Migraine With Aura Patients Research Articles

Replication study of the insulin receptor gene in migraine with aura

We performed the first replication study for the reported association of the insulin receptor gene ( INSR) with migraine with aura (MA). Two of 35 SNPs (rs1052371 and rs2860174) reached borderline significance (best uncorrected allelic p value of 0.052 for rs2860174) in stage 1 of our study (270 MA patients, 280 controls). As rs2860174 was 1 of the 5 SNPs with prior evidence of association, we also genotyped this SNP in our stage 2 sample (679 MA patients, 368 controls), and it was nonsignificant (allelic p value 0.478). The combined analysis of our samples showed just a nonsignificant trend for rs2860174 ( p = 0.1). However, the joint analysis of our study and the initial study reporting an association—including 1278 Caucasian MA patients and 1337 Caucasian controls altogether—displayed a significant allelic p value of 0.005. In conclusion, further association studies for rs2860174 with even larger numbers of individuals are required to exclude or confirm definitely a small effect of this SNP on migraine susceptibility.

Patent foramen ovale detected by near-infrared spectroscopy in patients suffering from migraine with aura

There is an increased prevalence of patent foramen ovale (PFO) in women with migraine with aura (MwA) compared to controls, but the role of PFO in triggering aura is still debated. The aim of this study was to test a group of women suffering from MwA with near-infrared spectroscopy (NIRS), to assess the NIRS capability of discriminating between subjects with and without PFO. Eighty-eight MwA patients (mean age 37.4+/-10.7 years, range 16-62 years) underwent NIRS measurement of the cerebral variations of the oxygenated (O2Hb) and reduced haemoglobin (HHb) during breath-holding. The prevalence of O2Hb vs. HHb was used to assess the presence of PFO. As a gold standard, the presence of PFO was assessed by transcranial Doppler sonography (TCD). At the TCD analysis 48 patients (55%) showed PFOs, 32 of which were permanent. NIRS correctly detected 36 subjects out of 40 without PFO, and 38 subjects out of 48 having PFO: sensitivity was 79%; specificity was 90%. All the false negatives were permanent shunts. MwA patients with PFO showed a delayed increase in the O2Hb concentration and a reduced oxygenation with respect to subjects without PFO. NIRS is effective in identifying the presence of PFO in a MwA population, but TCD achieves better diagnostic performances. The NIRS provides additional information about the cerebral vasoreactivity and highlights substantial differences between patients with latent and permanent shunts that warrant further studies.

Does closure of a patent foramen ovale have a role in the treatment of migraine with aura?

Patent foramen ovale (PFO) is associated with ischaemic stroke and migraine with aura (MA), and has been proposed as a cause of both. Numerous studies indicate that percutaneous PFO closure can improve MA, but they all suffer from methodological problems. It is recommended that the advantages and risks of PFO closure be carefully assessed in each individual, bearing in mind that effective prophylactic medications are available for MA patients with high attack frequency.

Is Migraine Associated with Right-to-Left Shunt a Separate Disease? Results of the SAM Study

Migraine with aura (MA) is associated with the persistence of patent foramen ovale (PFO) in about 50% of cases, and migraineurs tend to have larger shunts than controls, suggesting that right-to-left shunt (RILES) determined by PFO could play a role in triggering migraine attacks. Moreover, some preliminary reports have suggested that PFO closure may give relief to both migraine and aura attacks. The aim of this study was to clarify if shunt-associated migraine (SAM) has clinical features that allow a distinction from shunt-unrelated migraine (SUM), in a prospective, multicentre, observational study (SAM study). We enrolled consecutive MA patients, who underwent a structured, standardized questionnaire for family and personal history and for detailed migraine features. All were systematically screened for RILES with transcranial Doppler, and for coagulation disorders. Overall, 460 patients were included; the SUM and SAM classes comprised 58% and 42% of patients, respectively. SAM patients were significantly younger (34.1 +/- 10 vs. 37.1 +/- 11 years), had a more frequent family history of migraine (76% vs. 66%) and a higher frequency of sensory symptoms of aura (51% vs. 41%); by contrast, there was a lesser association of SAM with other cardiac abnormalities and with coagulation disorders. The SAM study suggests that the effect of RILES on migraine features is not relevant. The higher family history of migraine in SAM suggests a possible genetic linkage between migraine and RILES.

