Background: Migraine prodromal symptoms typically emerge 2-48 hours before headache onset and include cognitive, affective, and homeostatic disturbances. Although widely described in the literature, their reported prevalence varies considerably, likely due to methodological differences in symptom assessment. This multicenter observational study aimed to evaluate the prevalence, characteristics, timing, and distribution of prodromal symptoms across migraine subtypes in routine outpatient clinical practice. Methods: Consecutive adult patients diagnosed with migraine without aura, migraine with aura, or chronic migraine according to the International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria, were enrolled at multiple Italian headache centers between January and June 2025. Patients reporting prodromal symptoms constituted the study group, while those not reporting prodromal symptoms served as controls for prevalence analysis. An interviewer-administered questionnaire assessed symptom type, timing, duration, and recurrence. Descriptive statistics were performed; group differences were evaluated using t-tests and chi-square tests, with significance set at p<0.05. Results: Among 3,711 migraine patients (mean age 41.3±13.4 years; 86.0% female), 122 (3.3%) reported prodromal symptoms. Prevalence differed significantly across migraine subtypes (χ²=7.67, p=0.02): 3.5% in migraine without aura, 5.3% in migraine with aura, and 2.2% in chronic migraine. The most frequent prodromal manifestations were yawning/asthenia (37.7%), difficulty concentrating (33.6%), anxiety (26.2%), hunger (21.3%), and depressive symptoms (18.9%). Mean prodromal onset occurred 9.9±11.4 hours before headache onset, with a mean duration of 6.3±8.9 hours. Female patients reported significantly longer prodromal duration than males (6.9±9.3 vs. 1.1±1.9 hours; p<0.001). Prodromal symptoms recurred in approximately 30% of attacks within the same patient and remained clinically consistent over time. Conclusions: In this large outpatient cohort, migraine prodromal symptoms were infrequently reported, particularly in chronic migraine, suggesting substantial underrecognition in routine clinical practice. Prodromal manifestations were more common in episodic migraine and were mainly characterized by non-specific cognitive, affective, and homeostatic symptoms. Their variable recurrence and duration highlight the heterogeneity of the migraine prodrome and support the need for improved recognition to facilitate earlier therapeutic intervention.
Professor Giuseppe Nappi passed away peacefully on April 7, 2026, retaining until his final days an extraordinary clarity of mind – the same clarity that had enabled him, only a few years earlier, to publish the book Memoirs of an Octogenarian Neurologist, in which he retraced the evolution of neuroscience between 1970 and 2020, a phenomenon he had experienced firsthand as one of its leading protagonists. [...]
Background: Migraine attacks typically emerge in predisposed individuals after exposure to heterogeneous stimuli that vary widely across patients. A system-level perspective highlights migraine as a disturbance of homeostasis and allostasis: the brain integrates multiple inputs and generates adaptive responses to maintain physiological stability, but sustained physiological or paraphysiological stressors may impose excessive allostatic load. When compensatory mechanisms become energetically costly or insufficient, an “allostatic reset” may occur, clinically manifesting as a migraine attack. Within this framework, the concept of a migraine trigger is better viewed as a threshold modulator rather than a deterministic cause, i.e., a stimulus that lowers the attack threshold in susceptible individuals. Nutrition is among the most frequently implicated domains, including fasting, dehydration, specific foods and additives, and overall dietary patterns. Methods: This narrative review synthesizes current evidence on dietary exposures as potential migraine precipitants and modulators of disease course. Results: The most frequently reported food-related triggers include fasting, dehydration, alcohol, coffee and caffeine withdrawal, chocolate, milk and dairy products, processed and cured meats rich in nitrites and nitrates, citrus fruits, tea, onions, tomatoes, ice cream, nuts, spicy foods, and ultra-processed foods. Food additives such as monosodium glutamate, aspartame, sulfites, and other artificial sweeteners have also been repeatedly implicated, alongside dietary histamine and biogenic amines. Importantly, several studies suggest that overall dietary patterns, characterized by high glycemic load, irregular meal timing, excessive sugar and saturated fat intake, or ultra-processed foods, may exert a greater influence on migraine susceptibility than single food items. Conclusions: Overall, the literature is fragmented and often contradictory, with a frequent mismatch between patient-reported triggers and results from blinded challenge studies, underscoring the roles of recall bias, expectancy effects, and prodromal symptoms (e.g., food cravings) misattributed to causation. Inter- and intra-individual variability – shaped by genetic background, metabolic state, gut-brain axis mechanisms, and comorbidities – suggests that “one-size-fits-all” dietary restrictions are inappropriate. Rather than endorsing broad exclusion lists, current evidence supports personalized trigger identification and prioritization of protective dietary patterns, regular hydration, and consistent meal timing to reduce attack susceptibility and overall disease burden.
