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BackgroundPrimary headache disorders are common and burdensome conditions. They are associated to several comorbidities, such as cardiovascular or psychiatric ones, which, in turn, contribute to the global burden of headache. The aim of this study is to provide a comprehensive description of the pooled prevalence of comorbidities of primary headache disorders using a meta-analytical approach based on studies published between 2000 and 2020.MethodsScopus was searched for primary research (clinical and population studies) in which medical comorbidities were described in adults with primary headache disorders. Comorbidities were extracted using a taxonomy derived from the Global Burden of Disease (GBD) study. We compared prevalence of comorbidities among headache sufferers against general population using GBD-2019 estimates, and compared comorbidities’ proportions in clinical vs. population studies, and by age and gender.ResultsA total of 139 studies reporting information on 4.19 million subjects with primary headaches were included: in total 2.75 million comorbidities were reported (median per subject 0.64, interquartile range 0.32–1.07). The most frequently addressed comorbidities were: depressive disorders, addressed in 51 studies (pooled proportion 23 %, 95 % CI 20–26 %); hypertension, addressed in 48 studies (pooled proportion 24 %, 95 % CI 22–26 %); anxiety disorders addressed in 40 studies (pooled proportion 25 %, 95 % CI 22–28 %). For conditions such as anxiety, depression and back pain, prevalence among headache sufferers was higher than in GBD-2109 estimates. Associations with average age and female prevalence within studies showed that hypertension was more frequent in studies with higher age and less females, whereas fibromyalgia, restless leg syndrome, and depressive disorders were more frequent in studies with younger age and more female.ConclusionsSome of the most relevant comorbidities of primary headache disorders – back pain, anxiety and depression, diabetes, ischemic heart disease and stroke – are among the most burdensome conditions, together with headache themselves, according to the GBD study. A joint treatment of headaches and of these comorbidities may positively impact on headache sufferers’ health status and contribute to reduce the impact of a group of highly burdensome diseases.

Objective Nearly 60% of migraine patients treated with monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway experience a ≥ 50% reduction in monthly migraine days (MMD) at 12 weeks compared to baseline (responders) . However, approximately half of the patients not responding to anti-CGRP mAbs ≤ 12 weeks do respond ≤ 24 weeks ( late responders) . We assessed frequency and characteristics of patients responding to anti-CGRP mAbs only > 24 weeks ( ultra-late responders ). Methods In this multicenter ( n  = 16), prospective, observational, real-life study, we enrolled all consecutive adults affected by high-frequency episodic migraine (HFEM: ≥ 8 days/month) or chronic migraine (CM), with ≥ 3 prior therapeutic failures, treated with any anti-CGRP mAbs for ≥ 48 weeks. We defined responders patients with a ≥ 50% response rate ≤ 12 weeks, late responders those with a ≥ 50% response rate ≤ 24 weeks, and ultra-late responders those achieving a ≥ 50% response only > 24 weeks. Results A total of 572 migraine patients completed ≥ 48 weeks of anti-CGRP mAbs treatment. Responders accounted for 60.5% (346/572), late responders for 15% (86/572), and ultra-late responders for 15.7% (90/572). Among ultra-late responders , 7.3% (42/572) maintained the ≥ 50% response rate across all subsequent time intervals (weeks 28, 32, 36, 40, 44, and 48) and were considered persistent ultra-late responders , while 8.4% (48/572) missed the ≥ 50% response rate at ≥ 1 subsequent time interval and were classified as fluctuating ultra-late responders . Fifty patients (8.7%) did not respond at any time interval ≤ 48 weeks. Ultra-late responders differed from responders for higher BMI ( p  = 0.033), longer duration of medication overuse ( p  < 0.001), lower NRS ( p  = 0.017) and HIT-6 scores ( p  = 0.002), higher frequency of dopaminergic symptoms ( p  = 0.002), less common unilateral pain—either alone ( p  = 0.010) or in combination with UAS ( p  = 0.023), allodynia ( p  = 0.043), or UAS and allodynia ( p  = 0.012)—a higher number of comorbidities ( p  = 0.012), psychiatric comorbidities ( p  = 0.010) and a higher proportion of patients with ≥ 1 comorbidity ( p  = 0.020). Conclusion Two-thirds of patients not responding to anti-CGRP mAbs ≤ 24 weeks do respond later, while non-responders  ≤ 48 weeks are quite rare (8.7%). These findings suggest to rethink the duration of migraine prophylaxis and the definition of resistant and refractory migraine, currently based on the response after 2–3 months of treatment.

BackgroundVaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are used to reduce the risk of developing Coronavirus Disease 2019 (COVID-19). Despite the significant benefits in terms of reduced risk of hospitalization and death, different adverse events may present after vaccination: among them, headache is one of the most common, but nowadays there is no summary presentation of its incidence and no description of its main features.MethodsWe searched PubMed and EMBASE covering the period between January 1st 2020 and August 6th, 2021, looking for record in English and with an abstract and using three main search terms (with specific variations): COVID-19/SARS-CoV-2; Vaccination; headache/adverse events. We selected manuscript including information on subjects developing headache after injection, and such information had to be derived from a structured form (i.e. no free reporting). Pooled estimates and 95% confidence intervals were calculated. Analyses were carried out by vaccine vs. placebo, by first vs. second dose, and by mRNA-based vs. “traditional” vaccines; finally, we addressed the impact of age and gender on post-vaccine headache onset.ResultsOut of 9338 records, 84 papers were included in the review, accounting for 1.57 million participants, 94% of whom received BNT162b2 or ChAdOx1. Headache was generally the third most common AE: it was detected in 22% (95% CI 18–27%) of subjects after the first dose of vaccine and in 29% (95% CI 23–35%) after the second, with an extreme heterogeneity. Those receiving placebo reported headache in 10–12% of cases. No differences were detected across different vaccines or by mRNA-based vs. “traditional” ones. None of the studies reported information on headache features. A lower prevalence of headache after the first injection of BNT162b2 among older participants was shown.ConclusionsOur results show that vaccines are associated to a two-fold risk of developing headache within 7 days from injection, and the lack of difference between vaccine types enable to hypothesize that headache is secondary to systemic immunological reaction than to a vaccine-type specific reaction. Some descriptions report onset within the first 24 h and that in around one-third of the cases, headache has migraine-like features with pulsating quality, phono and photophobia; in 40–60% of the cases aggravation with activity is observed. The majority of patients used some medication to treat headache, the one perceived as the most effective being acetylsalicylic acid.

Background Atogepant, the first oral CGRP receptor antagonist approved for migraine prevention, has demonstrated efficacy and safety in randomized clinical trials (RCT). However, prospective real-world data are lacking. Objective To explore the effectiveness, safety, and tolerability of atogepant 60 mg at week 12 in patients with high-frequency episodic (HFEM: 8-14 days/month) or chronic migraine (CM) with multiple therapeutic failures. Methods This ongoing, multicenter ( n = 16), prospective real-world study included consecutive adults with HFEM or CM who had failed ≥3 prior preventive treatments, according to AIFA criteria. Participants received atogepant 60 mg daily, with treatment planned for up to 12 months. Primary endpoint: change from baseline to week 12 in monthly migraine days (MMD) for HFEM and monthly headache days (MHD) for CM. Secondary endpoints: changes in monthly analgesic intake (MAI), pain intensity (NRS), disability (HIT-6, MIDAS), interictal burden (MIBS-4), treatment satisfaction (PGIC), responder rates (≥ 50%, ≥ 75%, 100%), and changes in migraine frequency during the first treatment week compared to the last pre-treatment week. Adverse events were monitored throughout. Results A total of 183 patients were enrolled and 82 completed ≥ 12 weeks of follow-up. Of these, 41.5% had previously failed