Migraine With Aura Research Articles

C677T Methylenetetrahydrofolate Reductase Homozygosis and Vitamin Supplement in Migraineur Children

Purpose: Methylenetetrahydrofolate reductase (MTHFR) variant C677T has been associated with an increased genetic risk in migraine susceptibility. Individuals with the homozygous genotype show higher levels of plasma homocysteine (Hcy) [1,2,3].
 Methods: Open-label study evaluating clinical trial was performed on 148 children migraineurs among 236 children suffering from headache, admitted to the Headache Regional Centre in l’Aquila (Italy)-Neuropsychiatric clinic, recruited and observed sequentially during the years 2015-2017. 31 patients (16,6% of all the sample) MTHFR homozygous were selected and underwent clinical evaluation of migraine characteristics (frequency, severity of pain and use of acute treatment) at baseline and after a 12 month-period of daily supplement of vitamins B9(2 mg), B6(25 mg), B12(400 mcg). In 20 patients with hyper Hcy (>95° percentile for age) the second collection of blood sample was obtained for Hcy assessment. Diagnosis of headache according to ICHD-III criteria. Statistical analysis is made by Wilcoxon test.
 Results: 20 children suffer from Migraine without aura (MwoA) and 11 from Migraine with aura (MA). 86% of children aged >10 years had significantly higher Hcy values compared with controls (p<0.0001). 21 patients (70%), 14 F and 7 M (13 MwoA and 8 MA), have Hcy values > 95°percentile. In all the sample the vitamin supplementation was effective in producing significant reduction in Hcy levels (p=0.0001) and a significant improvement of migraine disability of frequency (p<0.0001), severity of pain (p<0.0003) and use of acute treatment (p<0.0001).
 Conclusions: The study results are encouraging and emphasize the importance of a comprehensive therapy in paediatric migraines.

How much do periventricular lesions assist in distinguishing migraine with aura from CIS?

To evaluate in clinically isolated syndrome (CIS) and migraine with aura (MA) how the number of periventricular lesions (PVLs) detected at MRI influences diagnostic performance when the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) or the 2017 revised criteria are applied. In this retrospective study, white matter hyperintensities (WMH) of 84 patients with MA and 79 patients with CIS were assessed using manual segmentation technique. Lesion probability maps (LPMs) and voxel-wise analysis of lesion distribution by diagnosis were obtained. Furthermore, we performed a logistic regression analysis based on lesion locations and volumes. Compared to patients with MA, patients with CIS showed a significant overall higher T2 WMH mean number and volume (17.9 ± 16.9 vs 6.2 ± 11.9 and 3.1 ± 4.2 vs 0.3 ± 0.6 mL; p < 0.0001) and a significantly higher T2 WMH mean number in infratentorial, periventricular, and juxtacortical areas (p < 0.0001). LPMs identified the periventricular regions as the sites with the highest probability of detecting T2 WMH in patients with CIS. Voxel-wise analysis of lesion distribution by diagnosis revealed a statistically significant association exclusively between the diagnosis of CIS and the PVLs. MAGNIMS criteria demonstrated the highest specificity in differentiating patients with CIS from patients with MA (100% vs 87%) against a predictable lower sensitivity (63% vs 72%). PVLs play a key role in the differential diagnosis between MA and CIS, particularly when there are more than 3. Future studies on multiple sclerosis criteria might reconsider the 3 PVLs to minimize the risk of misdiagnosis. This study provides Class IV evidence that the presence at least 3 PVLs increases the specificity in distinguishing MA from CIS.

Abstract P419: Migraine and Arterial Stiffness in the Brazilian Longitudinal Study of Adult Health ELSA-Brasil