This manuscript provides clinical recommendations for assessing and managing cervical musculoskeletal (MSK) comorbidities in patients with migraine. It explores the reciprocal influences between migraine and the cervical MSK system and proposes a theoretical model to explain the high prevalence of these comorbidities, emphasizing the need for proper assessment and targeted management. The text provides a detailed explanation of tests commonly used in clinical and research settings to identify cervical MSK involvement. Furthermore, it reports reference cut-off values to help clinicians profile patients based on the presence and relevance of these comorbidities. The role of neck pain in guiding the execution and interpretation of cervical MSK assessment is discussed in detail. These findings require careful clinical reasoning and an individualized understanding of their roles in each patient’s presentation. Finally, the manuscript presents therapeutic guidelines for the effective management of cervical MSK comorbidities in the migraine population.
Background: Stress can influence migraine burden and act as a trigger for attacks. However, the relationship between stress and migraine attacks, including its pathophysiological mechanisms, remains unclear. Methods: In this narrative review, we summarized the latest evidence on stress as a potential trigger of migraine attacks and investigated the underlying pathophysiological mechanisms. The literature search was conducted in PubMed, focusing on the time window from 2015 to September 2025. Results: Several studies reported stress as one of the most common migraine triggers. The hypothalamus plays a pivotal role in the stress response and influences its impact on migraine attacks. On one hand, it influences pain perception by modulating pain regions through direct anatomic connections and the release of neuropeptides, such as orexin A and B. On the other hand, through the hypothalamo-pituitary-adrenocortical (HPA) axis, the hypothalamus releases glucocorticoids that can influence cortical excitability and sensitize peripheral structures. Biological sex differences, such as female sex, seem to play an additional and significant role in all these mechanisms. Conclusions: Stress can increase the likelihood of a migraine attack, acting as a “catalyst” by influencing cortical excitability and predisposing to nociception. However, other permissive factors must be present to make stress an effective trigger. These include the patient’s state of brain excitability and other biological factors, such as the female sex. Additional and dedicated studies are needed to fully elucidate the relationship between stress and migraine attacks.
Background: Migraine is a neurological disorder that significantly impacts patients’ quality of life, with a growing global burden. This condition is characterized by recurrent headaches with symptoms like nausea and photophobia, with limited analysis of its cognitive effects, especially in social cognition. Methods: This narrative review investigates how migraine, especially in its chronic and medication-overuse forms, affects social cognition, focusing on domains such as Theory of Mind (ToM), emotion recognition, and empathy. Social cognition impairments in patients with migraine contribute to difficulties in maintaining relationships and effective communication, exacerbating the disorder’s emotional and social burden. Results: The reviewed literature shows that migraine is associated with a significant deficit in social cognition, particularly in chronic and medication-overuse headache (MOH). ToM deficits are frequently observed, as individuals with migraine struggle to attribute mental states to others, which impacts their ability to interpret social cues. Emotion recognition impairments, especially in recognizing subtle facial expressions, and difficulties with empathy are also reported, further complicating interpersonal interactions. Neuroimaging studies suggest that these cognitive deficits have a neural basis, with altered activation in areas involved in emotion processing. Alexithymia, often present in patients with migraine, is linked to these social cognitive difficulties, particularly affecting emotional awareness and empathy. Conclusions: These findings highlight the need for specific assessment tools and interventions aimed at improving social cognition in these patients. Such interventions could help improve the emotional and social impact of the disorder and improve overall patient outcomes. Future research should explore these mechanisms further and develop targeted therapies to support patients’ social and emotional well-being.
