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OBJECTIVE: Idiopathic intracranial hypertension (IIH) is a neurometabolic disease with an increasing incidence. The pathophysiology is unknown, but improvement of diagnosis and management requires discovery of novel biomarkers. Our objective was to identify such candidate biomarkers in IIH, and secondarily, test for associations between identified metabolites and disease severity. METHODS: This is a prospective case-control study with collection of cerebrospinal fluid (CSF), serum, and clinical data from new-onset, treatment-naïve patients with IIH (n = 60). Patients were included consecutively from 2 tertiary headache centers in Denmark, and age, sex, and body mass index (BMI) -matched healthy controls (n = 35) were recruited. Clinical data were retrieved at ocular remission (n = 55). Samples were analyzed using non-targeted mass spectrometry. RESULTS: Serum sphingosine 1-phosphate (S1P), adenosine, and glutamate were 0.46-fold (q < 0.0001), 0.25-fold (q = 0.0048), and 0.44-fold (q < 0.0001) lower, respectively, in IIH. CSF stearoyl-lysophosphatidylcholine (LysoPC-18) and 2-palmitoyl-lysophosphatidylcholine (LysoPC-16) were 0.42 (q = 0.0025) and 0.37 (q < 0.001) -fold lower. LysoPC-18 was higher in patients with moderate-severe versus mild papilledema (p = 0.022). LysoPC-18 correlated positively with retinal nerve fiber layer thickness (p = 0.0012, r = 0.42) and inversely with mean deviation on automated perimetry (p = 0.01, r = -0.35). Higher baseline serum S1P (p = 0.018) and lower CSF LysoPC-16 (p = 0.003) were associated with optic nerve atrophy at ocular remission. Pathway analysis suggests dysregulated lipid metabolism and redox disturbances in new-onset IIH. INTERPRETATION: We identify perturbed metabolism in new-onset IIH. S1P and LysoPC-16 demonstrate potential prognostic value due to association with subsequent optic nerve atrophy. This association between specific, differential metabolites and outcome provides substantial evidence for novel biomarkers of clinical significance that should be the focus of further targeted studies. ANN NEUROL 2024;96:595-607.
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Biomarcadores , Seudotumor Cerebral , Humanos , Femenino , Masculino , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Adulto , Seudotumor Cerebral/sangre , Seudotumor Cerebral/líquido cefalorraquídeo , Seudotumor Cerebral/complicaciones , Estudios de Casos y Controles , Estudios Prospectivos , Persona de Mediana Edad , Adulto JovenRESUMEN
INTRODUCTION: Migraine is a prevalent neurological headache disorder. Due to challenges associated with finding effective treatment, many individuals with migraine feel compelled to explore alternative treatment strategies, such as blood donation, hypothesized to provide migraine relief. METHODS: Through logistic, Poisson, and Cox regression methods, we examined the links between migraine and blood donation activities in two population cohorts: Danish blood donors in the Scandinavian Donations and Transfusions Database (SCANDAT-DK, N >1 million) and the Danish Blood Donor Study (N ~ 100,000). RESULTS: SCANDAT-DK analyses showed no link between migraine and the propensity to become a blood donor among males (odds ratio [OR]Males = 0.95 [95% Confidence Interval: 0.86-1.04], and a reduced propensity among females ORFemales = 0.88 [0.83-0.93]). The incidence of migraine was not reduced upon blood donation (standardized incidence ratio [SIR]Males = 0.94 [0.83-1.06]; SIRFemales = 1.04 [0.99-1.10]). Donors with migraine demonstrated longer intervals between donations (hazard ratio [HR]Males = 0.87 [0.85-0.91], HRFemales = 0.80 [0.78-0.82]), and an increased risk of donor lapse (ORMales = 1.23 [1.14-1.32]; ORFemales = 1.28 [1.22-1.33]). Results were corroborated in DBDS using self-reported migraine. Genetic predisposition to migraine associated with longer intervals in females (HRFemales = 0.98 [0.97-0.99]), but not in males. DISCUSSION: Our findings do not support the hypothesis that blood donation serves as a viable treatment strategy among migraine patients. Future prospective investigations may help to elucidate the underlying biological mechanisms by which blood donation may influence migraine pathology.
