Stroke genetics informs drug discovery and risk prediction across ancestries.

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Cluster headache polygenetic risk and known functional variants of CYP3A4 are not associated with treatment response.

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.

Dissecting the shared genetic basis of migraine and mental disorders using novel statistical tools.

Migraine is three times more prevalent in people with bipolar disorder or depression. The relationship between schizophrenia and migraine is less certain although glutamatergic and serotonergic neurotransmission are implicated in both. A shared genetic basis to migraine and mental disorders has been suggested but previous studies have reported weak or non-significant genetic correlations and five shared risk loci. Using the largest samples to date and novel statistical tools, we aimed to determine the extent to which migraine's polygenic architecture overlaps with bipolar disorder, depression and schizophrenia beyond genetic correlation, and to identify shared genetic loci. Summary statistics from genome-wide association studies were acquired from large-scale consortia for migraine (n cases = 59 674; n controls = 316 078), bipolar disorder (n cases = 20 352; n controls = 31 358), depression (n cases = 170 756; n controls = 328 443) and schizophrenia (n cases = 40 675, n controls = 64 643). We applied the bivariate causal mixture model to estimate the number of disorder-influencing variants shared between migraine and each mental disorder, and the conditional/conjunctional false discovery rate method to identify shared loci. Loci were functionally characterized to provide biological insights. Univariate MiXeR analysis revealed that migraine was substantially less polygenic (2.8 K disorder-influencing variants) compared to mental disorders (8100-12 300 disorder-influencing variants). Bivariate analysis estimated that 800 (SD = 300), 2100 (SD = 100) and 2300 (SD = 300) variants were shared between bipolar disorder, depression and schizophrenia, respectively. There was also extensive overlap with intelligence (1800, SD = 300) and educational attainment (2100, SD = 300) but not height (1000, SD = 100). We next identified 14 loci jointly associated with migraine and depression and 36 loci jointly associated with migraine and schizophrenia, with evidence of consistent genetic effects in independent samples. No loci were associated with migraine and bipolar disorder. Functional annotation mapped 37 and 298 genes to migraine and each of depression and schizophrenia, respectively, including several novel putative migraine genes such as L3MBTL2, CACNB2 and SLC9B1. Gene-set analysis identified several putative gene sets enriched with mapped genes including transmembrane transport in migraine and schizophrenia. Most migraine-influencing variants were predicted to influence depression and schizophrenia, although a minority of mental disorder-influencing variants were shared with migraine due to the difference in polygenicity. Similar overlap with other brain-related phenotypes suggests this represents a pool of 'pleiotropic' variants that influence vulnerability to diverse brain-related disorders and traits. We also identified specific loci shared between migraine and each of depression and schizophrenia, implicating shared molecular mechanisms and highlighting candidate migraine genes for experimental validation.

Acute stroke care during the first phase of COVID-19 pandemic in Norway.

OBJECTIVES: The aim of the present study was to investigate how the initial phase of the COVID-19 pandemic affected the hospital stroke management and research in Norway. MATERIALS AND METHODS: All neurological departments with a Stroke Unit in Norway (n = 17) were invited to participate in a questionnaire survey. The study focused on the first lockdown period, and all questions were thus answered in regard to the period between 12 March and 15 April 2020. RESULTS: The responder rate was 94% (16/17). Eighty-one % (13/16) reported that the pandemic affected their department, and 63% (10/16) changed their stroke care pathways. The number of new acute admissions in terms of both strokes and stroke mimics decreased at all 16 departments. Fewer patients received thrombolysis and endovascular treatment, and multidisciplinary stroke rehabilitation services were less available. The mandatory 3 months of follow-up of stroke patients was postponed at 73% of the hospitals. All departments conducting stroke research reported a stop in ongoing projects. CONCLUSION: In Norway, hospital-based stroke care and research were impacted during the initial phase of the COVID-19 pandemic, with likely repercussions for patient care and outcomes. In the future, stroke departments will require contingency plans in order to protect the entire stroke treatment chain.

The management and clinical knowledge of headache disorders among general practitioners in Norway: a questionnaire survey.

