NCOR2 is a novel candidate gene for migraine-epilepsy phenotype.

HYPOTHESIS: To identify genetic factors predisposing to migraine-epilepsy phenotype utilizing a multi-generational family with known linkage to chr12q24.2-q24.3. METHODS: We used single nucleotide polymorphism (SNP) genotyping and next-generation sequencing technologies to perform linkage, haplotype, and variant analyses in an extended Finnish migraine-epilepsy family (n = 120). In addition, we used a large genome-wide association study (GWAS) dataset of migraine and two biobank studies, UK Biobank and FinnGen, to test whether variants within the susceptibility region associate with migraine or epilepsy related phenotypes in a population setting. RESULTS: The family showed the highest evidence of linkage (LOD 3.42) between rs7966411 and epilepsy. The haplotype shared among 12 out of 13 epilepsy patients in the family covers almost the entire NCOR2 and co-localizes with one of the risk loci of the recent GWAS on migraine. The haplotype harbors nine low-frequency variants with potential regulatory functions. Three of them, in addition to two common variants, show nominal associations with neurological disorders in either UK Biobank or FinnGen. CONCLUSION: We provide several independent lines of evidence supporting association between migraine-epilepsy phenotype and NCOR2. Our study suggests that NCOR2 may have a role in both migraine and epilepsy and thus would provide evidence for shared pathophysiology underlying these two diseases.

Polygenic risk provides biological validity for the ICHD-3 criteria among Finnish migraine families.

BACKGROUND: Migraine is diagnosed using the extensively field-tested International Classification of Headache Disorders (ICHD-3) consensus criteria derived by the International Headache Society. To evaluate the criteria in respect to a measurable biomarker, we studied the relationship between the main ICHD-3 criteria and the polygenic risk score, a measure of common variant burden in migraine. METHODS: We used linear mixed models to study the correlation of ICHD-3 diagnostic criteria, underlying symptoms, and main diagnoses with the polygenic risk score of migraine in a cohort of 8602 individuals from the Finnish Migraine Genome Project. RESULTS: Main diagnostic categories and all underlying diagnostic criteria formed a consistent continuum along the increasing polygenic burden. Polygenic risk was associated with the heterogeneous clinical picture starting from the non-migraine headache (mean 0.07; 95% CI 0.02-0.12; p = 0.008 compared to the non-headache group), to probable migraine (mean 0.13; 95% CI 0.08-0.18; p < 0.001), migraine headache (mean 0.17; 95% CI 0.14-0.21; p < 0.001) and migraine with typical visual aura (mean 0.29; 95% CI 0.26-0.33; p < 0.001), all the way to the hemiplegic aura (mean 0.37; 95% CI 0.31-0.43; p < 0.001). All individual ICHD-3 symptoms and the total number of reported symptoms, a surrogate of migraine complexity, demonstrated a clear inclination with an increasing polygenic risk. CONCLUSIONS: The complex migraine phenotype progressively follows the polygenic burden from individuals with no headache to non-migrainous headache and up to patients with attacks manifesting all the features of the ICHD-3 headache and aura. Results provide further biological support for the ICHD-3 diagnostic criteria.

Electrocardiographic findings in migraineurs: results of the Finnish Health 2000 survey.

BACKGROUND: The precise relation between migraine and cardiovascular diseases remains unknown, but cardiac autonomic regulation as reflected by electrocardiography is poorly studied in migraineurs. AIMS OF THE STUDY: To search whether electrocardiographic findings may elucidate the mechanisms linking migraine with cardiovascular diseases. METHODS: We compared electrocardiographic findings in headache-free subjects (n=5,317) and people with migraine (n=490) in a Finnish population cohort. RESULTS: The frequency of cardiac rhythm and conduction disorders did not differ between the groups but left ventricular hypertrophy was more often seen in migraineurs than in non-migraineurs (odds ratio (OR)=1.32, 95% confidence interval (CI) 1.0; 1.74, p<0.05). In migraineurs reporting frequent attacks, cardiovascular diseases were associated with longer QTc intervals (p<0.05). After excluding confounders, migraineurs had longer PR intervals (160.3 vs 159.8 ms, mean difference (MD)=3.14, 95% CI 0.65; 5.62, p<0.05) than non-migraineurs. PR intervals (MD=6.6, CI 1.51; 11.68, p<0.05) and the probability of left ventricular hypertrophy (OR=1.98, CI 1.2; 3.26, p<0.05) were different in males with and without migraine, especially in patients with frequent attacks, but not in females. CONCLUSIONS: Our findings support the notion that there are interactions between migraine and cardiovascular disorders and suggest that electrocardiographic screening in migraineurs should be considered during clinical work-up.