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Donación de Sangre , Trastornos Migrañosos , Masculino , Femenino , Humanos , Estudios de Cohortes , Transfusión Sanguínea , Donantes de Sangre , Trastornos Migrañosos/epidemiología , Trastornos Migrañosos/terapia , Dinamarca/epidemiologíaRESUMEN
BACKGROUND/HYPOTHESIS: Experimental provocation studies have yielded important insights in migraine pathophysiology. Levcromakalim has been previously shown to induce migraine-like attacks with and without aura. In this study, we aim to further explore the migraine aura-inducing potential of levcromakalim. METHODS: In a double-blind, randomized, placebo-controlled cross-over study, 27 adult participants with migraine with aura received intravenous infusions of levcromakalim and saline. Headache, aura and associated symptoms were evaluated for 24 hours following administration of the study drug. The primary endpoint was occurrence of migraine-like attacks with or without aura in the 24-hour observation period. RESULTS: Thirteen participants developed migraine-like attacks on the active day only (P = 0.0098), and four participants developed aura on the active day only (P = 0.68). The median time to onset of migraine-like headache was three hours, and the median time to onset of aura was 27.5 minutes. CONCLUSION/INTERPRETATION: Our findings affirm the potent migraine-inducing effect of levcromakalim. We observed a lower induction-rate of migraine aura than previously reported. Further studies are warranted to identify predictors of migraine aura following levcromakalim. CLINICALTRIALS.GOV IDENTIFIER: NCT04905654.
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Epilepsia , Trastornos Migrañosos , Migraña con Aura , Adulto , Humanos , Cromakalim , Estudios Cruzados , Trastornos Migrañosos/tratamiento farmacológico , Cefalea , Método Doble CiegoRESUMEN
OBJECTIVES: Osteoarthritis is a common and severe, multifactorial disease with a well-established genetic component. However, little is known about how genetics affect disease progression, and thereby the need for joint placement. Therefore, we aimed to investigate whether the genetic associations of knee and hip osteoarthritis differ between patients treated with joint replacement and patients without joint replacement. METHODS: We included knee and hip osteoarthritis cases along with healthy controls, altogether counting >700 000 individuals. The cases were divided into two groups based on joint replacement status (surgical vs non-surgical) and included in four genome-wide association meta-analyses: surgical knee osteoarthritis (N = 22 525), non-surgical knee osteoarthritis (N = 38 626), surgical hip osteoarthritis (N = 20 221) and non-surgical hip osteoarthritis (N = 17 847). In addition, we tested for genetic correlation between the osteoarthritis groups and the pain phenotypes intervertebral disc disorder, dorsalgia, fibromyalgia, migraine and joint pain. RESULTS: We identified 52 sequence variants associated with knee osteoarthritis (surgical: 17, non-surgical: 3) or hip osteoarthritis (surgical: 34, non-surgical: 1). For the surgical phenotypes, we identified 10 novel variants, including genes involved in autophagy (rs2447606 in ATG7) and mechanotransduction (rs202127176 in PIEZO1). One variant, rs13107325 in SLC39A8, associated more strongly with non-surgical knee osteoarthritis than surgical knee osteoarthritis. For all other variants, significance and effect sizes were higher for the surgical phenotypes. In contrast, genetic correlations with pain phenotypes tended to be stronger in the non-surgical groups. CONCLUSIONS: Our results indicate differences in genetic associations between knee and hip osteoarthritis depending on joint replacement status.
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Artroplastia de Reemplazo de Cadera , Artroplastia de Reemplazo de Rodilla , Osteoartritis de la Cadera , Osteoartritis de la Rodilla , Humanos , Osteoartritis de la Cadera/genética , Osteoartritis de la Cadera/cirugía , Osteoartritis de la Cadera/complicaciones , Osteoartritis de la Rodilla/genética , Osteoartritis de la Rodilla/cirugía , Osteoartritis de la Rodilla/complicaciones , Estudio de Asociación del Genoma Completo , Mecanotransducción Celular , Articulación de la Rodilla/cirugía , Dolor , Canales IónicosRESUMEN
OBJECTIVE: To investigate whether medication-overuse headache patients have differential DNA-methylation pattern. METHODS: We collected blood samples from 120 medication-overuse headache-patients, 57 controls (29 episodic migraine patients and 28 healthy controls) in a hypothesis-generating cross-sectional case-control pilot study; 100 of the medication-overuse headache-patients were followed for six months and samples were collected at two and six months for the longitudinal methylation analyses. Blood cell proportions of leucocytes (neutrophils, NK-cells, monocytes, CD8+ and CD4+ T-cells, and B-cells) and the neutrophile-lymphocyte ratio were estimated using methylation data as a measure for immunological analysis and a cell type-specific epigenome wide association study was conducted between medication-overuse headache-patients and controls, and longitudinally for reduction in headache days/month among medication-overuse headache-patients. RESULTS: We found a higher neutrophile-lymphocyte ratio in medication-overuse headache-patients compared to controls, indicating a higher immunological response in medication-overuse headache-patients (false discovery rate (adjusted p-value)<0.001). Reduction in headache days/month (9.8; 95% CI 8.1-11.5) was associated with lower neutrophile-lymphocyte ratio (false discovery rate adjusted p-value = 0.041).Three genes (CORIN, CCKBR and CLDN9) were hypermethylated in specific cell types in medication-overuse headache-patients compared to controls. No methylation differences were associated with reduction in headache days in medication-overuse headache-patients after six months. CONCLUSION: This pilot study was consistent with higher immunological response in medication-overuse headache-patients which decreased with a reduction in headache days in longitudinal analysis. medication-overuse headache-patients exhibited differential methylation in innate immune cells but did not exhibit longitudinal differences with alterations in headache days. Our study creates hypotheses for further biomarker searches.ClinicalTrials.gov Identifier: NCT02993289.