BACKGROUND: General practitioners (GPs) diagnose and manage a majority of headache patients seeking health care. With the aim to understand the potential for clinical improvement and educational needs, we performed a study to investigate Norwegian GPs knowledge about headache and its clinical management. METHODS: We invited GPs from a random sample of 130 Norwegian continuous medical education (CME) groups to respond to an anonymous questionnaire survey. RESULTS: 367 GPs responded to the survey (73% of invited CME groups, 7.6% of all GPs in Norway). Mean age was 46 (SD 11) years, with an average of 18 (SD 10) years of clinical experience. In general the national treatment recommendations were followed, while the International Classification of Headache Disorders and other international guidelines were rarely used. Overall, 80% (n = 292) of the GPs suggested adequate prophylactic medication for frequent episodic migraine, while 28% (n = 101) suggested adequate prophylactic medication for chronic tension-type headache (CTTH). Half (52%, n = 191)) of the respondents were aware that different types of acute headache medication can lead to medication-overuse headache (MOH), and 59% (n = 217) knew that prophylactic headache medication does not lead to MOH. GPs often used MRI in the diagnostic work-up. GPs reported that lack of good treatment options was a main barrier to more optimized treatment of headache patients. CONCLUSION: The knowledge of management of CTTH and MOH was moderate compared to migraine among Norwegian GPs.

Migraine, obesity and body fat distribution - a population-based study.

BACKGROUND: Obesity has been linked to an increased prevalence of migraine, and to increased migraine attack frequency, but several questions are left unanswered by previous studies. We examined the relationship between obesity and headache in a large, population-based study where we could take into account body fat distribution, migraine subtypes and tension-type headache. METHODS: The third population-based Nord-Trøndelag Health Study (HUNT3) included validated headache questionnaires and objective anthropometric measurements. Using a cross-sectional design, our sample consisted of 18,191 women and 14,985 men, aged 19 to 96 years. Of these 4290 (12.9%) had migraine, 4447 (13.4%) had frequent tension-type headache (TTH), and 24,439 were headache-free controls. A total of 5049 individuals with unclassified headache were excluded from the analyses. Using logistic regression, we modeled the association between obesity and headache prevalence, adjusting for relevant confounders. RESULTS: Both total body obesity (TBO) and abdominal obesity (AO) were associated with a higher prevalence of migraine when compared to headache-free controls (OR 1.45 95% CI 1.32-1.59 and OR 1.29 95% CI 1.18-1.41, respectively), in particular for individuals < 50 years of age (OR 1.74 95% CI 1.54-1.98 and OR 1.89 95% CI 1.69-2.11). Similar results were seen for migraine with and without aura. Similar Overall, a weaker associations were as observed between obesity and TTH. There was a dose-response relationship between obesity categories and increased headache frequency in subjects with migraine. TBO was associated with migraine prevalence and attack frequency independent of AO. CONCLUSION: Both TBO and AO were associated with migraine prevalence and attack frequency. This association was largely limited to individuals < 50 years of age. TBO, rather than AO, may be a better measure of obesity in relation to migraine.

Correction to: Hospital-based headache care during the Covid-19 pandemic in Denmark and Norway.

An amendment to this paper has been published and can be accessed via the original article.

Hospital-based headache care during the Covid-19 pandemic in Denmark and Norway.

BACKGROUND: The Covid-19 pandemic is causing changes in delivery of medical care worldwide. It is not known how the management of headache patients was affected by the lockdown during the pandemic. The aim of the present study was to investigate how the initial phase of the Covid-19 pandemic affected the hospital management of headache in Denmark and Norway. METHODS: All neurological departments in Denmark (n = 14) and Norway (n = 18) were invited to a questionnaire survey. The study focused on the lockdown and all questions were answered in regard to the period between March 12th and April 15th, 2020. RESULTS: The responder rate was 91% (29/32). Of the neurological departments 86% changed their headache practice during the lockdown. The most common change was a shift to more telephone consultations (86%). Video consultations were offered by 45%. The number of new headache referrals decreased. Only 36% administered botulinum toxin A treatment according to usual schemes. Sixty% reported that fewer patients were admitted for in-hospital emergency diagnostics and treatment. Among departments conducting headache research 57% had to halt ongoing projects. Overall, 54% reported that the standard of care was worse for headache patients during the pandemic. CONCLUSION: Hospital-based headache care and research was impacted in Denmark and Norway during the initial phase of the Covid-19-pandemic.

Neurology residents' knowledge of the management of headache.

