Shared loci for migraine and epilepsy on chromosomes 14q12-q23 and 12q24.2-q24.3.

OBJECTIVES: To describe clinical characteristics and to identify susceptibility loci for epilepsy and migraine in a Finnish family with a complex phenotype. METHODS: Participating family members were interviewed and medical files were reviewed. The seizure classification was made according to International League Against Epilepsy criteria. Migraine diagnosis was made using the validated Finnish Migraine Specific Questionnaire for Family Studies and criteria according to the current International Classification of Headache Disorders-II. DNA samples were obtained from 56 family members and nonparametric genome-wide linkage analyses were performed using 382 polymorphic microsatellite markers. The most promising loci were fine-mapped with additional microsatellite markers. RESULTS: Clinical data were obtained from 60 family members of whom 12 (20%) had idiopathic epileptic seizures. Eight of those 12 (67%) also had migraine. Altogether 33 of the 60 family members (55%) had migraine. Significant evidence of linkage was found between a locus on 14q12-q23 and migraine (p = 0.0001). Suggestive evidence of linkage in this region was also found for epilepsy with generalized tonic-clonic seizures (p = 0.0034). In addition, significant evidence of linkage was found at a locus on 12q24.2-q24.3 (p < 0.001) for migraine alone and for the combined phenotype of migraine and epilepsy. CONCLUSIONS: Our data suggest the occurrence of common susceptibility loci for epilepsy and migraine on chromosomes 14q12-q23 and 12q24.2-q24.3, implicating a shared genetic etiology for these 2 diseases.

Migrainous infarction: a Nordic multicenter study.

BACKGROUND AND PURPOSE: Migrainous infarction (MI), i.e., an ischemic stroke developing during an attack of migraine with aura is rare and the knowledge of its clinical characteristics is limited. Previous case series using the International Classification of Headache Disorders (ICHD) included <10 cases which make conclusions less valid. This study aimed to describe characteristics and outcome of MI in a larger sample. METHODS: We analyzed demographic data, risk factors, migraine medication, stroke localization, symptoms, and outcome in a sample of 33 patients with MI according to second edition of the ICHD criteria collected from seven Nordic headache clinics. RESULTS: Amongst 33 patients with MI, there were 20 (61%) women and 13 (39%) men with the median age for stroke of 39 (range 19-76) years. Traditional risk factors for stroke were rare compared with Scandinavian young ischemic stroke populations. During the acute phase, 12 (36%) patients used ergotamines or triptans. Stroke was located in the posterior circulation in 27 (82%) patients and cerebellum was involved in 7 (21%). Except in two patients with brainstem infarctions, the outcome was favorable with total recovery or limited residual symptoms. CONCLUSIONS: The prevalence of traditional risk factors was low and the infarctions were predominantly located in posterior circulation territory, supporting theories of migraine specific mechanisms. The outcome was in general favorable.

Migraine with aura is a risk factor for cervical artery dissection: a case-control study.

BACKGROUND: Cervical artery dissection (CAD) is the most common single etiology for stroke in young adults. Migraine, especially with aura (MA), is a known risk factor for ischemic stroke. The association between CAD and migraine was suggested based on a few small studies, but there are no large-scale case-control data, and the mechanisms are not yet clear. METHODS: We compared the lifetime prevalence of migraine and migraine characteristics in 313 CAD patients with 313 healthy age- and sex-matched controls. We also analyzed clinical and radiological characteristics of CAD with respect to migraine subtypes to investigate whether clear phenotypical associations can be found that might help in the search for a possible shared genetic background for migraine and CAD. RESULTS: Migraine was clearly more common in CAD patients than in controls (36 vs. 23%; OR 2.15; 95% CI 1.48-3.14), and the association was also highly significant for MA (23 vs. 12%; OR 2.41; 95% CI 1.53-3.80). Percentages of reported migraine history and MA of CAD patients vs. controls compared separately for both sexes were as follows: for women, migraine 54 vs. 35% (OR 2.30; 95% CI 1.28-4.13), MA 35 vs. 18% (OR 2.79; 95% CI 1.40-5.59); for men, migraine 27 vs. 16% (OR 2.02; 95% CI 1.23-3.31), MA 16 vs. 10% (OR 2.21; 95% CI 1.19-4.11). Over 60% of the CAD patients with still active migraine at the time of dissection reported later alleviation of migraine activity. CONCLUSION: Our observations suggest that patients with CAD are a significant link between ischemic stroke and migraine. This connection may represent a common pathophysiological or genetic background, or both. Migraine activity appears to be alleviated by CAD.

