A study of differential microRNA expression profile in migraine: the microMIG exploratory study.

BACKGROUND: Several studies have described potential microRNA (miRNA) biomarkers associated with migraine, but studies are scarcely reproducible primarily due to the heterogeneous variability of participants. Increasing evidence shows that disease-related intrinsic factors together with lifestyle (environmental factors), influence epigenetic mechanisms and in turn, diseases. Hence, the main objective of this exploratory study was to find differentially expressed miRNAs (DE miRNA) in peripheral blood mononuclear cells (PBMC) of patients with migraine compared to healthy controls in a well-controlled homogeneous cohort of non-menopausal women. METHODS: Patients diagnosed with migraine according to the International Classification of Headache Disorders (ICHD-3) and healthy controls without familial history of headache disorders were recruited. All participants completed a very thorough questionnaire and structured-interview in order to control for environmental factors. RNA was extracted from PBMC and a microarray system (GeneChip miRNA 4.1 Array chip, Affymetrix) was used to determine the miRNA profiles between study groups. Principal components analysis and hierarchical clustering analysis were performed to study samples distribution and random forest (RF) algorithms were computed for the classification task. To evaluate the stability of the results and the prediction error rate, a bootstrap (.632 + rule) was run through all the procedure. Finally, a functional enrichment analysis of selected targets was computed through protein-protein interaction networks. RESULTS: After RF classification, three DE miRNA distinguished study groups in a very homogeneous female cohort, controlled by factors such as demographics (age and BMI), life-habits (physical activity, caffeine and alcohol consumptions), comorbidities and clinical features associated to the disease: miR-342-3p, miR-532-3p and miR-758-5p. Sixty-eight target genes were predicted which were linked mainly to enriched ion channels and signaling pathways, neurotransmitter and hormone homeostasis, infectious diseases and circadian entrainment. CONCLUSIONS: A 3-miRNA (miR-342-3p, miR-532-3p and miR-758-5p) novel signature has been found differentially expressed between controls and patients with migraine. Enrichment analysis showed that these pathways are closely associated with known migraine pathophysiology, which could lead to the first reliable epigenetic biomarker set. Further studies should be performed to validate these findings in a larger and more heterogeneous sample.

InterMiG: international differences in the therapeutic approach to migraine patients in specialized headache centers.

BACKGROUND: There is currently a wide therapeutic arsenal for migraine patients, without a single first-line preventive drug and we choose the different available alternatives taking into account comorbidities, national guidelines, previous treatments and personal experiences. Our objective was to evaluate the differences in the use of migraine treatments between neurologists from different countries. METHODS: This is a multi-centre observational study carried out by neurologists from specialized headache units in seven countries, retrospective with consecutive inclusion of all patients presenting with a migraine diagnosis, over a period of three months. RESULTS: A total of 734 patients were recruited but only 600 were considered in the analysis in order to homogenize the patient cohorts from countries: 200 Spain (ES), 100 Italy (IT), 85 Russia (RUS), 80 Germany (DE), 60 Portugal (PT), 45 Poland (PL) and 30 Australia (AU). 85.4 % of patients were women with a mean age of 42.6 ± 11.8 years. Considering previous and current preventive treatment, the order of use was: antidepressants (69.3 %), antiepileptic drugs (54.7 %), beta-blockers and antihypertensive drugs (49.7 %), OnabotulinumtoxinA (44.0 %) and others (36.2 %). Statistically significant differences were found between all pharmacological classes: antidepressants were commonly used in all countries, with the exception of Poland (AU: 76.7 %, IT: 71.0 %, DE: 60.0 %, PL: 31.1 %, PT: 71.7 %, RUS: 70.6 %, ES: 78.5 %; p < 0.0001); antiepileptic drugs were more frequently prescribed in Portugal, Australia and Spain (AU: 73.3 %, IT: 40.0 %, DE: 37.5 %, PL: 48.9 %, PT: 85.0 %, RUS: 29.4 % and ES: 69.0 %; p < 0.0001); beta-blockers and antihypertensive drugs were frequently used in all countries except Italy (AU: 60.0 %, IT: 14.0 %, DE: 53.8 %, PL: 48.9 %, PT: 68.3 %, RUS: 49.4 % and ES: 59.0 %; p < 0.0001); BTX-A were predominately used in Spain, Italy and Australia (AU:56.7 %, IT:58.0 %, DE:20.0 %, PL: 42.2 %, PT: 26.7 %, RUS: 24.7 % and ES: 58.5 %; p < 0.0001) and others were most frequently used in Poland (AU: 0.0 %, IT: 19.0 %, DE: 42.5 %, PL: 95.6 %, PT: 31.7 %, RUS: 3.5 % and ES: 49.5 %; p < 0.0001). If only patients without comorbidities are considered (200/600), statistically differences between countries persist in all preventive treatments. CONCLUSIONS: There is heterogeneity in the choice of preventive treatment between different countries. Prospective comparative studies of the different oral and subcutaneous alternatives would help to create a global therapeutic algorithm that would guarantee the best option for our patients.