BACKGROUND: In Norway, as in most other countries, the training program for clinical neurology has no mandatory headache program. Knowledge in headache management must therefore be acquired during everyday clinical training. The objectives of this study were to investigate neurology residents' knowledge of headache. METHODS: A questionnaire survey was undertaken among neurology residents in Norway. RESULTS: All 17 neurological departments in Norway participated, and 143 residents responded (86%). Sixty percent were women, mean age was 32.5 years, and the respondents had an average of 28 months clinical training in neurology. Fifty-six percent knew the approximate prevalence of migraine and chronic headache. Thirty-seven percent asked their patients about disability, quality of life, and social functioning at every consultation. Further, 72% would prescribe prophylaxis for chronic tension-type headache and 97% for very frequent migraine. One third wrongly stated that use of the most common headache prophylactics could lead to medication-overuse headache. Headache diaries were used regularly by 63% for diagnostic purposes, and 73% requested an MRI for all long-lasting headaches referred to neurological outpatient clinics. CONCLUSION: Although a major public health problem, headache knowledge is moderate at best, and its management clearly varies. There is an unmet need for a better and more structured headache training program in Norway.

The impact of C-reactive protein levels on headache frequency in the HUNT study 2006-2008.

BACKGROUND: Increased high sensitivity C- reactive protein (hs-CRP) levels have been found in many earlier studies on migraine, and recently also in persons with migraine and insomnia. The aim of this study was to see whether these findings could be reproduced in a large-scale population-based study. METHODS: A total of 50,807 (54%) out of 94,194 invited aged ≥20 years or older participated in the third wave of the Nord-Trøndelag Health Study study performed in 2006-2008. Among these, 38,807 (41%) had valid measures of hs-CRP and answered questions on headache and insomnia. Elevated hs-CRP was defined as > 3.0 mg/L. The cross-sectional association with headache was estimated by multivariate analyses using multiple logistic regression. The precision of the odds ratio (OR) was assessed with 95% confidence interval (CI). RESULTS: In the fully adjusted model, elevated hs-CRP was associated with migraine (OR 1.14, 95% CI 1.04-1.25) and migraine with aura (OR 1.15, 95% CI 1.03-1.29). The association was strongest among individuals with headache ≥15 days/month for any headache (OR 1.26, 95% CI 1.08-1.48), migraine (OR 1.62, 95% CI 1.21-2.17), and migraine with aura (OR 1.84, 95% CI 1.27-2.67). No clear relationship was found between elevated hs-CRP and headache less than 7 days/month or with insomnia. CONCLUSIONS: Cross-sectional data from this large-scale population-based study showed that elevated hs-CRP was associated with headache ≥7 days/month, especially evident for migraine with aura.

Prestige of neurological disorders among future neurologists in Norway.

BACKGROUND: Neurology has increasing subspecialization. Some disorders, such as cerebrovascular diseases, dementia and headache, are highly prevalent in the general population, while others, such as movement disorders and multiple sclerosis, are rarer. Thus, there may be a mismatch between neurologists' interests and the population needs. AIMS OF THE STUDY: To investigate the perceived prestige of neurological disorders among residents in neurology. METHODS: The study was conducted as a questionnaire survey among residents in neurology in Norway. RESULTS: All the 17 neurological departments in Norway participated. In total, 143 residents participated (86% response rate). Mean age was 32.5 years. The respondents had on average 28 months of clinical training in neurology. The subspecialty with the highest prestige was cerebrovascular diseases, scored by 62% as the most prestigious, followed by multiple sclerosis (36%) and epilepsy (7%). The subspecialties with the lowest prestige were headache (2.8%) and dementia (1.4%). None of the tested variables (gender, age, months in clinical training or type of hospital) were associated with the perceived prestige of neurological disorders. CONCLUSION: Cerebrovascular disease was perceived as the most prestigious subspecialty. Headache and dementia, which are major contributors to worldwide disability, have low status among residents in neurology.

Lifestyle factors and risk of migraine and tension-type headache. Follow-up data from the Nord-Trøndelag Health Surveys 1995-1997 and 2006-2008.

AIMS: The aim of this population-based historical cohort study was to investigate the influence of lifestyle factors on the risk of developing migraine or tension-type headache (TTH). METHODS: Data from the Nord-Trøndelag Health Study performed in 1995-1997 and 2006-2008 was used. A total of 15,276 participants without headache at baseline were included. A Poisson regression was used to evaluate the associations between lifestyle factors and risk ratios (RRs) of migraine and TTH 11 years later. Precision of the estimates was assessed by 95% confidence interval (CIs). RESULTS: Increased risk of migraine (RR 1.30, 95% CI 1.11-1.52) was found in smokers (past or current) compared to those who had never smoked. Hard physical exercise 1-2 hours per week reduced the risk of migraine (OR 0.71, 95% CI 0.54-0.94) compared to inactivity, and the risk of migraine was also lower among those who consumed alcohol (RR 0.73, 95% CI 0.57-0.94) compared to abstainers. No association was found between smoking, physical activity, alcohol use and risk of TTH. CONCLUSIONS: The main finding was that current and previous smoking was associated with increased risk of migraine, but not of TTH.

