, where multimorbidity, frailty, and polypharmacy complicate both diagnosis and management. Although traditionally considered a disorder of younger individuals, migraine frequently persists or presents after the age of 60 with atypical features, contributing to diagnostic uncertainty. Methods: This narrative review, conducted in accordance with the SANRA principles, aims to provide a comprehensive overview of the epidemiology, clinical presentation, pathophysiology, and management of migraine in older adults, with particular emphasis on age-related complexities, therapeutic challenges, and unmet clinical needs. Results: Migraine in this population often presents with atypical or misleading features, such as aura without headache, vestibular symptoms, or overlap with cerebrovascular conditions, leading to delayed or incorrect diagnoses. The burden of disease is substantial, affecting physical function, mobility, cognition, emotional well-being, and social participation, and is further amplified by comorbid conditions including cardiovascular and metabolic disorders, mood disturbances, and chronic pain syndromes. Aging-related neurobiological changes, such as impaired pain modulation, endothelial dysfunction, and neuroinflammation, may influence disease expression and treatment response. Therapeutic management is challenged by contraindications, increased susceptibility to adverse drug effects, and the complexity of polypharmacy, highlighting the importance of individualized and non-pharmacological approaches. Conclusions: Migraine in older adults is a significant but often overlooked contributor to disability and reduced quality of life. Improved recognition of its unique clinical features and age-specific vulnerabilities is essential to optimize patient-centered care. Future research should prioritize the inclusion of older populations and the development of tailored, safe, and effective management strategies.

BACKGROUND AND OBJECTIVES:fMRI has proven useful in dissecting the neurobiological underpinnings of migraine. However, the existing evidence is limited by small samples, use of suboptimal statistical thresholds, and different methods of clinical data acquisition. Given these limitations, we hypothesized that a large, well-characterized sample would allow a clearer distinction between resting-state functional connectivity (rs-FC) alterations specific to migraine and those related to migraine subtypes. METHODS:Adults with migraine and age-matched and sex-matched healthy controls (HCs) underwent a single 3T rs-fMRI scan. We compared rs-FC between migraine and HCs, and across migraine subtypes, using multi-voxel pattern and seed-based analysis. General linear models and analysis of covariance tests with Bonferroni-adjusted cluster-wise family-wise error correction (pFWE-Bonferroni ≤0.001) were applied. rs-FC measures, expressed as Z scores, were also compared across migraine subtypes using general linear models (pBonferroni < 0.05). RESULTS:We analyzed rs-fMRI data from 264 participants with migraine (mean age 42 ± 12 years, 234 women) and 151 HCs (mean age 41 ± 11 years, 130 women). The multi-voxel pattern analysis identified significant rs-FC differences in a cluster within the bilateral middle cingulate cortex when comparing participants with migraine to HCs (pFWE-Bonferroni <0.001). The seed-based analysis revealed that participants with migraine had increased rs-FC between the cluster in the bilateral middle cingulate cortex and both the right lateral occipital cortex and bilateral occipital pole (both pFWE-Bonferroni <0.001), compared with HCs. Furthermore, increased rs-FC was identified between the limbic lobe and the right occipital pole (pFWE-Bonferroni = 0.0014) and precuneus (pFWE-Bonferroni <0.001). The cingulate-occipital rs-FC was consistently increased in participants with migraine, irrespective of the migraine subtype (pBonferroni <0.001). In addition, ictal participants who were scanned during attacks exhibited an increased hypothalamic rs-FC with the bilateral precuneus, compared with HCs (pBonferroni <0.001). No significant associations emerged between rs-FC and clinical features in migraine. DISCUSSION:The identified rs-FC alterations between the middle cingulate cortex and occipital regions might represent a migraine-specific trait, suggesting an integration of nociceptive and visual processing. This discovery provides novel insights into the neurobiological underpinnings of migraine and proposes that altered cingulate-occipital rs-FC might serve as a potential biomarker for migraine.