Estimating the savings associated with a migraine-free life: results from the Spanish Atlas.

BACKGROUND AND PURPOSE: Migraine is a common and costly neurological disorder. The aims of this study were to quantify the costs of chronic (CM) and episodic migraine (EM) in Spain, evaluating the impact of psychiatric comorbidities and disability, and to estimate the economic savings associated with reducing the number of migraine-days by 50%. METHODS: This was an observational, cross-sectional analysis of data from migraine patients who participated in the Spanish Migraine Atlas. The participants were invited to complete a structured questionnaire including the following scales: the Headache Needs Assessment, the Hospital Anxiety and Depression Scale, and the Migraine Disability Assessment Scale (MIDAS). RESULTS: A total of 475 patients were included, of whom 187 had CM (39.4%). Total costs per patient/year were: €16 578.2 ± €34 568.1 for CM and €6227.8 ± €6515.7 for EM. A higher degree of disability, according to MIDAS, significantly increased the total cost of migraine, while the presence of psychiatric comorbidity increased costs for EM patients only. A reduction of 1 migraine-day per month decreased average total costs by €744.14 per patient/year for EM and €663.20 per patient/year for CM, while a reduction in the number of migraine-days by 50% would result in economic savings of €2232.44 per patient/year (R2  = 0.927) for EM and €6631.99 per patient/year (R2  = 0.886) for CM. CONCLUSIONS: The costs associated with migraine were driven by migraine frequency and the degree of disability, whereas psychiatric comorbidity only influenced the cost of EM. These results highlight the need to optimize migraine management to reduce the economic migraine burden. Future studies are needed to confirm our results.

Evaluation of the concomitant use of oral preventive treatments and onabotulinumtoxinA in chronic migraine: the PREVENBOX study.

BACKGROUND AND PURPOSE: OnabotulinumtoxinA is an effective preventive treatment for chronic migraine (CM). In CM, in addition to a reduction in headache frequency, a decreased reliance on oral prophylactics is also indicative of treatment effectiveness. This study aimed to quantify the change in the use of oral prophylactics after treatment with onabotulinumtoxinA in patients with CM. METHODS: This was a retrospective, multicentric, cross-sectional study. Patients with CM (International Classification of Headache Disorders-3beta) that had been treated with onabotulinumtoxinA were enrolled consecutively. We collected parameters related to each patient's pre-treatment situation, as well as their current situation, focusing on frequency and intensity of migraine, number of oral prophylactics and the respective cycle of onabotulinumtoxinA. Univariate and logistic regression analyses were performed. RESULTS: We included 542 patients, 90.0% of whom were taking oral preventive treatments. During treatment with onabotulinumtoxinA, 47.8% withdrew at least one prophylactic and 41.6% stopped using oral prophylactics altogether. Factors associated with a reduction or cessation of oral prophylactics were >50% improvement in frequency and intensity, remission to episodic migraine, use of topiramate as an initial treatment, increased number of infiltrations and shorter chronification period (P < 0.05). The multivariate analysis showed that a chronification period <20 months, more than five cycles of onabotulinumtoxinA, >50% improvement in pain intensity and topiramate as an initial treatment were predictors of a reduction in oral prophylactics (area under the curve, 70.3%; P < 0.001). CONCLUSIONS: Our study demonstrated the efficacy and safety of onabotulinumtoxinA. This treatment reduced the use of oral prophylactics. Withdrawal of oral prophylactics was most likely to occur after five cycles of treatment.

Early efficacy and late gain in chronic and high-frequency episodic migraine with onabotulinumtoxinA.