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Cefaleas Secundarias , Trastornos Migrañosos , Humanos , Estudios Transversales , Proyectos Piloto , Cefaleas Secundarias/genética , Cefaleas Secundarias/metabolismo , Trastornos Migrañosos/tratamiento farmacológico , CefaleaRESUMEN
BACKGROUND AND PURPOSE: The response to cluster headache treatments has a high interindividual variation. To date, treatment response has only been assessed by a candidate gene approach and no investigations into metabolic pathways have been performed. Our aim was to investigate the association between the polygenetic risk of cluster headache and treatment response to first-line cluster headache treatments as well as known functional variants of CYP3A4 and the response to verapamil. Further, it was aimed to replicate previous single nucleotide polymorphisms found to be associated with treatment response in cluster headache and/or migraine. METHODS: In, 508 cluster headache patients diagnosed according to the International Classification of Headache Disorders were genotyped and participated in a semi-structured interview to evaluate treatment response. Polygenetic risk scores were calculated by the effect retrieved from a meta-analysis of the latest two genome-wide association studies on cluster headache. RESULTS: Inferior treatment response to oxygen, triptans and verapamil is associated with chronicity of cluster headache were confirmed but no evidence was found that a response could be predicted by a high genetic risk of cluster headache. Likewise, verapamil response was not associated with functional variants of CYP3A4. No support of the genetic variants previously reported to be associated with treatment response to triptans or verapamil was found. CONCLUSION: The clinically relevant variation in treatment response for cluster headache was not influenced by genetic factors in the present study.
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Cefalalgia Histamínica , Citocromo P-450 CYP3A , Humanos , Citocromo P-450 CYP3A/genética , Estudio de Asociación del Genoma Completo , Cefalalgia Histamínica/tratamiento farmacológico , Cefalalgia Histamínica/genética , Triptaminas , Verapamilo/uso terapéuticoRESUMEN
BACKGROUND AND PURPOSE: Understanding migraine in a sex-specific manner is crucial for improving clinical care, diagnosis and therapy for both females and males. Here, data on sex differences are provided in the presentation of migraine in a large European-based population cohort, which is representative of the general population. METHODS: A population-based study of 62,672 Danish blood donors (both present and previous donors), of whom 12,658 had migraine, was performed. All participants completed a 105-item diagnostic migraine questionnaire sent via an electronic mailing system (e-Boks) between May 2020 and August 2020. The questionnaire allowed for correct diagnosis of migraine according to the International Classification of Headache Disorders, third edition. RESULTS: The migraine questionnaire was in-cohort validated and had a positive predictive value of 97% for any migraine, a specificity of 93% and a sensitivity of 93%. There were 9184 females (mean age 45.1 years) and 3434 males (mean age 48.0 years). The 3-month prevalence of migraine without aura was 11% in females and 3.59% in males. The 3-month prevalence of migraine with aura was 1.72% in females and 1.58% in males. In females, the age-related 3-month prevalence of migraine without aura increased markedly during childbearing age. In males, migraine both with and without aura showed less age variation. Females had a higher frequency of migraine attacks (odds ratio [OR] 1.22) but a lower frequency of non-migraine headaches (OR = 0.35). Females also had a greater intensity of pain, more unilateral and pulsatile pain, and exacerbation by physical activity (OR = 1.40-1.49) as well as more associated symptoms (OR = 1.26-1.98). Females carried 79% of the total migraine disease burden, which was almost exclusively driven by migraine without aura (77%), whilst there was no sex difference in the disease burden of migraine with aura. CONCLUSION: Females have more severe disease, resulting in a much higher migraine disease burden than indicated by prevalence alone.
