Editorial: Lifestyle modifications to manage migraine

Headache; Lifestyle and behavior; MigraineDolor de cabeza; Estilo de vida y comportamiento; MigrañaMal de cap; Estil de vida i comportament; MigranyaYW received research funding from the NINDS (National Institute of Neurological Disorders and Stroke), NIH (National Institutes of Health) (1K01NS124911-01). MV-P is a recipient of a Sara Borrell contract from the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Spain (CD20/00019)

The impact of epigenetic mechanisms in migraine: Current knowledge and future directions

DNA methylation; Biomarkers; EpigeneticsMetilació de l'ADN; Biomarcadors; EpigenèticaMetilación del ADN; Biomarcadores; EpigenéticaBackground Epigenetic mechanisms, including DNA methylation, microRNAs and histone modifications, may modulate the genetic expression in migraine and its interaction with internal and external factors, such as lifestyle and environmental changes. Objective To summarize, contextualize and critically analyze the published literature on the current state of epigenetic mechanisms in migraine in a narrative review. Findings The studies published to date have used different approaches and methodologies to determine the role of epigenetic mechanisms in migraine. Epigenetic changes seem to be involved in migraine and are increasing our knowledge of the disease. Conclusions Changes in DNA methylation, microRNA expression and histone modifications could be utilized as biomarkers that would be highly valuable for patient stratification, molecular diagnosis, and precision medicine in migraine.The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: MV-P was supported by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie IF grant agreement No. 101023175

Cutaneous Allodynia in Migraine: A Narrative Review

Cutaneous allodynia; Risk factors; TreatmentAlodinia cutánea; Factores de riesgo; TratamientoAlodínia cutània; Factors de risc; TractamentObjective: In the present work, we conduct a narrative review of the most relevant literature on cutaneous allodynia (CA) in migraine. Background: CA is regarded as the perception of pain in response to non-noxious skin stimulation. The number of research studies relating to CA and migraine has increased strikingly over the last few decades. Therefore, the clinician treating migraine patients must recognize this common symptom and have up-to-date knowledge of its importance from the pathophysiological, diagnostic, prognostic and therapeutic point of view. Methods: We performed a comprehensive narrative review to analyze existing literature regarding CA in migraine, with a special focus on epidemiology, pathophysiology, assessment methods, risk for chronification, diagnosis and management. PubMed and the Cochrane databases were used for the literature search. Results: The prevalence of CA in patients with migraine is approximately 60%. The mechanisms underlying CA in migraine are not completely clarified but include a sensitization phenomenon at different levels of the trigemino-talamo-cortical nociceptive pathway and dysfunction of brainstem and cortical areas that modulate thalamocortical inputs. The gold standard for the assessment of CA is quantitative sensory testing (QST), but the validated Allodynia 12-item questionnaire is preferred in clinical setting. The presence of CA is associated with an increased risk of migraine chronification and has therapeutic implications. Conclusions: CA is a marker of central sensitization in patients with migraine that has been associated with an increased risk of chronification and may influence therapeutic decisions

Screening of CACNA1A and ATP1A2 genes in hemiplegic migraine: clinical, genetic and functional studies

Hemiplegic migraine (HM) is a rare and severe subtype of autosomal dominant migraine, characterized by a complex aura including some degree of motor weakness. Mutations in four genes (CACNA1A, ATP1A2, SCN1A and PRRT2) have been detected in familial and in sporadic cases. This genetically and clinically heterogeneous disorder is often accompanied by permanent ataxia, epileptic seizures, mental retardation, and chronic progressive cerebellar atrophy. Here we report a mutation screening in the CACNA1A and ATP1A2 genes in 18 patients with HM. Furthermore, intragenic copy number variant (CNV) analysis was performed in CACNA1A using quantitative approaches. We identified four previously described missense CACNA1A mutations (p.Ser218Leu, p.Thr501Met, p.Arg583Gln, and p.Thr666Met) and two missense changes in the ATP1A2 gene, the previously described p.Ala606Thr and the novel variant p.Glu825Lys. No structural variants were found. This genetic screening allowed the identification of more than 30% of the disease alleles, all present in a heterozygous state. Functional consequences of the CACNA1A-p.Thr501Met mutation, previously described only in association with episodic ataxia, and ATP1A2-p.Glu825Lys, were investigated by means of electrophysiological studies, cell viability assays or Western blot analysis. Our data suggest that both these variants are disease-causing

