CGRP and PACAP-38 play an important role in diagnosing pediatric migraine

BackgroundAn increasing number of studies have suggested that the important role of vasoactive peptides, such as pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) and calcitonin gene-related peptide (CGRP), in the pathophysiology of migraine seems undeniable in adults, but studies in pediatric migraine patients remain scarce. We prospectively investigated CGRP and PACAP-38 plasma levels in children with migraine during ictal and interictal periods and compared the results between migraine patients with aura and without aura. We were the first to explore the diagnostic value of a combination of CGRP and PACAP-38.MethodsSeventy-six migraine patients aged 4–18 years and seventy-seven age-matched healthy children were included in the study. Plasma vasoactive peptides were measured using the enzyme-linked immunosorbent assay (ELISA). Differences and correlations of groups were analyzed using the independent samples t-test, analysis of variance (ANOVA), Mann-Whitney U test, and multiple linear regression. We also performed logistic regression and receiver operating characteristic curve (ROC) analyses to evaluate the diagnostic value of CGRP and PACAP-38 in pediatric migraine.ResultsPACAP-38 and CGRP levels in migraine patients during the ictal and interictal periods were higher than those in controls (p < 0.001). PACAP-38 and CGRP levels in migraine patients with aura and without aura were higher than those in controls (p < 0.001). PACAP-38 and CGRP were independent risk factors in diagnosing pediatric migraine (adjusted OR (PACAP-38) =1.331, 95% CI: 1.177–1.506, p < 0.001; adjusted OR (CGRP) = 1.113, 95% CI: 1.064–1.165, p < 0.001). Area Under Curve (AUC) comparison: Combination (0.926) > CGRP (0.869) > PACAP-38 (0.867).ConclusionsOur study found almost the same changes in CGRP and PACAP levels in pediatric migraine, suggesting that CGRP and PACAP-38 may work together to play an integral role in pediatric migraine. Higher CGRP levels were found in the ictal phase than in the interictal phase and with aura group than without aura group, indicating that CGRP may take part in the formation of pain and aura. Moreover, ROC and logistic regression analyses suggested that CGRP and PACAP-38 are good indicators to diagnose pediatric migraine, and the combination of CGRP and PACAP-38 was valuable in diagnosing pediatric migraine and differentiating pediatric migraine from non-migraine headaches.Trial registrationThe study has been registered at the Chinese Clinical Trial Registry (ChiCTR2100043157).     

Thalamo-cortical networks in subtypes of migraine with aura patients

BackgroundWe searched for differences in resting-state functional connectivity (FC) between brain networks and its relationship with the microstructure of the thalamus between migraine with pure visual auras (MA), and migraine with complex neurological auras (MA+), i.e. with the addition of at least one of sensory or language symptom.Methods3T MRI data were obtained from 20 patients with MA and 15 with MA + and compared with those from 19 healthy controls (HCs). We collected resting state data among independent component networks. Diffusivity metrics of bilateral thalami were calculated and correlated with resting state ICs-Z-scores.ResultsAs compared to HCs, both patients with MA and MA + disclosed disrupted FC between the default mode network (DMN) and the right dorsal attention system (DAS). The MA + subgroup had lower microstructural metrics than both HCs and the MA subgroup, which correlated negatively with the strength of DMN connectivity. Although the microstructural metrics of MA patients did not differ from those of HCs, these patients lacked the correlation with the strength of DAS connectivity found in HCs.ConclusionsThe present findings suggest that, as far as MRI profiles are concerned, the two clinical phenotypes of migraine with aura have both common and distinct morpho-functional features of nodes in the thalamo-cortical network.     

Exploring alterations in sensory pathways in migraine

BackgroundMigraine is a neurological disorder characterized by intense, debilitating headaches, often coupled with nausea, vomiting and sensitivity to light and sound. Whilst changes in sensory processes during a migraine attack have been well-described, there is growing evidence that even between migraine attacks, sensory abilities are disrupted in migraine. Brain imaging studies have investigated altered coupling between areas of the descending pain modulatory pathway but coupling between somatosensory processing regions between migraine attacks has not been properly studied. The aim of this study was to determine if ongoing functional connectivity between visual, auditory, olfactory, gustatory and somatosensory cortices are altered during the interictal phase of migraine.MethodsTo explore the neural mechanisms underpinning interictal changes in sensory processing, we used functional magnetic resonance imaging to compare resting brain activity patterns and connectivity in migraineurs between migraine attacks (n = 32) and in healthy controls (n = 71). Significant differences between groups were determined using two-sample random effects procedures (p < 0.05, corrected for multiple comparisons, minimum cluster size 10 contiguous voxels, age and gender included as nuisance variables).ResultsIn the migraine group, increases in infra-slow oscillatory activity were detected in the right primary visual cortex (V1), secondary visual cortex (V2) and third visual complex (V3), and left V3. In addition, resting connectivity analysis revealed that migraineurs displayed significantly enhanced connectivity between V1 and V2 with other sensory cortices including the auditory, gustatory, motor and somatosensory cortices.ConclusionsThese data provide evidence for a dysfunctional sensory network in pain-free migraine patients which may be underlying altered sensory processing between migraine attacks.     

