Right-to-left shunt and migraine: the strength of the relationship

Several studies have shown that the prevalence of a cardial right-to-left shunt (RLS) in patients with migraine with aura is significantly higher than in patients without migraine. To assess the strength of the possible relationship between RLS and migraine, the literature concerning this subject was systematically reviewed. We identified seven relevant studies. Among patients with RLS migraine with aura was 3.5 times more prevalent than among subjects without RLS [Mantel-Haenszel odds ratio (ORMH) 3.5; 95% confidence interval (CI) 2.1, 5.8]. In patients with ischaemic stroke migraine was more than two times more prevalent in patients with RLS than in patients without RLS (ORMH 2.1; 95% CI 1.6, 2.9). Our review shows that there is a clear association between RLS and migraine, especially migraine with aura. The relationship between RLS and migraine is further substantiated by the observations of disappearance and improvement of migraine symptoms after closure of the foramen ovale. However, the mechanism as well as the question about causality of this association has to be further elucidated.     

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.     

Migraine and tension-type headache in Croatia: a population-based survey of precipitating factors

The careful monitoring of the trigger factors of headache could be an important step in treatment, because their avoidance may lessen the frequency and severity of attacks. Furthermore, they may provide a clue to the aetiology of headache. The aim of the present study was to estimate the prevalence of tension-type headache (TTH) and to establish the frequency of precipitating factors in subjects with migraine and TTH in the adult population of Bakar, County of the Coast and Gorski Kotar, Croatia. Another important purpose of the study was to examine the relationship of the precipitating factors with migraine and TTH, and with migraine subtypes: migraine with aura (MA) and migraine without aura (MO). We performed a population-based survey using a 'face-to-face door-to-door' interview method. The surveyed population consisted of 5173 residents aged between 15 and 65 years. The 3794 participants (73.3%) were screened for headache history according to the International Headache Society (IHS) criteria. Headache screen-positive responders, 2475 (65.2%), were interviewed by trained medical students with a structured detailed interview focused on the precipitating factors. The following precipitating factors in lifetime migraineurs and tension-type headachers have been assessed: stress, sleep disturbances, eating habits, menstrual cycle, oral contraceptives, food items, afferent stimulation, changes in weather conditions and temperature, frequent travelling and physical activity. A total of 720 lifetime migraineurs and 1319 tension-type headachers have been identified. The most common precipitants for both migraine and TTH were stress and frequent travelling. Stress (odds ratio (OR) 1.4, 95% confidence interval (CI) 1.17, 1.69) was associated with migraine, whereas physical activity (OR 0.72, 95% CI 0.59, 0.87) was related to TTH. Considering MA and MO, frequent travelling (OR 2.2, 95% CI 1.59, 2.99), food items (OR 2.2, 95% CI 1.35, 3.51) and changes in weather conditions and temperature (OR 1.75, 95% CI 1.27, 2.41) exhibited a significant positive association with MA. The present study demonstrated that precipitant-dependent attacks are frequent among both migraineurs and tension-type headachers. Lifetime migraineurs experienced headache attacks preceded by triggering factors more frequently than tension-type headachers. MA was more frequently associated with precipitating factors than MO. We suggest that some triggering factors may contribute to the higher occurrence of precipitant-dependent headache attacks in susceptible individuals.     

Comorbidity in Finnish migraine families

The objective of the study was to investigate comorbidity of migraine in Finnish migraine families. One thousand consecutive participants in the Finnish Migraine Gene Project reported their medical illnesses in addition to migraine and headache. Migraine patients (n=678) reported significantly more hypotension (OR 1.43, CI 95% 1.02–2.01), allergy (OR 1.83, CI 95% 1.34–2.51) and psychiatric disorders (OR 4.09, CI 95% 2.11–7.92) compared to their family members without migraine (n=322). Subgroup analyses demonstrated that especially women and the group fulfilling the criteria for both migraine with and without aura were likely to have additional disorders besides their migraine. Interestingly, male migraineurs with aura reported a significant association with stroke and epilepsy. Familial migraine is comorbid with hypotension, allergy and psychiatric disorders. The association between migraine with aura and stroke and epilepsy among men of the studied families warrants further study. Clinical, pathophysiological and genetic implications of these results are discussed.     