A visual migraine aura locus maps to 9q21-q22.

OBJECTIVE: To identify susceptibility loci for visual migraine aura in migraine families primarily affected with scintillating scotoma type of aura. METHODS: We included Finnish migraine families with at least 2 affected family members with scintillating scotoma as defined by the International Criteria for Headache Disorders-II. A total of 36 multigenerational families containing 351 individuals were included, 185 of whom have visual aura and 159 have scintillating scotoma. Parametric and nonparametric linkage analyses were performed with 378 microsatellite markers. The most promising linkage loci found were fine-mapped with additional microsatellite markers. RESULTS: A novel locus on chromosome 9q22-q31 for migraine aura was identified (HLOD = 4.7 at 104 cM). Fine-mapping identified a shared haplotype segment of 12 cM (9.8 Mb) on 9q21-q22 among the aura affected. Four other loci showed linkage to aura: a locus on 12p13 showed significant evidence of linkage, and suggestive evidence of linkage was detected to loci on chromosomes 5q13, 6q25, and 13q14. CONCLUSIONS: A novel visual migraine aura locus has been mapped to chromosome 9q21-q22. Interestingly, this region has previously been linked to occipitotemporal lobe epilepsy with prominent visual symptoms. Our finding further supports a shared genetic background in migraine and epilepsy and suggests that susceptibility variant(s) to visual aura for both of these traits are located in the 9q21-q22 locus.

Short-term frovatriptan for the prevention of difficult-to-treat menstrual migraine attacks.

The efficacy of a 6-day regimen of frovatriptan for menstrual migraine (MM; attacks starting on day -2 to +3 of menses) prevention in women with difficult-to-treat MM was assessed. Women with a documented inadequate response to triptans for acute MM treatment were included in this placebo-controlled, parallel-group trial. Women were randomized to double-blind treatment for three perimenstrual periods (PMPs) with either frovatriptan 2.5 mg (q.d. or b.i.d.) or placebo initiated 2 days before anticipated MM. The efficacy analysis included 410 women with 85% completing three double-blind PMPs. The mean number of headache-free PMPs was 0.92 with frovatriptan b.i.d., 0.69 with frovatriptan q.d. and 0.42 with placebo [P < 0.001 (b.i.d.) and P < 0.02 (q.d.) vs. placebo]. When migraine occurred, severity was reduced with frovatriptan q.d. (P < 0.001) and b.i.d. (P < 0.001) vs. placebo. Both frovatriptan regimens were well tolerated. In women with difficult-to-treat MM, a 6-day regimen of frovatriptan significantly reduced MM incidence and severity.

Genetic association study of endothelin-1 and its receptors EDNRA and EDNRB in migraine with aura.

The effect of endothelin-1 and its receptors EDNRA and EDNRB in migraine with aura (MA) susceptibility is not established yet. We studied the association between the MA end-diagnosis and three migraine trait components and 32 single nucleotide polymorphisms (SNPs) capturing the variation of endothelin genes in 850 Finnish migraine patients and 890 non-migrainous individuals. The SNPs showing evidence of association were further studied in 648 German migraine patients and 651 non-migrainous individuals. No significant association was detected. However, the homozygous minor genotype (5% in cases) of the EDNRA SNP rs2048894 showed nominal association with MA both in the Finnish sample (P = 0.015) and in the pooled sample [odds ratio (OR) 1.61, 95% confidence interval (CI) 1.12-2.32, P = 0.010] when adjusted for gender and sample origin. The trait age of onset < 20 years was also associated with rs2048894 (OR 1.69, 95% CI 1.13-2.54, P = 0.011) in the pooled sample. To confirm this finding studies on even larger samples are required.

No association of migraine to the GABA-A receptor complex on chromosome 15.

To date, no gene variants predisposing to common forms of migraine have been convincingly identified. Recently, significant linkage to a cluster of gamma-amino butyric acid (GABA)-A receptors on Chr 15q11-q13 was reported. We performed an extensive association study using 898 MA cases and 900 matched controls by covering the same gene cluster with 34 single nucleotide polymorphisms (SNPs). No association to MA was detected, suggesting that common variants of the GABA cluster are unlikely to be major contributors of MA susceptibility.

Treatment of hemiplegic migraine with triptans.