Disconnectome of the migraine brain: a “connectopathy” model

BackgroundIn the past decades a plethora of studies has been conducted to explore resting-state functional connectivity (RS-FC) of the brain networks in migraine with conflicting results probably due to the variability and susceptibility of signal fluctuations across the course of RS-FC scan. On the other hand, the structural substrates enabling the functional communications among the brain connectome, characterized by higher stability and reproducibility, have not been widely investigated in migraine by means of graph analysis approach. We hypothesize a rearrangement of the brain connectome with an increase of both strength and density of connections between cortical areas specifically involved in pain perception, processing and modulation in migraine patients. Moreover, such connectome rearrangement, inducing an imbalance between the competing parameters of network efficiency and segregation, may underpin a mismatch between energy resources and demand representing the neuronal correlate of the energetically dysfunctional migraine brain.MethodsWe investigated, using diffusion-weighted MRI imaging tractography-based graph analysis, the graph-topological indices of the brain “connectome”, a set of grey matter regions (nodes) structurally connected by white matter paths (edges) in 94 patients with migraine without aura compared to 91 healthy controls.ResultsWe observed in migraine patients compared to healthy controls: i) higher local and global network efficiency (p < 0.001) and ii) higher local and global clustering coefficient (p < 0.001). Moreover, we found changes in the hubs topology in migraine patients with: i) posterior cingulate cortex and inferior parietal lobule (encompassing the so-called neurolimbic-pain network) assuming the hub role and ii) fronto-orbital cortex, involved in emotional aspects, and visual areas, involved in migraine pathophysiology, losing the hub role. Finally, we found higher connection (edges) probability between cortical nodes involved in pain perception and modulation as well as in cognitive and affective attribution of pain experiences, in migraine patients when compared to healthy controls (p < 0.001). No correlations were found between imaging and clinical parameters of disease severity.ConclusionThe imbalance between the need of investing resources to promote network efficiency and the need of minimizing the metabolic cost of wiring probably represents the mechanism underlying migraine patients’ susceptibility to triggers. Such changes in connectome topography suggest an intriguing pathophysiological model of migraine as brain “connectopathy”.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01315-6.     

Investigating the relationships between the burden of multiple sensory hypersensitivity symptoms and headache-related disability in patents with migraine

ObjectiveSensory hypersensitivities such as photophobia, phonophobia, and osmophobia are common in patients with migraine. We investigated the burden of these multiple sensory hypersensitivities in migraine.MethodsIn this cross-sectional study, 187 consecutive patients with migraine (26 men/161 women; age, 45.9 ± 13.2 years) were included. Sensory hypersensitivity symptoms such as photo−/phono−/osmophobia and accompanying symptoms were determined by neurologists in interviews. The Migraine Disability Assessment (MIDAS) was used to assess headache-related disability. The Kessler Psychological Distress Scale (K6) was also administered.ResultsPhotophobia, phonophobia and osmophobia were observed in 75.4%, 76.5% and 55.1% of the patients with migraine, respectively. A significant overlap in sensory hypersensitivities (photo−/phono−/osmophobia) was found; the proportions of patients with 2 and 3 coexisting sensory hypersensitivities were 33.2% and 41.7%, respectively. The MIDAS score was higher in those with 3 sensory hypersensitivity symptoms than in those with 0 to 2 sensory hypersensitivity symptoms. A generalized linear model with ordinal logistic regression analysis revealed that multiple sensory hypersensitivities, younger age, more migraine days per month, and a higher K6 score were significantly related to the higher MIDAS score.ConclusionOur study showed that sensory hypersensitivities commonly occur and overlap in patients with migraine and that multiple sensory hypersensitivity symptoms have a significant impact on headache-related disability.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01294-8.     

Osmophobia in primary headache patients: associated symptoms and response to preventive treatments

