Explicit diagnostic criteria for transient ischemic attacks to differentiate it from migraine with aura.

Background The diagnosis of transient ischemic attacks is fraught with problems. The inter-observer agreement has repeatedly been shown to be low even in a neurological setting, and the specificity of the diagnosis is modest to low, reflected in a poor separation of transient ischemic attacks and mimics, particularly migraine with aura with its varied symptomatology. In other disease areas, explicit diagnostic criteria have improved sensitivity and specificity of diagnoses. We therefore present novel explicit diagnostic criteria for transient ischemic attacks tested for sensitivity and for specificity against migraine with aura. Methods The proposed criteria were developed using the format of the international headache classification. We drew upon the existing literature about clinical characteristics and diagnosis of migraine with aura and transient ischemic attacks. We tested the criteria for sensitivity in a prospectively-collected material of 120 patients with transient ischemic attacks diagnosed before we developed the criteria using extensive semi-structured interview forms in the acute phase after admission. Eligible patients had focal brain or retinal ischemia with resolution of symptoms within 24 hours without presence of new infarction on magnetic resonance imaging with diffusion weighted imaging (n = 112) or computed tomography (n = 8). These criteria were also tested for specificity against a Danish (n = 1390) and a Russian (n = 152) material of patients with migraine with aura diagnosed according to the International Classification of Headache Disorders edition 3 (beta). Results The sensitivity of the proposed criteria was 99% in patients with transient ischemic attacks. The specificity was 95% in the Danish material of patients with migraine with aura and 96% in the Russian material. Conclusions Proposed explicit diagnostic criteria for transient ischemic attacks showed both high specificity and sensitivity. They are likely to improve the emergency room diagnosis of transient ischemic attacks. Further testing in unselected materials referred to transient ischemic attacks clinics was beyond the scope of the present study but is recommended for future study.

Family studies to find rare high risk variants in migraine.

INTRODUCTION: Migraine has long been known as a common complex disease caused by genetic and environmental factors. The pathophysiology and the specific genetic susceptibility are poorly understood. Common variants only explain a small part of the heritability of migraine. It is thought that rare genetic variants with bigger effect size may be involved in the disease. Since migraine has a tendency to cluster in families, a family approach might be the way to find these variants. This is also indicated by identification of migraine-associated loci in classical linkage-analyses in migraine families. A single migraine study using a candidate-gene approach was performed in 2010 identifying a rare mutation in the TRESK potassium channel segregating in a large family with migraine with aura, but this finding has later become questioned. The technologies of next-generation sequencing (NGS) now provides an affordable tool to investigate the genetic variation in the entire exome or genome. The family-based study design using NGS is described in this paper. We also review family studies using NGS that have been successful in finding rare variants in other common complex diseases in order to argue the promising application of a family approach to migraine. METHOD: PubMed was searched to find studies that looked for rare genetic variants in common complex diseases through a family-based design using NGS, excluding studies looking for de-novo mutations, or using a candidate-gene approach and studies on cancer. All issues from Nature Genetics and PLOS genetics 2014, 2015 and 2016 (UTAI June) were screened for relevant papers. Reference lists from included and other relevant papers were also searched. For the description of the family-based study design using NGS an in-house protocol was used. RESULTS: Thirty-two successful studies, which covered 16 different common complex diseases, were included in this paper. We also found a single migraine study. Twenty-three studies found one or a few family specific variants (less than five), while other studies found several possible variants. Not all of them were genome wide significant. Four studies performed follow-up analyses in unrelated cases and controls and calculated odds ratios that supported an association between detected variants and risk of disease. Studies of 11 diseases identified rare variants that segregated fully or to a large degree with the disease in the pedigrees. CONCLUSION: It is possible to find rare high risk variants for common complex diseases through a family-based approach. One study using a family approach and NGS to find rare variants in migraine has already been published but with strong limitations. More studies are under way.

Part I: Pituitary adenylate cyclase-activating polypeptide-38 induced migraine-like attacks in patients with and without familial aggregation of migraine.

Background Intravenous infusion of adenylate cyclase-activating polypeptide-38 (PACAP38) provokes migraine-like attacks in 65-70% of migraine sufferers. Whether aggregation of migraine in first-degree relatives contributes to this discrepancy in PACAP38-induced response is unknown. We hypothesized that genetic enrichment plays a role in triggering of migraine and that migraine without aura patients with a high family load ( ≥ 2 first-degree relatives with migraine) would report more migraine-like attacks after intravenous infusion of human PACAP38. Methods In this study, we allocated 32 previously genotyped migraine without aura patients to receive intravenous infusion of 10 pmol/kg/min PACAP38 and recorded migraine-like attacks including headache characteristics and associated symptoms. Information of familial aggregation was obtained by telephone interview of first-degree relatives using a validated semi-structured questionnaire. Results PACAP38 infusion induced a migraine-like attack in 75% (nine out of 12) of patients with high family load compared to 70% (14 out of 20) with low family load ( P = 0.761). In an explorative investigation, we found that the migraine response after PACAP38 was not associated with the risk allele of rs2274316 ( MEF2D), which confers increased risk of migraine without aura and may regulate PACAP38 expression. Conclusion Migraine response to PACAP38 infusion in migraine without aura patients is not associated with high family load or the risk allele of rs2274316 ( MEF2D).

Calcitonin gene-related peptide induced migraine attacks in patients with and without familial aggregation of migraine.