Genetic association study and meta-analysis of the HTR2C Cys23Ser polymorphism and migraine.

The objectives of this study were to determine if the HTR2C Cys23Ser polymorphism is associated with migraine in a case-control study, and to perform a meta-analysis with present and previous available studies. The HTR2C gene is located at the Xq24-q28 chromosomal band. This band was linked to migraine with aura (MA) in two Australian families. Using the HTR2C Cys23Ser allelic variant, this gene has been ruled out as a migraine gene in 3 out of 4 studies. Only the Japanese study reported a higher risk for MA (OR=6.11; 95% CI=1.70−21.97, p trend<0.01). We performed a case-control study with 335 migraine subjects and 335 sex- and age-matched controls, and a meta-analysis pooling the results of the available data from MA subsets of patients. In the association study we found no significant differences among migraine and MA patients for this polymorphism. In the meta-analysis, under the fixed-effect model, the Ser allele did not confer higher risk for suffering MA (pooled OR=1.1; 99% CI=0.8−1.5, p=0.499). Our study did not confirm the HTR2C Cys23Ser polymorphism as a risk factor for migraine and MA.

Genetic association studies of the chromosome 15 GABA‐A receptor cluster in migraine with aura

Recently, a novel susceptibility locus for migraine with aura (MA) on chromosome 15q containing three GABA-A receptor subunits has been identified by linkage analysis in several large pedigrees. To further study the role of this locus in MA etiology we genotyped 56 SNPs capturing the known common haplotype variations of these three candidate genes in a sample comprising 270 MA patients and 273 matched controls. In a single marker analysis, four SNPs displayed nominally significant (P < 0.05) association with MA. However, after permutation-based correction for the number of tests performed, the P-values of these SNPs were non-significant. Furthermore, a replication study of two of these SNPs in a second independent sample of 379 MA patients and 379 controls did not result in a significant finding. We also compared haplotype estimates based on case-control genotypes. Again we could not demonstrate a significant association with the phenotype after correction for multiple testing. In summary, we found no convincing evidence for an involvement of common SNPs at the GABA-A receptor cluster on 15q11-q12 in the pathophysiology of MA.

Subclinical Neuromuscular Transmission Abnormality Detected by Single-Fibre EMG is More Pronounced in Cluster Headache Than in Migraine With Aura

The aim was to investigate neuromuscular transmission (NMT) by single-fibre EMG (SFEMG) in a large series of patients having migraine with aura (MA) or cluster headache (CH). Recent studies using SFEMG have shown subclinical dysfunction of NMT in MA and CH. Forty-three patients having MA, 51 with CH and 38 healthy control subjects underwent nerve conduction studies, EMG and SFEMG during voluntary contraction of the extensor digitorum communis muscle. Twenty different potential pairs were recorded and individual, mean and total abnormal individual jitter values were calculated. The results obtained from MA patients were compared with those from CH patients. In MA patients, 32 of 860 jitters were abnormally high, whereas 73 of 1020 of the jitters showed this abnormality in CH patients. None of the control subjects, five MA patients (11.6%) and 11 CH patients (21.6%) were designated as having subclinical NMT abnormality. Thus, patients having junction dysfunction were significantly more common in the CH group. The subclinical NMT abnormality shown by SFEMG is more common in CH than in MA. These two primary headache syndromes may have some shared functional abnormality of NMT constituents which is more evident in CH.

Migraine, patent foramen ovale and migraine triggers

Little information exists about a causal association between PFO and migraine. Some patients identify Valsalva-provoking activities (VPA) as migraine triggers. Therefore, we speculate about a pathogenic connection. The object of the study is to investigate the prevalence of right-to-left shunt (RLS) in a cohort of patients suffering migraine with aura (MA) and its possible association with migraine attacks triggered by VPA. We investigated the circumstances triggering the migraine attacks, in a consecutive series of 72 MA patients and in a series of migraine without aura age and gender-matched. The presence and extent of RLS was assessed by transcranial Doppler. Massive RLS appeared in 38.9% of MA and in 6.5% of migraine without aura (p<0.001). MA patients identified at least one VPA as headache trigger in 45.8%. A trend was found between these triggering activities and massive RLS, both in MAgroup OR 2.7 [1.02–7.17] and in all migraine patients OR 2.5 [1.01–6.11]. According to our results, patients with migraine who have larger RLS tend to recognize activities that increase the extent of the shunt as a trigger of their migraine attacks.