BackgroundOsmophobia, is common among primary headaches, with prevalence of migraine.The study aimed to evaluate prevalence and clinical characteristics of patients with osmophobia in a cohort of primary headache patients selected at a tertiary headache center. The second aim was to verify the possible predicting role of osmophobia in preventive treatment response in a sub cohort of migraine patients.MethodsThis was an observational retrospective cohort study based on data collected in a tertiary headache center.We selected patients aged 18–65 years, diagnosed as migraine without aura (MO), migraine with aura (MA) or Chronic Migraine (CM), Tension-Type Headache (TTH); and Cluster Headache (CH). We also selected a sub-cohort of migraine patients who were prescribed preventive treatment, according to Italian Guidelines, visited after 3 months follow up.Patients were considered osmophobic, if reported this symptom in at least the 20% of headache episodes. Other considered variables were: headache frequeny, the migraine disability assessment (MIDAS), Allodynia Symptom Checklist, Self-rating Depression scale, Self-rating Anxiety scale, Pain intensity evaluated by Numerical Rating Scale-NRS- form 0 to 10.ResultsThe 37,9% of patients reported osmophobia (444 patients with osmophobia, 726 without osmophobia).Osmophobia prevailed in patients with the different migraine subtypes, and was absent in patients with episodic tension type headache and cluster headache (chi square 68.7 DF 7 p < 0.0001). Headache patients with osmophobia, presented with longer hedache duration (F 4.91 p 0.027; more severe anxiety (F 7.56 0.007), depression (F 5.3 p 0.019), allodynia (F 6 p 0.014), headache intensity (F 8.67 p 0.003). Tension type headache patients with osmophobia (n° 21), presented with more frequent headache and anxiety. A total of 711 migraine patients was visited after 3 months treatment. The change of main migraine features was similar between patients with and without osmophobia.ConclusionsWhile the present study confirmed prevalence of osmophobia in migraine patients, it also indicated its presence among chronic tension type headache cases, marking those with chronic headache and anxiety.Osmophobia was associated to symptoms of central sensitization, as allodynia. It was not relevant to predict migraine evolution after first line preventive approach.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01327-2.     

Early alterations of cortical thickness and gyrification in migraine without aura: a retrospective MRI study in pediatric patients

BackgroundMigraine is the most common neurological disease, with high social-economical burden. Although there is growing evidence of brain structural and functional abnormalities in patients with migraine, few studies have been conducted on children and no studies investigating cortical gyrification have been conducted on pediatric patients affected by migraine without aura.MethodsSeventy-two pediatric patients affected by migraine without aura and eighty-two controls aged between 6 and 18 were retrospectively recruited with the following inclusion criteria: MRI exam showing no morphological or signal abnormalities, no systemic comorbidities, no abnormal neurological examination. Cortical thickness (CT) and local gyrification index (LGI) were obtained through a dedicated algorithm, consisting of a combination of voxel-based and surface-based morphometric techniques. The statistical analysis was performed separately on CT and LGI between: patients and controls; subgroups of controls and subgroups of patients.ResultsPatients showed a decreased LGI in the left superior parietal lobule and in the supramarginal gyrus, compared to controls. Female patients presented a decreased LGI in the right superior, middle and transverse temporal gyri, right postcentral gyrus and supramarginal gyrus compared to male patients. Compared to migraine patients younger than 12 years, the ≥ 12-year-old subjects showed a decreased CT in the superior and middle frontal gyri, pre- and post-central cortex, paracentral lobule, superior and transverse temporal gyri, supramarginal gyrus and posterior insula. Migraine patients experiencing nausea and/or vomiting during headache attacks presented an increased CT in the pars opercularis of the left inferior frontal gyrus.ConclusionsDifferences in CT and LGI in patients affected by migraine without aura may suggest the presence of congenital and acquired abnormalities in migraine and that migraine might represent a vast spectrum of different entities. In particular, ≥ 12-year-old pediatric patients showed a decreased CT in areas related to the executive function and nociceptive networks compared to younger patients, while female patients compared to males showed a decreased CT of the auditory cortex compared to males. Therefore, early and tailored therapies are paramount to obtain migraine control, prevent cerebral reduction of cortical thickness and preserve executive function and nociception networks to ensure a high quality of life.     

Features of migraine aura in teenagers

Background

Complex migraine aura in teenagers can be complicated to diagnose. The aim of this study was to present detailed features of migraine aura in teenage migraineurs.

Methods

This cross-sectional study was conducted in the period from 2008 till 2013. A total number of 40 teenage migraineurs (20 females and 20 males) met criteria for this study. The patients were interviewed using a specially designed questionnaire for collecting data about migraine aura features. Main outcome measures were frequency of visual, somatosensory and higher cortical dysfunction (HCD) symptoms in teenage migraineurs population during the aura, and also within each individual.

Results

Visual aura was reported in every attack, followed by somatosensory (60%) and dysphasic (36.4%) aura. Scintillating scotoma and blurry vision were mostly reported and predominant visual symptoms. The most common somatosensory symptom was numbness in hand. HCD were reported by 22 (55%) patients. Slowed speech was mostly reported symptom of HCD, followed by dyslexia, déjà vu phenomenon, color dysgnosia, and dyspraxia. In patients with HCD, aura frequency per year (6.18 ± 3.17 vs. 3.33 ± 2.03, p = 0.003) and prevalence of somatosensory symptoms (77.3% vs. 38.9%, p = 0.014) were significantly higher than in patients without HCD.

Conclusions

Aura symptoms vary to a great extent in complexity in teenage migraineurs. Consequently, results obtained in this study provide useful information for clinicians when faced with unusual migraine aura.     