The objective of this study was to investigate the efficacy, safety and tolerability of triptans in patients who suffer from familial or sporadic hemiplegic migraine. Seventy-six subjects had used triptans at least once as an abortive treatment. Average triptan response was 6.9 (SD +/-3.1) and adverse event severity 4.9 (SD +/-3.3) on a scale from 0 to 10 (no response or side effect 0, excellent response or unbearable side effects 10). None of the patients had an ischaemic stroke or a heart attack. One patient reported prolonged neurological symptoms, related to a single dose of rizatriptan, but there were no pathological findings in several MRI-scans. Triptans seem to be safe and effective treatment for most hemiplegic migraine patients.

Testing of variants of the MTHFR and ESR1 genes in 1798 Finnish individuals fails to confirm the association with migraine with aura.

Among the few independently replicated genetic associations in migraine are polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) and oestrogen receptor (ESR1) genes. We studied the contribution of these genes to migraine susceptibility by genotyping six MTHFR and 26 ESR1 polymorphisms in 898 unrelated migraine with aura (MA) patients and in 900 unrelated healthy controls. There were no differences in the genotype distributions of the previously migraine-associated SNPs C677T (MTHFR) and G2014A (ESR1) between cases and controls (P-values 0.83 and 0.55, respectively). Thus, we were not able to replicate the previous findings, although our study had considerable power. However, five of the ESR1 SNPs (rs6557170, rs2347867, rs6557171, rs4870062 and rs1801132) that were in strong linkage disequilibrium were nominally associated with MA (uncorrected P-values 0.007-0.034). These results did not, however, remain significant after taking multiple testing into account. Thus it seems unlikely that the studied genes are involved in migraine susceptibility, at least in this sample.

Door to thrombolysis: ER reorganization and reduced delays to acute stroke treatment.

The authors reorganized the emergency room (ER) by moving CT to the ER and streamlining triage by prenotification by emergency medical services (EMS), which reduced in-hospital delays and enhanced access to stroke thrombolysis. CT delay dropped from 1 hour 3 minutes +/- 14 minutes in 1999 to 7 +/- 2 minutes in 2004 (p < 0.0001). Door-to-needle time dropped from 1 hour 28 minutes +/- 7 minutes to 50 +/- 3 minutes (p < 0.001), while symptom-to-needle time dropped from 2 hours 44 minutes +/- 6 minutes to 2 hours 5 minutes +/- 4 minutes (p < 0.0001). From 23 patients in 1999, thrombolysis access was increased to 100 patients in 2004 and 183 patients in 2005.

Trait components provide tools to dissect the genetic susceptibility of migraine.

The commonly used "end diagnosis" phenotype that is adopted in linkage and association studies of complex traits is likely to represent an oversimplified model of the genetic background of a disease. This is also likely to be the case for common types of migraine, for which no convincingly associated genetic variants have been reported. In headache disorders, most genetic studies have used end diagnoses of the International Headache Society (IHS) classification as phenotypes. Here, we introduce an alternative strategy; we use trait components--individual clinical symptoms of migraine--to determine affection status in genomewide linkage analyses of migraine-affected families. We identified linkage between several traits and markers on chromosome 4q24 (highest LOD score under locus heterogeneity [HLOD] 4.52), a locus we previously reported to be linked to the end diagnosis migraine with aura. The pulsation trait identified a novel locus on 17p13 (HLOD 4.65). Additionally, a trait combination phenotype (IHS full criteria) revealed a locus on 18q12 (HLOD 3.29), and the age at onset trait revealed a locus on 4q28 (HLOD 2.99). Furthermore, suggestive or nearly suggestive evidence of linkage to four additional loci was observed with the traits phonophobia (10q22) and aggravation by physical exercise (12q21, 15q14, and Xp21), and, interestingly, these loci have been linked to migraine in previous studies. Our findings suggest that the use of symptom components of migraine instead of the end diagnosis provides a useful tool in stratifying the sample for genetic studies.

Decreased cerebellar total creatine in episodic ataxia type 2: a 1H MRS study.

Episodic ataxia type 2 (EA2) affects mainly the cerebellum via mutations in the CACNA1A gene. The authors used proton MR spectroscopy to examine cerebellar and thalamic metabolism of nine mostly nonataxic EA2 family members (all with proven CACNA1A mutation) and nine healthy control subjects. Cerebellar total creatine was lower in the patient group (p = 0.005) than in control subjects, possibly reflecting an early sign of calcium channel dysfunction in EA2.

A novel missense ATP1A2 mutation in a Finnish family with familial hemiplegic migraine type 2.