Introduction: Migraine with aura has been associated with cardiovascular events however the mechanisms are unclear. Arterial stiffness is a validated predictor of cardiovascular events and could play a role in that association. Hypothesis: We tested the hypothesis that migraine is associated with arterial stiffness in a well-defined middle-aged population. Methods: In a cross-sectional analysis of a well-defined population with complete and validated information about migraine and aura according to International Headache Society criteria, the arterial stiffness measured by carotid-to-femural pulse wave velocity was tested with multiple linear regression models comparing migraine without aura (MO) and migraine with aura (MA) to the reference group no migraine (NM) . Subsequent adjustments were made for age, sex, education, physical activity, alcohol use, diabetes, smoking, use of anti-hypertensive medication, waist circumference, LDL-cholesterol and triglycerides levels to test the independence of the association between migraine status and arterial stiffness. Results: We studied 4649 participants, 2521 women (25.7% MO and 15% MA)and 2128 men (11% MO and 4.3% MA). NM, MO and MA presented mean age 52.3 ±9.2 , 49.2 ± 7.7 and 47.9 ±7.1 years respectively (P&lt;0.001 for trend); mean systolic blood pressure 120.96 (±16.5), 117.35(±14.9) and 115 (±15.2) mmHg respectively (p&lt;0.001 for trend); mean fasting glucose 112.5 (± 29.37), 108.9(±30.7) and 103.12 (±24.6) mg/dl respectively (p&lt;0.001 for trend). Hypertension and diabetes were less prevalent in MA compared to NM (25,5% vs 33 % ) and (17.4% vs 21.3%) (p&lt;0.001 for both) and arterial stiffness was not significantly different across groups 9.22(±1.8), 9.28(±1.9) and 9.26(±2) m/s, respectively (p=0.746 for trend). Fully adjusted models yielded non-significant linear coefficients β (CI95%) 0.43 (-0.105;0.191)m/s when MA was compared with NM. Conclusion: In a large population of middle-aged with validated aura information, migraine status was not associated with arterial stiffness measured by carotid-to-femural pulse wave velocity.

Retinal vascular density evaluation of migraine patients with and without aura and association with white matter hyperintensities.

Underlying pathophysiological mechanism of migraine is not all clear; however, recent reports suggested that neurovascular system is involved. We aimed to evaluate the retinal vessel densities of migraine patients with and without aura and the associations with white matter hyperintensities (WMH), using optical coherence tomography angiography (OCTA). We recruited 28 migraine with aura (MWA) patients, 26 migraine without aura (MWO) and age and sex-matched 34 healthy controls in our study. All participants were evaluated with optical coherence tomography (OCT) and OCTA for optic nerve parameters and retinal vessel densities with RTVue XR AVANTI. On macular OCTA, superficial and deeper retinal foveal vessel density (VD) were significantly lesser in MWA and MWO than controls. On optic nerve OCTA, whole optic disc, peripapillary, superior hemisphere, superior layer and temporal layer VD were significantly lesser in MWA and MWO. In group of MWA with the WMH, deeper foveal VD and superior hemisphere VD, average RNFL, superior hemisphere and superior layer were significantly lesser and also foveal avascular zone was significantly larger than the group of without WMH. Alterations of VD in patients with migraine are showed in our study. In addition, in group of MWA these alterations have associations with WMH. Supporting these findings with further reports can be useful to understand the pathophysiology of this disease.

Abstract WP233: Distinct Vascular Profile in Middle-Aged Migraineurs: Higher Pulse Wave Velocity, Putaminal État Criblé and Incomplete Posterior Circle of Willis

Background: Migraineurs may develop stroke and cardiovascular diseases (CVD). We evaluated vascular findings in middle-aged migraineurs without CVD risks. Methods: Migraine was diagnosed according to ICHD-3 by direct interview and neurological examination. Migraine was classified into migraine with aura (MA) and migraine without aura (MO). Frequency of migraine attacks were denoted as &lt; 1 /mo or ≥ 1 /mo. Severity of migraine was scaled by Headache Impact Test-6. Usual CVD risk factors of smoking, obesity, hypertension, diabetes mellitus and dyslipidemia were examined. Brachial-ankle pulse wave velocity (baPWV) and ankle brachial index (ABI) were measured using a plethysmography. Brain magnetic resonance imaging (MRI) and angiography (MRA) were performed. Circle of Willis (CW) on MRA was morphologically classified into 2 types: complete posterior CW defined as the presence of both posterior communicating arteries and both P1 segments of posterior cerebral arteries, and other patterns of incomplete posterior CW (Ikeda et al. Headache 2007). Results: A total of 317 migraineurs (235 women and 82 men) were diagnosed. Thirty patients with CVD risk factors were excluded, and the study was completed in 287 migraineurs (215 women and 72 men), MA (n=56) and MO (n=231). Mean age (SD) was 44.0 (9.3) years. Consecutive 300 age- and sex-matched controls without migraine and CVD risks were prepared during the study. Compared to controls, baPWV was increased in migraineurs (P&lt;0.05) and MA patients (P&lt;0.01). ABI did not differ between migraineurs and controls. Other clinical findings of migraineurs were not linked to baPWV and ABI. MRI disclosed higher frequency of putaminal état criblé in migraineurs (P&lt;0.05) and MA patients (P&lt;0.01) compared to controls. Three MA patients were diagnosed with hereditary cerebral angiopathy of CADASIL (n=1), Moyamoya disease (n=1) and cavernous angioma (n=1). Morphological CW studies lower frequency of complete posterior CW in migraineurs (P&lt;0.05) and MA patients (P&lt;0.01) compared to controls. Conclusion: The present study suggested vascular changes of baPWV, putaminal état criblé and CW shape in migraineurs, especially in MA sufferers. The distinct vascular profile could contribute to higher risk of stroke and CVD in migraineurs.