Early response to eptinezumab indicates high likelihood of continued response in patients with chronic migraine

BackgroundA clinical ability to describe the response trajectory of patients receiving preventive migraine treatment could expedite and improve therapeutic management decisions. This post hoc analysis of the PROMISE-2 study evaluated the consistency and predictive power of Month 1 treatment response on later response in patients with chronic migraine.MethodsPROMISE-2 was a double-blind, placebo-controlled trial that randomized adults with chronic migraine to eptinezumab 100 mg, 300 mg, or placebo administered IV every 12 weeks for up to 24 weeks (2 infusions over 6 study months). Migraine responder rates (MRRs) were calculated from monthly migraine days over 4-week intervals compared with baseline. Patients were grouped by MRR during Month 1 (< 25%, 25–< 50%, 50–< 75%, and ≥ 75%), with the number of subsequent study months (Months 2–6) with ≥50% and ≥ 75% MRR calculated in each subgroup. A similar analysis was conducted using Patient Global Impression of Change (PGIC) rating to define Month 1 subgroups (very much improved, much improved, minimally improved, and no change/worse) and rates of very much improved or much improved PGIC during Months 2–6.ResultsIn the eptinezumab 100 mg, 300 mg, and placebo groups, respectively, 194/356 (54.5%), 212/350 (60.6%), and 132/366 (36.1%) patients were ≥ 50% migraine responders during Month 1. More eptinezumab-treated patients were ≥ 75% migraine responders (100 mg, 110/356 [30.9%]; 300 mg, 129/350 [36.9%]; placebo, 57/366 [15.6%]) and more placebo-treated patients were < 25% migraine responders (eptinezumab 100 mg, 103/356 [28.9%]; 300 mg, 80/350 [22.9%]; placebo, 153/366 [41.8%]). Among patients who achieved ≥75% migraine response in Month 1, more than one-third attained ≥75% migraine response for all 5 subsequent study months and more than two-thirds achieved ≥75% migraine response for ≥3 months. More than two-thirds of those in the very much improved (PGIC) subgroup at Month 1 were much or very much improved for all 5 subsequent months.ConclusionsIn this post hoc analysis of data from PROMISE-2, more eptinezumab-treated than placebo-treated patients were early (Month 1) responders, and most early responders went on to achieve a high level of response for at least half of the 24-week treatment period. Potential for later response in early non-responders was also observed.Trial registrationClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT02974153","term_id":"NCT02974153"}}NCT02974153; registered November 23, 2016.     

Real-world evidence data on the monoclonal antibody erenumab in migraine prevention: perspectives of treating physicians in Germany

BackgroundErenumab, the first-in-class fully human monoclonal antibody targeting the calcitonin gene-related peptide receptor, was shown to be efficacious and safe for the prophylactic treatment of migraine in adults in randomized clinical trials. Large-scale, real-world evidence in multi-centre settings is still needed to confirm these results. Erenumab patient profiles outside clinical trials and physicians’ treatment patterns, as well as data from patients treated in Germany, a severely impacted population, are not published yet.MethodsTELESCOPE was a multi-centre survey gathering real-world data from 45 German headache centres between July 2019 and December 2019. The project consisted of two parts. In the first part, treating physicians shared their experiences on current erenumab treatment with regard to patient profiles, treatment patterns and treatment responses. In the second part, a retrospective chart review was conducted of 542 migraine patients treated with erenumab for at least three months. Treatment responses focused on various aspects of patients’ quality of life.ResultsThe analysis of 542 patients’ charts revealed that three-month treatment with erenumab significantly reduced monthly headaches, migraine and acute medication days. Furthermore, headache intensity and frequency were reduced in over 75 % and accompanying aura in 35 % of patients. The clinical global impression scale revealed a general improvement in 91 % of patients. According to the treating physicians’ professional judgement, 83 % of patients responded to erenumab and 80 % were satisfied with the treatment. Physicians evaluated restricted quality of life, the number of monthly migraine days and previous, prophylactic treatments as the main components of the current patient profile for monoclonal antibody recipients. Based on the assessment of physicians, erenumab reduced migraine symptoms in 65 % and increased quality of life in more than 75 % of their patients.ConclusionsTELESCOPE confirms positive treatment responses with erenumab shown in clinical trials in a real-world multi-centre setting. The results show consistently positive experiences of physicians utilizing erenumab in clinical practice and underline that therapy with this monoclonal antibody is effective in migraine patients, particular in those, who have failed several prophylactic therapies.     