Familial hemiplegic migraine (FHM), a rare autosomal dominant subtype of migraine with aura, has been linked to two chromosomal loci, 19p13 and 1q23. Mutations in the Na+K+-ATPase alpha2 subunit gene, ATP1A2, on 1q23 have recently been shown to cause familial hemiplegic migraine type 2 (FHM2). We sequenced the coding regions of this gene in a Finnish chromosome 1q23-linked FHM family with associated symptoms such as coma and identified a novel A1033G mutation in exon 9. This mutation results in a threonine-to-alanine substitution at codon 345. This residue is located in a highly conserved N-terminal region of the M4-5 loop of the Na+,K+-ATPase. Furthermore, the T345A mutation co-segregated with the disorder in our family and was not present in 132 healthy Finnish control individuals. For these reasons it is most likely the FHM-causing mutation in this family.

Novel splice site CACNA1A mutation causing episodic ataxia type 2.

Episodic ataxia type 2 (EA-2) is an autosomal dominant neurological disorder, characterized by episodes of ataxia, vertigo, nausea, nystagmus, and fatigue, associated with acetazolamide responsiveness. The disease is caused by mutations in the P/Q-type calcium channel Ca(v)2.1 subunit gene, CACNA1A, located on chromosome 19p13.2. We analyzed a family with 13 affected individuals for linkage to this locus and reached a two-point maximum LOD score of 4.48. A novel CACNA1A mutation, IVS36-2A>G, at the 3' acceptor splice site of intron 36 was identified by sequencing. It is the first described CACNA1A acceptor splice site mutation and the most C-terminal EA-2-causing mutation reported to date.

Subclinical vestibulocerebellar dysfunction in migraine with and without aura.

OBJECTIVE: In patients with migraine, neurotologic symptoms and signs occur commonly. The authors' aim was to determine whether neurotologic findings are in accordance with the type of migraine and whether test findings differ from those of healthy controls. METHODS: The authors examined 36 patients with various types of migraine classified by International Headache Society criteria. Comprehensive neurotologic tests were performed between attacks: video-oculography (VOG), electronystagmography, static posturography, and audiometry on 12 patients with migraine with aura (MA) and 24 patients with migraine without aura (MO). Results were compared to those of test-specific nonmigrainous control groups. Only eight migraineurs (six with MA and two with MO) had vertigo or dizziness. RESULTS: Despite the absence of clinical neurotologic symptoms, most of the patients with migraine (83%) showed abnormalities in at least one of these tests. Both migraine types differed significantly from the control group (in VOG, in saccadic accuracy, and in static posturography). Vestibular findings tended to be more severe in MA than in MO. CONCLUSIONS: These data suggest that interictal neurotologic dysfunction in MA and MO share similar features and that the defective oculomotor function is mostly of vestibulocerebellar origin.

Wernicke's encephalopathy: is diffusion-weighted MRI useful?

We present the clinical and magnetic resonance imaging (MRI) findings of five patients with acute Wernicke's encephalopathy. T2-weighted and fluid-attenuated inversion recovery (FLAIR) images demonstrated symmetrical hyperintense lesions within the dorsomedial thalami, periaqueductal white matter, and the tectum of the midbrain. None of the lesions enhanced with gadolinium. In addition to conventional MRI sequences, we performed diffusion-weighted imaging (DWI). In all patients, DWI showed symmetrical pathologic thalamic and midbrain signal hyperintensities more distinctly than did conventional T2-weighted or FLAIR sequences. The apparent diffusion coefficient (ADC) map images showed slight signal reductions in four patients, suggesting restricted diffusion within these regions. In one patient, the signal intensity within the affected thalami was isointense with the ipsilateral basal ganglia on ADC map images. For enhanced detection of pathology, we conclude that DWI should be included in the imaging protocols of patients suspected to suffer from Wernicke's encephalopathy.

Familial migraine with and without aura: clinical characteristics and co-occurrence.

Migraine with aura (MwA) and migraine without aura (MwoA) are the two common forms of migraine. Many migraine patients suffer from both kinds of attacks. In a questionnaire-based study using the current International Headache Society (IHS) criteria we determined the clinical characteristics and occurrence of MwA + MwoA in 1000 migraine patients belonging to 210 Finnish migraine families. Nine hundred and six patients were able to indicate whether they suffered from MwA (but not MwoA), migraine aura without headache (migraine equivalent) (but not MwA) or MwA and MwoA. Of these patients, 3.2% had experienced MwoA, 11.1% MwA, 40.6% MwA + MwoA, 23.5% MwoA and 20.3% MwA-like symptoms not meeting the IHS criteria. The high prevalence of MwA attacks in the families studied supports the belief that aura has a strong hereditary component. The MwA + MwoA patients had significantly more severe attacks, more typical headache and more prodromal symptoms than the MwA and MwoA subjects. Therefore, it is possible that there is a continuum with pure MwA at the neural and pure MwoA at the headache end of the spectrum, and MwA + MwoA lying in between the two. The MwA + MwoA patients would thus be liable to both types of migraine, making their attacks more characteristic and more severe. This would also explain why the co-occurrence of MwA and MwoA is more common in the clinic compared with population based epidemiological studies. These findings have consequences for future research on liability genes for migraine.

