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Question: Migraine is a cyclic and complex disorder, characterized by attacks of headache, sensory and cognitive disturbances1. Thalamocortical connectivity in migraine has been found to be transiently abnormal2. Our aim was to assess if the dynamical properties of the migraine brain are affected during the interictal phase. Methods: Resting-state functional MRI data was collected from 14 menstrual migraine patients without aura (interictal phase) and 12 healthy controls (menstrual post-ovulation phase). fMRI data processing included3: motion and distortion correction, temporal highpass filter, regression of motion and physiological confounds, spatial smoothing, and parcellation with the Desikan atlas. Dynamic functional connectivity (dFC) between regions was computed using phase coherence, and recurrent dFC states were identified by kmeans clustering (k ranging between 3 and 15) of the leading eigenvectors of dFC in each time point4. Permutation tests were performed to evaluate statistically significant differences between patients and controls in the probability of occurrence and the mean lifetime of the dFC states. Results: Similar dFC states were found consistently across different numbers of clusters, k, which resembled the canonical resting-state networks as expected. Compared to healthy controls, migraine patients show a significantly lower mean lifetime in one dFC state, when grouping in 4, 5 and 6 clusters. No differences were found for the probability of occurrence. Conclusions: Migraine may be linked to a disruption of brain networks dynamics. This emphasizes the need to adopt time-resolved methods, in addition to static, to study functional connectivity, to better understand the mechanisms of migraine. Our next step will be to assess the dynamics of the migraine brain throughout the migraine cycle.

Question. We evaluated if EHF criteria for resistant (RES) and refractory (REF) migraine identify patients with more severe migraine burden. Methods. We performed an observational, multi center, international study to compare baseline characteristics, comorbidities, and PROMs of non-resistant and non-refractory (NRNR) migraine, RES and REF individuals in the REFINE study. Results. We included 175 individuals with NRNR migraine, 133 (39.7%) with RES and 27 (8.0%) with REF. Individuals with RES and REF migraine as compared to those with NRNR reported higher monthly migraine days (median=8, IQR=5-14 vs. median=13, IQR=10- 17 and median=15, IQR=10-20; p≤0.001), months of chronification (median=24, IQR=12-72 vs. median=40, IQR=12-108 and median=60, IQR=18-96; p=0.044), monthly days of symptomatic drugs assumption (median=8, IQR=5-15 vs. median=12, IQR=9-20 and median=15, IQR=10-20; p≤0.001), medication overuse (19.4% vs. 45.9% and 40.7%; p≤0.001). They also had more comorbidities such as depression (18.3% vs. 31.1% and 44.4%; p=0.002) and anxiety (13.7% vs. 21.1% and 37%; p=0.009). In these groups, PROMs also revealed a higher presence of anxiety (p≤0.001) and depression (p≤0.001) symptoms and poorer sleep quality (p=0.006). Regarding specific perceptions about migraine, RES and REF individuals reported higher impact of migraine on daily life (p≤0.001) and work, household work, and social life (p≤0.001), along with a lower perception of the effectiveness of their ongoing treatment for migraine (p≤0.001), when compared to NRNR subjects (Table 1). Conclusion. RES and REF migraine is associated with relevant migraine burden considering migraine features, comorbidities and scores at several scales; the severe burdensome condition of RES and REF is confirmed by the median number of monthly migraine days and PROMs.

QUESTION: Hormones play a preponderant role in triggering migraine attacks, with women having higher prevalence and severity of migraine due to their influence along the reproductive cycle1. The preictal, ictal and postictal phases tend to include cognitive executive difficulties along with the rest of the attack symptoms2. Fluctuations in neural sensitivity observed in migraine could underlie such difficulties3. On the other hand, functional and structural changes in brain structures related to cognitive processes along the menstrual cycle have also been documented4. We aim to use functional Magnetic Resonance Imaging (fMRI) to evaluate working memory at different stages of the migraine cycle and compare to a non-migraine population while controlling for their menstrual phases. METHODS: A clinical sample of 15 women suffering from episodic migraine with menstrual-related attacks were recruited. They underwent fMRI sessions with a verbal N-back task in different phases of the migraine cycle, namely, preictal, ictal, postictal and interictal phase. 15 nonmigraine controls matched for gender and age were assessed during premenstrual and post ovulation phase. A neuropsychological battery and questionnaires quantifying clinical symptoms and attack description at the time of the exam were also applied. RESULTS: We report results for 70 sessions of acquisition in whole brain group analysis using a cluster threshold of z > 2.3. We observed left orbital prefrontal areas with significantly higher activation during preictal (z =3.44), ictal (z=3.49) and interictal (z=3.3) phases compared to postictal phase. CONCLUSIONS: The brain activation observed in prefrontal regions during the migraine attack phases could be related to cognitive inhibition while performing a working memory task.