Left ventricular hypertrophy and other cardiac risk factors in migraineurs.

BACKGROUND: The influence of cardiovascular risk factors on the probability of cardiovascular diseases in migraineurs is still being discussed. AIMS OF THE STUDY: To further elucidate the mechanisms of these relationships, we assessed the associations between migraine and cardiovascular risk factors, including those that have been recently shown to improve the prediction of cardiovascular events. METHODS: We used the data of the Finnish Health 2000 Survey (BRIF8901), consisting of 5737 subjects aged 30 years or older. In total, 488 participants reported migraine. In addition to conventional cardiovascular risk factors, educational attainment, presence of electrocardiographic signs of left ventricular hypertrophy and hemoglobin A1c were also included in the logistic regression analyses. RESULTS: Migraine was found to be associated with female sex (Odds ratio (OR) = 3.75, p < .001), lower age (B = 0.99, p < .001), lower high-density lipoprotein cholesterol (OR = 1.23, p < .05), higher diastolic blood pressure (OR = 1.31, p < .05), and left ventricular hypertrophy (OR = 1.32, p < .05), the probability of the last one increasing with migraine attack frequency. CONCLUSIONS: Left ventricular hypertrophy, most probably as a consequence of migraine-related arterial hypertension and dyslipidemia, may play a role in the relationship between migraine and cardiovascular events. The nature of this finding calls for further studies.

The contribution of CACNA1A, ATP1A2 and SCN1A mutations in hemiplegic migraine: A clinical and genetic study in Finnish migraine families.

Objective To study the position of hemiplegic migraine in the clinical spectrum of migraine with aura and to reveal the importance of CACNA1A, ATP1A2 and SCN1A in the development of hemiplegic migraine in Finnish migraine families. Methods The International Classification of Headache Disorders 3rd edition criteria were used to determine clinical characteristics and occurrence of hemiplegic migraine, based on detailed questionnaires, in a Finnish migraine family collection consisting of 9087 subjects. Involvement of CACNA1A, ATP1A2 and SCN1A was studied using whole exome sequencing data from 293 patients with hemiplegic migraine. Results Overall, hemiplegic migraine patients reported clinically more severe headache and aura episodes than non-hemiplegic migraine with aura patients. We identified two mutations, c.1816G>A (p.Ala606Thr) and c.1148G>A (p.Arg383His), in ATP1A2 and one mutation, c.1994C>T (p.Thr665Met) in CACNA1A. Conclusions The results highlight hemiplegic migraine as a clinically and genetically heterogeneous disease. Hemiplegic migraine patients do not form a clearly separate group with distinct symptoms, but rather have an extreme phenotype in the migraine with aura continuum. We have shown that mutations in CACNA1A, ATP1A2 and SCN1A are not the major cause of the disease in Finnish hemiplegic migraine patients, suggesting that there are additional genetic factors contributing to the phenotype.

Premonitory symptoms in migraine: A cross-sectional study in 2714 persons.