BACKGROUND:Migraine and sleep disturbances share a bidirectional relationship, influencing each other's frequency and severity. The aim of this systematic review is to examine the effects of migraine-targeted interventions on both migraine outcomes and sleep parameters (including sleep quality and insomnia symptoms), as well as the effects of sleep-focused interventions on both sleep and migraine outcomes. METHODS:Following PRISMA 2020 guidelines, a systematic search was conducted across six databases (PubMed, Medline, Scopus, Embase, PsycINFO, CINAHL) for studies published until December 5, 2023. Eligible studies included Randomized Clinical Trials, Controlled Clinical Trials, and observational studies assessing migraine and/or sleep-targeted interventions in adults. The risk of bias was evaluated using RoB 2 and ROBINS-E tools. RESULTS:Twenty-three studies (1941 participants) were included. Pharmacological treatments such as erenumab, amitriptyline, propranolol, and onabotulinumtoxinA reduced migraine frequency and pain intensity, with variable effects on sleep quality. Melatonin showed no significant impact. Among non-pharmacological treatments, percutaneous electrical nerve stimulation, greater occipital nerve block, green light therapy, binaural beats, mindfulness, and dietary modifications improved both migraine symptoms and sleep. Digital Cognitive-Behavioral Therapy for Insomnia (CBT-I) significantly reduced headache days and improved sleep parameters, whereas evidence on standard CBT-I was mixed. LIMITATIONS:Study heterogeneity, small sample sizes, and variability in outcome measures limit generalizability. Few studies focused on sleep-targeted interventions and their effects on migraine, highlighting a research gap. CONCLUSIONS:Integrated approaches combining migraine and sleep interventions show promise for symptom management. Further research is needed to refine treatment strategies and assess long-term effects. REGISTRATION:CRD42024617217.

Headache is a common symptom that can be frequently caused by multiple secondary causes. Every person with headache fears to have a severe cause, and healthcare providers must be trained to identify which patients may suffer from these. This manuscript continues the series of hallmarks of headache disorders describing the state of the art regarding the pathophysiology, clinical aspects, diagnosis, red flags, biomarkers, acute treatment, and preventive therapies of secondary headache disorders. Identification of secondary headache disorders is challenging, due to the large number of different causes and varied phenotypic presentations. Prompt recognition and targeted treatment can save patients’ lives and prevent chronic sequelae. Changes in the headache phenotype or new-onset neurological or systemic symptoms may reflect the occurrence of a subsequent complication and require further investigation. In patients who develop a persistent headache following to the secondary cause a phenotypic-based acute and preventive treatment is usually recommended. Secondary headache disorders are major contributors to the global burden of headache. Their true prevalence is the hidden part of the iceberg, but their consequences are evident. Research on secondary headache disorders could be key in the understanding of primary headache disorders pathophysiology.

Migraine and cluster headache are two highly disabling primary headache disorders, each characterized by distinct clinical phases. Both conditions feature a premonitory phase that precedes the onset of pain or the emergence of cluster bouts, and the symptoms occurring during this stage may provide critical insight into their underlying pathophysiology. This narrative review aims to synthesize current evidence on the premonitory phase of migraine and cluster headache, including its clinical manifestations, neurobiological mechanisms, and potential implications for early or pre-emptive therapeutic strategies. Migraine patients frequently experience premonitory symptoms before the onset of headache, and multimodal neuroimaging indicates that migraine initiation involves coordinated functional alterations within hypothalamic–brainstem circuits. In cluster headache, premonitory phenomena can be categorized into pre-cluster symptoms, which emerge hours to days before a bout, and pre-attack symptoms, which develop minutes to an hour before an individual attack. Evidence from neuroimaging, genetic, and provocation studies implicates hypothalamic dysfunction, circadian dysregulation, and trigeminal-autonomic network activation as key mechanisms underlying the pre-attack and pre-cluster phases. Across both migraine and cluster headache, early recognition and targeted intervention during the premonitory phase may help prevent or attenuate attacks before the full cascade of nociceptive activation is initiated. The premonitory phase represents a critical window for understanding the initiation and progression of both migraine and cluster headache. Current evidence suggests that these disorders share partially overlapping neurobiological substrates, particularly involving alterations in hypothalamic function. By elucidating the mechanisms underlying these early phases, future research may help reshape the current clinical paradigm toward truly pre-emptive intervention.

The introduction of CGRP-pathway inhibitors has markedly changed the management of migraine, providing effective and well-tolerated options for many patients who were previously difficult to treat. Their overall safety profile appears favorable; however, emerging observations have prompted questions regarding possible infectious complications related to CGRP blockade. This review summarizes the available evidence on infection risk associated with CGRP-targeted therapies, integrating data from randomized clinical trials, post-marketing pharmacovigilance, and experimental immunological studies. While no consistent signal of increased infections has been observed in controlled trials, real-world data and mechanistic considerations suggest that interference with CGRP pathways might, under certain conditions, influence host immune defense. Although infections remain uncommon, awareness of this potential risk is important, particularly in patients with pre-existing immunological frailty or multiple comorbidities. Ongoing surveillance and focused clinical studies will be essential to clarify these aspects and guide safe, long-term use of CGRP inhibitors in everyday clinical practice.