Background: Nummular headache (NH) is a primary headache disorder, although secondary cases have also been reported. It was first described in 2002 and included in the International Classification of Headache Disorders, 3rd Edition (ICHD-3), 2018. Methods: This narrative review examines epidemiological and clinical features, secondary cases, pathogenesis, and treatment of NH, drawing on updated literature. We conducted a systematic review searching the PubMed database and carefully reviewing the reference lists of all identified articles. Results: Although NH is considered a rare condition, its incidence and prevalence are likely underreported. More than 700 cases have been described so far, and in a tertiary headache clinic, the diagnosis of NH is not uncommon. In other settings, some cases may be missed, and many patients with NH do not seek medical attention due to mild pain intensity. The clinical features include continuous or intermittent pain, generally of mild to moderate intensity, sometimes with exacerbations. The pain is localized in a round or elliptic area of the scalp, typically measuring 1-6 cm, mainly situated in the parietal, temporal, or occipital regions. Although most cases are unilateral, bilateral or midline localizations have also been reported. Conclusions: The pathogenesis of NH is poorly understood; however, some clinical data suggest a peripheral origin of pain, such as a dysfunction of C-fibers in the epicranial cutaneous nerves. Diagnosis, primarily clinical, requires exclusion of other causes through comprehensive patient history, clinical examination, neuroimaging, and blood tests. Secondary cases due to underlying lesions, including systemic diseases or previous surgical treatments, must be ruled out. The most commonly used and effective prophylactic treatments are onabotulinumtoxinA and gabapentin, although various other drugs and non-pharmacological treatments have been proposed over the years.
Background: Monoclonal antibodies against the calcitonin gene-related peptide (anti-CGRP mAbs) have been a game-changer in migraine treatment over the last decade. However, data regarding the reduction in the frequency of episodes of migraine with aura are limited, as no trials have been specifically designed to evaluate this outcome. Methods: In this narrative review, we summarized clinical data from both randomized controlled trials (RCTs) and real-world studies (RWSs) on the efficacy and effectiveness of anti-CGRP mAbs in patients with migraine with aura and aura symptoms. Results: Overall, anti-CGRP mAbs can reduce migraine frequency and burden regardless of the presence of aura, with efficacy and effectiveness in both patients with and without aura. A few studies suggested a potential influence on reducing aura occurrence. However, several limitations affect the available studies and prevent definitive conclusions regarding the effects of anti-CGRP mAbs on aura. Conclusions: Further studies specifically aimed at assessing the impact of anti-CGRP therapies on the frequency, duration, and characteristics of aura are necessary. Such research could help elucidate the complex relationship between CGRP and aura.
Background: Calcitonin gene-related peptide (CGRP) is a neuropeptide involved in pain transmission and modulation, and implicated in migraine pathophysiology. Due to the vasodilatory action of CGRP, anti-CGRP drugs, while ameliorating migraine, may increase hypertension, a major risk factor for cerebrovascular diseases. Although most studies support the safety of this class of drugs, the use of anti-CGRP drugs in some individuals has been associated with elevated blood pressure. Case Presentation: We report a case of a cerebral hemorrhage in a patient treated with an anti-CGRP monoclonal antibody and a poorly controlled blood pressure. Discussion: Migraine is associated with increased cerebrovascular risk and hypertension, and anti-CGRP therapies could potentially contribute to acute hypertensive episodes, possibly increasing the risk of complications, including cerebral hemorrhage, in vulnerable individuals. Conclusions: Limited evidence links anti-CGRP therapies to hypertension. Pending additional data, caution is recommended when prescribing these drugs, especially in patients with cardiovascular risk factors.