Migraine and stroke. / Migrene og hjerneslag.

BAKGRUNN: Migrene er en vanlig nevrologisk sykdom som medfører betydelig belastning for den enkelte som rammes, og store helseøkonomiske kostnader for samfunnet. Migrene er forbundet med økt risiko for hjerneslag. Formålet med denne artikkelen er å gi en oversikt over sammenhengen mellom migrene og hjerneslag: både hjerneinfarkt og hjerneblødning, mulige underliggende mekanismer, kliniske implikasjoner og behovet for videre forskning innen feltet. KUNNSKAPSGRUNNLAG: Denne oversikten er basert på litteratursøk i PubMed med definert søkestreng supplert med et pyramidesøk i søkemotoren McMaster PLUS med ordene «migraine¼ og «stroke¼, samt gjennomgang av artiklenes referanselister. RESULTAT: Migrene med aura er assosiert med en dobling av risikoen for hjerneinfarkt, men det er ingen sikker økt risiko blant personer med migrene uten aura. Røyking, p-pillebruk og hyppige migreneanfall øker risikoen. Det ser også ut til å være en noe høyere forekomst av hjerneblødning hos personer med migrene med og uten aura. FORTOLKNING: Sammenhengen mellom migrene og hjerneslag er kompleks. Det er med bakgrunn i økt risiko for hjerneinfarkt ved migrene med aura anbefalt at modifiserbare risikofaktorer som røyking, hypertensjon og p-pillebruk kartlegges grundig og behandles.

Migraine as a predictor of mortality: The HUNT study.

BACKGROUND: There is conflicting evidence for the association between migraine and increased mortality risk. The aim of this study was to investigate the relationship between migraine and non-migrainous headache, and all-cause mortality and cardiovascular mortality. METHODS: In this prospective population-based cohort study from Norway, we used baseline data from the second Nord-Trøndelag Health Survey (HUNT2), performed between 1995 and 1997 in the County of Nord-Trøndelag. These data were linked with a comprehensive mortality database with follow-up through the year 2011. A total of 51,853 (56% of invited) people were categorized based on their answers to the headache questions in HUNT2 (headache free, migraine or non-migrainous headache). Hazard ratios (HRs) of mortality during a mean of 14.1 years of follow-up were estimated using Cox regression. RESULTS: During the follow-up period 9408 died, 4321 of these from cardiovascular causes. There was no difference in all-cause mortality between individuals with migraine and non-migrainous headache compared to those without headache or between headache status and mortality by cardiovascular disease. There was, however, among men with migraine without aura a reduced risk of death by cardiovascular diseases (HR 0.72, 95% confidence interval 0.56-0.93). This relationship was not evident in women. CONCLUSION: In this large, prospective cohort study there was no evidence for a higher all-cause mortality or cardiovascular mortality among individuals with migraine.

Psychiatric comorbidity in relation to clinical characteristics of epilepsy: A retrospective observational study.

PURPOSE: Prevalence of psychiatric disorders in people with epilepsy is high. However, diagnostic validity and information about the nature of the seizure disorders are often poor in population-based studies. In a well validated and classified patient sample, we investigated psychiatric comorbidity according to clinical characteristics. METHOD: Participants in The Trøndelag Health Study (HUNT) with ≥ 2 diagnostic epilepsy codes during 1987-2019 were identified. Medical records were reviewed, and epilepsy was validated and classified according to ILAE. Psychiatric comorbidity was defined by ICD-codes. RESULTS: In 448 individuals with epilepsy, 35% had at least one psychiatric disorder (anxiety and related disorders 23%, mood disorders 15%, substance abuse and personality disorders 7%, and psychosis 3%). Comorbidity was significantly higher in women than in men (p = 0.007). The prevalence of psychiatric disorders was 37% in both focal and generalized epilepsy. In focal epilepsy, it was significantly lower when etiology was structural (p = 0.011), whereas it was higher when the cause was unknown (p = 0.024). Comorbidity prevalence was 35% both in patients achieving seizure freedom and in those with active epilepsy but 38% among 73 patients with epilepsy resolved. CONCLUSION: Just over one third of people with epilepsy had psychiatric comorbidities. The prevalence was equal in focal and generalized epilepsy but was significantly higher in focal epilepsy of unknown cause compared to lesional epilepsy. Comorbidity was independent of seizure control at last follow-up but was slightly more common in those with resolved epilepsy, often having non-acquired genetic etiologies possibly linked to neuropsychiatric susceptibility.