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Migraña con Aura , Migraña sin Aura , Humanos , Masculino , Femenino , Persona de Mediana Edad , Migraña con Aura/diagnóstico , Migraña con Aura/epidemiología , Cefalea/epidemiología , Encuestas y Cuestionarios , Caracteres SexualesRESUMEN
BACKGROUND: The cold pressor test (CPT) is a widely used pain provocation test to investigate both pain tolerance and cardiovascular responses. We hypothesize, that performing multi-omic analyses during CPT gives the opportunity to home in on molecular mechanisms involved. Twenty-two females were phenotypically assessed before and after a CPT, and blood samples were taken. RNA-Sequencing, steroid profiling and untargeted metabolomics were performed. Each 'omic level was analyzed separately at both single-feature and systems-level (principal component [PCA] and partial least squares [PLS] regression analysis) and all 'omic levels were combined using an integrative multi-omics approach, all using the paired-sample design. RESULTS: We showed that PCA was not able to discriminate time points, while PLS did significantly distinguish time points using metabolomics and/or transcriptomic data, but not using conventional physiological measures. Transcriptomic and metabolomic data revealed at feature-, systems- and integrative- level biologically relevant processes involved during CPT, e.g. lipid metabolism and stress response. CONCLUSION: Multi-omics strategies have a great potential in pain research, both at feature- and systems- level. Therefore, they should be exploited in intervention studies, such as pain provocation tests, to gain knowledge on the biological mechanisms involved in complex traits.
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Metabolómica , Transcriptoma , Humanos , Análisis de los Mínimos Cuadrados , DolorRESUMEN
INTRODUCTION: In the general population 4% have never experienced a headache. Freedom from headache could be due to distinctive protective mechanisms or a lack of environmental risk factors for headache. Isosorbide-5-mononitrate is an organic nitrate which in the body is metabolised to nitric oxide. The nitric oxide pathway plays a crucial role in the primary headaches. We hypothesized that people who are free from headache are protected by distinctive mechanisms in the nitric oxide pathway. METHODS: We performed an observer blinded case-control study using nitric oxide to provoke a headache. 32 headache free male participants and 26 randomly selected male controls received 60 mg Isosorbide-5-mononitrate orally on the study day. Participants fill out a headache diary with headache intensity and characteristics until 12 hours after administration of Isosorbide-5-mononitrate. Primary endpoint were areas under the curve of headache intensity score. RESULTS: All 58 participants completed the study. There was no significant difference in headache incidence, headache intensity score or migraine-like attack between headache free participants and controls. CONCLUSION: We show that men who have never experienced a headache develop a headache when provoked with Isosorbide-5-mononitrate. This indicates that freedom from headache in men is not related to the nitric oxide pathway which is involved in the primary headache disorders.
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Maduración Cervical , Óxido Nítrico , Estudios de Casos y Controles , Femenino , Cefalea/inducido químicamente , Humanos , Dinitrato de Isosorbide , Masculino , Donantes de Óxido Nítrico , EmbarazoRESUMEN
BACKGROUND: Migraine with cranial autonomic symptoms is well described in the literature, but its prevalence in previous studies varies enormously. A precise estimate of the prevalence in a population-based material is important because migraine with cranial autonomic symptoms might represent an endophenotype, in which genetic and pathophysiological features differ from those without cranial autonomic features. The aim of the present study, therefore, was to estimate the prevalence in a big population-based sample using both questionnaire-based diagnosis (N = 12,620) and interview-based diagnosis (N = 302). We validate questionnaire-based diagnosis of migraine with cranial autonomic symptoms and develop the first diagnostic criteria for future research of this possible endophenotype. METHODS: The Danish Blood Donor Study included 127,802 persons who all received a migraine diagnostic questionnaire. Participants who had answered the diagnostic questionnaire constituted the Danish Migraine Population Cohort (N = 62,677) of whom 12,620 had migraine. The diagnostic migraine questionnaire included questions about the following cranial autonomic symptoms: Facial/forehead sweating, lacrimation, ptosis, conjunctival injection, rhinorrhea, nasal congestion, and miosis. Validation was performed by a follow-up semi-structured, purpose-built interview of 302 participants with migraine, where detailed questions were asked to ascertain the validity of the symptoms. RESULTS: The questionnaire-based prevalences of one, respectively two cranial autonomic symptoms were 57% and 31%. The semi-structured interview-based prevalences of one, respectively two symptoms were 44% and 22%. The most common symptoms were facial/forehead sweating (39%) and lacrimation (24%). The specificity of the questionnaire was 80% and the sensitivity was 68%. Correlation analysis showed a weak correlation between symptoms ranging from 0.07 - 0.41, and no clear clustering of symptoms was detected. We suggest the first diagnostic appendix criteria for genetic and epidemiological studies and tighter criteria for clinical and pathophysiological studies. We encourage further studies of severity and consistency of symptoms. CONCLUSION: Migraine with cranial autonomic symptoms is prevalent in the general population. Suggested diagnostic appendix criteria are important for future studies of this possible migraine endophenotype.