Altered levels of serotonin in lymphoblasts derived from migraine patients

We previously reported that dysfunctions in the autonomic nervous systems of patients with migraines occur not only in the brain, but throughout the whole body. Serotonin and neuropeptides are also known to have important roles in the pathophysiology of migraine. With this background in mind, we analyzed human lymphoblast cell lines from migraine with aura (MwA) patients to investigate the pathophysiology of migraine. The characteristics of these lymphoblasts and the involvement of the lymphoblasts in serotonin metabolism were examined. The lymphoblasts expressed serotonin receptors as well as some enzymes related to serotonin metabolism. The serotonin level in the MwA lymphoblasts was higher than that in the control cells. However, serotonin uptake into the lymphoblasts in MwA patients was similar to that in the control subjects. These findings suggest that lymphoblasts in MwA patients have altered levels of serotonin metabolism. Moreover, we propose that this lymphoblast cell system could serve as a novel modality for migraine research.

Prevalence of Patent Foramen Ovale in Migraine Patients with and Without Aura Compared with Stroke Patients. A Transcranial Doppler Study

The aim of this study was to investigate the prevalence of patent foramen ovale (PFO) in a consecutive unselected cohort of migraine patients (with and without aura) and compare it with a group of ischaemic young and elderly stroke patients. One hundred and forty-one migraine patients were compared with 330 stroke patients (130 young patients; 200 elderly patients) selected from our hospital stroke data bank. PFO was assessed with transcranial Doppler sonography with i.v. injection of agitated saline. The prevalence of PFO was 51.7% in migraine with aura (MA) patients, 33.7% in migraine without aura (MoA) patients, 33.8% in young stroke patients and 20.5% in elderly stroke patients (P < 0.001). The prevalence of PFO in cryptogenic stroke in young and elderly stroke patients was, respectively, 41.1% and 25% (P = 0.04). The difference between MA and MoA patients was significant (odds ratio = 2.1). The prevalence of PFO in MA patients is higher than in MoA patients and in young cryptogenic stroke patients.

Abnormal Platelet Trace Amine Profiles in Migraine With and Without Aura

Trace amines, including tyramine, octopamine and synephrine, are closely related to classic biogenic amines. In one study, where these substances were found elevated in plasma of migraineurs, it was hypothesized that trace amine metabolism is deranged in migraine. To confirm these findings, we studied, using a multichannel electrochemical high-performance liquid chromatography system, the concentrations of trace amines in platelets of migraine without aura (MoA) and migraine with aura (MA) patients in headache-free period, compared with controls. Platelet concentrations of trace amines, although elevated in both migraine types, showed a different profile in MoA and MA. Octopamine was significantly higher in MoA sufferers (0.69 +/- 0.43 ng/10(8) platelets) compared with both control subjects (0.22 +/- 0.16 ng/10(8) platelets) and MA patients (0.39 +/- 0.37 ng/10(8) platelets). Synephrine was significantly higher in MA patients (0.72 +/- 0.44 ng/10(8) platelets) with respect to both controls (0.33 +/- 0.25 ng/10(8) platelets) and MoA sufferers (0.37 +/- 0.29 ng/10(8) platelets). These results strengthen the hypothesis that tyrosine metabolism is deranged in migraine and may participate in its pathophysiology.