Clinical Presentation and Outcome of COVID-19 in a Latin American Versus Spanish Population: Matched Case-Control Study

Introduction: Increased mortality has been reported in the Latin American population. The objective is to compare the clinical characteristics and outcome of Latin American and Spanish populations in a cohort of patients hospitalized with COVID-19 during the first year of the pandemic. Methods: We retrospectively analysed all the Latin American patients (born in South or Central America) hospitalized in our centre from February 2020 to February 2021 and compared them with an age- and gender-matched group of Spanish subjects. Variables included were demographics, co-morbidities, clinical and analytical parameters at admission and treatment received. The primary outcomes were ICU admission and mortality at 60 days. A conditional regression analysis was performed to evaluate the independent baseline predictors of both outcomes. Results: From the 3216 patients in the whole cohort, 216 pairs of case-controls (Latin American and Spanish patients, respectively) with same age and gender were analysed. COPD was more frequent in the Spanish group, while HIV was more prevalent in the Latin American group. Other co-morbidities showed no significant difference. Both groups presented with similar numbers of days from symptom onset, but the Latin American population had a higher respiratory rate (21 vs. 20 bpm, P = 0.041), CRP (9.13 vs. 6.22 mg/dl, P = 0.001), ferritin (571 vs. 383 ng/ml, P = 0.012) and procalcitonin (0.10 vs. 0.07 ng/ml, P = 0.020) at admission and lower cycle threshold of PCR (27 vs. 28.8, P = 0.045). While ICU admission and IVM were higher in the Latin American group (17.1% vs. 13% and 9.7% vs. 5.1%, respectively), this was not statistically significant. Latin American patients received remdesivir and anti-inflammatory therapies more often, and no difference in the 60-day mortality rate was found (3.2% for both groups). Conclusion: Latin American patients with COVID-19 have more severe disease than Spanish patients, requiring ICU admission, antiviral and anti-inflammatory therapies more frequently. However, the mortality rate was similar in both groups

C-reactive protein cut-off for early tocilizumab and dexamethasone prescription in hospitalized patients with COVID-19

Dexamethasone and tocilizumab have been associated with reduction in mortality, however, the beneficial effect is not for all patients and the impact on viral replication is not well defined. We hypostatized that C-reactive protein (CRP) could help in the identification of patients requiring anti-inflammatory therapy. Patients admitted for > 48 h in our hospital for a confirmed or suspected infection by SARS-CoV-2 from February 2020 to February 2021 were retrospectively evaluated. The primary outcome was mortality at 30 days. Demographics and the most relevant variables related with the outcome were included. CRP was stratified by percentiles. Univariate and multivariate analysis were performed. A total of 3218 patients were included with a median (IQR) age of 66 (74-78) years and 58.9% were males. The rate of intensive care unit admission was 24.4% and the 30-day mortality rate was 11.8%. Within the first 5 days from admission, 1018 (31.7%) patients received dexamethasone and 549 tocilizumab (17.1%). The crude analysis showed a mortality reduction in patients receiving dexamethasone when CRP was > 13.75 mg/dL and > 3.5 mg/dL for those receiving tocilizumab. Multivariate analysis identified the interaction of CRP > 13.75 mg/dL with dexamethasone (OR 0.57; CI 95% 0.37-0.89, P = 0014) and CRP > 3.5 mg/dL with tocilizumab (0.65; CI95%:0.44-0.95, P = 0.029) as independent predictors of mortality. Our results suggest that dexamethasone and tocilizumab are associated with a reduction in mortality when prescribed to patients with a certain inflammatory activity assessed by C-reactive protein

Guia per a la implementació territorial de projectes de millora en l’atenció a la complexitat

Pacients crònics complexos; Atenció a la cronicitat avançada; Ruta assistencial de la complexitatPacientes crónicos complejos; Atención a la cronicidad avanzada; Ruta asistencial de la complejidadComplex chronic patients; Attention to advanced chronicity; Complexity care routeEls objectius d’aquesta guia són: definir les característiques, les estratègies d’identificació i el model genèric d’atenció de PCC i MACA i aportar una visió pragmàtica de la implementació d’iniciatives de base territorial per a l’atenció d’aquests pacients

Migraine polygenic risk score associates with efficacy of migraine-specific drugs