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Apéndice , Enfermedades del Sistema Nervioso Autónomo , Trastornos Migrañosos , Enfermedades del Sistema Nervioso Autónomo/diagnóstico , Enfermedades del Sistema Nervioso Autónomo/epidemiología , Enfermedades del Sistema Nervioso Autónomo/etiología , Estudios de Cohortes , Humanos , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/epidemiología , PrevalenciaRESUMEN
BACKGROUND: The efficacy of triptans as the main acute treatment strategy for migraine headache at the population-wide level needs to be understood to inform clinical decision-making. We summarise key trends in triptan use using more than 25 years of Danish nationwide data. METHODS: We conducted a nationwide register-based cohort study based on all Danish residents with access to public healthcare between 1 January 1994 and 31 October 2019 and summarise informative trends of all purchases of triptans in Denmark in the same period. Complete purchase records of Sumatriptan, Naratriptan, Zolmitriptan, Rizatriptan, Almotriptan, Eletriptan, and Frovatriptan were used. FINDINGS: Over a 25-year period, triptan use increased from 345 to 945 defined daily doses (DDD) per 1000 inhabitants per year and the yearly prevalence of triptan use increased from 5.17 to 14.57 per 1000 inhabitants. Between 2014 and 2019, 12.3% of the Danish migraine population purchased a triptan. Following their initial purchase, 43% of patients had not repurchased triptans within 5 years. At most, 10% of patients indicating triptan discontinuation tried more than one triptan. The prevalence of triptan overuse, defined as having purchased at least 20 DDDs of triptans per month for 3 consecutive months, increased in parallel with the prevalence of triptan use, prevalent in 56 of every 1000 triptan users every year between 2014 and 2019. INTERPRETATION: In a cohort with access to free clinical consultations and low medication costs, we observed low rates of triptan adherence, likely due to disappointing efficacy and/or unpleasant side effects rather than economic considerations. Triptan success continues to be hindered by poor implementation of clinical guidelines and high rates of treatment discontinuance.
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Trastornos Migrañosos/tratamiento farmacológico , Agonistas del Receptor de Serotonina 5-HT1/uso terapéutico , Triptaminas/uso terapéutico , Estudios de Cohortes , Dinamarca/epidemiología , Femenino , Humanos , Masculino , Trastornos Migrañosos/epidemiología , Vigilancia de la Población , Sumatriptán , Resultado del TratamientoRESUMEN
BACKGROUND: The transition from episodic migraine to chronic migraine, migraine chronification, is usually a gradual process, which involves multiple risk factors. To date, studies of the genetic risk factors for chronic migraine have focused primarily on candidate-gene approaches using healthy individuals as controls. AIMS AND METHODS: In this study, we used a large cohort of migraine families and unrelated migraine patients (n > 2200) with supporting genotype and whole-genome sequencing data. We evaluated whether there are any genetic variants, common or rare, with a specific association to chronic migraine compared with episodic migraine. RESULTS: We found no aggregation of chronic migraine in families with a clustering of migraine. No specific rare variants gave rise to migraine chronification, and migraine chronification was not associated with a higher polygenic risk score. Migraine chronification was not associated with allelic associations with an odds ratio above 2.65. Assessment of effect sizes with genome-wide significance below an odds ratio of 2.65 requires a genome-wide association study of at least 7500 chronic migraine patients. CONCLUSION: Our results suggest that migraine chronification is caused by environmental factors rather than genetic factors.