Abstract WP542: Basilar Artery Curvature is Associated With Migraine With Aura in the Northern Manhattan Study

Introduction: Genetic and imaging studies demonstrate a link between vascular morphology and migraine with aura (MA). As aura typically originates from the occipital cortex, the vertebrobasilar system that supplies this area is of particular interest. We examined the relationship between basilar artery (BA) curvature and MA in a large, population-based cohort of stroke-free participants. Methods: We analyzed Northern Manhattan Study participants who had undergone time of flight MRA at 1.5 Tesla. Migraine, with or without aura, was ascertained through structured interviews. BA curvature was defined as the sum of the total horizontal deviation of the BA at the distal tip, mid-pons, and vertebrobasilar junction, and was used as the primary independent variable in unadjusted and adjusted logistic regression analyses. BA measurements were obtained blinded to migraine status. Results: Of 805 participants (mean age 70±9.3 years, 55% women, 66% Hispanic), migraine without aura was present in 13% (N=105) and MA in 3% (N=24). MA was more common among women (P=0.03) and Hispanics (P=0.001). Mean BA curvature was 16 ± 10 mm. In unadjusted analysis, BA curvature was greater in participants with MA than those without MA (19 vs 15 mm, P=0.02). In a model adjusted for demographics, vascular risk factors, head size and height, greater BA curvature was associated with MA (OR 1.06 per mm, 95% CI 1.01-1.11) compared to participants with no migraine. The association between BA curvature and migraine without aura did not reach significance (OR 1.01, 95% CI 0.99-1.04). Conclusions: Greater BA curvature was associated with migraine with aura but not migraine without aura. Understanding the physiopathology of this association may provide clues to the underlying mechanisms of migraine and the relationship between migraine and stroke.

Rs2651899 variant is associated with risk for migraine without aura from North Indian population.

Recently a GWAS study had identified 38 genomic variants commonly found in humans that influence migraine risk. For further replicate these findings, we selected two SNPs; rs2651899 on chromosome 1p36.32 in PRDM16 gene and rs10166942 on chromosome 2q37.1 close to TRPM8 gene for their associations with migraine in the North Indian population as much work has not been done on these variants before from this population. In this case-control association study, 300 unrelated subjects, including 150 migraineurs (43 migraine with aura and 107 migraine without aura) and 150 healthy controls were selected to collect genomic DNA. Polymerase chain reaction and restriction-fragment-length polymorphism methods were performed for genotyping of these variants. Univariate and multivariate analyses were done to find the association of different genotypes and alleles of these SNPs with migraine and its subgroups. We found a statistically significant difference in migraineurs with control for PRDM16 rs2651899 polymorphism at genotypic (p < 0.05), allelic (p = 0.022; OR 1.462; 95% CI 1.058-2.022) and for dominant model (p = 0.011; OR 1.957; 95% CI 1.169-3.276). A similar trend was observed both on subgroup and gender analysis in migraine without aura (MO) and females respectively for rs2651899 variant. For the other SNP (rs10166942), statistically non-significant differences were reported in the allelic/genotypic frequencies between migraineurs and controls as p > 0.05. However, on subgroup analysis we found statistically significant differences at genotypic (p < 0.05) and dominant models in migraine with aura (MA) and in males with that of entire controls. But no significant association was found at allelic level in both subgroup and gender analysis for rs10166942. This research study showed that rs2651899 is a potential genetic marker for migraine susceptibility in MO and female subgroup at both genotypic and allelic level in the North Indian population and found that rs10166942 variant may be a potential marker for MA and male subgroup. Further work with large sample size is required for these SNPs to understand their functional mechanisms and to strengthen our results.

Volume alterations of brainstem subregions in migraine with aura.