Pain perception and laser evoked potentials during menstrual cycle in migraine

The association between estrogens “withdrawal” and attacks of migraine without aura is well-known. The aim of the study was to examine the features of laser evoked potentials (LEPs), including habituation, in women suffering from migraine without aura versus healthy controls, during the pre-menstrual and late luteal phases. Nine migraine without aura and 10 non-migraine healthy women, were evaluated during the pre-menstrual phase and late luteal phase. The LEPs were recorded during the inter-critical phase. The right supraorbital zone and the dorsum of the right hand were stimulated. Three consecutive series of 20 laser stimuli were obtained for each stimulation site. Laser pain perception was rated by a 0–100 VAS after each stimulation series. Migraine patients exhibited increased LEPs amplitude and reduced habituation compared to normal subjects. Laser-pain perception was increased during the pre-menstrual phase in both patients and controls. Migraine patients and controls showed increased P2 and N2–P2 amplitude in the pre-menstrual phase, on both stimulation sites. During the pre-menstrual phase the N2–P2 habituation appeared to be reduced in both migraine and healthy women. The estrogen withdrawal occurring during the menstrual cycle may favor reduced habituation of nociceptive cortex, which may facilitate pain symptoms and migraine in predisposed women.     

Prevalence of patent foramen ovale in a large series of patients with migraine with aura, migraine without aura and cluster headache, and relationship with clinical phenotype

A relationship between migraine and patent foramen ovale (PFO) has been observed in relatively small series of patients so far. Furthermore, the exact mechanism underlying such an association remains unknown. In the present study we determined the prevalence of PFO by contrast–enhanced transcranial Doppler (TCD) in a group of 260 patients with migraine with aura (MA+), 74 patients with migraine without aura (MA–), and 38 patients with cluster headache (CH). One–hundred–sixty–one MA+subjects (61.9%), 12 MA–subjects (16.2%), and 14 CH–subjects (36.8%) were PFO–carriers. The association was independent on the frequency of migraine attacks and complexity of aura. Finally, among the 15 patients who had a history of at least one migraine attack occurring during a Valsalva maneuver only one subject turned out to be PFO–carrier. Our findings confirm previous observations of a link between MA+, CH, and PFO. They also suggest that such an association is independent on migraine clinical phenotype and is probably unrelated to the pathogenic mechanism of paradoxical embolism.     

Migraineurs with patent foramen ovale have larger right-to-left shunt despite similar atrial septal characteristics

The objective of the study was to assess differences in proportion of large right-to-left shunt (RLS) and atrial septal characteristics between migraineurs and non-migraineurs referred for transcatheter closure of patent foramen ovale (PF0). This retrospective study took place in a large metropolitan medical centre. The patients were migraineurs with aura (n=52), migraineurs without aura (n=19) and non-migraineurs (n=149). RLS was evaluated before closure using bilateral power m-mode transcranial Doppler at rest and after calibrated, sustained Valsalva manoeuvre, and graded with a validated 0–5 scale. Intracardiac echocardiography was used to assess atrial septal characteristics. Migraineurs had a higher proportion of large RLS (Grade IV or V) than nonmigraineurs at rest and after calibrated Valsalva (rest, p=0.04; Valsalva, p=0.01). Atrial septal characteristics were similar between groups. Migraine is associated with larger RLS at rest and strain; however migraine status does not predict PFO characteristics.     

Sex-hormone-related events in migrainous females. A clinical comparative study between migraine with aura and migraine without aura

In this study, the relationship between hormonal-related events and migraine with aura (MA) and without aura (MO) was investigated. Subjects included 268 women suffering from MA (88) and MO (180). Data were collected on the relationship between sex-hormone-related events and migraine. Migraine during menses was observed in a significantly higher percentage of MO than MA patients ( p < 0.03). Menstrual migraine was significantly more common in MO than in MA patients ( p < 0.01). Migraine began during pregnancy in a significantly higher percentage of MA than of MO patients ( p < 0.01). No significant difference was observed between the two groups of patients regarding the onset of migraine at menarche, after menopause, in the postpartum period or during the early cycles of oral contraceptives. Also, both groups of patients showed a similar migraine course during pregnancy, oral contraceptive use and menopause. Eight patients with coexisting migraine with aura and migraine without aura attacks reported the appearance of the aura symptom for the first time in the early cycles of oral contraceptive intake. These findings suggest that gonadal hormone fluctuation may influence both types of migraine.     

Migraine aura without headache compared to migraine with aura in patients with affective disorders

The characteristics of psychiatric comorbidity in migraine have been studied in migraine with aura (MA) and migraine without aura (MO). Little information is available concerning patients with migraine aura without headache. In a study of 201 patients with major affective disorders (DSM–IV) we have described the clinical characteristics of patients with these three sub–types of migraine (IHS criteria) and compared the MA and migraine aura without headache groups. Compared to patients having MA (n=57), the group with migraine aura without headache (n=18) had a higher age of onset of migraine (28.5 vs. 19.2, p=0.001), significantly lower prevalences of affective temperaments (28% vs. 56%, p=0.036), suicide attempts (17% vs. 53%, p=0.013) and Raynaud’s syndrome (0% vs. 25%, p=0.017). These results indicate that there seem to be differences in the clinical characteristics found in patients with migraine with aura when compared to those having the migraine subtype without a headache phase. This may convey new information concerning the comorbid expression of migraine and affective disorders or concerning the processes that differentiates the migraine types with and without a subsequent pain attack.     