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Estudio de Asociación del Genoma Completo , Trastornos Migrañosos , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Trastornos Migrañosos/epidemiología , Trastornos Migrañosos/genética , Factores de RiesgoRESUMEN
Migraine is the most common neurological disorder worldwide and it has been shown to have complex polygenic origins with a heritability of estimated 40-70%. Both common and rare genetic variants are believed to underlie the pathophysiology of the prevalent types of migraine, migraine with typical aura and migraine without aura. However, only common variants have been identified so far. Here we identify for the first time a gene module with rare mutations through a systems genetics approach integrating RNA sequencing data from brain and vascular tissues likely to be involved in migraine pathology in combination with whole genome sequencing of 117 migraine families. We found a gene module in the visual cortex, based on single nuclei RNA sequencing data, that had increased rare mutations in the migraine families and replicated this in a second independent cohort of 1930 patients. This module was mainly expressed by interneurons, pyramidal CA1, and pyramidal SS cells, and pathway analysis showed association with hormonal signalling (thyrotropin-releasing hormone receptor and oxytocin receptor signalling pathways), Alzheimer's disease pathway, serotonin receptor pathway and general heterotrimeric G-protein signalling pathways. Our results demonstrate that rare functional gene variants are strongly implicated in the pathophysiology of migraine. Furthermore, we anticipate that the results can be used to explain the critical mechanisms behind migraine and potentially improving the treatment regime for migraine patients.
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Bases de Datos Genéticas , Familia , Redes Reguladoras de Genes/fisiología , Variación Genética/fisiología , Trastornos Migrañosos/genética , Mapas de Interacción de Proteínas/fisiología , Estudios de Cohortes , Bases de Datos Genéticas/tendencias , Humanos , Trastornos Migrañosos/diagnóstico , Análisis de Secuencia de ADN/métodos , Análisis de Secuencia de ARN/métodos , Ganglio del Trigémino/patología , Corteza Visual/patologíaRESUMEN
BACKGROUND: Familial hemiplegic migraine (FHM) is a rare form of migraine with aura that often has an autosomal dominant mode of inheritance. Rare mutations in the CACNA1A, ATP1A2 and SCN1A genes can all cause FHM revealing genetic heterogeneity in the disorder. Furthermore, only a small subset of the affected individuals has a causal mutation. We set out to investigate what differentiates patients with FHM with no mutation in any known FHM gene from patients with common types of migraine in both familial and sporadic cases. METHODS: 2558 male and female participants from a migraine cohort from the Danish Headache Center were included. 112 had FHM; 743 had familial migraine; and 1703 had sporadic migraine. Using a linear regression model, we analysed for over-representation of rare functional variants in FHM versus familial migraine and sporadic migraine. Post hoc analyses included pathway analysis and testing for tissue specificity. RESULTS: We found that patients with FHM have significantly more rare frameshift indels compared with patients with familial migraine and sporadic migraine. Pathway analysis revealed that the 'ligand-gated ion channel activity' and 'G protein-coupled receptor downstream signalling' pathways were significantly associated with mutated genes. We moreover found that the mutated genes showed tissue specificity towards nervous tissue and muscle tissue. CONCLUSION: We show that patients with FHM compared with patients with common types of migraine suffer from a higher load of rare frameshift indels in genes associated with synaptic signalling in the central nervous system and possibly in muscle tissue contributing to vascular dysfunction.
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Canales de Calcio/genética , Trastornos Migrañosos/genética , Migraña con Aura/genética , Canal de Sodio Activado por Voltaje NAV1.1/genética , ATPasa Intercambiadora de Sodio-Potasio/genética , Diagnóstico Diferencial , Femenino , Mutación del Sistema de Lectura/genética , Predisposición Genética a la Enfermedad , Humanos , Mutación INDEL/genética , Masculino , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/patología , Migraña con Aura/diagnóstico , Migraña con Aura/patología , Linaje , Transmisión Sináptica/genéticaRESUMEN
BACKGROUND: Headache affects 90-99% of the population. Based on the question "Do you think that you never ever in your whole life have had a headache?" 4% of the population say that they have never experienced a headache. The rarity of never having had a headache suggests that distinct biological and environmental factors may be at play. We hypothesized that people who have never experienced a headache had a lower general pain sensitivity than controls. METHODS: We included 99 male participants, 47 headache free participants and 52 controls, in an observer blinded nested case-control study. We investigated cold pain threshold and heat pain threshold using a standardized quantitative sensory testing protocol, pericranial tenderness with total tenderness score and pain tolerance with the cold pressor test. Differences between the two groups were assessed with the unpaired Student's t-test or Mann-Whitney U test as appropriate. RESULTS: There was no difference in age, weight or mean arterial pressure between headache free participants and controls. We found no difference in pain detection threshold, pericranial tenderness or pain tolerance between headache free participants and controls. CONCLUSION: Our study clearly shows that freedom from headache is not caused by a lower general pain sensitivity. The results support the hypothesis that headache is caused by specific mechanisms, which are present in the primary headache disorders, rather than by a decreased general sensitivity to painful stimuli. TRIAL REGISTRATION: Registered at ClinicalTrials.gov ( NCT04217616 ), 3rd January 2020, retrospectively registered.
