Udar kryptogenny – drożny otwór owalny – migrena z aurą: przypadkowa triada czy związek przyczynowo-skutkowy? Część II

In the second part of the paper, we discuss the relationship between migraine with aura and either patent foramen ovale (PFO) or stroke. The results of the studies suggest that PFO with right-to-left shunt is more prevalent among patients suffering from migraine with aura. Moreover, migraine with aura is a risk factor for ischaemic stroke in women and the risk increases when they have additional vascular risk factors such as taking oral contraception and smoking. However, the pathophysiology of these phenomena remains hypothetical. The most frequently reported theory suggests paradoxical embolism as a mechanism of the above-mentioned pathologies. In this paper we compare the pros and cons of the general theories. We discuss the percutaneous closure of PFO in patients with migraine, regarding the benefit/risk ratio.     

Frequency of the C677T variant of the methylenetetrahydrofolate reductase (MTHFR) gene in patients with migraine with or without aura – a preliminary report

Background and purposeThe aim of our study was to evaluate the frequency of the C677T variant in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with migraine with or without aura and to find an association between this variant and vascular lesions in magnetic resonance imaging of the head, presence of patent foramen ovale (PFO) and increased level of homocysteine.Material and methodsNinety-one patients with migraine, aged 19–57, were investigated in this study. The MTHFR C677T variant was genotyped in this group and levels of homocysteine, folic acid and vitamin were measured. Transcranial Doppler sonography with test for PFO detection by injection of air contrast during the Valsalva manoeuvre was performed in each patient.ResultsFrequency of the C677T variant in the MTHFR gene was similar in patients and controls. Hyperhomocysteinaemia was significantly more frequent in migraine patients with the C677T variant. The prevalence of PFO was significantly higher in migraine patients with aura and the homozygous variant of the MTHFR gene.ConclusionsFrequency of the C677T variant in the MTHFR gene was similar in patients and controls. Significantly more frequent prevalence of PFO in migraine patients with aura (with homozygous recessive genotype of MTHFR) probably suggests their common genetic basis. Hyperhomocysteinaemia was significantly more frequent in migraine patients with the C677T variant, which could be an additional risk factor of this disease.     

应用对比经颅多普勒技术评价偏头痛和卵圆孔未闭的关系

目的：观察门诊有先兆偏头痛（MA），无先兆偏头痛（M0）患者和无头痛人群中卵圆孔未闭（PFO）的发生率，以及产生中或大分流PFO的发生率。方法：经受试者同意后，随机抽取我院神经内科门诊从2006年3月至2007年3月就诊的MA患者38例（男14例，女24例），MO患者44例（男15例，女29例），无头痛对照24例（男10例，女14例）。以肘前静脉注射手振生理盐水作为造影剂，并结合Valsaval动作，行经颅多普勒（TCD）监测，诊断PFO并对分流量进行分级。结果：MA组与对照组比，具有PFO者占42％，高于对照组的20％；其中中分流或大分流者高于对照组，差异有统计学意义。MO组具有PFO者也高于对照组，但差异无统计学意义。结论：MA患者比无头痛人群存在较多的PFO，其巾出现中分流或大分流的显著增多。     

A single-fibre electromyography study of neuromuscular transmission in patients with cluster headache

Background and purposeMutations of CACNA1A, which encodes a neuronal P/Q Ca²⁺ channel, are present in patients with familial hemiplegic migraine, and possibly in other types of migraine as well. This calcium channel is also involved in neuromuscular transmission. In our previous study we confirmed that the single-fibre electromyography (SFEMG) method can demonstrate a neuromuscular transmission deficit in migraine with aura. The aim of our present study was to estimate the neurotransmitter dysfunction in cluster headache and to compare the results between patients with cluster headache and those with migraine with aura.Material and methodsWe selected 6 patients with cluster headache and 6 patients with migraine with typical aura. SFEMG of the voluntarily activated extensor digitorum communis muscle was performed.ResultsThe SFEMG results were in the normal range in the cluster headache group and in the healthy controls. Slight neuromuscular transmission disturbances were present in patients with migraine with aura.ConclusionsThe abnormal neuromuscular transmission detectable by SFEMG may reflect a genetically determined dysfunction of the P/Q Ca²⁺ channels in a group of migraineurs with aura. Conversely, absence of neuromuscular abnormalities in cluster headache patients could be explained by different aetiology not resulting in channelopathy. Single-fibre electromyography could be a helpful tool in clinically questionable cases in differentiating between cluster headache and migraine with aura.     