INTRODUCTION:Migraine is a highly prevalent and disabling neurological disorder whose diagnosis remains clinical. However, overlap with secondary headache disorders represents a major diagnostic challenge, particularly in patients with atypical features or changes in headache pattern, making neuroimaging crucial in selected cases. AREAS COVERED:This review provides an updated overview of the differential diagnosis of migraine in adults, focusing on the role of clinical assessment, red flags, and neuroimaging in identifying secondary causes. A comprehensive, narrative review of the literature was conducted, integrating current guidelines and recent evidence on imaging indications and modalities. We discuss key conditions that may mimic migraine, including vascular, neoplastic, infectious, cerebrospinal fluid pressure-related, and cervicogenic disorders, highlighting their clinical and radiological features. Attention is given to the concept of pretest probability to guide imaging decisions and to the limitations of red flags in clinical practice. EXPERT OPINION:Neuroimaging should not be routinely performed in patients with typical migraine and normal neurological examination but rather tailored to the individual clinical context. An integrated approach combining clinical judgment, awareness of red flags, and targeted imaging is essential to avoid both underdiagnosis of secondary headaches and overuse of unnecessary investigations.

Migraine is a complex neurological disorder with diverse clinical phenotypes and a multifaceted pathophysiology, which poses substantial challenges for accurate diagnosis, subtype differentiation, and biomarker discovery. Machine learning (ML) techniques have emerged as promising tools for classifying migraine patients and uncovering the underlying neurobiological mechanisms that differentiate migraine types and subtypes. This systematic review identifies current ML classification models for migraine types and subtypes, evaluating the quality, reproducibility, and clinical utility of published studies. The findings demonstrate that current ML models, particularly support vector machines and linear discriminant analysis, can accurately classify migraine patients based on structural and functional neuroimaging features with accuracies ranging from 75 to 98

BackgroundStructural imaging offers insight into migraine pathogenesis. Magnetic resonance imaging (MRI) morphometry plays a crucial role in identifying these alterations, yet the clinical significance remains debated. While gray matter volume and cortical curvature are commonly analyzed, cortical thickness offers a more direct measure of cytoarchitectural differences and neuroplastic changes in migraine. Advanced structural MRI techniques, including surface-based morphometry and voxel-based morphometry, have provided insights into cortical thickness alterations in migraine. These methods enable high-resolution assessment of brain morphometry, revealing dynamic changes associated with migraine phases and treatment.MethodsThis narrative review synthesizes findings from cortical thickness studies, focusing on methodological approaches, variations in imaging sequences and study designs, including cross-sectional and longitudinal studies.ResultsStudies using surface-based morphometry (i.e. SBM) and voxel-based morphometry (i.e. VBM) have reported inconsistent findings. Increased thickness is frequently observed in pain-processing regions, such as the somatosensory cortex, insula and anterior cingulate cortex reflecting hyperexcitability or maladaptive neuroplasticity. by contrast, cortical thinning has been noted in regions such as the orbitofrontal cortex, posterior cingulate cortex and visual cortex, suggesting neuronal loss or impaired cortical integrity. Differences between episodic and chronic migraine further highlight progressive structural changes associated with disease burden. Emerging evidence also suggests that preventive treatments, including calcitonin gene-related peptide monoclonal antibodies and botulinum toxin A, may reverse some of these cortical alterations, particularly in treatment responders.ConclusionsCortical thickness analysis provides valuable insights into migraine pathophysiology, offering a potential biomarker for disease progression and treatment response. However, inconsistencies across studies highlight the need for standardized MRI protocols and larger longitudinal investigations to clarify the clinical relevance of cortical thickness changes in migraine.

“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. 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. 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.

Headache disorders are prevalent and disabling conditions. Despite the recent introduction of modern therapies, a large portion of patients are still sub-optimally treated, resulting in a minor or no decrease in health loss nor disability. The Global Burden of Disease (GBD) study classifies 88 risk factors which impact several conditions, thus enabling the estimation of the potential health gain due to addressing these risk factors, but such analysis is not available for headache disorders yet. To address which risk factors, as intended by the taxonomy of the GBD study, are associated to disability in primary headaches. Primary research studies addressing primary headache disorders and disability were searched in PubMed, Web of Science and SCOPUS, in the period between 2000 and 2025. The GBD taxonomy, which classifies risk factors into environmental and occupational, behavioural, and metabolic factors, was used. A descriptive analysis was employed to report the associations between disability measures and the presence/absence of specific risk factors, accounting for diagnoses and the age of patients. A total of 64 studies (97,846 patients) were included, and a total of 86 single associations were found. Metabolic risk factors (high BMI, high fasting plasma glucose, and LDL cholesterol), and behavioural risk factors (low physical activity, inadequate dietary habits, tobacco smoking, and alcohol consumption) were the most frequently reported. Our results suggest that it is possible to address headache-related disability by acting on a set of modifiable factors, with interventions tailored to the specific needs of patients or addressing the exposed populations as a whole. In particular, targeting dietary aspects and exercise is reasonably expected to promote weight loss, and might have an impact on the reduction in fasting plasma glucose and LDL cholesterol, ultimately improving patients’ overall health status and reducing headache-related disability.