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Umbral del Dolor , Cefalea de Tipo Tensional , Estudios de Casos y Controles , Cefalea/epidemiología , Humanos , Masculino , DolorRESUMEN
The most recent genome-wide association study of migraine increased the total number of known migraine risk loci to 38. Still, most of the heritability of migraine remains unexplained, and it has been suggested that rare gene dysregulatory variants play an important role in migraine etiology. Addressing the missing heritability of migraine, we aim to fine-map signals from the known migraine risk loci to regulatory mechanisms and associate these to downstream genic targets. We analyzed a large cohort of whole-genome sequenced patients from extended migraine pedigrees (1040 individuals from 155 families). We test for association between rare variants segregating in regulatory regions with migraine. The findings were replicated in an independent case-control cohort (2027 migraineurs, 1650 controls). We report an increased burden of rare variants in one CpG island and three polycomb group response elements near four migraine risk loci. We found that the association is independent of the common risk variants in the loci. The regulatory regions are suggested to affect different genes than those originally tagged by the index SNPs of the migraine loci. Families with familial clustering of migraine have an increased burden of rare variants in regulatory regions near known migraine risk loci, with effects that are independent of the variants in the loci. The possible regulatory targets suggest different genes than those originally tagged by the index SNPs of the migraine loci.
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Salud de la Familia , Trastornos Migrañosos/genética , Secuencias Reguladoras de Ácidos Nucleicos , Secuenciación Completa del Genoma , Estudios de Casos y Controles , Estudios de Cohortes , Islas de CpG , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Linaje , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , RiesgoRESUMEN
INTRODUCTION: ICHD-3 criteria for chronic migraine (CM) include a mixture of migraine and tension-type-like headaches and do not account for patients who have a high frequency of migraine but no other headaches. MATERIALS AND METHODS: Patients from the Danish Headache Center and their relatives with ICHD-3 defined CM were compared with patients with high frequency episodic migraine (HFEM). Danish registries were used to compare the socioeconomic impact in these two groups. A Russian student population was used to determine the generalizability of the number of patients fulfilling CM and the proposed diagnostic criteria for CM. RESULTS: There was no difference in the demographic profile between the two groups in the Danish cohort. The number of lifelong or annual attacks (p > 0.3), comorbid diseases, or self-reported effect of triptans (p = 1) did not differ. HFEM patients purchased more triptans than CM patients (p = 0.01). CM patients received more early pension (p = 0.00135) but did not differ from HFEM patients with regard to sickness benefit (p = 0.207), cash assistance (p = 0.139), or rehabilitation benefit (p = 1). DISCUSSION: Patients with HFEM are comparable to CM patients with regard to chronicity and disability. We therefore suggest classifying CM as ≥ 8 migraine days per month (proposed CM), disregarding the need for ≥ 15 headache days per month. The proposed diagnostic criteria for CM approximately doubled the number of patients with CM in both the Danish and the Russian materials. Extending the definition of CM to include patients with HFEM will ensure that patients with significant disease burden and unmet treatment needs are identified and provided appropriate access to the range of treatment options and resources available to those with CM. CONCLUSION: Patients with migraine on eight or more days but not 15 days with headache a month are as disabled as patients with ICHD-3 defined CM. They should be included in revised diagnostic criteria for chronic migraine.
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Clasificación Internacional de Enfermedades/tendencias , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/epidemiología , Sistema de Registros , Adolescente , Adulto , Anciano , Enfermedad Crónica , Dinamarca/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Migrañosos/clasificación , Sistema de Registros/clasificación , Federación de Rusia/epidemiología , Adulto JovenRESUMEN
INTRODUCTION: Headache is an extremely prevalent disorder with a lifetime prevalence of 90-99%. However, a small fraction of people never experiences a headache. Research on people without headache could uncover protective factors in headache, but to our knowledge no study on headache-free individuals has been published. We aim to estimate the prevalence of headache-free individuals among Danish blood donors, and to describe the socio-demographics and health factors of headache-free participants. MATERIALS AND METHODS: In all, 38,557 healthy volunteers were recruited as part of the Danish Blood Donor Study. Headache-free participants were identified based on the question "Have you ever experienced a headache of any kind?". Utilising the Danish registries and self-reported questionnaires, we analysed socio-demographic and lifestyle factors using logistic regression adjusted for age and sex. RESULTS: The prevalence of headache-free individuals was 4.1% (n = 1362) with a female-male ratio of 1:2.2. To be headache free was significantly associated with an employment status as a student, a low level of income and a regular alcohol consumption. DISCUSSION: The prevalence of headache-free individuals was comparable to population-wide studies of headache. To be headache free was not associated with a high socio-economic status. Further studies on people without headache will hopefully reveal protective factors in headache, and this novel approach might be useful in other very prevalent disorders.