The prevalence of patent foramen ovale in patients with migraine

BACKGROUND AND PURPOSE: Migraine is a common neurologic disorder whose etiology remains unknown. Migraine has been reported as a possible risk factor for ischemic stroke, especially in young women. The relationship between migraine and stroke is stronger in patients suffering from migraine with aura compared to those with common migraine. Coexistence of migraine and patent foramen ovale (PFO) should be also considered. The aim of our study was to evaluate the frequency of PFO in patients with migraine with aura (MA) and compare it with the prevalence of PFO in migraine patients without aura (M) and in a healthy age-matched control group. MATERIAL AND METHODS: We assessed 62 patients (48 females) suffering from migraine with aura, 60 without aura (53 females) and 65 normal controls (51 females). In order to detect PFO the contrast transcranial Doppler was performed during Valsalva maneuver. RESULTS: The presence of PFO was found in 33/62 (53%) patients with MA compared to 15/60 (25%) without aura, and in 16/65 (25%) control subjects. The difference in PFO prevalence between MA patients and M patients and the difference between MA patients and the control group was statistically significant (p<0.05). CONCLUSIONS: Our findings suggest that at least some attacks of migraine with aura may be associated with paradoxical embolism.     

Evaluation of serum transforming growth factor β1 and C-reactive protein levels in migraine patients

Background and purposeMigraine is a frequent form of headache. Although many mechanisms describing onset of migraine with and without visual aura have been suggested, the aetiology of migraine headaches is still not clear. Neurogenic inflammation may play a key role in the development of migraine headaches. We evaluated the discriminative power of serum levels of C-reactive protein (CRP) and transforming growth factor beta 1 (TGF-β1) in patients who presented to our clinic with migraine headaches with or without visual aura.Material and methodsWe designed a prospective case-control study of 51 patients with migraine (27 with migraine with aura and 24 with migraine without aura; all had headache) and compared them with 27 healthy subjects during the study period. Demographic and clinical characteristics recorded were age, sex, marital status, occupation, characteristics of headache, laboratory values, and serum CRP and TGF-β1 levels. Statistical analyses used Student t-test, the χ² test, and ANOVA followed by the post-hoc Bonferroni test for multiple comparisons. Receiver operator characteristic (ROC)-curve analysis for CRP and TGF-β1 was also conducted.ResultsThere was no difference between the groups in terms of demographic characteristics, marital status, and socioeconomic status. Statistically, white blood cell levels, serum glucose levels, triglyceride levels, high-density lipoprotein levels, and serum CRP and TGF-β1 were significantly higher in patients with migraine (p < 0.05). The ROC curve results in this study identified that CRP and TGF-β1 may discriminate patients who have different types of migraine headache.ConclusionsThis study suggests that serum CRP and TGF-β1 levels may be diagnostic factors to differentiate migraine patients with and without aura. These findings show that neurogenic inflammation may have a role in the aetiology of migraines.     

Increased risk of migraine with typical aura in probands with familial hemiplegic migraine and their relatives

We investigated the occurrence of migraine without aura (MO) and migraine with typical aura (MA) amongst probands with familial hemiplegic migraine (FHM) and their first degree relatives in order to evaluate the relations between these syndromes. A total of 44 FHM probands and 240 first degree relatives were identified in the Danish population. The pattern of familial aggregation was assessed by population relative risk (PRR) calculations. Amongst FHM probands the PRR of MO was 1.5 (95% CI: 0.8-2.2), whereas the PRR of MA was 7.1 (95% CI: 5.0-9.2). Thus, compared with the general population, FHM probands had no increased risk of MO but a significantly increased risk of MA. A similar pattern was seen amongst their first degree relatives, who had no increased risk of MO, whereas the risk of MA was significantly increased; 7.6 times in FHM-affected first degree relatives and 2.4-times in non-FHM-affected first degree relatives. These results are contrary to a sharing of genetic mechanisms between FHM and MO. Furthermore, they suggest that the genetic abnormality causing FHM may also cause attacks with the symptomatology of MA.     

Potential source of cerebral embolism in migraine with aura: a transcranial Doppler study.