Background: Migraine is a prevalent neurological disorder, with chronic migraine (CM) and medication overuse headache (MOH) often comorbid with psychiatric conditions. Patients with CM may experience social cognitive impairments, including alexithymia, which could contribute to their condition’s severity and prognosis. This study aims to characterize alexithymia in patients with episodic migraine (EM) and CM and explore differences in alexithymia between patients with and without aura. Methods: This cross-sectional study included adult patients with EM, CM (with or without MOH), and healthy controls (HCs), conducted at two tertiary headache centers in Italy. Participants completed the Toronto Alexithymia Scale-20 (TAS-20) to assess alexithymia levels. Demographic, clinical, and cognitive functioning data were collected. Migraine features, including frequency, aura symptoms, and medication usage, were also recorded. Results: The cohort included 200 migraine individuals and 79 HCs. Patients with CM exhibited significantly higher alexithymia scores (56.0±13.2) compared to EM patients (47.8±12.0, p<0.001) and HCs (44.5±11.9, p<0.001). A higher proportion of CM patients (32.0%) had pathological alexithymia compared to EM patients (16.0%) and HCs (9.0%) (overall difference, p<0.001). No significant differences were found in TAS-20 scores between migraine individuals with aura (45.2±9.9) and those without aura (49.5±13.0, p=0.182). Conclusions: Patients with CM exhibit higher levels of alexithymia compared to those with EM and HCs. These findings suggest that alexithymia may be a more specific trait of CM. Future research should investigate the role of alexithymia in migraine management, particularly in relation to its impact on quality of life and treatment outcomes.
Background: The Pain Catastrophizing Scale (PCS) is a questionnaire used to assess the extent to which individuals experience negative and exaggerated thoughts and feelings about their pain. This study aimed to evaluate changes in pain catastrophizing over time, from baseline to 9 months, in migraine patients undergoing Eptinezumab treatment. Methods: The PCS was used to assess 34 patients undergoing treatment with Eptinezumab at the Headache Center of the Carlo Besta Neurological Institute in Milan. This instrument was administered and explained during a regularly scheduled visit. Results: Participants had a mean age of 46.97 years (median: 49.5, SD: 12.3), and included 33 females and 1 male. Eight patients dropped out due to adverse events. Although baseline scores did not always reach the clinical significance cut-off (>30), a high level of Pain Catastrophizing was observed (median PCS tot = 22, SD = 8.24), mainly driven by high scores in Helplessness (12 ± 3.77) and Rumination (10 ± 4.07). Magnification is lower at baseline (median: 1.5, SD: 1.42). The comparison at T9 was conducted only for a subset of 16 patients who have completed the follow-up thus far. A significant reduction in the total PCS score was observed (T0 = 19.5 ± 7.93 vs T9 = 12 ± 10.17), with marked decreases in Helplessness (T0 = 11 ± 4.10 vs T9 = 6 ± 4.30) and Rumination (T0 = 8.5 ± 3.84 vs T9 = 6.5 ± 5.13). While PCS scores showed a downward trend by T9, it is also important to consider the high standard deviations across scores, which highlight considerable inter-individual variability. Conclusion: Baseline Pain Catastrophizing levels in our sample of chronic migraine patients were close to the upper limit of the normal range. This supports the tendency of these patients to experience intrusive thoughts, persistent worry, and feelings of Helplessness, which amplify the subjective experience of pain. By 9 months, significant improvements were observed in overall catastrophizing, particularly in Helplessness & Rumination subscales. These findings emphasize the need to study psychological factors, given their potential impact on the progression and outcomes of migraine treatment.