Asunto(s)
Cefalea/epidemiología , Estilo de Vida , Adolescente , Adulto , Donantes de Sangre , Estudios de Casos y Controles , Dinamarca/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
BACKGROUND: Genomic sequencing of children in research raises complex ethical issues. This study aims to gain more knowledge on the attitudes towards the inclusion of children as research subjects in genomic research and towards the disclosure of pertinent and incidental findings to the parents and the child. METHODS: Qualitative data were collected from interviews with a wide range of informants: experts engaged in genomic research, clinical geneticists, persons with mental disorders, relatives, and blood donors. Quantitative data were collected from a cross-sectional web-based survey among 1227 parents and 1406 non-parents who were potential stakeholders in psychiatric genomic research. RESULTS: Participants generally expressed positive views on children's participation in genomic research. The informants in the qualitative interviews highlighted the age of the child as a critical aspect when disclosing genetic information. Other important aspects were the child's right to an autonomous choice, the emotional burden of knowing imposed on both the child and the parents, and the possibility of receiving beneficial clinical information regarding the future health of the child. Nevertheless, there was no consensus whether the parent or the child should receive the findings. A majority of survey stakeholders agreed that children should be able to participate in genomic research. The majority agreed that both pertinent and incidental findings should be returned to the parents and to the child when of legal age. Having children does not affect the stakeholder's attitudes towards the inclusion of children as research subjects in genomic research. CONCLUSION: Our findings illustrate that both the child's right to autonomy and the parents' interest to be informed are important factors that are found valuable by the participants. In future guidelines governing children as subjects in genomic research, it would thus be essential to incorporate the child's right to an open future, including the right to receive information on adult-onset genetic disorders.
Asunto(s)
Genoma Humano/genética , Genómica/ética , Trastornos Mentales/epidemiología , Participación de los Interesados , Actitud , Revelación/ética , Femenino , Humanos , Masculino , Trastornos Mentales/psicología , Padres , Psiquiatría/éticaRESUMEN
INTRODUCTION: Osmophobia has been suggested as an additional symptom of migraine without aura, and a high prevalence of osmophobia of up to 50% has been reported in the literature. We conducted a nosographic study of osmophobia in all migraineurs and tension-type headache patients and a field testing of suggested diagnostic criteria of osmophobia, presented in the appendix of the second edition of The International Classification of Headache Disorders and suggested by Silva-Néto et al. and Wang et al ., in migraine without aura and tension-type headache patients (n = 1934). MATERIALS AND METHODS: Each patient received a validated semi-structured interview. All subjects fulfilled the diagnostic criteria of the second edition of The International Classification of Headache Disorders for migraine or tension-type headache. Statistical analyses were performed using statistical software R. The statistical R package "Caret" was used to construct a confusion matrix and retrieve sensitivity, which is defined as the suggested criteria's ability to correctly diagnose migraine without aura patients, and specificity, defined as the suggested criteria's ability to not wrongly diagnose tension-type headache patients. RESULTS: Osmophobia was present in 33.5% of patients with migraine with aura, in 36.0% of patients with migraine without aura, and in 1.2% of patients with tension-type headache. All migraineurs with osmophobia also fulfilled the current criteria for migraine by having nausea or photophobia and phonophobia. The appendix criteria had a sensitivity of 0.96 and a specificity of 0.99 for migraine without aura, and a sensitivity of 0.65 and a specificity of 0.99 for probable migraine without aura. Both the criteria by Silva-Néto et al. and Wang et al. had a sensitivity of 0.98 and a specificity of 0.99 for migraine without aura, and a sensitivity of 0.66 and a specificity of 0.99 for probable migraine without aura. DISCUSSION: This study demonstrates the remarkable specificity of osmophobia. The criteria by Silva-Néto et al. and Wang et al. both had a higher sensitivity than the appendix criteria for migraine without aura; all three criteria had a low sensitivity for probable migraine without aura. However, neither the appendix criteria nor the criteria by Silva-Néto et al. or Wang et al. added any extra patients that would not have been diagnosed by the current diagnostic criteria for migraine. Osmophobia is a valuable symptom that may be useful to differentiate between migraine without aura and tension-type headache in difficult clinical cases. CONCLUSION: Our results do not suggest that alterations of the current diagnostic criteria for migraine without aura are needed.