AIM: To describe the frequency and number of premonitory symptoms (PS) in migraine, the co-occurrence of different PS, and their association with migraine-related factors. METHODS: In this cross-sectional study, a validated questionnaire was sent to Finnish migraine families between 2002 and 2013 to obtain data on 14 predefined PS, migraine diagnoses, demographic factors, and migraine characteristics. The estimated response rate was 80%. RESULTS: Out of 2714 persons, 2223 were diagnosed with migraine. Among these, 77% reported PS, with a mean number of 3.0 symptoms compared to 30% (p < 0.001) and 0.5 symptoms (p < 0.001) among 491 persons with non-migraine headaches. Yawning was the most commonly reported symptom (34%) among migraineurs. Females reported PS more frequently than males (81 versus 64%, p < 0.001) and experienced a higher number of different symptoms (mean 3.3 versus 1.8, p < 0.001). All measures of migraine severity were associated with a higher burden of PS. Light and sound sensitivity showed the highest co-occurrence (kappa = 0.51, 95% CI 0.47-0.55). In a generalized linear model, age, gender, higher frequency, duration and intensity of headache, reduced working capacity, most aura symptoms, and associated symptoms of the headache phase were significantly associated with an increased in the number of PS. CONCLUSION: PS are experienced by a majority of migraineurs. More severe migraine is associated with a higher burden of PS. Since the material was not entirely representative of the general population of migraineurs, caution should be exercised in generalizing the results.

Systematic re-evaluation of genes from candidate gene association studies in migraine using a large genome-wide association data set.

BACKGROUND: Before the genome-wide association (GWA) era, many hypothesis-driven candidate gene association studies were performed that tested whether DNA variants in genes that had been selected based on prior knowledge about migraine pathophysiology were associated with migraine. Most studies involved small sample sets without robust replication, thereby making the risk of false-positive findings high. Genome-wide marker data of thousands of migraine patients and controls from the International Headache Genetics Consortium provide a unique opportunity to re-evaluate key findings from candidate gene association studies (and other non-GWA genetic studies) in a much larger data set. METHODS: We selected 21 genes from published candidate gene association studies and six additional genes from other non-GWA genetic studies in migraine. Single nucleotide polymorphisms (SNPs) in these genes, as well as in the regions 500 kb up- and downstream, were inspected in IHGC GWAS data from 5175 clinic-based migraine patients with and without aura and 13,972 controls. RESULTS: None of the SNPs in or near the 27 genes, including the SNPs that were previously found to be associated with migraine, reached the Bonferroni-corrected significance threshold; neither when analyzing all migraine patients together, nor when analyzing the migraine with and without aura patients or males and females separately. CONCLUSION: The available migraine GWAS data provide no clear evidence for involvement of the previously reported most promising candidate genes in migraine.

Gene-based pleiotropy across migraine with aura and migraine without aura patient groups.

INTRODUCTION: It is unclear whether patients diagnosed according to International Classification of Headache Disorders criteria for migraine with aura (MA) and migraine without aura (MO) experience distinct disorders or whether their migraine subtypes are genetically related. AIM: Using a novel gene-based (statistical) approach, we aimed to identify individual genes and pathways associated both with MA and MO. METHODS: Gene-based tests were performed using genome-wide association summary statistic results from the most recent International Headache Genetics Consortium study comparing 4505 MA cases with 34,813 controls and 4038 MO cases with 40,294 controls. After accounting for non-independence of gene-based test results, we examined the significance of the proportion of shared genes associated with MA and MO. RESULTS: We found a significant overlap in genes associated with MA and MO. Of the total 1514 genes with a nominally significant gene-based p value (pgene-based ≤ 0.05) in the MA subgroup, 107 also produced pgene-based ≤ 0.05 in the MO subgroup. The proportion of overlapping genes is almost double the empirically derived null expectation, producing significant evidence of gene-based overlap (pleiotropy) (pbinomial-test = 1.5 × 10(-4)). Combining results across MA and MO, six genes produced genome-wide significant gene-based p values. Four of these genes (TRPM8, UFL1, FHL5 and LRP1) were located in close proximity to previously reported genome-wide significant SNPs for migraine, while two genes, TARBP2 and NPFF separated by just 259 bp on chromosome 12q13.13, represent a novel risk locus. The genes overlapping in both migraine types were enriched for functions related to inflammation, the cardiovascular system and connective tissue. CONCLUSIONS: Our results provide novel insight into the likely genes and biological mechanisms that underlie both MA and MO, and when combined with previous data, highlight the neuropeptide FF-amide peptide encoding gene (NPFF) as a novel candidate risk gene for both types of migraine.