BACKGROUND AND PURPOSE: The aim was to analyse the clinical characteristics of a long-term follow-up of patients with chronic and high-frequency episodic migraine in treatment with onabotulinumtoxinA. METHODS: Patients diagnosed with high-frequency episodic migraine (HFEM) or chronic migraine (CM) according to the International Classification of Headache Disorders 3 beta were included. A comparative analysis was carried out at each study time point identifying outcome measures according to initial diagnosis and treatment duration. RESULTS: In all, 578 patients were recruited and after 24 months outcome data were collected from 100 patients: 84.0% CM and 16.0% HFEM. After 24 months, headache frequency was significantly reduced by 10.5 days from baseline, 64.0% reported a ≥50% reduction in pain intensity and 70.0% of patients had ≥50% reduction in analgesic use. Comparing baseline diagnoses, at month 6 CM patients presented higher mean reduction in frequency (CM 44.3% ± 32.6% vs. HFEM 34.6% ± 24.8%) and analgesic use (CM 53.6% ± 35.4% vs. HFEM 39.3% ± 33.2%). At month 12, the mean reduction in frequency was similar in CM and HFEM patients (CM 44.7% ± 33.4% vs. HFEM 41.2% ± 28.2%). Improvement in pain intensity, analgesic use and Migraine Disability Assessment were proportional in both diagnoses. CONCLUSIONS: OnabotulinumtoxinA efficacy is significant at 6 months in frequency and analgesic intake and remains stable during follow-up, whilst the intensity of pain decreases in a stepwise manner at each time point of the analysis. The improvement in CM and HFEM patients is proportional and significant after 1 year of treatment.

OnabotulinumtoxinA in chronic migraine: predictors of response. A prospective multicentre descriptive study.

BACKGROUND AND PURPOSE: OnabotulinumtoxinA is a treatment specifically approved for the prophylaxis of chronic migraine in adults. The aim of this study was to assess the effectiveness of OnabotulinumtoxinA in chronic migraine after 1 year of treatment in a real-life setting and to identify clinical predictors of outcome. METHODS: We designed a prospective multicentre study performed in 13 hospitals in Spain. Patients underwent a complete medical history and examination. They were treated with OnabotulinumtoxinA every 12 weeks for 1 year. Data about outcome, adverse events, abortive medication use, emergency room use and disability were collected at 3 and 12 months. RESULTS: A total of 725 subjects completed the study. At 12 months, 79.3% showed >50% reduction in number of headaches per month and 94.9% reported no adverse events. Unilaterality of pain, fewer days of disability per month and milder headache at baseline were correlated with good outcome. Duration of disease <12 months increased the chances of response to treatment with OnabotulinumtoxinA (odds ratio, 1.470; 95% confidence interval, 1.123-2.174; P = 0.045). CONCLUSIONS: This study confirmed the effectiveness of treatment with OnabotulinumtoxinA after 1 year of treatment. The chances of a good outcome may be increased by starting treatment in the first 12 months after chronic migraine diagnosis.

When does chronic migraine strike? A clinical comparison of migraine according to the headache days suffered per month.

Introduction According to the IHCD-3ß classification, chronic migraine (CM) is headache occurring on 15 or more days/month. Episodic migraine (EM) can be divided into low frequency (LFEM) and high frequency (HFEM) depending on the headache days suffered per month. Methods We performed a clinical comparison of migraine characteristics according to monthly headache days suffered. Patients were divided into three groups: LFEM (1-9 headache days/month), HFEM (10-14 headache days/month) and CM (≥15 headache days/month). Results The analysis included 1109 patients. Previously reported differences between EM and CM were replicated. However, there were three times more clinical differences between LFEM and HFEM than between HFEM and CM (15 vs. 6). A new model that takes 10 headache days as a cut-off value for CM would have a minimally higher predictive capacity (72.8%) and no statistical differences (71.8%) when comparing it to the current classification. Conclusions HFEM patients have few clinical differences compared with CM patients. This includes the poor outcomes regarding headache-related disability and impact on daily life. According to these findings, neurologists and headache specialists should consider that the emotional and functional impact in HFEM patients could be as disabling as in those with CM.

Consensus recommendations for anaesthetic peripheral nerve block. / Guía consenso sobre técnicas de infiltración anestésica de nervios pericraneales.