Background: Around 30% of migraine individuals do not achieve a satisfactory disease control (Non-responders) with monoclonal antibodies targeting the CGRP pathway (mAbs). These subjects may bear a non CGRP-dependent migraine phenotype. We previously reported alterations in the endocannabinoid system (eCBome) in subjects with migraine, with alterations of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) peripheral expression. The primary objective of the SPHERA project is to assess whether migraine individuals Non-Responder to mAbs present specific dysfunctions of the eCBome system. Methods: In this longitudinal prospective study, we enrolled 45 subjects (86.7% women, age 42.5±10.1) with either high frequency episodic or chronic migraine. 40% of participants were treated with fremanezumab, 34% with galcanezumab, 21% with erenumab and 5% with eptinezumab. Participants were evaluated at baseline (T0) and after three months of treatment with an anti-CGRP mAB (T1). Non-Responders were defined as those individuals who did not achieve a reduction of at least 50% in monthly migraine days (MMDs) at T1. At T0 and T1, all subjects underwent an extensive biochemical profiling, analyzing miRNA expression of MAGL and FAAH in peripheral blood mononuclear cells (PBMC), plasma levels of PEA and related lipids (AEA, 2-AG, OEA), neuropeptides (CGRP, PACAP, VIP), kinurenic and quinolinic acid, and pro- and anti-inflammatory cytokines (IL-1b, TNF-a, IL-4, IL-10). Results: Of the 45 subjects who completed T1 evaluation, 26 were Responders (57.8%) and 19 were Non-Responders (42.2%). MAGL expression was higher in Non-responders (1.97±0.61 Relative quantification-RQ) compared to Responders (1.58±0.63 RQ, p=0.018), while FAAH expression did not differ between the two groups (Responders: 0.74±0.25 RQ vs. Non-responders 0.75±0.22 RQ, p=0.868). No differences were found in the other molecular markers assessed. Conclusions: Non-responders to mAbs showed higher levels of MAGL, which suggests an increased turnover of the endocannabinoid 2-arachidonoylglycerol. This finding is in keeping with the demonstration that MAGL inhibitors block acute and chronic migraine-associated pain in experimental models and points to an additional pathway worth targeting in CGRP-resistant patients.
Background: Migraine is a disabling neurovascular disorder characterized by recurrent attacks that lead to extracranial and visual involvement. Several studies have investigated the retinal vasculature features in individuals with migraine, but there have been conflicting results. This study aims to evaluate retinal structure in migraine patients before (T0) and after six months of therapy (T1) with anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs), using optical coherence tomography (OCT) imaging. Methods: A case-control longitudinal study was conducted from January 2021 to December 2023, including 20 eyes from 10 healthy controls (HCs) and 32 eyes from 16 migraine patients treated with anti-CGRP mAbs according to AIFA criteria. Patients underwent OCT angiography (OCT-A) to assess retinal vessel density and spectral-domain OCT (SD-OCT) to measure central retinal thickness, macular structure, and peripapillary retinal nerve fiber layer (pRNFL) thickness. Measurements were performed in both groups at baseline (T0) and after six months (T1) as part of routine clinical care. Results: All migraineurs exhibited a significant reduction in disease disability at T1, as assessed by clinical parameters. OCT data analysis revealed that individuals with migraine showed a significant increase in temporal RNFL thickness and a reduction in nasal RNFL thickness compared to healthy controls (HCs). No differences in retinal circulation were observed between the groups at baseline. At T1, RNFL thickness remained sustained in the superior-temporal sector, while the percentage vessel density of the superficial capillary plexus and radial peripapillary capillary significantly increased in the nasal perifoveal, inferior-temporal, and hemi-inferior subregions. Conclusion: Our findings suggest that specific retinal structural changes may precede vascular dysfunction in migraine and can be detected early by combining SD-OCT and OCT-A. Short-term treatment with anti-CGRP mAbs may have neuroprotective effects, potentially preventing permanent ocular damage.
Background: Complex Medication Overuse Headache (or type II MOH) is a secondary chronic headache characterized by daily use of acute headache medications for over one year, multiple psychiatric comorbidities and/or a history of relapse following previous withdrawal attempts. Certain medications as well, including opioids, are associated with poorer prognosis and higher risk of relapse, making management particularly challenging. Methods: We report two cases, a 48-year-old man and a 69-year-old woman, with chronic migraine and MOH, experiencing an average of 45 and 90 acute medications per month respectively, including opioids. Both patients were referred to our Headache Clinic in Alessandria after prior management at other centers. They both shared psychiatric comorbidities such as depression, generalized anxiety disorder, bulimia, and self-harming thoughts. Brain MRI was unremarkable, excluding other secondary causes of headache. They underwent multiple prophylactic treatments (10-5) which were discontinued due to poor tolerability or lack of efficacy, along with several unsuccessful detoxification protocols (5-1). We decided to combine detoxification, prophylactic therapy with eptinezumab and a psychoeducational program in order to gain awareness about pain and medication management. Results: Headache diary monitoring revealed a gradual reduction in both frequency and intensity of attacks, initially without drug withdrawal. Subsequently, patients have learned to attend to their emotional dimension, whereas previously they relied on opioids for mood stabilization. At follow-up, the female patient transitioned to an episodic migraine pattern (4 attacks/month), while the male patient, despite persistent chronic migraine, no longer required the overuse of triptans or opioids. Conclusion: A tailored approach combining detoxification, target therapy and psychoeducational support appears effective in reducing both frequency and intensity of the attacks, while also improving emotional awareness, even in cases involving opioid overuse. There is no universal agreement on the best treatment protocols for complex MOH; therefore, further studies are needed to assess the long-term effectiveness of this combined strategy.
