Genome-wide association study reveals a locus in ADARB2 for complete freedom from headache in Danish Blood Donors.

Headache disorders are the most common disorders of the nervous system. The lifetime prevalence of headache disorders show that some individuals never experience headache. The etiology of complete freedom from headache is not known. To assess genetic variants associated with complete freedom from headache, we performed a genome-wide association study of individuals who have never experienced a headache. We included 63,992 individuals (2,998 individuals with complete freedom from headache and 60,994 controls) from the Danish Blood Donor Study Genomic Cohort. Participants were included in two rounds, from 2015 to 2018 and in 2020. We discovered a genome-wide significant association, with the lead variant rs7904615[G] in ADARB2 (EAF = 27%, OR = 1.20 [1.13-1.27], p = 3.92 × 10-9). The genomic locus was replicated in a non-overlapping cohort of 13,032 individuals (539 individuals with complete freedom from headache and 12,493 controls) from the Danish Blood Donor Study Genomic Cohort (p < 0.05, two-sided). Participants for the replication were included from 2015 to 2020. In conclusion, we show that complete freedom from headache has a genetic component, and we suggest that ADARB2 is involved in complete freedom from headache. The genomic locus was specific for complete freedom from headache and was not associated with any primary headache disorders.

Sex differences in clinical characteristics of migraine and its burden: a population-based study.

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.

Childhood cancer confers increased risk of migraine - A Danish nationwide register study.

BACKGROUND: Investigations of migraine among childhood cancer survivors have predominantly relied on self-reported information and hospital discharge diagnoses. Alone, both approaches are liable to bias. We used Danish nationwide registers to obtain data on both prescriptions of acute migraine medications (antimigraines) and hospital discharge diagnoses of migraine to assess the relative risk of migraine across a wider spectrum of migraine presentations than previously studied. METHODS: We followed a Danish population-based cohort of 7771 individuals with childhood cancer diagnosed in the period from Jan 1st, 1978 to Dec 31st, 2017, for risk of prescription antimigraine initiation and for risk of hospitalization due to migraine. Rates of hospitalization were assessed for the entire follow-up period whereas rates of antimigraine initiations were assessed in the period from Jan 1st, 1997, to Dec 31st, 2017. Relative to the general population without childhood cancer, standardized incidence ratios (SIRs) were calculated for each outcome. RESULTS: Individuals exposed to childhood cancer were at increased risk of antimigraine initiation (SIR of 1.24, 95% CI: 1.11-1.38) and of migraine hospitalization (SIR of 2.44, 95% CI: 1.87-3.12) from the day of their cancer diagnosis and up to 40 years after. CONCLUSIONS: Individuals diagnosed with childhood cancer have a higher risk of migraine of varying presentations, in addition to migraine resulting in hospitalization as previously reported. This potentially preventable problem warrants clinical attention.

Headache provocation by nitric oxide in men who have never experienced a headache.

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.

Pain sensitivity in men who have never experienced a headache: an observer blinded case control study.

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.

Twenty-five years of triptans - a nationwide population study.

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.

Prevalence and socio-demographic characteristics of persons who have never had a headache among healthy voluntary blood donors - a population-based study.

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.

Familial analysis reveals rare risk variants for migraine in regulatory regions.

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.

Higher burden of rare frameshift indels in genes related to synaptic transmission separate familial hemiplegic migraine from common types of migraine.

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.

[Demyelinating diseases in children with acute neurological symptoms]. / Demyeliniserende sygdom hos børn med akutte neurologiske symptomer

Demyelinating diseases in children is a broad group of illnesses, which affect the central nervous system. Demyelinating diseases can be monophasic or chronic and comprise acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, multiple sclerosis and neuromyelitis optica. Demyelinating diseases are rare, but it is important for the physician to recognize these diseases, as well as to understand the differential diagnoses. This review summarizes the current knowledge of demyelinating disorders in children, focusing on an approach to diagnosis and management.

[Acute disseminated encephalomyelitis is an important differential diagnosis in the acutely affected child]. / Akut dissemineret encefalomyelitis er en vigtig differentialdiagnose hos det akut påvirkede barn.

Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory paediatric disorder of the central nervous system (CNS). ADEM primarily affects the white matter of the brain and spinal cord. The aetiology of ADEM is unknown, but the illness is often precipitated by an infection, less often by vaccination. ADEM is characterized by acute polyfocal CNS deficit, including encephalopathy. This can be seen on MRI as simultaneously occurring multifocal lesions. Empirical treatment with steroids or immunoglobulins is often used. The prognosis of ADEM is usually favourable. This article describes two Danish cases both demonstrating trait characteristics of ADEM as well as the importance of an MRI considering an ADEM diagnosis early in the course of the illness.