BACKGROUND: The recently found association between patent foramen ovale (PFO) and transient global amnesia (TGA) has suggested that paradoxical microembolization in the terminal vertebrobasilar territory might underlie at least some TGA cases. Migraine with visual aura is another paroxysmal disturbance in which a sudden dysfunction of cortical areas fed by the terminal branches of the basilar artery is believed to trigger the attack. Therefore we investigated the prevalence of PFO in a consecutive unselected cohort of migraine patients. OBJECTIVE: To investigate the prevalence of PFO in a consecutive unselected cohort of migraine patients to search for a possible mechanism for the reported association of migraine with stroke. METHODS AND RESULTS: A total of 113 patients, consecutively referred by the Headache Outpatient Clinic for migraine with aura (MA+, mean age 34+/-12 years) were compared with 53 patients with migraine without aura (MA-, mean age 36+/-13 years) and with 25 age-matched nonmigraine subjects (mean age 31+/-10 years) selected from the hospital staff. PFO was assessed with transcranial Doppler sonography with IV injection of agitated saline, a technique that is 90% sensitive and 100% specific. The prevalence of PFO was 48% (54/113) in MA+ patients, 23% (12/53) in MA- patients, and 20% (5/25) in control subjects. The difference between MA+ and MA- patients was significant (odds ratio [OR] = 3.13, 95% confidence interval [CI] = 1.41 to 7.04, chi2 = 9.52,p = 0.002) as was the difference between MA+ patients and controls (OR = 3.66, 95% CI = 1.21 to 13.25, chi2 = 6.46, p = 0.01), whereas MA- patients did not differ from controls (OR = 1.17, 95% CI = 0.32 to 4.45, chi2 = 0.07). MRI was negative in 22 MA+ and 8 MA- patients. CONCLUSIONS: Patency of the foramen ovale is associated with migraine with aura but not with migraine without aura. The increased risk of stroke found in epidemiologic studies in patients with migraine with aura may be explained by an increased propensity to paradoxical cerebral embolism.     

The genetics of migraine

Clinical, pathophysiological and genetic studies indicate that migraine without aura (MO) and migraine with aura (MA) are distinct entities. Compared with the general population, first degree relatives of probands with MO have a two-fold increased risk of MO. The mode of inheritance is most likely multifactorial inheritance without generational difference, but genetic heterogeneity can not be excluded. Compared with the general population, first degree relatives of probands with MA have a four-fold increased risk of MA. The mode of inheritance is most likely multifactorial inheritance without generational differences. Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of MA. A gene for FHM maps to chromosome 19. Some families with FHM do not link to this locus, indicating genetic heterogeneity of FHM. The gene for FHM is soon to be cloned. Loci for the more common types of migraine MO; and MA will problably be identified in the near future.     

Relation between migraine and stroke

A complex bidirectional relation between migraine, mostly migraine with aura (MA), and ischaemic stroke is known. A cerebral infarction can occur during a MA, and MA is a risk factor for ischaemic stroke, particularly in young women. Conversely, cerebral ischaemia can induce MA. Both ischaemic stroke and MA might be consequences of many underlying vascular disorders. Despite the relation between migraine and stroke, migraine as a primary headache disorder is mostly benign.     

Patent foramen ovale, a possible cause of symptomatic migraine: a study of 74 patients with acute ischemic stroke

Recent studies reported an increased prevalence of patent foramen ovale (PFO) in patients with migraine with aura (MA+). To investigate the possible relationship between MA+ and paradoxical embolism, we studied the prevalence of both conditions. Investigation of PFO was undertaken in 74 consecutive patients presenting with an acute stroke of undetermined origin. The patients were questioned about MA+ or migraine without aura (MA-) according to the criteria of the International Headache Society. Follow-up was performed to investigate the evolution of MA+ and MA- according to different treatments of stroke. PFO was found in 44 of 74 patients, 16 of whom had MA+ (36%), compared to 4 (13%) MA+ patients without PFO (p = 0.03). Of 25 patients in whom the PFO was considered to play a causal role in the stroke, 13 (52%) had MA+, whereas only 3 (16%) of 19 patients in whom PFO was considered unrelated had MA+ (p = 0.014). Thirty-nine of the patients with MA+ and MA- were studied over a mean follow-up of 13 months. Seven of 15 patients with MA+ and PFO, treated either with surgical closure or anticoagulants, noticed complete disappearance of MA+ attacks. The prevalence of MA+ is high among stroke patients with PFO. In patients with a high presumption of paradoxical embolism, the proportion of MA+ is increased, and this suggests a possible role of this association in the occurrence of the cerebrovascular event. Forty-seven percent of patients with PFO and MA+ reported complete suppression of their aura attacks after surgical closure or anticoagulant treatment. This finding suggests that at least in some patients, MA+ attacks may be due to paradoxical embolism.     