Experiences of telemedicine in neurological out-patient clinics during the COVID-19 pandemic.

OBJECTIVE: The COVID-19 pandemic has led to rapid changes in the delivery of medical care worldwide. The main objective of this survey was to investigate the initial experiences of neurologists with the use of telemedicine for different neurological conditions during the first phase of the COVID-19. METHODS: All hospital-based neurologists in Norway (n = 400) were invited to a questionnaire survey by e-mail in April 2020. The study focused on telemedicine and all questions were answered with regard to the first weeks of the pandemic lockdown in Norway. RESULTS: One-hundred and thirty-five neurologists responded. Overall, 87% reported a shift toward more telemedicine, with significantly more use of telephone than video consultations for both new referrals (54% vs. 30%, P < 0.001) and follow-ups (99% vs. 50%, P < 0.001). Respondents deemed it much more professionally satisfactory to conduct follow-up consultations by telephone, than to carry out consultations with new patients by telephone (85% vs. 13%, P < 0.001). Teleconsultations were better suited for headache and epilepsy patients as compared to multiple sclerosis and movement disorder patients. There was no significant difference between residents and senior consultants regarding how they experienced teleconsultations. Female neurologists found telemedicine better and more effective than male neurologists. INTERPRETATION: Telemedicine was rapidly implemented in Norwegian neurological departments during the first weeks of the COVID-19 pandemic. Teleconsultations were better suited for follow-ups than for new referrals, and better for headache and epilepsy patients as compared to multiple sclerosis and movement disorder patients.

Experiences, distress and burden among neurologists in Norway during the COVID-19 pandemic.

BACKGROUND: The ongoing COVID-19 pandemic has caused rapid changes in the healthcare system. Workforce reorganization, reduced standard of care and a lack of personal protection equipment (PPE) for health care workers were among the concerns raised in the first wave of the pandemic. Our aim was to explore the experiences, distress and burden among Norwegian neurologists during the first weeks of the pandemic. METHODS: Hospital-based neurologists in Norway (n = 400) were invited to a web-based survey in April 2020. The study focused on patient management, organizational changes and personal stress during the first weeks of the pandemic lockdown. Work-home interface stress was assessed by the Cooper Job Stress Questionnaire. RESULTS: In total, 135 neurologists participated. Seventy-three% experienced a change in their personal work situation, and 67% examined patients with suspected COVID-19 infection and neurological disease. Changed access to resources, and the perception that medical follow-up was unsatisfactory, were associated with a high degree of burden and stress. Neurologists were also worried about the potential lack of PPE and the fear of spreading SARS CoV-2 to close family members. The mean score of work-home interface stress was 2.8 with no significant differences between gender or specialist status. Reduced standard of care was reported for all neurological conditions, and in particular for non-emergency treatments. CONCLUSION: The vast majority of neurologists in Norway experienced a change in their personal work situation during the first phase of the pandemic. The fear of becoming infected and ill was not a major contributor to burden and stress.

Caesarean section and the association with migraine: a retrospective register-linked HUNT population cohort study.

OBJECTIVES: To evaluate the association between caesarean section and migraine in a population-based register-linked cohort study. SETTING: Data from the population-based Nord-Trøndelag Health Studies (HUNT2 and HUNT3) were linked to information from the Norwegian Medical Birth Registry. PARTICIPANTS: 65 343 participants responded to the headache questions in any of the two HUNT studies. Only those answering the headache questions in HUNT2 or 3 and had information about mode of delivery in the Norwegian Medical Birth Registry (born after 1967) were included. Our final sample consisted of 6592 women and 4602 men, aged 19-41 years. OUTCOMES: ORs for migraine given caesarean section. Analyses were performed in multivariate logistic regression models. RESULTS: After adjusting for sex, age and fetal growth restriction, delivery by caesarean section was not associated with migraine later in life (OR 0.86, 95% CI 0.64 to 1.15). Delivery by caesarean section was associated with a reduced OR of non-migrainous headache (OR 0.77, 95% CI 0.60 to 0.99). CONCLUSION: No association was found between caesarean section and migraine in this population-based register-linked study.