Headache as symptom of intracranial hemorrhage.

The most important signs of danger of a headache patient include exceptionally intense or acute headache, transient loss or progressive impairment of consciousness, and neurological deficit symptoms. These patients are referred to an urgent assessment by a physician. Computed tomography scanning of the head is carried out in the case of suspected hemorrhage of a headache patient. Routine diagnosis employing cerebrospinal fluid analysis can be abandoned when excluding subarachnoid hemorrhage in a patient with headache symptoms, if blood is with certainty not observed in the CT scan of the head and no more than six hours have passed after the onset of the symptom. If subarachnoid hemorrhage is detected, cerebral CT angiography will be performed at the same time and a neurosurgeon consulted about the need of operative treatment.

Concordance of genetic risk across migraine subgroups: Impact on current and future genetic association studies.

BACKGROUND: There has been intensive debate whether migraine with aura (MA) and migraine without aura (MO) should be considered distinct subtypes or part of the same disease spectrum. There is also discussion to what extent migraine cases collected in specialised headache clinics differ from cases from population cohorts, and how female cases differ from male cases with respect to their migraine. To assess the genetic overlap between these migraine subgroups, we examined genome-wide association (GWA) results from analysis of 23,285 migraine cases and 95,425 population-matched controls. METHODS: Detailed heterogeneity analysis of single-nucleotide polymorphism (SNP) effects (odds ratios) between migraine subgroups was performed for the 12 independent SNP loci significantly associated (p < 5 × 10(-8); thus surpassing the threshold for genome-wide significance) with migraine susceptibility. Overall genetic overlap was assessed using SNP effect concordance analysis (SECA) at over 23,000 independent SNPs. RESULTS: Significant heterogeneity of SNP effects (p het < 1.4 × 10(-3)) was observed between the MA and MO subgroups (for SNP rs9349379), and between the clinic- and population-based subgroups (for SNPs rs10915437, rs6790925 and rs6478241). However, for all 12 SNPs the risk-increasing allele was the same, and SECA found the majority of genome-wide SNP effects to be in the same direction across the subgroups. CONCLUSIONS: Any differences in common genetic risk across these subgroups are outweighed by the similarities. Meta-analysis of additional migraine GWA datasets, regardless of their major subgroup composition, will identify new susceptibility loci for migraine.

The relationship between headache and religious attendance (the Nord-Trøndelag health study-HUNT).

BACKGROUND: Religious belief can be used as a pain coping strategy. Our purpose was to evaluate the relationship between headache and religious activity using prospective data from a large population-based study. METHODS: This longitudinal cohort study used data from two consecutive surveys in the Nord-Trøndelag Health Survey (HUNT 2 and 3) performed in 1995-1997; and 2006-2008. Among the 51,383 participants aged ≥ 20 years who answered headache questions at baseline, 41,766 were eligible approximately 11 years later. Of these, 25,177 (60%) completed the question in HUNT 3 regarding religious activity. Frequent religious attendees (fRA) (used as a marker of stronger religious belief than average) were defined as those who had been to church/prayer house at least once monthly during the last six months. RESULTS: In the multivariate analyses, adjusting for known potential confounders, individuals with headache 1-14 days/month in HUNT 2 were more likely to be fRA 11 years later than headache-free individuals. Migraine at baseline predisposed more strongly to fRA at follow-up (OR = 1.25; 95% CI 1.19-1.40) than did non-migrainous headache (OR = 1.13; 95% 1.04-1.23). The odds of being fRA was 48% increased (OR 1.48; 95% 1.19-1.83) among those with migraine 7-14 days/month at baseline compared to subjects without headache. In contrast, headache status at baseline did not influence the odds of being frequent visitors of concerts, cinema and/or theatre at follow-up 11 years later. CONCLUSIONS: In this prospective study, headache, in particular migraine, at baseline slightly increased the odds of being fRA 11 years later.