Migraine with Visual aura and the Risk of Stroke- a Narrative Review

ObjectivesPatients with migraine with visual aura (MwvA) often present to eye care providers for evaluation. A thorough ophthalmological history and examination is needed to exclude ophthalmologic disorders. Additionally, it has been increasingly recognized that MwvA is associated with ischemic stroke (IS). The aim of this narrative review is to provide a comprehensive overview of the differential diagnosis of MwvA and its association with IS.Materials and methodsWe conducted a PubMed search using key words including “migraine aura”, “visual aura without headache”, “late onset migraine accompaniment”, “migraine and stroke”, “migraine and atrial fibrillation”, and “migraine and patent foramen ovale (PFO)”. We narratively summarized the main findings of the identified studies in sections including age of onset and frequency of migraine with aura, stroke subtypes, and the role of cardioembolism in the migraine-stroke association.Results and ConclusionFor women younger than 50 years, MwvA is associated with an increased risk of IS, and the risk further increases in patients who also smoke and use oral contraceptives. Age of onset of MwvA 50 years or greater is associated with IS that occurs in late life. Studies reported that increased frequency of aura is associated with an increased risk of IS in women. MwvA is associated with an increased risk of cardioembolic stroke and a higher incidence of atrial fibrillation compared to migraine without aura. Most studies that assessed the migraine-stroke association were based on patients with MwvA. The risks of stroke associated with other types of migraine aura or aura without headache, as well as such association in men require further investigation. More data is needed to determine the absolute risk of stroke when evaluating MwvA in situations including smoking and low dose estrogen use, new or late onset (>50 years) MwvA, to facilitate the development of practice guidelines for stroke prevention in specific clinical scenarios.     

Predictors of Triptan Response in Pediatric Migraine

BackgroundMigraine is common in children and adolescents and can be disabling. Being able to predict which patients will respond to triptans based on their clinical phenotype would be helpful. Adult data suggest cranial autonomic symptoms and aura predict triptan response. This study examined clinical predictors of triptan response in pediatric migraineurs.MethodsThis chart review study included all patients less than 18 years old with migraine who were seen at the University of California, San Francisco Headache Center in 2014. Univariate χ² analyses were performed, followed by multivariate logistic regression modeling.ResultsOf 127 pediatric migraineurs, 70 (55%) had chronic migraine and 24 (19%) had aura. The majority (55%) had at least one cranial autonomic symptom. Of 65 with triptan outcome data, 47 (73%) benefitted from a triptan. In univariate analyses, triptan benefit was seen in 65% with chronic migraine versus 88% with episodic migraine (P = 0.048), 67% with aura versus 74% without (P = 0.66), and 70% with cranial autonomic symptom versus 74% without (P = 0.76). In a multivariate logistic regression model, chronic migraine, aura, and cranial autonomic symptom were not statistically significant predictors of triptan benefit: chronic migraine: 0.25 (0.06-1.04); aura: 0.65 (0.09-4.45); cranial autonomic symptom: 0.75 (0.22-2.52).ConclusionsIn univariate analysis, individuals with chronic migraine were less likely to benefit from triptans. In contrast to what has been documented in adults, cranial autonomic symptoms and aura did not predict triptan response, although our small sample size limited the study's power. Larger pediatric studies are needed, and future pediatric triptan trials should provide response rates stratified by clinical variables such as aura.     

New international classification of migraine with aura (ICHD-2) applied to 362 migraine patients

The International Classification of Headache Disorders 2nd edition (ICHD-2) subdivides migraine with aura (MA) differently from the ICHD-1 and includes new diagnostic criteria. The aim of the present study was to evaluate how the new classification works in practice and in comparison with the ICHD-1. The patients were recruited from a screen of the Danish National Patient Registry and from Danish neurologists. We included 362 patients diagnosed with MA according to the ICHD-1 in a validated semistructured physician-conducted interview. According to the ICHD-2, 89% (322 of 362) had MA and 11% (40 of 362) had probable MA. The MA patients had one or more ICHD-2 subtype of MA: 54% (173 of 322) had typical aura with migraine headache (MA-MH), 40% (129 of 322) had typical aura with non-migraine headache (MA-NMH), 37% (120 of 322) had aura without headache (MA-WOH), and 7% (26 of 322) had basilar-type migraine (MA-B). Of patients with MA-MH 34% (59 of 173) had co-occurrence of MA-WOH, 9% (16 of 173) had co-occurrence of MA-B and 5% (8 of 173) had co-occurrence of both MA-WOH and MA-B. Of patients with MA-NMH 27% (35 of 129) had co-occurrence of MA-WOH. Only 6% (18 of 322) of the MA patients had exclusively MA-WOH and <1% (2 of 322) had exclusively MA-B. Patients with MA-MH had an earlier age at onset (P = 0.044), an increased lifetime number of MA attacks (P = 0.054) and a higher co-occurrence of migraine without aura (P = 0.002) than patients with MA-NMH. Patients with MA-B tended to have an earlier age at onset and more severe attacks and patients with MA-WOH had a higher age at onset and less severe attacks than patients with MA-MH. The variations between ICHD-2 subtypes of MA indicate that patients with similar subtype of MA share phenotype and very likely have similar underlying aetiology.     