Background Calcitonin gene-related peptide provokes migraine attacks in 65% of patients with migraine without aura. Whether aggregation of migraine in first-degree relatives (family load) or a high number of risk-conferring single nucleotide polymorphisms contributes to migraine susceptibility to calcitonin gene-related peptide infusion in migraine patients is unknown. We hypothesized that genetic enrichment plays a role in triggering of migraine and, therefore, migraine without aura patients with high family load would report more migraine attacks after calcitonin gene-related peptide infusion than patients with low family load. Methods We allocated 40 previously genotyped migraine without aura patients to receive intravenous infusion of 1.5 µg/min calcitonin gene-related peptide and recorded migraine attacks including headache characteristics and associated symptoms. Information of familial aggregation was obtained by telephone interview of first-degree relatives using a validated semi-structured questionnaire. Results Calcitonin gene-related peptide infusion induced a migraine-like attack in 75% (12 out of 16) of patients with high family load compared to 52% (12 out of 23) with low family load ( P = 0.150). In addition, we found that the migraine response after calcitonin gene-related peptide was not associated with specific or a high number of risk-conferring single nucleotide polymorphisms of migraine without aura. Conclusion We found no statistical association between familial aggregation of migraine and hypersensitivity to calcitonin gene-related peptide infusion in migraine without aura patients. We also demonstrated that the currently known single nucleotide polymorphisms conferring risk of migraine without aura have no additive effect on calcitonin gene-related peptide induced migraine-like attacks.

The influence of genetic constitution on migraine drug responses.

OBJECTIVE: Specific acute treatments of migraine are 5HT1B/D receptor agonists; triptans and ergotamine, but only two-thirds of patients respond well without side effects. No migraine-prophylactic drugs are specific to migraine. Prophylactic drugs are selected by time-consuming "trial and error." Personalized treatment is therefore much needed. The objective of this study was to test the effect of 12 single nucleotide polymorphisms (SNPs) significantly associated with migraine on migraine drug responses. METHODS: Semi-structured migraine interviews including questions on drug responses, blood samples and genotyping were performed on 1806 unrelated migraine cases recruited from the Danish Headache Center. Association analyses were carried out using logistic regression, assuming an additive model for the genetic effect. The effect on drug responses was tested for a combined genetic score and for each of the 12 SNPs. Significant findings were subsequently tested in an independent replication sample of 392 unrelated Danish migraine cases. RESULTS: A single risk variant, rs2651899 in PRDM16, was significantly associated with efficacy of triptans with an odds ratio (OR) of treatment success of 1.3, and a higher combined genetic score was significantly associated with efficacy of triptans with an OR of success of up to 2.6. A number of SNPs showed nominal preferential association with the efficacy of triptans and others with prophylactic drugs. Analyses of triptans and ergotamine complemented each other and gave a stronger signal when analyzed together. The associations between response to triptans and genetic load and rs2651899 were partially confirmed in the independent sample. CONCLUSION: We show for the first time an association between genetic constitution and migraine drug response. This is a first step toward future individualized medicine.

The association between candidate migraine susceptibility loci and severe migraine phenotype in a clinical sample.

INTRODUCTION: The objective of the study was to follow up and to test whether 12 previously identified migraine-associated single nucleotide polymorphisms were associated as risk factors and/or modifying factors for severe migraine traits in a Danish clinic-based population. METHODS: Semi-structured migraine interviews, blood sampling and genotyping were performed on 1806 unrelated migraineurs recruited from the Danish Headache Center. Genotyping was also performed on a control group of 6415 people with no history of migraine. Association analyses were carried out using logistic regression and odds ratios were calculated assuming an additive model for risk. The proxies for severe migraine traits (early onset of migraine; many lifetime attacks, prolonged migraine and tendency to chronification of migraine) were tested against the 12 single nucleotide polymorphisms and a combined genetic score in both a case-control and case-only logistic regression model. RESULTS: We successfully replicated five out of the 12 previously reported loci and confirmed the same direction of effects for all the 12 single nucleotide polymorphisms. In line with the recently published genome-wide association meta-analysis, the associations were significant for all migraine and migraine without aura but not for migraine with typical aura. Two single nucleotide polymorphisms (rs2274316 and rs11172113) conferred risk of many lifetime attacks inthe case-control analysis. In the case-only analysis, only three single nucleotide polymorphisms showed nominal association with many lifetime attacks and prolonged migraine attacks. CONCLUSION: Our study supports previously reported findings on the association of several single nucleotide polymorphisms with migraine. It also suggests that the migraine susceptibility loci may be risk factors for severe migraine traits.

Genotype-phenotype correlation in migraine without aura focusing on the rs1835740 variant on 8q22.1.

A large two-stage GWAS by Antilla et al. reported the minor allele of rs1835740 on 8q22.1 to be associated with common types of migraine. The objective of the present study was to determine the clinical correlate of the variant in migraine without aura (MO). Clinical data on 339 successfully genotyped MO patients (patients with attacks of migraine without aura and no attacks of migraine with aura) were obtained by an extensive validated semi-structured telephone interview performed by a physician or a trained senior medical student. Reliable, systematic and extensive data on symptoms, age of onset, attack frequencies and duration, relevant comorbidity, specific provoking factors including different hormonal factors in females, and effect and use of medication, both abortive and prophylactic, were thereby obtained. A comparison of carriers and non-carriers were performed. Comparison of homozygotes with heterozygotes was not performed as the number of homozygotes was too small for statistical purposes. Data from other MO populations in the GWAS by Antilla et al. were not included as phenotype and clinical data were obtained differently. While thousands of patients are needed to detect a genetic variant like rs1835740, 339 are sufficient to detect meaningful clinical differences. 136 of 339 patients were carriers of the variant, 15 were homozygous. Comparison of carriers with non-carriers showed no significant difference in any of the parameters studied. In conclusion, the rs1835740 variant has no significant influence on the clinical expression of MO.