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.     

High prevalence of patent foramen ovale in migraine with aura

In this study we evaluated the presence of patent foramen ovale (PFO) in a cohort of 25 consecutive patients suffering from migraine with aura (MA) during an attack presenting to the emergency ward of an Italian hospital. Patients underwent brain magnetic resonance imaging (MRI) with contrast medium, routine coagulation tests, contrast transcranial echocolour–coded sonography (c–TCCS) and transoesophageal echocardiography (TEE). Of the enrolled patients, 88.7% showed a PFO according to the c–TCCS test, whereas only in 72% TEE confirmed the presence of PFO. This discordance could be due to the fact that c–TCCS is more sensitive even with shunts with minimal capacity also located in the pulmonary vasculature. After surgical treatment of the PFO, MA disappeared within two months. Also, the treatment with warfarin as well as with acetylsalicylic acid and flunarizine was able to dramatically reduce the frequency of migraine attacks. These data indicate a higher prevalence of PFO in MA vs. normal population (OR=2.92) and could suggest that the presence of arteriovenous (AV) shunts could represent a trigger for MA attacks as well as for stroke, but more studies are needed to confirm this preliminary hypothesis.     

Glyceryl trinitrate triggers premonitory symptoms in migraineurs

Studying attacks of migraine is considerably hampered by its fundamentally episodic nature. Developing approaches to triggering migraine reliably is important for advancing understanding of the disorder by facilitating its study. Based on the work of the Copenhagen Group we administered an intravenous infusion of 0.5 μg/kg/min glyceryl trinitrate (GTN) to 44 migraineurs, 23 migraine without aura, 21 migraine with aura, and to 12 healthy controls. We sought to characterise the GTN-induced migraine in terms of the clinical features of the attacks and reproducibility of triggering, and included a non-migraine control group for the purpose of comparing any effects to exclude an ordering effect. Of the 44 patients administered GTN, 33 had a migraine attack fulfilling International Headache Society criteria. Thirty-two attacks were of migraine without aura and one of migraine with aura. Twelve patients described typical premonitory symptoms, which have not been previously documented with GTN-induced migraine. A repeat attack was triggered in all subjects but one. In one case a visual aura was also triggered both times. Our study shows that GTN-induced triggering is common in our patients, and remarkably reproducible. The data will facilitate the use of the GTN model in studies requiring extensive planning, such as brain imaging, or where preventive questions are at issue. We also report the first patient with a reproducible GTN-triggered migraine with aura.     

Migraine with aura and reproductive life events: a case control study

The course of migraine without aura (MO) is greatly influenced by the events of female reproductive life. Much less is known about migraine with aura (MA). The aim of this study was to evaluate the relationship between MA and the milestones of reproductive life. A retrospective case control study was carried out on 100 women affected by migraine with typical aura (cases) and 200 age-matched women with MO (controls). Premenstrual syndrome was found to be much more common among the patients with MA (odds ratio (OR) 6.0; confidence interval (CI) 3.1-11.6). Menstrually triggered migraine was more frequently encountered among MO than among MA patients (MA 15.0%; MO 53.5%; OR 0.1; CI 0.1-0.3). In both forms of migraine, pregnancy had a favourable effect; however, a lower percentage of MA (43.6%) than MO patients (76.8%; OR 0.2; CI 0.1-0.5) showed improvement or remission. The use of oral contraceptives worsened migraine in MA more frequently than in MO patients (MA 56.4%; MO 25.3%; OR 3.8; CI 1.6-9.3). The course of MA seems to be influenced by female reproductive life events, but in a different way with respect to MO.     

Pattern reversal visual evoked potentials in migraine with aura and migraine aura without headache

Pattern reversal visual evoked potentials (PVEPs) were recorded in 20 patients with migraine with aura (MA), 19 patients with migraine without headache (migraine equivalent; ME.) during interictal periods, and 34 normal subjects. All migraine patients had hemianopsia or fortification spectra during attacks. In both MA and ME patients of less than 49 years of age, there were significant ( p <0.01) differences in amplitude of PVEPs at the mid-occipital and contralateral to visual aura electrode sites compared to normal subjects. Amplitude of PVEPs in MA and ME showed significant ( p <0.001) increases when recorded soon after attacks, especially within 10 days. There was a significant ( p <0.0l) correlation between percentage asymmetries and the duration of illness in both MA and ME. We conclude from our PVEP findings that cortical spreading depression remains the most likely explanation for the migraine visual aura.     