Background: Headache is a frequent symptom in children, which often leads to the execution of neuroradiological examinations and to finding of incidentalomas. In fact, headache is often attributed to primary headache, neurological disorder common in the developmental age. Recent widespread access to neuroradiological examinations has led to a consequent increase in the number of incidental brain lesions in children with headache. Methods: We conducted a retrospective study including 28 patients under 18 years with primary headache and incidental findings of suspected low-grade lesion at brain MRI. Data were collected on age, sex, headache characteristics. Neurological and fundus oculi evaluation were normal. All patients were treated conservatively with neuroimaging surveillance of suspected low-grade lesion. All lesions detected were defined as hyperintense in T2/FLAIR sequences, negative DWI, no increase, surrounding edema and mass effect. The lesions were divided into supratentorial (thalamic) and infratentorial (cerebellar). The first follow-up MRI was performed after 6 months and follow-ups were carried out every 12 to 18 months. Results: Patients included 13 females (46%) and 15 males (54%): 67.8% presented migraine without aura, 25% tensive headache, 14.3% migraine with aura, 7% both tensive headache and migraine without aura. Average frequency of attacks was 2.9 attack/month. Regarding intensity of attacks: 32% presented slight attack, 57% moderate and 11% had severe attacks. Average follow-up period was 43.7 months. In following period: 7% was stable at 84 months, 17.8% at 72 months, 21.5% at 60 months, 46.5% at 48 months, 64.3% at 36 months, 96.5% at 24 months. 96.5% of the patients showed radiological stability during the whole follow-up period. No significant radiological changes were found during follow-up in 27 of 28 patients. Conclusion: With the increasing detail of imaging techniques and their execution, there has been an increase in number of incidentally brain lesions in children with primary headache, leading to a management dilemma for pediatric neurologists. The incidentally low-grade lesions are not related to headache. This study reports data on long-term clinical and radiological follow-up period in patients with primary headache and occasional low-grade lesion findings during headache assessment, showing the stability over time and safety of conservative management.
Background: The recent availability of CGRP-targeting drugs has improved migraine management, although it is now clear that a large portion of patients are CGRP-resistant. Inhibition of the degradation pathway of endocannabinoids may represent a new therapeutic target for non CGRP-responding patients. Indeed, the inhibition of fatty acid amide hydrolase (FAAH), the main catabolic enzyme of N-arachidonoylethanolamine (AEA), and of N-acylethanolamine-hydrolysing acid amidase (NAAA), which preferentially hydrolyses palmitoylethanolamide (PEA), may exert analgesic and anti-inflammatory effects. The aim of the study was to investigate and compare the effects of peripheral FAAH inhibition (URB937) and NAAA inhibition (ARN726) on trigeminal hyperalgesia induced in the animal model of migraine based on dural neurogenic inflammation. Methods: Migraine-like dural inflammation was induced in male Sprague-Dawley rats via a 5-minute infusion of inflammatory soup (IS, 10 μL) onto the dura. Animals were treated intraperitoneally with ARN726 (3 mg/kg; at the end of IS infusion) or URB937 (1 mg/kg; injected 1h after IS infusion), or vehicle. To further investigate the URB937 effects, additional groups were treated with cannabinoid (CB) 1 or CB2 receptor antagonists (AM251 or AM630, 1 mg/kg) in combination with URB937 treatment. Two hours after IS infusion, trigeminal nocifensive behavior was assessed using the orofacial formalin test (OFT) (1.5%, 50 µl, s.c.). Results: IS infusion produced a significant increase in trigeminal hyperalgesia during the second phase of the OFT compared to controls. URB937 treatment significantly reduced the IS-induced hyperalgesic behavior, while ARN726 had no effect. Antagonism of CB1 or CB2 receptors did not reverse URB937 anti-hyperalgesic effect. Conclusion: The combination of IS infusion with OFT shows that inflammatory mediators in the meninges activate and sensitize the nociceptive terminals of the trigeminal nerve. Peripheral inhibition of FAAH through URB937 significantly reduces IS-induced trigeminal hyperalgesia, whereas inhibition of NAAA does not produce similar effects. These findings suggest a prominent role for AEA in the pain modulation in this model of neurogenic inflammation. Notably, the anti-hyperalgesic effects of URB937 appear to be independent of CB1 and CB2 receptor activation, pointing toward alternative mechanisms of action for AEA. Overall, the data confirm peripheral FAAH as a promising therapeutic target for modulating migraine-related pain.