Objective Assessment of Cortical Excitability in Migraine With and Without Aura

Recent progress in the genetics of migraine has refocused attention on cortical dysfunction as an important component of the pathophysiology of this disorder. In previous work, we have demonstrated functional changes in the visual cortex of migraine patients, using an objective transcranial magnetic stimulation technique, termed magnetic suppression of perceptual accuracy (MSPA). This study aimed to replicate previous findings in migraine with aura (MA) and to use the technique to examine migraine without aura (MoA). Eight MA patients, 14 MoA patients and 13 migraine-free controls participated. MSPA assessments were undertaken using a standardized protocol in which computer-presented letter targets were followed at a variable delay interval by a single magnetic pulse delivered over the occiput. MSPA performance is expressed as a profile of response accuracy across target-pulse delay intervals. The profiles of migraine-free controls exhibited a normal U-shape. MA patients had significantly shallower profiles, showing little or no suppression at intermediate delay intervals. MoA patients had profiles that were similar to controls. Recent animal evidence strongly indicates that the U-shape of the normal MSPA function is caused by preferential activation of inhibitory neurons. Shallower MPSA profiles in MA patients are therefore likely to indicate a functional hyperexcitability caused by impaired inhibition. The finding of normal MPSA profiles in MoA patients is novel and will require further investigation.

Migraine with aura. A risk factor for unprovoked seizures in children?

Ludvigsson and colleagues point out that children with migraine with aura (MA) have a substantially increased risk for development of subsequent epilepsy. However, the methods used raise considerable concern about the validity of this conclusion. In a nationwide surveillance in Iceland, the authors identified children with a first unprovoked seizure and newly diagnosed epilepsy. A structured interview was used to assess headache characteristics in 94 patients and 188 control subjects. The interval between the interview and the first seizure is not given. The authors do not provide data on the time of onset of migraine. Accordingly, the conclusion that MA patients are at increased risk for development of subsequent epilepsy is unfounded. It remains unclear whether the children, the parents, or both were interviewed, an essential point for the validity of data on childhood headache. Reducing the minimum number of attacks for diagnosing migraine without aura from five, as required in the criteria of the International Headache Society, to two may have caused an overestimation of migraine without aura. The authors justify this reduction with an adult study, thereby ignoring age-associated differences of migraine; they use the incorrect argument of a low diagnostic value of five lifetime attacks, and they cite the wrong references. In addition, a recall bias, as Bille demonstrates, cannot be excluded. Patients with a seizure (or their parents) may recall lifetime headache or aura more likely than healthy control subjects. Another matter of concern is the way MA was diagnosed. It remains unclear whether the authors strictly followed the International Headache Society criteria. By including “blurry vision” they definitely did not follow these criteria, because isolated “blurry vision” is not an accepted symptom of aura. Thus, MA probably was overestimated. The authors do not mention whether they used specific International Headache Society diagnoses such as typical aura with migraine or nonmigraine headache or typical aura without headache before classifying all as MA. Finally, further details on the relation among headaches, visual symptoms, and seizures are missing. What about headache attributed to epileptic seizure, seizures with visual symptoms, and childhood epilepsy with occipital paroxysms? In summary, the unclear temporal relation between the onset of migraine and the occurrence of the first seizure, the possible overestimation of migraine without aura and MA, the possible recall bias for lifetime headache and aura, and the lack of information about the relation among headaches, visual symptoms, and seizures reduce considerably the validity of Ludvigsson and colleagues’ article.

The extent of right-to-left shunt fails to correlate with severity of clinical picture in migraine with aura

Several investigations have documented an increased incidence of right-to-left shunt (RLS) in migraine with aura (MA) and have emphasised its role in the physiopathology of aura; so far, however, no data are available concerning a possible correlation between the extent of the RLS and the clinical picture of MA patients. To investigate the possible relationship between the extent of the RLS, revealed by the number of microbubbles (MB) detected during transcranial Doppler with IV injection of ultrasound contrast (TCDc), and the clinical characteristics of MA (age at first onset of migraine, mean annual frequency of attacks and mean duration of the aura phase), 30 consecutive patients with typical aura and migraine headache positive on TCDc evaluation for RLS were enrolled. Permanent RLS was found in 12 patients and latent RLS was found in 18 patients; of these, 6 had a high-grade RLS, 5 medium-grade RLS and 7 low-grade RLS. No correlation has been documented between the number of MBs and the clinical parameters of both patients with latent shunts and those with permanent ones, nor between the clinical parameters of the two groups of patients. These data show that RLS does not seem to affect the clinical manifestation of MA and that the extent of RLS fails to correlate with the severity of the clinical picture of the disorder.