BackgroundThe brainstem plays a significant role in migraine pathogenesis, but a relationship between volume alterations of brainstem subregions and migraine aura characteristics has not been sufficiently investigated. The aim of this study is to compare the volume of the brainstem, and its subregions, between patients with a migraine with aura (MwA) and healthy controls (HC), and also to correlate characteristics of MwA and the volume of the brainstem subregions.MethodsForty-two MwA and 42 HCs, balanced by sex and age, were selected for this study. Total brainstem volume changes as well as volume changes in the pons, medulla, midbrain and the superior cerebellar peduncles were investigated in MwA relative to HCs. In addition, the relationships between brainstem subregions and aura characteristics (aura duration, the frequency of the aura, occurrence of somatosensory and dysphasic aura, duration of a headache, intensity of headache pain and disease duration) were explored in MwA.ResultsMwA patients had a larger brainstem volume relative to HCs (25,941.35 ± 2559.2 mm3 vs. 25,179.32 ± 2019.1 mm3; p = .008), as well as the midbrain and pons (6155.98 ± 565.7 mm3 vs. 5964.22 ± 457.0 mm3, p = .002; 15,105.13 ± 1765.5 mm3 vs. 14,539.89 ± 1408.4 mm3, p = .007, respectively). Total brainstem volume, as well as volumes of brainstem subregions, were not significantly correlated to the MwA characteristics.ConclusionThe results of this study reveal that a migraine with aura is associated with a larger volume of the brainstem with a particular involvement of the midbrain and pons.

Subcortical Volume Changes in Migraine with Aura.

Background and PurposeVarious features of the cerebral cortex and white matter have been extensively investigated in migraine with aura (MwA), but the morphological characteristics of subcortical structures have been largely neglected. The aim of this study was to identify possible differences in subcortical structures between MwA patients and healthy subjects (HS), and also to determine the correlations between the characteristics of migraine aura and the volumes of subcortical structures.MethodsThirty-two MwA patients and 32 HS matched by sex and age were analyzed in this study. Regional subcortical brain volumes were automatically calculated using the FSL/FMRIB Image Registration and Segmentation Tool software (https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/Glossary). A general linear model analysis was used to investigate differences in the volume of subcortical structures between the MwA patients and HS. A partial correlation test was used to assess correlations between the volume of subcortical structures and characteristics of MwA.ResultsThe volumes of the right globus pallidus, left globus pallidus, and left putamen were significantly smaller in MwA patients than in HS (mean±SD): 1,427±135 mm3 vs. 1,557±136 mm3 (p<0.001), 1,436±126 mm3 vs. 1,550±139 mm3 (p=0.001), and 4,235±437 mm3 vs. 4,522±412 mm3 (p=0.006), respectively. There were no significant relationships between subcortical structures and clinical parameters.ConclusionsThese findings suggest that both the globus pallidi and left putamen play significant roles in the pathophysiology of the MwA. Future studies should determine the cause-and-effect relationships, since these could not be discriminated in this study due to its cross-sectional design.

Characteristics and clinical correlates of white matter changes in brain magnetic resonance of migraine females

ObjectiveWhite matter hyperintensities (WMHs) were often found in migraine patients. The aim of study was to characterize WMHs, assess their prevalence, determine relationship to clinical symptoms and homocysteine levels in migraine females. Methods69 women 38 with migraine without aura (MO), 31 with migraine with aura (MA) who underwent brain MRI with 1.5T scanner were enrolled. The WMHs number, location and size in FLAIR sequence were evaluated. Migraine severity was measured by pain intensity, number of attacks per month and MIDAS scale. ResultsWMHs were found in 39.1% females. There was no WMHs and migraine type correlation. The total WMHs number was higher in MO (p=0.027). Patients with WMHs were older (p=0.025), have higher BMI (p=0.042), suffered longer (p=0.001), more often had positive pregnancy history (p=0.010) and less frequent prodromal symptoms. The age of onset, migraine's severity and homocysteine did not correlate with WMHs. No effect of antimigraine medication and oral contraceptive pills (OCP) was found. Both in MO and MA groups WMHs were located only supratentorially. In MO females WMHs were mainly located in one cerebral hemisphere (p=0.024) whereas in MA were found bilaterally. WMHs were most commonly located in the frontal lobes. In MO lesions were small ≤3mm and present in almost all MO patients (p=0.027). ConclusionWMHs are present in more than one third of migraine females, regardless of aura. WHMs are located supratentorially, subcortically and in the frontal lobes. Older age, longer disease's duration, obesity and positive history of pregnancy are main risk factors for WMHs. Symptomatology and migraine severity, hyperhomocysteinemia, OCP and anti-migraine medications do not increase WMHs.