Validation of a migraine-specific questionnaire for use in family studies.

The availability of valid migraine-specific questionnaires is important when large numbers of migraine patients have to be analysed. The Finnish Migraine-Specific Questionnaire has been validated in two stages. In the first, a clinical diagnosis of migraine was reached, using International Headache Society criteria, in 100 consecutive patients. Migraine was then diagnosed independently on the basis of responses to the Finnish Migraine-Specific Questionnaire. In the second stage, responses to 100 questionnaires returned consecutively in a family study in progress were analysed, and respondents were contacted by telephone for interview and diagnosis of migraine. Contact proved impossible in six cases. The sensitivity of the questionnaire for migraine was 0.99 (167 out of 168; validation stages 1 and 2 combined) and specificity was 0.96 (25 out of 26 cases; validation stage 2). It also proved possible to differentiate between migraine with and without aura on the basis of responses to the Finnish Migraine-Specific Questionnaire: chance-corrected agreement (Cohen's kappa) was 0.804 in relation to diagnoses reached on the basis of responses to the Finnish Migraine-Specific Questionnaire and clinically was 0.858 in relation to diagnoses reached on the basis of responses to the Finnish Migraine-Specific Questionnaire combined with the results of the telephone interviews. A value for Cohen's kappa > 0.75 indicates good agreement. Therefore, use of the Finnish Migraine-Specific Questionnaire in research into migraine genetics is justified.

Clinical characteristics of migraine concordant monozygotic twin pairs.

OBJECTIVES: The aim of the study was to search for clinical differences between migraine with and without aura. MATERIALS AND METHODS: From a population-based Finnish Twin Cohort we studied 51 migraine concordant monozygotic twin pairs. RESULTS: There were 20 pairs concordant for migraine with aura, 6 pairs concordant for migraine without aura and 12 "mixed" pairs. In the remaining 13 pairs the aura of at least 1 twin could not be classified. All 20 migraine with aura pairs were concordant for visual aura and 19 for moderate or severe headache while all 6 pairs with migraine without aura were concordant for headache duration of 4 to 24 h, moderate or severe headache and nausea. The 12 "mixed" pairs had more often unilateral and pulsating headache compared to both the migraine with or without aura pairs. Overall individual migraine with aura twins had more photophobia (P = 0.032) and the migraine without aura twins more nausea (P = 0.025). CONCLUSIONS: The difference between migraine with and without aura is not explained entirely by genetical factors: 12 genetically identical twin pairs were discordant for the aura. The headache phase in migraine with and without aura is very similar, but not identical. Probably there are several and different liability loci for the migraine aura and the migraine headache. The distribution of these several loci along with acquired factors will decide whether the phenotype is migraine with or without aura.

Clinical characteristics of migraine in a population-based twin sample: similarities and differences between migraine with and without aura.

OBJECTIVE: To look into clinical differences between migraine with and without aura in a population-based sample of migraineurs. BACKGROUND: Migraine presents in two major forms, migraine with and migraine without aura. With the exception of the aura phase, the clinical characteristics of these entities are very similar. Despite this, however, the recent epidemiological data underline differences between migraine with and without aura. We tried to examine whether other features besides the aura differ between these two major forms of migraine. METHODS: We studied 321 twins suffering from migraine with aura and 166 twins with migraine without aura from the population-based Finnish Twin Cohort. Migraine was diagnosed according to the criteria of the International Headache Society (IHS). Analysis was based on the combination of a mailed questionnaire and a telephone interview by a neurologist. Special attention was paid to differences between migraine with and without aura. RESULTS: Some qualities of headaches differed between IHS defined migraine with and without aura. Unilateral headache (Chi-squared p = 0.039) and photophobia (Chi-squared p = 0.010) were more typical for migraine with aura, while nausea was more typical for migraine without aura (Chi-squared p = 0.002). Duration of headache in migraine without aura was also longer than in migraine with aura (Mann-Whitney U-test 0.007). CONCLUSIONS: There are clinical differences between IHS defined migraine with and without aura; even the headache phase between the two entities differs. It is worthwhile distinguishing between them when looking for the elusive genes for these more common forms of migraine.