Mild traumatic brain injury affects the features of migraine

BackgroundHeadache is one of the most common symptoms after concussion, and mild traumatic brain injury (mTBI) is a risk factor for chronic migraine (CM). However, there remains a paucity of data regarding the impact of mTBI on migraine-related symptoms and clinical course.MethodsOf 2161 migraine patients who participated in the American Registry for Migraine Research between February 2016 and March 2020, 1098 completed questions assessing history of TBI (50.8%). Forty-four patients reported a history of moderate to severe TBI, 413 patients reported a history of mTBI. Patients’ demographics, headache symptoms and triggers, history of physical abuse, allodynia symptoms (ASC-12), migraine disability (MIDAS), depression (PHQ-2), and anxiety (GAD-7) were compared between migraine groups with (n = 413) and without (n = 641) a history of mTBI. Either the chi-square-test or Fisher’s exact test, as appropriate, was used for the analyses of categorical variables. The Mann-Whitney test was used for the analyses of continuous variables. Logistic regression models were used to compare variables of interest while adjusting for age, gender, and CM.ResultsA significantly higher proportion of patients with mTBI had CM (74.3% [307/413] vs. 65.8% [422/641], P = 0.004), had never been married or were divorced (36.6% [147/402] vs. 29.4% [187/636], P = 0.007), self-reported a history of physical abuse (24.3% [84/345] vs. 14.3% [70/491], P <  0.001), had mild to severe anxiety (50.5% [205/406] vs. 41.0% [258/630], P = 0.003), had headache-related vertigo (23.0% [95/413] vs. 15.9% [102/640], P = 0.009), and difficulty finding words (43.0% [174/405] vs. 32.9% [208/633], P <  0.001) in more than half their attacks, and headaches triggered by lack of sleep (39.4% [155/393] vs. 32.6% [198/607], P = 0.018) and reading (6.6% [26/393] vs. 3.0% [18/607], P = 0.016), compared to patients without mTBI. Patients with mTBI had significantly greater ASC-12 scores (median [interquartile range]; 5 [1–9] vs. 4 [1–7], P < 0.001), MIDAS scores (42 [18–85] vs. 34.5 [15–72], P = 0.034), and PHQ-2 scores (1 [0–2] vs. 1 [0–2], P = 0.012).ConclusionPatients with a history of mTBI are more likely to have a self-reported a history of physical abuse, vertigo, and allodynia during headache attacks, headaches triggered by lack of sleep and reading, greater headache burden and headache disability, and symptoms of anxiety and depression. This study suggests that a history of mTBI is associated with the phenotype, burden, clinical course, and associated comorbid diseases in patients with migraine, and highlights the importance of inquiring about a lifetime history of mTBI in patients being evaluated for migraine.     

Prolonged acute migraine with aura and reversible brain MRI abnormalities after liquid sclerotherapy

Transient visual disturbances constitute the most commonly reported neurological side effect during and immediately after sclerotherapy. A few studies, based on clinical and diffusion-weighted MRI assessments, have suggested that these transient neurological symptoms correspond to migraine with aura. Recently, it has been reported that brain magnetic resonance imaging can reveal transient T2*-weighted abnormalities during the acute phase of migraine with aura. We reported a 36-year-old man who presented with transient neurological symptoms and concomitant T2*-weighted abnormalities on brain magnetic resonance imaging immediately after liquid sclerotherapy. We hypothesize that the reversible nature of the patient’s T2*-weighted abnormalities may indicate a relationship with the post-sclerotherapy migraine with aura attack.     

Delayed headache after COVID-19 vaccination: a red flag for vaccine induced cerebral venous thrombosis

BackgroundHeadache is a frequent symptom following COVID-19 immunization with a typical onset within days post-vaccination. Cases of cerebral venous thrombosis (CVT) have been reported in adenovirus vector-based COVID-19 vaccine recipients.FindingsWe reviewed all vaccine related CVT published cases by April 30, 2021. We assessed demographic, clinical variables and the interval between the vaccination and onset of headache. We assessed whether the presence of headache was associated with higher probability of death or intracranial hemorrhage.We identified 77 cases of CVT after COVID-19 vaccination. Patients’ age was below 60 years in 74/77 (95.8%) cases and 61/68 (89.7%) were women. Headache was described in 38/77 (49.4%) cases, and in 35/38 (92.1%) was associated with other symptoms. Multiple organ thrombosis was reported in 19/77 (24.7%) cases, intracranial hemorrhage in 33/77 (42.9%) cases and 19/77 (24.7%) patients died. The median time between vaccination and CVT-related headache onset was 8 (interquartile range 7.0–9.7) days. The presence of headache was associated with a higher odd of intracranial hemorrhage (OR 7.4; 95% CI: 2.7–20.8, p < 0.001), but not with death (OR: 0.51, 95% CI: 0.18–1.47, p = 0.213).ConclusionDelayed onset of headache following an adenovirus vector-based COVID-19 vaccine is associated with development of CVT. Patients with new-onset headache, 1 week after vaccination with an adenovirus vector-based vaccine, should receive a thorough clinical evaluation and CVT must be ruled out.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01324-5.     