[Vertigo from the practitioner's standpoint]. / Huimaus käytännön lääkärin kannalta.

One third of the population suffer from vertigo at some stage of their life. Some of its causes are harmless, some life-threatening, some will resolve spontaneously and some never. Vertigo is divided into four main types: vertigo, syncope, disturbance of balance and nonspecific vertigo. Medical history is the most important method of examination and leads to diagnosis in two out of three cases. Attempts are always made to provoke the sensation of vertigo and the possible nystagmus during the consultation. The success of the specific treatment in accordance with the primary cause determines the patient's prognosis.

[Unconsciousness]. / Tajuttomuus.

Unconsciousness is a directly life-threatening condition that requires immediate action to reveal its cause. The cause of unconsciousness is usually metabolic or toxic and in the rest of the cases structural and intracranial. Unconsciousness results from a disturbance of function of either the reticular activating system or both cerebral hemispheres. Treatment of an unconscious person begins with the confirmation of vital functions. Special attention is paid on head and neck injuries, meningism, pupillary inequality and papillary stasis. Both radiological and laboratory investigations are usually required. Owing to its quickness, CT scan of the head is the basic neurological examination, adequately revealing the common intracranial causes. Treating an unconscious patient calls for the complete range of a physician's expertise. Determined action and knowledge of common and treatable diseases will, however, bring the situation under control.

[Treatment of prolonged migraine attack (status migrenosus)]. / Pitkittyneen migreenikohtauksen (status migrenosus) hoito.

If a migraine attack takes more than 72 hours it is called status migrenosus (SM). The most important contributing factor in SM is prolonged excessive use of anti-migraine drugs. Before starting any treatments for SM, severe causes underlying the prolonged pain should be excluded. The cornerstones of pharmacological therapy for SM are parenterally administered anti-inflammatory drugs and triptans as well as valproate and dopamine antagonists. With regard to long-term prognosis, the recognition and treatment of medication overuse headache is essential.

[How do I distinguish migraine aura from TIA attack?]. / Miten erotan migreeniauran TIA-kohtauksesta?

Migraine aura is almost always a visual disturbance involving "positive" (rippling, stars) and "negative" (visual field defect) phenomena. It expands and gradually vanishes within 5 to 60 minutes. Evolution of symptoms and positivity are typical for migraine. TIA appears more abruptly and is usually of shorter duration. Negativity is typical for it, i.e. part of the visual field, speech, eye movement, ability to swallow, sensation or muscle strength disappear without the above mentioned features of migraine. In migraine, aura is usually followed by headache, whereas in TIA headache is less frequent.

Consistently replicating locus linked to migraine on 10q22-q23.

Here, we present the results of two genome-wide scans in two diverse populations in which a consistent use of recently introduced migraine-phenotyping methods detects and replicates a locus on 10q22-q23, with an additional independent replication. No genetic variants have been convincingly established in migraine, and although several loci have been reported, none of them has been consistently replicated. We employed the three known migraine-phenotyping methods (clinical end diagnosis, latent-class analysis, and trait-component analysis) with robust multiple testing correction in a large sample set of 1675 individuals from 210 migraine families from Finland and Australia. Genome-wide multipoint linkage analysis that used the Kong and Cox exponential model in Finns detected a locus on 10q22-q23 with highly significant evidence of linkage (LOD 7.68 at 103 cM in female-specific analysis). The Australian sample showed a LOD score of 3.50 at the same locus (100 cM), as did the independent Finnish replication study (LOD score 2.41, at 102 cM). In addition, four previously reported loci on 8q21, 14q21, 18q12, and Xp21 were also replicated. A shared-segment analysis of 10q22-q23 linked Finnish families identified a 1.6-9.5 cM segment, centered on 101 cM, which shows in-family homology in 95% of affected Finns. This region was further studied with 1323 SNPs. Although no significant association was observed, four regions warranting follow-up studies were identified. These results support the use of symptomology-based phenotyping in migraine and suggest that the 10q22-q23 locus probably contains one or more migraine susceptibility variants.