INTRODUCTION: Anaesthetic block, alone or in combination with other treatments, represents a therapeutic resource for treating different types of headaches. However, there is significant heterogeneity in patterns of use among different professionals. DEVELOPMENT: This consensus document has been drafted after a thorough review and analysis of the existing literature and our own clinical experience. The aim of this document is to serve as guidelines for professionals applying anaesthetic blocks. Recommendations are based on the levels of evidence of published studies on migraine, trigeminal autonomic cephalalgias, cervicogenic headache, and pericranial neuralgias. We describe the main technical and formal considerations of the different procedures, the potential adverse reactions, and the recommended approach. CONCLUSION: Anaesthetic block in patients with headache should always be individualised and based on a thorough medical history, a complete neurological examination, and expert technical execution.

Periaqueductal gray calcitonin gene-related peptide modulates trigeminovascular neurons.

BACKGROUND: Calcitonin gene-related peptide (CGRP) receptor antagonism is an approach to migraine therapy. The locus of action of antimigraine treatment is not resolved. The objective was to investigate CGRP receptors in the ventrolateral periaqueductal gray (vlPAG) involved in the modulation of trigeminovascular nociception by descending influences on neurotransmission. METHODS: The presence of calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1), which form functional CGRP receptors, was investigated. CGRP and its receptor antagonists, olcegepant and CGRP (8-37), were microinjected into the vlPAG while changes of neural responses in the trigeminocervical complex (TCC) were monitored. RESULTS: Immunoreactivity indicated the presence of functional CGRP receptor components in the vlPAG and adjacent mesencephalic trigeminal nucleus. Inhibition of TCC responses to stimulation of dural afferents and ophthalmic cutaneous receptive fields after microinjection of bicuculline into vlPAG indicated a connection between the vlPAG and TCC neurons. CGRP facilitated these TCC responses, whereas olcegepant and CGRP (8-37) decreased them. CONCLUSIONS: CGRP and its receptor antagonists act on neurons in the region of vlPAG to influence nociceptive transmission in the TCC. This suggests CGRP receptor antagonists may act at loci outside of the TCC and reinforces the concept of migraine as a disorder of the brain.

Candidate-gene association study searching for genetic factors involved in migraine chronification.

INTRODUCTION: Chronic migraine (CM) is at the severe end of the clinical migraine spectrum, but its genetic background is unknown. Our study searched for evidence that genetic factors are involved in the chronification process. METHODS: We initially selected 144 single-nucleotide polymorphisms (SNPs) from 48 candidate genes, which we tested for association in two stages: The first stage encompassed 262 CM patients, the second investigated 226 patients with high-frequency migraine (HFM). Subsequently, SNPs with p values < 0.05 were forwarded to the replication stage containing 531 patients with CM or HFM. RESULTS: Eight SNPs were significantly associated with CM and HFM in the two-stage phase. None survived replication in the third stage. DISCUSSION: We present the first comprehensive genetic association study for migraine chronification. There were no significant findings. Future studies may benefit from larger, genome-wide data sets or should use other genetic approaches to identify genetic factors involved in migraine chronification.

Estimation of the density of veins from susceptibility-weighted imaging by using Mamdani fuzzy-type rule-based system. Investigating the neurovascular coupling in migraine.