Risk for ischemic stroke and coronary heart disease associated with migraine and migraine medication among older adults

BackgroundMigraine has been associated with cardiovascular disease (CVD) events among middle-aged adults. The objective of this study was to determine the risk for ischemic stroke and coronary heart disease (CHD) events among older adults with versus without migraine.MethodsThis retrospective cohort study was conducted using data from US adults ≥66 years of age with Medicare health insurance between 2008 and 2017. After stratification by history of CVD, patients with a history of migraine were matched 1:4 to those without a history of migraine, based on calendar year, age, and sex. Patients were followed through December 31, 2017 for ischemic stroke and CHD events including myocardial infarction or coronary revascularization. All analyses were done separately for patients with and without a history of CVD.ResultsAmong patients without a history of CVD (n = 109,950 including n = 21,990 with migraine and n = 87,960 without migraine), 1789 had an ischemic stroke and 3552 had a CHD event. The adjusted hazard ratio (HR) among patients with versus without migraine was 1.20 (95% confidence interval [95%CI], 1.07–1.35) for ischemic stroke and 1.02 (95%CI, 0.93–1.11) for CHD events. Compared to patients without migraine, those with migraine who were taking an opioid medication had a higher risk for ischemic stroke (adjusted HR 1.43 [95%CI, 1.20–1.69]), while those taking a triptan had a lower risk for CHD events (adjusted HR 0.79 [95%CI, 0.67–0.93]). Among patients with a history of CVD (n = 79,515 including n = 15,903 with migraine and n = 63,612 without migraine), 2960 had an ischemic stroke and 7981 had a CHD event. The adjusted HRs (95%CI) for ischemic stroke and CHD events associated with migraine were 1.27 (1.17–1.39) and 0.99 (0.93–1.05), respectively. Patients with migraine taking an opioid medication had a higher risk for ischemic stroke (adjusted HR 1.21 [95%CI, 1.07–1.36]), while those taking a triptan had a lower risk for CHD events (adjusted HR 0.83 [95%CI, 0.72–0.95]), each versus those without migraine.ConclusionsOlder adults with migraine are at increased risk for ischemic stroke. The risk for ischemic stroke among older adults with migraine may differ by migraine medication classes.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01338-z.     

Patient-reported outcomes,health-related quality of life,and acute medication use in patients with a ≥ 75% response to eptinezumab: subgroup pooled analysis of the PROMISE trials

BackgroundPROMISE-1 and PROMISE-2 evaluated the preventive efficacy, tolerability, and safety of eptinezumab, a calcitonin gene-related peptide–targeted monoclonal antibody, in adults with episodic (EM) and chronic migraine (CM), finding significant reductions in migraine frequency. This post hoc analysis compared patient-reported outcomes (PROs), health-related quality of life (HRQoL) and acute medication use in patients with a ≥ 75% migraine responder rate (MRR) after treatment with eptinezumab to patients with a ≥ 50– < 75% MRR.MethodsPROMISE-1 and PROMISE-2 were phase 3, randomized, double-blind, placebo-controlled studies. This analysis included patients from both studies treated with eptinezumab 100 mg or 300 mg who experienced ≥ 75% and ≥ 50–< 75% MRR over Weeks 1–12 (wks1–12). In both studies, HRQoL was measured by the 36-item Short-Form Health Survey (SF-36) and acute medication usage. PROMISE-2 also included the 6-item Headache Impact Test (HIT-6), patient-identified most bothersome symptom (PI-MBS), and Patient Global Impression of Change (PGIC).ResultsIn PROMISE-1, a total of 115/443 (26.0%; 100 mg, n = 49, 300 mg, n = 66) and 120/443 (27.0%; 100 mg, n = 61, 300 mg, n = 59) eptinezumab-treated patients achieved ≥ 75% and ≥ 50–< 75% MRR over wks1–12, respectively. In PROMISE-2, a total of 211/706 (30.0%; 100 mg, n = 95; 300 mg, n = 116) and 209/706 (29.6%; 100 mg, n = 110, 300 mg, n = 99) eptinezumab-treated patients achieved ≥ 75% and ≥ 50–< 75% MRR over wks1–12, respectively. EM and CM patients with ≥ 75% and ≥ 50–< 75% MRR over wks1–12 showed reduced use of acute headache medication and increased HRQoL to normative levels across SF-36 domains of bodily pain, social functioning, and physical functioning. In CM patients with ≥ 75% and ≥ 50–< 75% MRR over wks1–12, the mean change in HIT-6 total score with eptinezumab (pooled) was − 11.7 and − 7.6, respectively. “Very much” or “much” improvement responses were reported in 41.8% and 16.5% on PI-MBS and 36.2% and 20.0% on PGIC in ≥ 75% and ≥ 50–< 75% MRR, respectively.ConclusionEptinezumab treatment induced a ≥ 75% MRR over wks1–12 in the majority of patients. This patient subgroup reported substantial improvements in PROs associated with headache-related life impact and HRQoL, and reductions in acute headache medication use, which were more marked than those in the ≥ 50–< 75% responders. This study supports the clinical meaningfulness of ≥ 75% MRR for patients with either EM or CM.Trial registrationClinicalTrials.gov identifiers: {"type":"clinical-trial","attrs":{"text":"NCT02559895","term_id":"NCT02559895"}}NCT02559895 (PROMISE-1), {"type":"clinical-trial","attrs":{"text":"NCT02974153","term_id":"NCT02974153"}}NCT02974153 (PROMISE-2).Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-022-01386-z.     