anti-CGRP mAbs. At week 12, significant reductions ( p  < 0.001) were observed in MMD (–6.0) and MHD (–11.2). Secondary outcomes also improved significantly ( p  < 0.001): MAI (–10.9), NRS (–2.7), HIT-6 (–13.2), MIDAS (–61.1), and MIBS-4 (–5.4). Responder rates were 65.9% (≥ 50%), 36.6% (≥ 75%), and 6.1% (100%). PGIC documented high satisfaction (much/very much improved: 70.7%). A significant decrease ( p  < 0.001) in migraine frequency was already evident by week 1 (overall: − 2.5 days, HFEM: − 1.5, CM: − 3.1). In the mAb-failure subgroup, ≥ 50% and ≥ 75% response rates were 52.9% and 23.5%, with significant improvements in all primary and secondary endpoints ( p  < 0.001). Adverse events occurred in 5.5% of patients, and 1.6% discontinued treatment. Conclusion The GIANT study provides real-world evidence of atogepant’s effectiveness, safety, and tolerability in patients with HFEM and CM with multiple therapeutic failures and comorbidities. It extends RCT data by showing rapid onset of action, meaningful reductions in pain intensity and interictal disability, high patient satisfaction, and effectiveness even in patients with anti-CGRP mAb failures.

Background Although migraine attacks have been precisely characterized over the years − with significant advances in pathophysiology and treatment − the comprehensive identity of the migraine patient remains poorly defined. Real-world data capturing the full sociodemographic and clinical spectrum of individuals with migraine is still limited. The Italian National Migraine Registry (I-GRAINE) was established to address this gap by systematically collecting data on individuals with migraine across Italy’s public healthcare system. Methods I-GRAINE is an ongoing, nationwide, multicenter, prospective registry involving 43 publicly funded headache centers. Since 19/04/2021, patients diagnosed with episodic migraine (EM) or chronic migraine (CM) have been systematically enrolled. Data were collected through face-to-face interviews conducted by trained neurologists using a dedicated electronic platform. Information included sociodemographic and lifestyle factors, comorbidities, and detailed clinical characteristics. We aimed to define the patient profile, explore the broad clinical phenotype, and compare EM and CM subgroups. Results As of 02/05/2025, 1,630 patients had been enrolled (81.7% EM, 18.3% CM), predominantly female (85.4%), mean age 45.7 years, normal BMI (23.2 kg/m 2 ), and high education level. Over 70% were physically inactive, and 32.2% reported sleep disturbances. Headache was typically unilateral (69.1%), pulsating (64.0%), and lasted > 24 h (57.1%). Frequently reported non-ICHD-3 symptoms included osmophobia (41.5%), allodynia (40.5%), dopaminergic symptoms (37.2%), cephalalgiaphobia (34.0%), and dizziness (16.9%). ≥ 1 comorbidity was present in 41.2% of patients. Compared to those with EM, CM patients had higher BMI (24.0 vs. 23.0, p < 0.001), greater sleep disturbances (39.1% vs. 30.6%, p = 0.006), earlier onset (16.5 vs. 17.7 years, p = 0.032), more severe pain (NRS: 8.1 vs. 7.5, p < 0.001), and higher prevalence of medication overuse (58.3% vs. 14.5%, p < 0.001), dopaminergic symptoms (45.1% vs. 35.4%, p = 0.002), allodynia (47.5% vs. 38.9%, p = 0.009), and cephalalgiaphobia (41.4% vs. 32.3%, p = 0.004). Disability was also greater (MIDAS: 76.3 vs. 41.9; HIT-6: 64.3 vs. 61.2; both p  < 0.001). Conclusions The typical patient attending Italian headache centers is a 45-year-old, normal-weight, well-educated, employed woman, often physically inactive, affected by sleep disturbances, and experiencing an average of 9.8 migraine days/month. I-GRAINE identifies migraine symptoms that may represent endophenotypes and distinct patterns associated with CM, offering valuable real-world insights to inform personalized care, research, and health policy.