BACKGROUND AND PURPOSE: An impaired neurovascular coupling has been described as a possible player in neurodegeneration and cognitive decline. Migraine is a recurrent and incapacitating disorder that starts early in life and has shown neurovascular coupling abnormalities. Despite its high prevalence, the physiology and underlying mechanisms are poorly understood. In this context, new biomarkers from magnetic resonance imaging (MRI) are needed to bring new knowledge into the field. The aim of this study was to determine the vein density from Susceptibility-Weighted Imaging (SWI) MRI, in subjects with migraine and healthy controls; and to assess whether it relates to Resting-State functional MRI (RS-fMRI). MATERIALS AND METHODS: The cohort included 30 healthy controls and 70 subjects with migraine (26 episodic, 44 chronic) who underwent a brain 3.0 T MRI. Clinical characteristics were also collected. Maps of density of veins were generated based on a Mamdani Fuzzy-Type Rule-Based System from the SWI MRI. Mean values of vein density were obtained in grey (GM) and white matter (WM) Freesurfer lobar parcellations. The Amplitude of Low-Frequency Fluctuations (ALFF) image was calculated for the RS-fMRI, and the mean values over the parcellated GM lobes were estimated. Differences between groups were assessed through and analysis of variance (age, sex, education and anxiety as covariates; p < 0.05), followed by post-hoc comparisons. Associations were run between clinical and MRI-derived variables. RESULTS: When comparing the density of veins in GM, no differences between groups were found, neither associations with clinical variables. The density of veins was significantly higher in the WM of the occipital lobe for subjects with chronic migraine compared to controls (30%, p < 0.05). WM vein density in either frontal, temporal or cingulate regions was associated with clinical variables such as headache days, disability scores, and cognitive impairment (r between 0.25 and 0.41; p < 0.05). Mean values of ALFF did not differ significantly between controls and subjects with migraine. Strong significant associations between vein density and ALFF measures were obtained in most GM lobes for healthy subjects (r between 0.50 and 0.67; p < 0.05), instead, vein density in WM was significantly associated with ALFF for subjects with migraine (r between 0.32 and 0.58; p < 0.05). CONCLUSIONS: Results point towards an increase in vein density in subjects with migraine, when compared to healthy controls. In addition, the association between GM vein density and ALFF found in healthy subjects was lost in migraine. Taken together, these results support the idea of abnormalities in the neurovascular coupling in migraine. Quantitative SWI MRI indicators in migraine might be an interesting target that may contribute to its comprehension.

The MIGREX study: Prevalence and risk factors of sexual dysfunction among migraine patients.

BACKGROUND: Migraine attacks have a high impact on daily activities. There is limited research on the burden of migraine on sexual functioning. OBJECTIVE: To determine the prevalence of sexual dysfunction in patients with migraine and its relationship with migraine features and comorbidities. METHOD: This is a cross-sectional study. We included migraine patients between 18 and 60 years-old from 8 Headache Clinics in Spain. We recorded demographic data and migraine features. Patients fulfilled a survey including comorbidities, Arizona Sexual Experiences Scale, Hospital Anxiety and Depression Scale and a questionnaire about migraine impact on sexual activity. A K-nearest neighbor supervised learning algorithm was used to identify differences between migraine patients with and without sexual dysfunction. RESULTS: We included 306 patients (85.6% women, mean age 42.3±11.1 years). A 41.8% of participants had sexual dysfunction. Sexual dysfunction was associated with being female (OR [95% CI]: 2.42 [1.17-5.00]; p<0.001), being older than 46.5 years (4.04 [2.48-6.59]; p<0.001), having chronic migraine (2.31 [1.41-3.77]; p=0.001), using preventive medication (2.45 [1.35-4.45]; p=0.004), analgesic overusing (3.51 [2.03-6.07]; p<0.001), menopause (4.18 [2.43-7.17]; p<0.001) and anxiety (2.90 [1.80-4.67]; p<0.001) and depression (6.14 [3.18-11.83]; p<0.001). However, only female gender, age, menopause and depression were the statistically significant variables selected in the model to classify migraine patients with or without sexual dysfunction (Accuracy [95% CI]: 0.75 (0.62-0.85), Kappa: 0.48, p=0.005). CONCLUSIONS: Sexual dysfunction is frequent in migraine patients visited in a headache clinic. However, migraine characteristics or use of preventive medication are not directly associated with sexual dysfunction. Instead, risk factors for sexual dysfunction were female gender, higher age, menopause and depression.

OnabotulinumtoxinA in elderly patients with chronic migraine: insights from a real-life European multicenter study.