New CACNA1A deletions are associated to migraine phenotypes

BackgroundFamilial hemiplegic migraine type 1 (FHM1) is a form of migraine with aura caused by heterozygous mutations in 4 genes: CACNA1A, ATP1A2, SNC1A and PRRT2, but further heterogeneity is expected. Here have been described clinical and molecular features in patients suffering from migraine with Aura (MA), without (MO) and hemiplegic migraine attacks.Next Generation Sequencing by TruSeq Custom Amplicon for CACNA1A and ATP1A2 gene has been performed. All genetic variants have been confirmed by Sanger sequencing and all samples were also analyzed with MLPA assay for ATP1A2-CACNA1A genes to detect duplication or deletion. All MLPA data were verified by Real Time PCR.ResultsSequencing analysis showed 3 point mutations, two novel variants and one already described in literature. Moreover, MLPA analysis showed 3 deletions in 9 sporadic hemiplegic migraine (18%), in 3 patients with non-hemiplegic migraine (4.1%) and in 3 patients affected by episodic ataxia (20%). Two sporadic patients showed a deletion in exons 41–43, while the rest of HM patients (5) showed a deletion in the terminal part of the CACNA1A gene.About episodic ataxia, we have identified deletions in exon 12–15 and in exon 47. Finally, in migraine patients, we have found different subjects affected by different phenotypes deleted in exon 47.ConclusionThis work highlights the importance to complement analysis as direct sequencing with quantitative analysis (MLPA). In fact, intragenic CACNA1A rearrangements have been detected. Our work demonstrated that deletions in CACNA1A gene may be associated also to different migraine phenotypes.

Prevalence of restless legs syndrome in individuals with migraine: a systematic review and meta-analysis of observational studies.

Recent studies have shown an association between migraine and restless legs syndrome (RLS), but RLS prevalence among individuals with migraine differs substantially across studies. The present work aimed to comprehensively assess available evidence to estimate RLS prevalence among individuals with migraine and non-migraine controls. Web of Science, PubMed, Embase, Chinese National Knowledge Infrastructure, Wanfang, and SinoMed databases were searched for observational and case-control studies of RLS prevalence among individuals with migraine. Eligible studies were meta-analyzed using Stata 12.0 software. Pooled RLS prevalence in migraine was 19%, and the prevalence was lower in Asia (16%) than outside Asia (21%). Pooled RLS prevalence was 18.8% among individuals with migraine with aura, and 18.5% among individuals with migraine without aura; the RLS prevalence in migraine with aura (MA) was higher than that of migraine without aura (MO) (OR 1.17, 95%CI 1.01-1.34; p = 0.037). Pooled RLS prevalence in a case-control study was significantly higher among individuals with migraine (17.9%) than among non-migraine controls (7.1%) (OR 2.65, 95%CI 2.26-3.10; p < 0.001). Our meta-analysis provides the first reliable pooled estimate of RLS prevalence among individuals with migraine, and it provides strong evidence that RLS risk is higher among individuals with migraine than among controls.

Effects of Add-On Ultramicronized N-Palmitol Ethanol Amide in Patients Suffering of Migraine With Aura: A Pilot Study

Background: Palmitoyl ethanol amide (PEA) is an endogenously produced substance showing anti-nociceptive effect through both receptor and non-receptor mediated effects at the level of different cellular and tissue sites. This study showed the results of a single blind study that was conducted to evaluate both the safety and the efficacy of ultramicronized PEA (umPEA; 1,200 mg/day) for up 90 days in patients suffering of Migraine with Aura (MA) treated with NSAIDs.Methods: A total of 20 patients, 8 male (33–56-years, average 41.4 ± 7.8) and 12 female (19–61-years, average 38.5 ± 11.9) with MA were admitted to our observation and diagnosed according to ICHD-3 criteria, they received umPEA (1,200 mg/day) in combination with NSAIDs for up to 90 days. They were revaluated at 30, 60, and 90 days after treatment.Results: umPEA administration induced a statistically significant and time dependent pain relief. In particular, these effects were evident at 60 days (male P = 0.01189; female P = <0.01) and they lasted until the end of the study (male P = 0.0066; female P = 0.01473).Conclusion: Although further studies are needed, our findings indicate that in patients suffering of MA treatment with umPEA had good efficacy and safety which candidate this compound as a therapeutic tool in pain migraine management.

Migraine with aura and white matter tract changes.