Background: The prevalence of headaches in children and adolescents has increased in recent years. Diagnosing headaches in children can be challenging, as the symptoms may not always align with the diagnostic criteria used for adults. Treatment options for children are limited and the high placebo response rate complicates the determination of the true efficacy of most drugs. Although headaches in childhood are common, there are few data available on their long-term prognosis, based on the available data it seems that in the majority of cases headache tends to persist in adulthood. This retrospective and prospective longitudinal monocentric study aims to investigate the long-term outcomes of pediatric patients with headache disorders. It also explores whether early diagnosis and therapeutic intervention is associated with improved long-term prognosis, including symptom control, quality of life, and reduced progression to chronic forms. Methods: This is a longitudinal observational study. We retrospectively included 560 patients, aged between 4 and 17 years old, diagnosed with headache disorders who accessed our Centre between 2019 and 2024. Data collected from these visits included medical history, family history, headache characteristics, and treatment history. Clinical data were gathered at three time points: T0: Initial visit at our Centre T1: Follow-up visit, between 6 and 18 months after the initial assessment T2: Final follow-up, prospectively via a phone interview. Results: This is an ongoing study and data are currently being analyzed. The study allows for tracking changes in the pediatric migraine pattern and in the response to therapy over time. It also aims to evaluate how early intervention and different treatment strategies can influence clinical outcomes, symptoms persistence and overall quality of life. Conclusion: Through this study, we aim to identify the most common characteristics of headaches in children attending our hospital and to monitor changes in migraine patterns and treatment strategies over time. This study may serve as both an epidemiological model of pediatric migraine and a tool to identify prognostic factors, ultimately supporting the development of more personalized treatment approaches and guiding clinicians toward tailored care for young migraine patients.
Background: This observational study presents preliminary real-world evidence on the comparative efficacy and safety of combination therapy with onabotulinumtoxinA and the CGRP receptor antagonist atogepant versus atogepant monotherapy in patients with treatment-refractory chronic migraine. Methods: Twenty adult patients (aged 18-75) meeting ICHD-3 criteria for refractory chronic migraine - defined by 8 monthly migraine days, MIDAS ³11, and inadequate response or intolerance to ³ 3 preventive therapies - were enrolled. Ten patients received atogepant monotherapy, while ten initiated combination therapy with onabotulinumtoxinA and atogepant. Efficacy was assessed over three months using changes in monthly migraine days, headache severity (Numerical Rating Scale, NRS), and disability scores (HIT-6, MIDAS). Acute medication use and tolerability were also evaluated. Results: The combination therapy group demonstrated significantly greater reductions in monthly migraine days, headache intensity, and disability scores compared to the monotherapy group. Responders - defined as patients remaining migraine-free for 36 consecutive weeks - were more frequent in the combination cohort. Both treatments were well tolerated, with no serious adverse events reported. Chronic migraine remains a debilitating condition, often resistant to standard preventive treatments. Dual blockade of the CGRP pathway - via onabotulinumtoxinA and a CGRP receptor antagonist - may offer synergistic benefits by targeting both peripheral and central CGRP mechanisms. Conclusion: These preliminary findings support the enhanced clinical efficacy and safety of combining onabotulinumtoxinA with CGRP receptor antagonists in managing refractory chronic migraine. This multimodal strategy may provide a personalized, mechanism-based approach to care and warrants further investigation in larger, controlled studies.