Objective To assess whether the polygenic risk score (PRS) for migraine is associated with acute and/or prophylactic migraine treatment response. Methods We interviewed 2,219 unrelated patients at the Danish Headache Center using a semistructured interview to diagnose migraine and assess acute and prophylactic drug response. All patients were genotyped. A PRS was calculated with the linkage disequilibrium pred algorithm using summary statistics from the most recent migraine genome-wide association study comprising ∼375,000 cases and controls. The PRS was scaled to a unit corresponding to a twofold increase in migraine risk, using 929 unrelated Danish controls as reference. The association of the PRS with treatment response was assessed by logistic regression, and the predictive power of the model by area under the curve using a case-control design with treatment response as outcome. Results A twofold increase in migraine risk associates with positive response to migraine-specific acute treatment (odds ratio [OR] = 1.25 [95% confidence interval (CI) = 1.05–1.49]). The association between migraine risk and migraine-specific acute treatment was replicated in an independent cohort consisting of 5,616 triptan users with prescription history (OR = 3.20 [95% CI = 1.26–8.14]). No association was found for acute treatment with non–migraine-specific weak analgesics and prophylactic treatment response. Conclusions The migraine PRS can significantly identify subgroups of patients with a higher-than-average likelihood of a positive response to triptans, which provides a first step toward genetics-based precision medicine in migraine