We aimed to explore whether a migraine with aura (MA) is associated with structural changes in tracts of a white matter and to compare parameters of diffusivity between subgroups in migraineurs. Forty-three MA and 20 healthy subjects (HS), balanced by sex and age, were selected for this study. Analysis of diffusion tensor parameters was used to identify differences between MA patients and HS, and then between MA subgroups. A diffusion tensor probabilistic tractography analysis showed that there is no difference between MA patients and HS. However, using more-liberal uncorrected statistical threshold, we noted a trend in MA patients toward lower diffusivity indices of selected white matter tracts located in the forceps minor and right anterior thalamic radiation (ATR), superior longitudinal fasciculus (temporal part) (SLFT), cingulum-cingulate tract, and left uncinate fasciculus. Migraineurs who experienced somatosensory and dysphasic aura, besides visual symptoms, had tendency toward lower diffusivity indices, relative to migraineurs who experienced only visual symptoms, in the right inferior longitudinal fasciculus, forceps minor, and right superior longitudinal fasciculus (parietal part), SLFT, and cingulum-angular bundle. Aura frequency were negatively correlated with axial diffusivity and mean diffusivity of the right ATR (partial correlation = - 0.474; p = 0.002; partial correlation = - 0.460; p = 0.002), respectively. There were no significant differences between MA patients and HS, neither between MA subgroups. Migraineurs with abundant symptoms during the aura possibly have more myelinated fibers relative to those who experience only visual symptoms. Lower diffusivity indices of the right ATR are linked to more frequent migraine with aura attacks.

The New *G29A and G1222A of HCRTR1, 5-HTTLPR of SLC6A4 Polymorphisms and Hypocretin-1, Serotonin Concentrations in Migraine Patients.

Migraine is one of the most common primary headache disorders that affects 11% of the adult population. The disease is divided into two main clinical subtypes: migraine with aura (MA) and migraine without aura (MO). Both serotonergic and hypocretinergic systems are involved in the migraine pathomechanism. Polymorphisms in the serotonin transporter gene (SLC6A4) and the hypocretin receptor 1 gene (HCRTR1) may be risk factors for migraine development due to their ability to affect serotonin and hypocretin-1 (HCRT-1) concentrations. The aim of the study was to analyze, for the first time in the Polish population, the 5-HT transporter linked polymorphic region (5-HTTLPR) in SLC6A4, G1222A (rs2271933) and the never before studied *G29A (rs41263963) polymorphisms in the HCRTR1 gene, as well as the 5-HT and hypocretin-1 plasma concentrations in migraine patients (MA, MO) and control subjects. The study included 123 patients that were diagnosed with migraine and 123 control subjects. Methods such as PCR, HRMA and sequencing were used for genotyping, while 5-HT was determined by HPLC/EC and hypocretin-1 by ELISA. No significant differences were observed in 5-HTTLPR frequencies. The A allele of HCRTR1 G1222A occurred more often in MO, while the GA genotype of HCRTR1 *G29A was more frequent among MA when compared to control group (p < 0.05). The mean age of migraine onset in individuals with HCRTR1 *G29A was 18 years old for patients with MA and 26 years old for MO patients. The localization and type of HCRTR1 polymorphisms (G1222A—missense variant in exon 7, *G29A−3′UTR variant) may predispose patients to the clinical subtype of migraine: MO or MA, respectively. In control subjects, the short allele of 5-HTTLPR tended to decrease the 5-HT concentration, while the A allele of HCRTR1 G1222A decreased both 5-HT and hypocretin-1 levels. Serotonin concentrations differed in terms of clinical features of migraine. The relation between genotypes of 5-HTTLPR, HCRTR1 G1222A, and 5-HT concentrations may bedisturbed in migraine. It seems that HCRTR1 *G29A is more strongly associated with regulating the 5-HT in patients with MA than MO, and therefore may contribute to the early age of onset for migraine.

Estrogen, migraine, and vascular risk.

Migraine has a predilection for female sex and the course of symptoms is influenced by life stage (presence of menstrual cycle, pregnancy, puerperium, menopause) and use of hormone therapy, such as hormonal contraception and hormone replacement therapy. Hormonal changes figure among common migraine triggers, especially sudden estrogen drop. Moreover, estrogens can modulate neuronal excitability, through serotonin, norepinephrine, dopamine, and endorphin regulation, and they interact with the vascular endothelium of the brain. The risk of vascular disease, and ischemic stroke in particular, is increased in women with migraine with aura (MA), but the link is unclear. One hypothesis posits for a causal association: migraine may cause clinical or subclinical brain lesions following repeated episodes of cortical spreading depression (CSD) and a second hypothesis that may explain the association between migraine and vascular diseases is the presence of common risk factors and comorbidities. Estrogens can play a differential role depending on their action on healthy or damaged endothelium, their endogenous or exogenous origin, and the duration of their treatment. Moreover, platelet activity is increased in migraineurs women, and it is further stimulated by estrogens.This review article describes the course of migraine during various life stages, with a special focus on its hormonal pathogenesis and the associated risk of vascular diseases.

