Migraine heritability and beyond: A scoping review of twin studies.

OBJECTIVE: This scoping review aimed to summarize current knowledge from twin studies on migraine. Migraine heritability, genetic correlations with migraine comorbid disorders, and the use of discordant twin pairs in migraine research are described. Further, the review considers the unused potential of twin studies in migraine research and reflects on future directions. BACKGROUND: Twin studies can be used to understand how heritable and environmental factors influence human traits and disorders. The classical twin design compares the resemblance of a trait in monozygotic twins to that in dizygotic twins. The classical twin design can be extended to estimate the genetic correlation between disorders, model causality, and describe differences within discordant twin pairs. METHODS: Studies focusing on migraine and using a twin study design were included. The search was performed on the PubMed-MEDLINE database using the search terms "migraine" AND "twin" OR "twins." It was done in May 2023, rerun in November 2023, and managed with the Covidence software. RESULTS: The search identified 52 twin studies on migraine. In 24 papers, the heritability of migraine was estimated with a classical twin design. Heritability estimates ranged from 0.36 to 0.48 for studies with adults, both men and women, and unspecified migraine. Migraine heritability was predominantly estimated with twin cohorts of North European ancestry, and only two studies examined migraine subtypes. A multilevel classical twin design was used in 11 studies to examine the co-occurrence between migraine and comorbid disorders. The differences within migraine discordant twin pairs were examined in nine studies. CONCLUSION: The heritability of migraine was estimated with a classical twin design in twin cohorts from seven different countries, with remarkably similar results across studies. Future studies should include migraine subtypes and twin cohorts of non-North European ancestry to better reflect the global population. Beyond heritability estimations, the twin method is a valuable tool for understanding causality and describing differences within discordant twin pairs. Despite more than 80 years of twin studies in migraine research, the twin design has a large unused potential to advance our understanding of migraine.

No association between migraine and HLA alleles in a cohort of 13,210 individuals with migraine from the Danish Blood Donor Study.

OBJECTIVE: To determine the association between human leukocyte antigen (HLA) alleles and migraine, migraine subtypes, and sex-specific factors. BACKGROUND: It has long been hypothesized that inflammation contributes to migraine pathophysiology. This study examined the association between migraine and alleles in the HLA system, a key player in immune response and genetic diversity. METHODS: We performed a case-control study and included 13,210 individuals with migraine and 86,738 controls. All participants were part of the Danish Blood Donor Study Genomic Cohort. Participants were genotyped and 111 HLA alleles on 15 HLA genes were imputed. We examined the association between HLA alleles and migraine subtypes, considering sex-specific differences. RESULTS: We found no association between HLA alleles and migraine, neither overall, nor in the sex-specific analysis. In the migraine subtype analysis, three HLA alleles were associated with migraine without aura; however, these associations could not be replicated in an independent Icelandic cohort (2191 individuals with migraine without aura and 278,858 controls). Furthermore, we found no association between HLA alleles and migraine with aura or chronic migraine. CONCLUSION: We found no evidence of an association between the HLA system and migraine, suggesting that genetic factors related to the HLA system do not play a significant role in migraine susceptibility.

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.

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.

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.

[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.