Question: Do patients with episodic menstrual migraine exhibit white-matter microstructural changes? Methods: 14 women with episodic menstrual migraine (35±8yrs) were assessed during interictal phase together with 11 healthy women (29±10yrs) during a matching phase of their menstrual cycle (post-ovulation). 2D-EPI multi-shell DWI data were acquired on a 3T Siemens Vida (64-ch coil) and preprocessed using DESIGNER [1]. Diffusion tensor / kurtosis imaging (DTI/DKI) parameter maps were estimated and skeletonised [2] and histogram-metrics were computed for each subject: median, peak height, width, and value. Results: Voxelwise statistical analysis [3] revealed multiple whitematter regions with lower MD and AD in patients, with no differences in FA and RD. Interestingly, migraineurs showed increased MK, AK and RK. Moreover, significant groups differences (Mann- Whitney test with Bonferroni correction) were found in histogram-metrics MD peak value, AD median and peak height and AK median. Median AK was positively associated (Spearman correlation) with disease duration but not with attack frequency and pain intensity. Conclusion: Our findings extended previous reports of whitematter microstructural changes in migraineurs across multiple brain regions [4, 5]. DKI histogram-metrics showed potential as disease biomarkers.

Background New treatments are currently offering new opportunities and challenges in clinical management and research in the migraine field. There is the need of homogenous criteria to identify candidates for treatment escalation as well as of reliable criteria to identify refractoriness to treatment. To overcome those issues, the European Headache Federation (EHF) issued a Consensus document to propose criteria to approach difficult-to-treat migraine patients in a standardized way. The Consensus proposed well-defined criteria for resistant migraine (i.e., patients who do not respond to some treatment but who have residual therapeutic opportunities) and refractory migraine (i.e., patients who still have debilitating migraine despite maximal treatment efforts). The aim of this study was to better understand the perceived impact of resistant and refractory migraine and the attitude of physicians involved in migraine care toward those conditions. Methods We conducted a web-questionnaire-based cross-sectional international study involving physicians with interest in headache care. Results There were 277 questionnaires available for analysis. A relevant proportion of participants reported that patients with resistant and refractory migraine were frequently seen in their clinical practice (49.5% for resistant and 28.9% for refractory migraine); percentages were higher when considering only those working in specialized headache centers (75% and 46% respectively). However, many physicians reported low or moderate confidence in managing resistant (8.1% and 43.3%, respectively) and refractory (20.7% and 48.4%, respectively) migraine patients; confidence in treating resistant and refractory migraine patients was different according to the level of care and to the number of patients visited per week. Patients with resistant and refractory migraine were infrequently referred to more specialized centers (12% and 19%, respectively); also in this case, figures were different according to the level of care. Conclusions This report highlights the clinical relevance of difficult-to-treat migraine and the presence of unmet needs in this field. There is the need of more evidence regarding the management of those patients and clear guidance referring to the organization of care and available opportunities.

In joint initiatives, the European Headache Federation and Lifting The Burden have described a model of structured headache services (with their basis in primary care), defined service quality in this context, and developed practical methods for its evaluation. Here, in a continuation of the service quality evaluation programme, we set out ten suggested role- and performance-defining standards for specialized headache centres operating as an integral component of these services. Verifiable criteria for evaluation accompany each standard. The purposes are five-fold: (i) to inspire and promote, or stimulate the establishment of, specialized headache centres as centres of excellence; (ii) to define the role of such centres within optimally structured and organized national headache services; (iii) to set out criteria by which such centres may be recognized as exemplary in their fulfilment of this role; (iv) to provide the basis for, and to initiate and motivate, collaboration and networking between such centres both nationally and internationally; (v) ultimately to improve the delivery and quality of health care for headache. © 2019 The Author(s).

Mètode Delphi; Eficàcia dels fàrmacs preventius de la migranya Delphi survey; Effectiveness of migraine preventive drugs Método Delfos; Eficacia de los medicamentos preventivos contra la migraña Background Clinical guidelines agree that preventive treatment should be considered in patients with uncontrolled migraine despite acute medications or patients with ≥4 migraine days per month. However, the criteria to define the effectiveness of treatment and the factors that inform the decision to (dis)continue it are not clearly defined in clinical practice. Methods Overall, 148 healthcare practitioners from five European countries completed a two-wave questionnaire. The Steering Committee defined a simulated set of 108 migraine patient profiles based on the combination of five factors (frequency of the attacks, intensity of the attacks, use of acute migraine medications, patient perception and presence/absence of tolerable side effects). These profiles were used in a Delphi survey among European neurologists to identify the criteria that should be used to decide treatment response and continuation using a conjoint analysis approach. Results Consensus was reached for 82/108 (76%) of profiles regarding treatment response, and for 86/108 (80%) regarding treatment continuation. Multivariable logistic regression analysis showed that a ≥50% reduction in the use of acute migraine medications and positive patient's perception of treatment were the most important factors that lead to the decision of continuing (combined factors, OR = 18.3, 95% CI 13.4–25.05). Conclusions This survey identifies two relevant outcome measures: one objective (use of acute migraine treatment medications) and one subjective (positive patient perception) that guide the clinician decision to continue preventive treatment in migraine patients. Significance In clinical practice, criteria to define the effectiveness of migraine preventive treatment and factors that guide treatment stop or continuation are not clearly defined. In this simulated clinical setting study, a reduction in the use of acute migraine medications was the factor associated with preventive treatment effectiveness definition. This study also revealed that factors strongly associated with the decision of treatment continuation in real life are the acute migraine medications use and a positive patient's perception of treatment effectiveness. Novartis Pharma AG financially supported the development of this project, the medical writing assistance and the page processing charges for this article. The authors have received no payment to write this article.