INTRODUCTION: Although migraine prevalence decreases with aging, some older patients still suffer from chronic migraine (CM). This study aimed to investigate the outcome of OnabotulinumtoxinA (OBT-A) as preventative therapy in elderly CM patients. METHODS: This is a post hoc analysis of real-life prospectively collected data at 16 European headache centers on CM patients treated with OBT-A over the first three treatment cycles (i.e., Cy1-3). We defined: OLD patients aged ≥ 65 years and nonOLD those < 65-year-old. The primary endpoint was the changes in monthly headache days (MHDs) from baseline to Cy 1-3 in OLD compared with nonOLD participants. The secondary endpoints were the responder rate (RR) ≥ 50%, conversion to episodic migraine (EM) and the changes in days with acute medication use (DAMs). RESULTS: In a cohort of 2831 CM patients, 235 were OLD (8.3%, 73.2% females, 69.6 years SD 4.7). MHDs decreased from baseline (24.8 SD 6.2) to Cy-1 (17.5 SD 9.1, p < 0.000001), from Cy-1 to Cy-2 (14.8 SD 9.2, p < 0.0001), and from Cy-2 to Cy-3 (11.9 SD 7.9, p = 0.001). DAMs progressively reduced from baseline (19.2 SD 9.8) to Cy-1 (11.9 SD 8.8, p < 0.00001), to Cy-2 (10.9 SD 8.6, p = 0.012), to Cy-3 (9.6 SD 7.4, p = 0.049). The 50%RR increased from 30.7% (Cy-1) to 34.5% (Cy-2), to 38.7% (Cy-3). The above outcome measures did not differ in OLD compared with nonOLD patients. CONCLUSION: In a population of elderly CM patients with a long history of migraine OBT-A provided a significant benefit, over the first three treatment cycles, as good as in non-old patients.

Headache: pregnancy and breastfeeding. Recommendations of the Spanish Society of Neurology's Headache Study Group.

INTRODUCTION: Headache is one of the most common neurological complaints, and is most frequent during reproductive age. As a result, we are routinely faced with pregnant or breastfeeding women with this symptom in clinical practice. It is important to know which pharmacological choices are the safest, which should not be used, and when we should suspect secondary headache. To this end, the Spanish Society of Neurology's Headache Study Group has prepared a series of consensus recommendations on the diagnostic and therapeutic algorithms that should be followed during pregnancy and breastfeeding. DEVELOPMENT: This guide was prepared by a group of young neurologists with special interest and experience in headache, in collaboration with the Group's Executive Committee. Recommendations focus on which drugs should be used for the most frequent primary headaches, both during the acute phase and for prevention. The second part addresses when secondary headache should be suspected and which diagnostic tests should be performed in the event of possible secondary headache during pregnancy and breastfeeding. CONCLUSIONS: We hope this guide will be practical and useful in daily clinical practice and that it will help update and improve understanding of headache management during pregnancy and breastfeeding, enabling physicians to more confidently treat these patients.

Headache: what to ask, how to examine, and what scales to use. Recommendations of the Spanish society of neurology's headache study group.

INTRODUCCIóN: La cefalea es el motivo de consulta neurológico más prevalente en los distintos niveles asistenciales, donde la anamnesis y exploración son primordiales para realizar un diagnóstico y tratamiento adecuados. Con la intención de unificar la atención de esta patología, el Grupo de Estudio de Cefalea de la Sociedad Española de Neurología (GECSEN) ha decidido elaborar unas recomendaciones consensuadas para mejorar y garantizar una adecuada asistencia en Atención Primaria, Urgencias y Neurología. METODOLOGíA: El documento es práctico, sigue el orden de la dinámica de actuación durante una consulta: anamnesis, escalas que cuantifican el impacto y la discapacidad y exploración. Además, finaliza con pautas para realizar un seguimiento adecuado y un manejo de las expectativas del paciente con el tratamiento pautado. CONCLUSIONES: Esperamos ofrecer una herramienta que mejore la atención al paciente con cefalea para garantizar una asistencia adecuada y homogénea a nivel nacional.

Calcitonin gene-related peptide in migraine: from pathophysiology to treatment.

INTRODUCTION: It has been observed in recent years that levels of such molecules as calcitonin gene-related peptide (CGRP) and, to a lesser extent, the pituitary adenylate cyclase-activating peptide are elevated during migraine attacks and in chronic migraine, both in the cerebrospinal fluid and in the serum. Pharmacological reduction of these proteins is clinically significant, with an improvement in patients' migraines. It therefore seems logical that one of the main lines of migraine research should be based on the role of CGRP in the pathophysiology of this entity. DEVELOPMENT: The Spanish Society of Neurology's Headache Study Group decided to draft this document in order to address the evidence on such important issues as the role of CGRP in the pathophysiology of migraine and the mechanism of action of monoclonal antibodies and gepants; and to critically analyse the results of different studies and the profile of patients eligible for treatment with monoclonal antibodies, and the impact in terms of pharmacoeconomics. CONCLUSIONS: The clinical development of gepants, which are CGRP antagonists, for the acute treatment of migraine attacks, and CGRP ligand and receptor monoclonal antibodies offer promising results for these patients.