Magnetic suppression of perceptual accuracy is not reduced in episodic migraine without aura

Background

Altered cortical excitability is thought to be part of migraine pathophysiology. Reduced magnetic suppression of perceptual accuracy (MSPA) has been found in episodic migraine with aura and in chronic migraine, and has been interpreted as reduced inhibition of the occipital cortex in these migraine subtypes. Results are less clear for episodic migraine without aura. In the present study we compared MSPA between 24 healthy controls and 22 interictally measured episodic migraine patients without aura. In addition, we investigated test-retest reliability in 33 subjects (24 controls, 9 migraine).

Findings

Visual accuracy was assessed by letter recognition and modulated by transcranial magnetic stimulation delivered to the occipital cortex at different intervals to the letter presentation (40, 100 and 190 ms). The results confirm suppression of visual accuracy at the 100 ms interval (p < 0.001), but there were no significant group differences (percentage of correctly recognized letters, control: 36.1 ± 36.2; migraine: 44.0 ± 32.3, p = 0.44). Controls and migraine patients were pooled for assessment of test-retest reliability (n = 33). Levels of suppression at 100 ms were similar at test (percentage of correctly recognized letters: 42.3 ± 32.6) and retest (41.9 ± 33.8, p = 0.90) and test-retest correlations were good (r = 0.82, p < 0.001).

Conclusions

The results demonstrate that occipital cortex inhibition as assessed with MSPA is not reduced in episodic migraine without aura. This suggests a larger role of occipital cortex excitability in episodic migraine with aura and in chronic migraine compared to episodic migraine without aura. Test-retest reliability of MSPA was good.     

Fremanezumab in the prevention of high-frequency episodic and chronic migraine: a 12-week,multicenter, real-life,cohort study (the FRIEND study)

BackgroundFremanezumab has demonstrated to be effective, safe, and tolerated in the prevention of episodic or chronic migraine (CM) in randomized, placebo-controlled trials (RCTs). Real-life studies are needed to explore drug effects in unselected patients in routine circumstances and to provide higher generalizability results. This study explores the effectiveness, safety, and tolerability of fremanezumab in a real-life population of individuals affected by high-frequency episodic (HFEM: 8–14 days/month) or CM.MethodsThis is a 12-week multicenter, prospective, cohort, real-life study. We considered all consecutive patients affected by HFEM or CM visited at 9 Italian headache centers from 28/07/2020 to 11/11/2020. Eligible patients were given subcutaneous fremanezumab at the doses of 225 mg monthly or 675 mg quarterly, according to their preference. Primary study endpoints were the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients at weeks 9–12 compared to baseline. Secondary endpoints encompassed variation in monthly analgesic intake (MAI), Numerical Rating Scale (NRS), HIT-6 and MIDAS scores, and ≥ 50%, ≥ 75% and 100% responder rates at the same time intervals.ResultsSixty-seventh number migraine patients had received ≥ 1 subcutaneous fremanezumab dose and were considered for safety analysis, while 53 patients completed 12 weeks of treatment and were included also in the effectiveness analysis. Fremanezumab was effective in both HFEM and CM, inducing at week 12 a significant reduction in MMDs (-4.6, p < 0.05), MHDs (-9.4, p < 0.001), MAI (-5.7, p < 0.05; -11.1, p < 0.001), NRS (-3.1, p < 0.001; -2.5, p < 0.001), and MIDAS scores (-58.3, p < 0.05; -43.7; p < 0.001). HIT-6 was significantly reduced only in HFEM patients (-18.1, p < 0.001). Remission from CM to episodic migraine and from MO to no-MO occurred in 75% and 67.7% of the patients. The ≥ 50%, ≥ 75% and 100% responder rates at week 12 were 76.5%, 29.4% and 9.9% in HFEM and 58.3%, 25% and 0% in CM. Younger age emerged as a positive response predictor (OR = 0.91; 95% CI 0.85–0.98, p = 0.013). Treatment-emergent adverse events were uncommon (5.7%) and mild. No patient discontinued fremanezumab for any reason.ConclusionsFremanezumab seems more effective in real-life than in RCTs. Younger age emerges as a potential response predictor.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-022-01396-x.     

Efficacy of galcanezumab in patients with migraine and history of failure to 3–4 preventive medication categories: subgroup analysis from CONQUER study