Is ocular vascularity affected in young migraine patients? A pilot study

ObjectiveThis study aimed to evaluate ocular vascularity in young adult migraine patients with visual aura and without visual aura.Material and MethodsThe study included 30 patients with migraine with visual aura (MWVA), 30 patients with migraine without visual aura (MWOVA), and 30 healthy control subjects, all between ages ≥18 and <45. Migraine patients were applied Headache Impact Test (HIT) and Migraine Disability Assessment Scale (MIDAS). Retinal nerve fiber layer thickness and ocular vascularity of all participants were evaluated with optical coherence tomography (OCT) and OCT angiography (OCTA).ResultsThe MWVA group had significantly lower superficial and deep foveal vascular density values compared to the control group (p = 0.039, p = 0.028, respectively). The foveal avascular zone was significantly enlarged in the MWVA group compared to the control group (p = 0.033). MWVA patients had significantly lower whole optic disc, optic disc inside, peripapillary, superior hemisphere, inferior hemisphere, superior quadrant, and temporal quadrant vascular density values compared to the control group (p < 0.05 all), while there was no significant difference in the nasal quadrant (p = 0.083). Migraine attack frequency, MIDAS, and HIT were negatively correlated with ocular vascular density values.ConclusionThe results of our study indicate that young adult patients with MWVA are at risk of decreased ocular vascularity and that this risk may increase with frequency and severity of migraine attacks.     

Anger and impulsiveness in migraine patients with and without aura

ABSTRACT

Background and purpose: Migraine is a common primary headache disorder triggered by internal or external stimuli. Impulsitivity and anger are associated with many neurological and psychiatric disorders. The aim of this study was to investigate the anger and impulsivity in migraine patients with or without aura.

Methods: A total of 55 patients aged between 18 and 55, who were diagnosed with episodic migraine (31 with aura and 24 without aura) and 40 healthy controls were enrolled in this prospective cross-sectional study.

Migraine diagnosis and classification were based on criteria from the International Classification of Headache Disorders, 3rd edition (beta version). Multidimensional Anger Scale and Barratt Impulsivity Scale-11 were administered to the patient and control groups.

Results:Migraine patients with aura, migraine patients without aura and control groups were compared, anger symptoms were significantly higher in migraine patients with aura (p < 0.001), but between these groups there was no significant difference in terms of impulsivity (p = 0.711).

Conclusions: It was found that anger symptoms were more common in migraine patients with aura compared to migraine patients without aura and control group, but in impulsitivity there was no difference between groups.

Further studies in future investigating the relation between migraine with aura and anger may pave the way for different and more specified treatment approach.     

Patent foramen ovale and migraine

Recent epidemiological data suggest a bidirectional link between patent foramen ovale (PFO) and migraine with aura (MA) with a relative risk of 2 for PFO in subjects with MA and for MA in subjects with PFO. There is no evidence for a link between PFO and migraine without aura. This link is not systematic and applies only to subsets of PFO, mostly large ones, and to subsets of patients with MA. Although comorbidity cannot be ruled out, it may be that this link is partly causal and that some large PFOs may favor MA attacks in genetically predisposed subjects, by allowing vasoactive substances, platelet emboli or paradoxical emboli to bypass the lung filter and trigger the cortical spreading depression of the aura. The first double blind randomised trial of PFO closure in refractory MA, "MIST", has failed to show a benefit on the primary efficacy end point: cessation of attacks during the analysis period included between 3 and 6 months after the procedure. There is thus at present no scientific reason to look for PFO or to close PFO in migraine patients.     

Udar kryptogenny – drożny otwór owalny – migrena z aurą: przypadkowa triada czy związek przyczynowo-skutkowy? Część I

In the first part of the paper we discuss the association between patent foramen ovale (PFO) and cryptogenic stroke. Patent foramen ovale is a remnant of the fetal circulation, found in about quarter of the general population. According to many authors, this common anatomical anomaly is of no or limited clinical significance. However, the results of some clinical studies suggest higher prevalence of PFO among subjects with either cryptogenic stroke or migraine with aura. To date, the answer to the question whether PFO is an independent risk factor for stroke remains equivocal. The purpose of this review is to discuss the role of PFO in pathophysiology of both symptomatic and asymptomatic ischaemic lesions and to analyze the coexisting factors that increase the risk of stroke. We also discuss the effectiveness of either pharmacological treatment or PFO closure in secondary stroke prevention.     

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.     

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.