Genètica i epigènetica dels trastorns neurològics paroxístics

Aquesta tesi es centra en l’anàlisi genètica dels següents trastorns neurològics paroxístics pediàtrics: el torticoli paroxístic benigne del lactant (TPBL), l’hemiplegia alternant de la infància (HAI), la discinèsia paroxística cinesigènica (DPC) i el síndrome de la deficiència del transportador de glucosa GLUT1 (GLUT1DS); i en l’anàlisi genètica i epigenètica de la migranya, un trastorn neurològic paroxístic majoritàriament de l’adult. Els trastorns neurològics paroxístics pediàtrics analitzats són trastorns rars, poc estudiats, en els quals la simptomatologia i el patró d’herència han portat a sospitar-ne una base monogènica i un vincle amb el grup de les canalopaties neuronals. La dificultat en el seu estudi deriva, majoritàriament, de la manca de sèries importants de pacients de les quals se’n puguin obtenir conclusions extrapolables. L’interès d’aprofundir en el seu coneixement, a banda del propi interès científic, rau en trobar les causes que els originen i, així, poder trobar un tractament contra aquests trastorns, millorar la qualitat de vida dels pacients que els sofreixen i/o poder oferir consell genètic als familiars dels individus afectes. - El cribratge mutacional en 2 pacients afectes de TPBL ha identificat la mutació p.Glu533Lys en el gen CACNA1A com a causant de la malaltia, junt amb els estudis funcionals que indiquen que aquesta mutació provoca una pèrdua de funció de la proteïna codificada. - El cribratge mutacional en una cohort de 10 pacients d’HAI ha identificat 3 mutacions en el gen ATP1A3 (p.Asp801Asn, p.Glu815Lys i p.Gly947Arg) en 5 dels pacients, remarcant l’existència d’una heterogeneïtat genètica major de l’esperada en aquest trastorn. - El cribratge mutacional en la DPC ha identificat 3 mutacions diferents en el gen PRRT2 en 8 dels 10 pacients (c.649dupC, c.649delC i c.219_220delGA) descrivint per primera vegada tant la mutació c.219_220delGA com la presència de la c.649dupC i la c.649delC en un mateix pacient. - El cribratge mutacional en la GLUT1DS va permetre trobar mutacions de novo en el gen SLC2A1 en 3 dels 5 pacients analitzats: la c.667C>T, la c.710_711delGA i una deleció de tot l’exó 1; remarcant l’interès en cercar delecions GLUT1DS. La migranya és un trastorn neurològic primari molt prevalent que es manifesta amb crisis episòdiques i recurrents de mal de cap incapacitant. Els criteris de la International Headache Society subclassifiquen la malaltia en diferents subtipus, incloent la migranya sense aura (MO), la migranya amb aura (MA) i la migranya hemiplègica (MH). - El cribratge mutacional de la MH va permetre identificar 4 mutacions en el gen CACNA1A (p.Ser218Leu, p.Thr501Met, p.Arg583Gln i p.Thr666Met), 2 mutacions en el gen ATP1A2 (p.Ala606Thr i p.Glu825Lys) i la mutació p.Phe1661Leu en el gen SCN1A. - L’estudi d’associació genètica a nivell genòmic (GWAS) de la MO va permetre la identificació de 2 SNPs associats a MO, un localitzat en el gen MEF2D i l’altre proper al gen TGFBR2. També es van trobar SNPs que suggerien una tendència a la replicació en el gens PHACTR1 i ASTN2. A més a més, es van replicar els resultats obtinguts en un GWAS anterior, trobant novament associats a migranya els gens TRPM8 i LRP1. Aquest estudi va permetre identificar el primer loci d’associació a susceptibilitat a patir MO. - L’estudi epigenètic en un model de MA va permetre trobar diferències de metilació de l’ADN degudes al tractament amb àcid valproic o topiramat o a l’efecte de la depressió cortical propagant (DCP), el fenomen subjacent de l’aura, en gens que podrien estar relacionats amb la susceptibilitat a patir migranya. Els resultats podrien indicar que ambdós tractaments protegeixen davant les DCPs degut al seu efecte sobre la metilació de l’ADN, emfatitzant la importància dels mecanismes epigenètics en la susceptibilitat de la migranya.This thesis is focused on the genetic analysis of the following neurological paediatric paroxysmal disorders: benign paroxysmal torticollis of infancy (BPTI), alternating hemiplegia of childhood (AHC), paroxysmal kinesigenic dyskinesia (PKD) and GLUT1 deficiency syndrome (GLUT1DS); and on the genetic and epigenetic analysis of migraine, a neurological paroxysmal disorder mainly found in adults. The neurological paediatric paroxysmal disorders analyzed are rare and present a simptomatology and an inheritance that suggest a monogenic origin and a link with the neuronal channelopathies. The lack of significant cohorts of patients from which obtain transferable conclusions makes it difficult to study them. The main interest of their study, besides the own scientific interest, is based on finding the underlying causes of the disorder which would be the first step to find the appropriate treatment, improve the quality of life of the patients and/or be able to offer genetic counselling to the patients relatives. The results of this study are resumed below: - The mutational screening in 2 patients of BPTI identified the p.Glu533Lys mutation in the CACNA1A gene as the genetic cause of this disorder, in line with the functional studies that indicate that this mutation induces a loss-of-function of the coding protein. - The mutational screening in a cohort of 10 patients of AHC identified 3 mutations in the ATP1A3 gene (p.Asp801Asn, p.Glu815Lys and p.Gly947Arg) in 5 patients, highlighting the existence of a greater genetic heterogeneity than expected in this disorder. - The mutational screening in PKD identified 3 different mutations in the PRRT2 gene in 8 out of 10 patients (c.649dupC, c.649delC and c.219_220delGA), describing for the first time the mutation c.219_220delGA and also the presence of both the duplication and the deletion in the c.649 position in the same patient. - The mutational screening in 5 patients of GLUT1DS identified de novo mutations in the SLC2A1 gene in 3 patients, specifically c.667C>T, c.710_711delGA and a deletion affecting the whole first exon, highlighting the interest in looking for deletions in GLUT1DS. Migraine is a common primary neurological disorder that presents with episodic and recurrent attacks of disabling headache. The criteria of the International Headache Society divide the disorder into different subclasses, including migraine without aura (MO), migraine with aura (MA) and hemiplegic migraine (HM). The results of the genetic and epigenetic studies of migraine are resumed below: - The mutational screening of HM identified 4 mutations in the CACNA1A gene (p.Ser218Leu, p.Thr501Met, p.Arg583Gln and p.Thr666Met), 2 mutations in the ATP1A2 gene (p.Ala606Thr i p.Glu825Lys) and the mutation p.Thr501Met in the SCN1A gene. - The genome wide association study (GWAS) of MO identified 2 SNPs associated with MO, one in the MEF2D gene and the other close to the TGFBR2 gene. There were SNPs that showed suggestive evidence of replication at PHACTR1 and ASTN2 genes. Moreover, previous GWAS findings were replicated, finding the genes TRPM8 and LRP1 associated with migraine. This study allowed the identification of the first loci associated with MO. - The epigenetic study in a MA rat model identified DNA methylation differences due to the administration of valproate and topiramate drugs and/or due to the cortical spreading depression (CSD) effects in genes that could be related to the migraine susceptibility. These results could indicate that both treatments protect against CSD due to their effects on DNA methylation, highlighting the importance of the epigenetic mechanisms in the migraine susceptibility