Impact of monthly headache days on anxiety, depression and disability in migraine patients: results from the Spanish Atlas.

Identifying highly disabled patients or at high risk of psychiatric comorbidity is crucial for migraine management. The burden of migraine increases with headache frequency, but the number of headache days (HDs) per month after which disability becomes severe or the risk of anxiety and depression is higher has not been established. Here, we estimate the number of HDs per month after which migraine is associated with higher risk of anxiety and depression, severe disability and lower quality of life. We analysed 468 migraine patients (mean age 36.8 ± 10.7; 90.2% female), of whom 38.5% had ≥ 15 HDs per month. Our results show a positive linear correlation between the number of HDs per month and the risk of anxiety (r = 0.273; p < 0.001), depression (r = 0.337; p < 0.001) and severe disability (r = 0.519; p < 0.001). The risk of anxiety is higher in patients having ≥ 3HDs per month, and those with ≥ 19HDs per month are at risk of depression. Moreover, patients suffering ≥ 10HDs per month have very severe disability. Our results suggest that migraine patients with ≥ 10HDs per month are very disabled and also that those with ≥ 3HDs per month should be screened for anxiety.

Neuromodulation in headache and craniofacial neuralgia: guidelines from the Spanish Society of Neurology and the Spanish Society of Neurosurgery. / Neuromodulación en cefaleas y neuralgias craneofaciales: Guía de la Sociedad Española de Neurología y de la Sociedad Española de Neurocirugía.

INTRODUCTION: Numerous invasive and non-invasive neuromodulation devices have been developed and applied to patients with headache and neuralgia in recent years. However, no updated review addresses their safety and efficacy, and no healthcare institution has issued specific recommendations on their use for these 2 conditions. METHODS: Neurologists from the Spanish Society of Neurology's (SEN) Headache Study Group and neurosurgeons specialising in functional neurosurgery, selected by the Spanish Society of Neurosurgery (SENEC), performed a comprehensive review of articles on the MEDLINE database addressing the use of the technique in patients with headache and neuralgia. RESULTS: We present an updated review and establish the first set of consensus recommendations of the SEN and SENC on the use of neuromodulation to treat headache and neuralgia, analysing the current levels of evidence on its effectiveness for each specific condition. CONCLUSIONS: Current evidence supports the indication of neuromodulation techniques for patients with refractory headache and neuralgia (especially migraine, cluster headache, and trigeminal neuralgia) selected by neurologists and headache specialists, after pharmacological treatment options are exhausted. Furthermore, we recommend that invasive neuromodulation be debated by multidisciplinary committees, and that the procedure be performed by teams of neurosurgeons specialising in functional neurosurgery, with acceptable rates of morbidity and mortality.

Persistent headache after COVID-19: Pathophysioloy, clinic and treatment.

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. The acute infection is characterised not only by respiratory symptoms, but also by multiple systemic manifestations, including neurological symptoms. Among these, headache is a frequent complaint. As the pandemic progresses and the population of patients recovering from COVID-19 grows, it is becoming apparent that the headache present in the acute stage of the infection may persist for an indeterminate period, becoming a major problem for the patient and potentially leading to disability. In this review we describe the pathophysiological and clinical aspects of persistent headache after COVID-19 based on the information currently available in the literature and the authors' clinical experience.

El SARS-CoV-2 (Síndrome Respiratorio Agudo Grave ­ Coronavirus 2) es el virus responsable de la pandemia por la Enfermedad por el Coronavirus de 2019 (COVID-19). La fase aguda de la enfermedad se caracteriza no sólo por síntomas respiratorios, sino que el cuadro clínico puede estar acompañado de múltiples síntomas sistémicos, incluyendo los neurológicos. Entre ellos, la cefalea es una queja frecuente. A medida que avanza la pandemia y crece la población de pacientes que se recuperan del COVID-19, se está observando que la cefalea presente en la fase aguda de la infección puede persistir durante un periodo de tiempo indeterminado, convirtiéndose un problema capital para el paciente y llegando a condicionar discapacidad. En esta revisión proporcionamos información acerca de los aspectos fisiopatológicos y clínicos de la cefalea persistente tras el COVID-19 en base a la información disponible en la literatura actual y la experiencia clínica de los autores.