Haplotype‐based systematic association studies of ATP1A2 in migraine with aura

Mutations in ATP1A2 cause familial hemiplegic migraine (FHM) type 2, a rare monogenic form of migraine with aura (MA). Moreover, rare ATP1A2 missense variants are found in familial clustering of common forms of migraine in single pedigrees. To determine whether also common ATP1A2 polymorphisms contribute to MA pathogenesis, we performed systematic case-control association studies in 284 MA cases and 241 control individuals. By direct sequencing of the 23 coding exons and adjacent intronic regions in 45 MA patients, 16 polymorphisms (12 SNPs, 3 small indels, 1 microsatellite marker) were identified. The sequencing results were used to estimate seven common ATP1A2 haplotypes (with a frequency >5%) covering about 97% of total haplotype diversity for this region. Subsequently, six haplotype-tagging SNPs/polymorphisms were genotyped in 95 individuals with a family history of MA, in 189 individuals with sporadic MA, and in a gender-matched control sample. A haplotype analysis was performed using the program FAMHAP. No significant differences in the ATP1A2 haplotype distribution could be detected between MA patients (or patient subgroups) and the control group. In a single-marker analysis the allele and genotype frequencies of ATP1A2 polymorphisms between cases and controls were compared. Neither the six ht-SNPs nor a single allele of the microsatellite marker were significantly associated with MA. In summary, we found no evidence for a common contribution of ATP1A2 to the pathogenesis of complex inherited MA.

The Visual Aura Rating Scale (VARS) for Migraine Aura Diagnosis

To supplement the traditional ICHD-2 diagnosis for migraine with aura (MA) we developed a diagnostic scale for migraine aura that quantifies the importance of the cardinal characteristics of MA. Since more than 99% of MA patients have visual aura, we developed for simplicity a Visual Aura Rating Scale (VARS). In total 427 patients with MA (ICHD-2) or nonaura visual disturbances were diagnosed in a validated semistructured interview by a trained physician. The patients were separated into a derivation sample and a validation sample. By regression analysis we identified the visual aura characteristics associated with MA in the derivation sample. Based on the identified characteristics we developed VARS and derived a predictive VARS score which was tested in the validation sample. The VARS score is the weighted sum of the presence of five visual symptom characteristics: duration 5-60 min (3 points), develops gradually > or = 5 min (2 points), scotoma (2 points), zig-zag lines (2 points), and unilateral (1 point). The maximum score is 10 points. A VARS score of 5 or more diagnosed MA with a sensitivity of 96% (95% CI 92-99%) and a specificity of 98%(95% CI 95-100%) in the derivation sample, and a sensitivity of 91% (95% CI 86-95%) and a specificity of 96% (95% CI 91-100%) in the validation sample. VARS adds evidence based weights to a number of clearly specified characteristics; it is easy to learn, apply and teach and may therefore be a valuable addition to traditional ICHD-2 diagnosis.

Clinic–based study of family history of vascular risk factors and migraine

The objective was to evaluate the presence of a positive family history (FH) of vascular risk factors between patients with migraine with aura (MA) and migraine without aura (MO), and in chronic migraine (CM) compared to other headache types. As migraine patients are typically too young to have developed vascular events, studying older relatives of migraine patients may be a practical means of evaluating associations between vascular risk factors and migraine. A cross–sectional study of a clinicbased sample of adults with migraine headache was carried out at the University of Utah. Predictor variables comprised first or second degree relatives with stroke, hypertension, diabetes or hypercholesterolaemia. Outcome measures comprised diagnosis of MA, MO or CM according to the revised International Headache Society criteria. There was no significant difference in FH of vascular risk factors in MA compared to MO (adjusted OR 1.04, 95% CI 0.61–1.78). CM was associated with a decreased risk of FH of stroke (OR=0.11, 95% CI 0.02–0.87, p=0.036). There was no significant difference in FH of vascular risk factors in MA patients compared to MO. CM patients were more likely to have a negative FH of stroke compared to other headache types, suggesting that CM is likely a neuronal disease rather than a vascular one.