A high-density association screen of 155 ion transport genes for involvement with common migraine.

The clinical overlap between monogenic Familial Hemiplegic Migraine (FHM) and common migraine subtypes, and the fact that all three FHM genes are involved in the transport of ions, suggest that ion transport genes may underlie susceptibility to common forms of migraine. To test this leading hypothesis, we examined common variation in 155 ion transport genes using 5257 single nucleotide polymorphisms (SNPs) in a Finnish sample of 841 unrelated migraine with aura cases and 884 unrelated non-migraine controls. The top signals were then tested for replication in four independent migraine case-control samples from the Netherlands, Germany and Australia, totalling 2835 unrelated migraine cases and 2740 unrelated controls. SNPs within 12 genes (KCNB2, KCNQ3, CLIC5, ATP2C2, CACNA1E, CACNB2, KCNE2, KCNK12, KCNK2, KCNS3, SCN5A and SCN9A) with promising nominal association (0.00041 < P < 0.005) in the Finnish sample were selected for replication. Although no variant remained significant after adjusting for multiple testing nor produced consistent evidence for association across all cohorts, a significant epistatic interaction between KCNB2 SNP rs1431656 (chromosome 8q13.3) and CACNB2 SNP rs7076100 (chromosome 10p12.33) (pointwise P = 0.00002; global P = 0.02) was observed in the Finnish case-control sample. We conclude that common variants of moderate effect size in ion transport genes do not play a major role in susceptibility to common migraine within these European populations, although there is some evidence for epistatic interaction between potassium and calcium channel genes, KCNB2 and CACNB2. Multiple rare variants or trans-regulatory elements of these genes are not ruled out.

A data-driven medication score predicts 10-year mortality among aging adults.

Health differences among the elderly and the role of medical treatments are topical issues in aging societies. We demonstrate the use of modern statistical learning methods to develop a data-driven health measure based on 21 years of pharmacy purchase and mortality data of 12,047 aging individuals. The resulting score was validated with 33,616 individuals from two fully independent datasets and it is strongly associated with all-cause mortality (HR 1.18 per point increase in score; 95% CI 1.14-1.22; p = 2.25e-16). When combined with Charlson comorbidity index, individuals with elevated medication score and comorbidity index had over six times higher risk (HR 6.30; 95% CI 3.84-10.3; AUC = 0.802) compared to individuals with a protective score profile. Alone, the medication score performs similarly to the Charlson comorbidity index and is associated with polygenic risk for coronary heart disease and type 2 diabetes.

Valsalva maneuver as migraine inducer: a case report of a woman with patent foramen ovale and an ischemic stroke.

The association between patent foramen ovale, ischemic stroke, and migraine with aura is well known. It is, however, complicated and generates a considerable debate about the features and clinical consequences of the phenomenon. We report a case of a woman for whom patent foramen ovale has possibly acted as an inducer of both migraine attacks and ischemic stroke.

Lateralization in cluster headache: a Nordic multicenter study.

A slight predominance of cluster pain on the right side has been reported in several studies. The aim of this large retrospective Nordic multicenter study was to estimate the prevalence of right- and left-sided pain in cluster headache (CH) patients with side-locked pain, the prevalence of side shifts in episodic and chronic CH patients, and the occurrence of cranial autonomic symptoms related to pain side. Among 383 cluster patients, 55 (14%) had experienced pain side shift. Of the remaining 328 individuals without side shift, there was no significant difference between the occurrence of right-sided and left-sided pain (54 vs. 46%). The prevalence of side shift was similar for episodic and chronic CH and the occurrence of cranial autonomic symptoms was not influenced by the pain side. In conclusion, previous reports of a side difference in location of cluster pain could not be confirmed in this large Nordic sample.