BackgroundChronic migraine (CM) and episodic migraine (EM) are associated with substantial headache-related disability, poor quality of life and global societal burden. In this subgroup analysis from the CONQUER study, we report efficacy outcomes from a pre-specified analysis of galcanezumab versus placebo in patients with CM or EM and 3–4 prior preventive medication category failures due to inadequate efficacy (after at least 2 months at maximum tolerated dose), or safety or tolerability reasons. The patient population is of particular interest due to evidence of decreased quality of life and increased economic burden among patients with migraine that is inadequately managed and is of interest to decision-makers globally.MethodsKey outcomes included overall mean change from baseline in monthly migraine headache days and proportions of patients achieving ≥30% (CM), ≥50%, and ≥ 75% reduction (response rates) in monthly migraine headache days across Months 1–3. Patient functioning and disability were evaluated at Month 3.ResultsOf the 462 randomized patients, 186 (40.3%) had a history of 3–4 preventive category failures. Galcanezumab versus placebo resulted in significantly (P ≤ .001) larger overall mean reduction in monthly migraine headache days (total: − 5.49 versus − 1.03; CM: − 6.70 versus − 1.56; EM: − 3.64 versus − 0.65). Similarly, the ≥50% response rate was significantly (P ≤ .001) higher with galcanezumab versus placebo (total: 41.0 versus 12.7; CM: 41.5 versus 8.4; EM: 41.1 versus 16.5). In the CM group, the ≥30% response rate was significantly higher in the galcanezumab group than the placebo group (CM, 57.5 versus 19.8, P ≤ .0001) as was the ≥75% response rate (13.3 versus 2.6, P ≤ .05). Galcanezumab also resulted in significant (P < .0001) improvements in patient functioning and reductions in disability.ConclusionsGalcanezumab was effective in a difficult-to-treat population of patients with CM or EM who had failed 3–4 prior preventive medication categories.Trial registrationCONQUER. Clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT03559257","term_id":"NCT03559257"}}NCT03559257.     

Clinical relevance of depressed kynurenine pathway in episodic migraine patients: potential prognostic markers in the peripheral plasma during the interictal period

BackgroundAltered glutamatergic neurotransmission and neuropeptide levels play a central role in migraine pathomechanism. Previously, we confirmed that kynurenic acid, an endogenous glutamatergic antagonist, was able to decrease the expression of pituitary adenylate cyclase-activating polypeptide 1–38, a neuropeptide with known migraine-inducing properties. Hence, our aim was to reveal the role of the peripheral kynurenine pathway (KP) in episodic migraineurs. We focused on the complete tryptophan (Trp) catabolism, which comprises the serotonin and melatonin routes in addition to kynurenine metabolites. We investigated the relationship between metabolic alterations and clinical characteristics of migraine patients.MethodsFemale migraine patients aged between 25 and 50 years (n = 50) and healthy control subjects (n = 34) participated in this study. Blood samples were collected from the cubital veins of subjects (during both the interictal/ictal periods in migraineurs, n = 47/12, respectively). 12 metabolites of Trp pathway were determined by neurochemical measurements (UHPLC-MS/MS).ResultsPlasma concentrations of the most Trp metabolites were remarkably decreased in the interictal period of migraineurs compared to healthy control subjects, especially in the migraine without aura (MWoA) subgroup: Trp (p < 0.025), L-kynurenine (p < 0.001), kynurenic acid (p < 0.016), anthranilic acid (p < 0.007), picolinic acid (p < 0.03), 5-hydroxy-indoleaceticacid (p < 0.025) and melatonin (p < 0.023). Several metabolites showed a tendency to elevate during the ictal phase, but this was significant only in the cases of anthranilic acid, 5-hydroxy-indoleaceticacid and melatonin in MWoA patients. In the same subgroup, higher interictal kynurenic acid levels were identified in patients whose headache was severe and not related to their menstruation cycle. Negative linear correlation was detected between the interictal levels of xanthurenic acid/melatonin and attack frequency. Positive associations were found between the ictal 3-hydroxykynurenine levels and the beginning of attacks, just as between ictal picolinic acid levels and last attack before ictal sampling.ConclusionsOur results suggest that there is a widespread metabolic imbalance in migraineurs, which manifests in a completely depressed peripheral Trp catabolism during the interictal period. It might act as trigger for the migraine attack, contributing to glutamate excess induced neurotoxicity and generalised hyperexcitability. This data can draw attention to the clinical relevance of KP in migraine.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01239-1.     

Central auditory processing and migraine: a controlled study

Background

This study aimed to verify and compare central auditory processing (CAP) performance in migraine with and without aura patients and healthy controls.

Methods

Forty-one volunteers of both genders, aged between 18 and 40 years, diagnosed with migraine with and without aura by the criteria of “The International Classification of Headache Disorders” (ICDH-3 beta) and a control group of the same age range and with no headache history, were included. Gaps-in-noise (GIN), Duration Pattern test (DPT) and Dichotic Digits Test (DDT) tests were used to assess central auditory processing performance.

Results

The volunteers were divided into 3 groups: Migraine with aura (11), migraine without aura (15), and control group (15), matched by age and schooling. Subjects with aura and without aura performed significantly worse in GIN test for right ear (p = .006), for left ear (p = .005) and for DPT test (p < .001) when compared with controls without headache, however no significant differences were found in the DDT test for the right ear (p = .362) and for the left ear (p = .190).

Conclusions

Subjects with migraine performed worsened in auditory gap detection, in the discrimination of short and long duration. They also presented impairment in the physiological mechanism of temporal processing, especially in temporal resolution and temporal ordering when compared with controls. Migraine could be related to an impaired central auditory processing.

Clinical trial registration

Research Ethics Committee (CEP 0480.10) – UNIFESP