Patients' Management of Migraine and Chronic Daily Headache: A Study of the Members of the Migraine Action Association (United Kingdom)

Many strategies are available to treat and prevent migraine and chronic daily headache (CDH). Broadly these strategies can be divided into four groups, including (i) health care consultations, (ii) medication and alternative remedies, (iii) general (acute and prophylactic) strategies, and (iv) social support. This study aimed to compare headache management between migraine (MO), migraine with aura (MA), and those with CDH over the last 12 months. A postal questionnaire was sent to 887 members of the Migraine Action Association (MAA). The response rate was 60.5% (n=537), and 438 questionnaires were included in the analysis. Migraine (n=117) and MA (n=239) patients were classed according to the International Headache Society (IHS). CDH (n=82) was diagnosed when respondents had 15 or more headache days per month. Descriptive tests, analysis of variances (ANOVAs), chi2, and Kruskal-Wallis tests were used for statistical analysis (P<.05). The three groups did not differ in age, gender, ethnicity, level of education, and employment status. Significant differences in management strategies between the groups were found in the number of respondents who had consulted headache specialists (P=.002) and neurologists (P=.004), the number and types of acute medications (eg, triptans, P=.002), the use of antidepressants (P=.004), and some acute and prophylactic avoidance techniques. Although, no significant differences between the groups were found in the use of other health professionals (eg, GP), alternative health professionals, general acute management, and the use of social support, they all actively used these strategies. The respondents of this study were active users of management strategies that are based on a combination of health care consultations, medication and alternative remedies, general management, and social support. In comparison to previous findings, the respondents in this study frequently reported higher use of management strategies (such as the use of triptans), which may be related to this group of patients being better informed about headache management than those with headache within the general population. Thus, the findings may not be representative for the general population, but they give an indication of the influence and importance of headache-related education carried out by patient organizations such as the MAA.

A prospective study of the headache phase in 32 migraine with aura patients.

For an accurate description of the clinical features of the headache phase in migraine with aura (MA) attacks, we thought it useful to conduct a prospective study of consecutively referred MA patients seeking treatment at the Headache Centre of the University of Parma Institute of Neurology. The case series included 32 patients (22 women and 10 men). At the time of the first visit, each patient was given a questionnaire to be filled in at the next MA attack. Six patients (four women and two men) had attacks of migraine aura without headache. Among the remaining 26 patients (18 women and eight men), the duration of the headache phase was <24 h in 23 (88.5%); pain location was bilateral in 14 (53.8%) and unilateral in 12, but occurring on the opposite side to aura only in one patient; pain intensity was mild or moderate in 13 (50.0%). The headache phase of MA appeared to have clinical features that differed widely from patient to patient and was consistent with the International Headache Society diagnostic criteria for migraine without aura in 26.9% of patients and for tension-type headache (TTH) in 23.1%.

Modulation of trigeminal reflex excitability in migraine: effects of attention and habituation on the blink reflex

The modulation of trigeminal reflex excitability in migraine patients was evaluated during the asymptomatic phase by studying the effects of attention, habituation and preconditioning stimulus on the R2 and R3 components of the blink reflex (BR). Fifty patients suffering from migraine without aura, 20 affected by migraine with aura and 35 sex- and age-matched controls were selected. In subgroups of migraine with-aura and without-aura patients, and normal controls, the blink reflex was elicited during different cognitive situations: (a) spontaneous mental activity; (b) stimulus anticipation; (c) recognition of target numbers. In the remaining subjects, R2 and R3 habituation was evaluated by repetitive stimulation at 1, 5, 10, 15, 20, 25 and 30 s intervals. The R2 and R3 recovery curves were also computed. A reduced R3 threshold with a normal pain threshold was found in migraine with-aura and without-aura patients; the R3 component was not significantly correlated with the pain thresholds in patients and controls. The R2 and R3 components were less influenced by the warning of the stimulus in migraine without-aura and migraine with-aura patients, in comparison with the control group. A slight increase of both R2 and R3 recovery after preconditioning stimulus was also observed in migraine patients, probably caused by a phenomenon of trigeminal hyperexcitability persisting after the last attack. The abnormal BR modulation by alerting expresses in migraine a dysfunction of adaptation capacity to environmental conditions, probably predisposing to migraine.