Background: Primary headaches are common in pediatric age and can significantly impact children's quality of life especially when they have a high frequency. Best practices in headache management involve a multidisciplinary approach combining pharmacological and non-pharmacological strategies. Among the latter, psychological interventions targeting cognitive, behavioral, and emotional factors have shown efficacy in reducing migraine-related pain, distress, and disability. Mindfulness is a recent behavioral approach that offers an effective option for adolescents with headache, helping reduce pain and disability by increasing awareness and teaching techniques alternative to medications. Methods: This is a prospective study involving patients aged 11–18 years, referred to four juvenile headache centers and meeting defined inclusion and exclusion criteria. Selected patients participated in eight weekly online 1-hour sessions of guided mindfulness-based meditation combined with education on healthy lifestyle habits to prevent or reduce the impact of headache. Follow-up assessments are scheduled at 3, 6 and 12 months, including clinical evaluations and standardized questionnaires completed by both patients and parents. Results: Twenty-eight adolescents with frequent primary headaches (migraine or tension-type headache) were enrolled. The intervention demonstrated good feasibility with high participation and adherence rates to the weekly sessions. Only 3 participants have dropped out, with an overall adherence rate of 89.3%. No significant side effects were reported; in one case, dropout was due to increased anxiety. In preliminary analysis, patients reported a subjective impression of global improvement. We expect positive changes in standardized tests at 3, 6 and 12-months follow up. Conclusion: This study investigated a well-tolerated, promising and feasible behavioral intervention for adolescents with high-frequency primary headaches. Our preliminary results showed high compliance and favorable disease progression in our population, demonstrating that mindfulness (made online in small groups) is a valuable and safe approach in adjunct to preventive drugs.
Background: Headache disorders are highly prevalent in children and adolescents but frequently underdiagnosed due to diagnostic complexity and symptom underreporting. A notable gap persists in high-quality epidemiological data on pediatric headache in Italy. This study aims to validate the Italian version of the Child and Adolescents Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire, a standardized tool for assessing headache prevalence and burden, developed by the Global Campaign Against Headache. Methods: The study was conducted within the REPICEF registry (Registro Epidemiologico delle Cefalee in Età Evolutiva), approved by the Ethics Committee of the Abruzzo Region (protocol 035018). Children and adolescents aged 6–17 years from selected schools in L’Aquila were enrolled between February and December 2024. The Italian version of the HARDSHIP questionnaire was developed via TRAPD methodology. Questionnaire-based diagnoses were compared against clinical assessments performed by headache specialists using ICHD-3 criteria. Diagnostic performance was evaluated through sensitivity, specificity, positive and negative predictive values (PPV-NPV), and Cohen’s kappa. Statistical analyses were performed using R (v.4.3.0). Results: Of 1053 screened students, 858 were included in the cohort; the first 535 (62.4%) were selected for validation analyses. Based on the HARDSHIP questionnaire, the most common diagnoses were migraine in 68 (7.9%), Tension-Type Headache (TTH) in 86 (10.0%), probable Migraine (pMig) in 175 (20.7%), probable Tension-Type Headache (pTTH) in 144 (16.7%), and Undifferentiated Headache (UDH) in 105 (12.2%) children and adolescents. The agreement between questionnaire-based and clinical diagnoses was moderate for pMIG (κ = 0.432) and fair for pTTH (κ = 0.327). Specificity was high for both pMIG and pTTH, while sensitivity remained low. Conclusion: The Italian HARDSHIP questionnaire demonstrates adequate specificity and moderate agreement with clinical diagnosis for pediatric migraine, supporting its use as an epidemiological screening tool. While clinical confirmation remains essential, this instrument facilitates population-level monitoring and may inform targeted interventions for headache disorders in youth.