The NRP1 migraine risk variant shows evidence of association with menstrual migraine

BackgroundIn 2016, a large meta-analysis brought the number of susceptibility loci for migraine to 38. While sub-type analysis for migraine without aura (MO) and migraine with aura (MA) found some loci showed specificity to MO, the study did not test the loci with respect to other subtypes of migraine. This study aimed to test the hypothesis that single nucleotide polymorphisms (SNPs) robustly associated with migraine are individually or collectively associated with menstrual migraine (MM).MethodsGenotyping of migraine susceptibility SNPs was conducted using the Agena MassARRAY platform on DNA samples from 235 women diagnosed with menstrual migraine as per International Classification for Headache Disorders II (ICHD-II) criteria and 140 controls. Alternative genotyping methods including restriction fragment length polymorphism, pyrosequencing and Sanger sequencing were used for validation. Statistical analysis was performed using PLINK and SPSS.ResultsGenotypes of 34 SNPs were obtained and investigated for their potential association with menstrual migraine. Of these SNPs, rs2506142 located near the neuropilin 1 gene (NRP1), was found to be significantly associated with menstrual migraine (p = 0.003). Genomic risk scores were calculated for all 34 SNPs as well as a subset of 7 SNPs that were nearing individual significance. Overall, this analysis suggested these SNPs to be weakly predictive of MM, but of no prognostic or diagnostic value.ConclusionsOur results suggest that NRP1 may be important in the etiology of MM. It also suggests some genetic commonality between common migraine subtypes (MA and MO) and MM. The identification of associated SNPs may be the starting point to a better understanding of how genetic factors may contribute to the menstrual migraine sub-type.

Association of expression of DRD2 rs1800497 polymorphism with migraine risk in Han Chinese individuals.

BackgroundPrevious studies suggested that single-nucleotide polymorphisms in dopamine receptor D2 (DRD2) are the susceptibility loci for migraine. This study was aimed at evaluating the contribution of DRD2 rs1800497 and its expression to migraine risk in Han Chinese subjects.MethodsIn total, 250 patients with migraine and 250 age- and sex-matched control subjects were included in this study. TaqMan allelic discrimination assay was used for DRD2 rs1800497 genotyping. Plasma DRD2 concentration was determined using enzyme-linked immunosorbent assay.ResultsSignificant associations were observed for the rs1800497 genotype (c2=6.37, p=0.041) and allele (c2=4.69, p=0.03; odds ratio [OR]=1.33, 95% CI=1.03–1.72, power=58%) frequencies between the migraine and control groups. Sex analysis indicated a positive association for rs1800497 between female patients with migraine and control individuals (genotype: c2=7.84, p=0.019; allele: c2=6.60, p=0.010; OR=1.61, 95% CI=1.12–2.30, power=73.4%). Furthermore, a significant association was observed only in female patients with migraine without aura (MO) (genotype: c2=6.88, p=0.032; allele: c2=5.65, p=0.017; OR=1.59, 95% CI=1.08–2.36, power=65.1%). The mean plasma DRD2 levels in the control group (mean±SD: 24.20±2.78) were significantly lower than those in the migraine with aura (MA) (30.86±3.69, p<0.0001) and MO groups (31.88±4.99, p<0.0001). Additionally, there was a sex-based difference in DRD2 expression in the MA (male vs female: 29.46±3.59 vs 32.27±3.27, p<0.01) and MO groups (male vs female: 29.18±3.50 vs 34.58±4.84, p<0.0001). Moreover, plasma DRD2 levels in patients were significantly different among the three genotypes (CC vs CT vs TT: 24.76±3.76 vs 30.93±3.85 vs 37.06±3.95, p<0.0001). Similar results were observed both in the MA (CC vs CT vs TT: 25.09±3.84 vs 28.57±2.84 vs 33.37±1.58, p<0.0001) and MO groups (CC vs CT vs TT: 24.65±3.79 vs 31.65±3.86 vs 38.29±3.74, p<0.0001).ConclusionOur case–control study suggested that the DRD2 polymorphism rs1800497 was significantly associated with the risk of migraine in Han Chinese females. Additionally, the plasma DRD2 level was high in patients with migraine. Females with migraine had considerably higher DRD2 levels than males with migraine. DRD2 expression may be regulated by DRD2 rs1800497 genotype in patients with migraine.

Current Treatment Options: Headache Related to Menopause-Diagnosis and Management.

Menopause is a life-changing event in numerous ways. Many women with migraine hold hope that the transition to the climacteric state will coincide with a cessation or improvement of migraine. This assumption is based mainly on common lay perceptions as well as assertions from many in the healthcare community. Unfortunately, evidence suggests this is far from the rule. Many women turn to a general practitioner or a headache specialist for prognosis and management. A natural instinct is to manipulate the offending agent, but in some cases, this approach backfires, or the concern for adverse events outweighs the desire for a therapeutic trial, and other strategies must be pursued. Our aim was to review the frequency and type of headache syndromes associated with menopause, to review the evidence for specific treatments for headache associated with menopause, and to provide management recommendations and prognostic guidance. We reviewed both clinic- and population-based studies assessing headache associated with menopause. Headache in menopause is less common than headache at earlier ages but can present a unique challenge. Migraine phenotype predominates, but presentations can vary or be due to secondary causes. Other headache types, such as tension-type headache (TTH) and cluster headache (CH) may also be linked to or altered by hormonal changes. There is a lack of well-defined diagnostic criteria for headache syndromes associated with menopause. Women with surgical menopause often experience a worse course of disease status than those with natural menopause. Hormonal replacement therapy (HRT) often results in worsening of migraine and carries potential for increased cardiovascular and ischemic stroke risk. Estrogen replacement therapy (ERT) in patients with migraine with aura (MA) may increase the risk of ischemic stroke; however, the effect is likely dose-dependent. Some medications used in the prophylaxis of migraine may be useful in ameliorating the vasomotor and mood effects of menopause, including venlafaxine, escitalopram, paroxetine, and gabapentin. Other non-medication strategies such as acupuncture, vitamin E, black cohosh, aerobic exercise, and yoga may also be helpful in reducing headache and/or vasomotor symptoms associated with menopause. The frequency and type of headache associated with menopause is variable, though migraine and TTH are most common. Women may experience a worsening, an improvement, or no change in headache during the menopausal transition. Treatment may be limited by vascular risks or other medical and psychiatric factors. We recommend using medications with dual benefit for migraine and vasomotor symptoms including venlafaxine, escitalopram, paroxetine, and gabapentin, as well as non-medication strategies such as acupuncture, vitamin E, black cohosh, aerobic exercise, and yoga. If HRT is pursued, continuous (rather than cyclical) physiological doses should be used, transdermal route of administration is recommended, and the patient should be counseled on the potential for increased risk of adverse events (AEs). Concomitant use of a progestogen decreases the risk of endometrial hyperplasia with ERT. Biological mechanisms are incompletely understood, and there is a lack of consensus on how to define and classify headache in menopause. Further research to focus on pathophysiology and nuanced management is desired.

Basilar Artery Lateral Displacement May Be Associated with Migraine with Aura.

The objective of this study is to determine whether structural features of the vertebrobasilar arterial system are related to migraine. Alterations in cerebral vascular structure and function have been associated with migraine, possibly mediated by hypoperfusion and/or endothelial dysfunction triggering cortical spreading depression. Vessel tortuosity, in particular, has been associated with both altered hemodynamics and endothelial function. Symptoms of migraine with aura (MWA) often localize to the occipital cortex, and evidence supports the localization of a migraine generator to the brain stem, suggesting that the vertebrobasilar system may be of particular relevance. We performed a post hoc exploratory analysis of data collected in a prospective, observational, case-control study enrolling MWA, migraine without aura (MwoA), and control subjects in a 1:1:1 ratio. 3 T high-resolution MR angiography was used to assess vascular structure, and arterial spin-labeled perfusion MRI to measure interictal cerebral blood flow (CBF). White matter lesions were assessed using T2/FLAIR. Vertebral and basilar artery (BA) diameters and BA total lateral displacement were measured. 162 subjects were included (52 control/52 MWA/58 MwoA). Mean age was 33 ± 6 years, and 78% were female. BA diameter was similar across groups (3.6 ± 0.6 mm in all 3 groups). BA displacement was similar in MwoA (5.1 ± 3.0 mm) and controls (4.9 ± 3.1 mm), but tended to be greater in MWA (6.3 ± 3.8 mm, p = 0.055 vs. controls). BA displacement increased with age (p < 0.001) was greater in men vs. women (6.6 ± 4.2 vs. 5.1 ± 3.0, p = 0.02) and with increased migraine frequency (p = 0.03). In multivariate analysis, BA displacement was significantly greater in MWA subjects (p = 0.02), with older age (p = 0.003), and in men (p = 0.046). In regression analysis adjusted for age and sex, BA displacement remained significantly greater with increasing migraine frequency (p = 0.02). There was no association between BA displacement and interictal posterior cerebral artery territory CBF or overall white matter lesions. BA lateral displacement may be associated with MWA as well as headache frequency. This association does not appear to be mediated by cerebral hypoperfusion.