Prognosis of migraine with aura

The present study is a 16-year follow-up study assessing the long-term outcome of migraine with aura (MA). Additionally possible predictive factors in the prognosis of MA were evaluated. Patients were recruited from the files of Danish headache clinics. A total of 53 patients (11M:42F) with MA (IHS criteria) participated in a follow-up interview. At follow-up attacks had ceased (no MA for 2 years) in 36% of patients. Attacks had ceased in 55% of males and 31% of females (P = 0.17). Attacks had ceased in 41% of patients with visual aura without other aura symptoms and in 25% of those with sensory or aphasic aura besides their visual aura (P = 0.36). Among those with attacks of MA at follow-up frequency of attacks and headache intensity was improved in 44% and 41% of the patients, respectively. The results point to a favourable evolution of MA and suggest possible predictive factors.     

Migraine exacerbation during Ramadan fasting

Fasting for approximately 1 month is an obligatory practice for Muslims during the month of Ramadan. We attempted to evaluate the effect of the Ramadan fasting on the frequency of migraine attacks among observant Muslim migraine sufferers using a cohort cross-over study. Thirty-two observant Muslim migraine sufferers filled a migraine diary during the Ramadan month and the following month (control). Two patients failed to complete the fast because of migraine suffering. During the Ramadan month, the patient expressed 9.4 ± 4.3 migraine days in average (range 3–20) when compared with 3.7 ± 2.1 migraine days in average (range 1–10) during the control month (p < 0.001). This phenomenon was associated with longer duration of migraine, lower frequency of migraine attacks, and migraine with aura. It seemed to be less pronounced in patients experiencing throbbing headaches and in married patients. Previous prophylactic therapy did not dampen this. Physicians treating Muslim migraine patients should discuss potential Ramadan month exacerbation with their patients and provide counseling regarding the prevention of dehydration and caffeine withdrawal. Pharmacological prophylactic treatment should be considered.     

Differences in short-term primary motor cortex synaptic potentiation as assessed by repetitive transcranial magnetic stimulation in migraine patients with and without aura

To find out more about glutamatergic and gabaergic transmission in migraine, in this study we investigated glutamate-dependent short-term synaptic potentiation and GABA-dependent inhibitory cortical interneuron excitability as assessed by 5 Hz-rTMS delivered over primary motor cortex (M1) (motor evoked potential, MEP, amplitude facilitation and cortical silent period, CSP, duration lengthening) in migraine patients with (MA) and without aura (MwoA) and healthy controls. We studied 37 patients with migraine (19 MA and 18 MwoA) and 19 healthy control subjects. 5 Hz-rTMS was delivered at 120% resting motor threshold to the hand motor area of the left hemisphere with the target muscle at rest and during contraction. Three of the MA patients were also tested at the end of visual aura during a spontaneous migraine attack. ANOVA showed that the MEP significantly increased in size and CSP significantly lengthened during 5 Hz-rTMS in the three groups tested. The 5 Hz-rTMS-induced MEP facilitation differed significantly being highest in MA patients. In the three patients tested both ictally and interictally the MEP increased during the interictal session but remained unchanged when the visual aura ended. Our study shows that the neurophysiological feature that differentiates MA patients from MwoA patients and healthy controls is an abnormal M1 susceptibility to 5 Hz-rTMS both outside and during the attack suggesting that glutamate-dependent short-term M1 cortical potentiation patterns differ in migraine with and without aura.     

Relationship between migraine and patent foramen ovale: a study of 121 patients with migraine

BACKGROUND: Migraine is a common neurological disorder, the origins of which remain unknown. Patent foramen ovale (PFO) is considered to have a role in migraine. The relationship between migraine and patent foramen ovale may be stronger in patients suffering from migraine with aura compared to patients with common migraine. OBJECTIVES: The aim of the 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 (MA-), and in a healthy age-matched control group. We investigated PFO association with migraine, considering such factors as: A type of migraine aura, frequency of attacks, familial occurrence, sex and age of patients. Patients.-121 patients: 61 patients suffering from migraine with aura, 60 without aura and 65 normal controls. The group of patients with migraine with aura was divided into subgroups regarding to the type of aura. METHODS: In order to detect PFO the contrast transcranial Doppler was performed during Valsalva maneuver. RESULTS: The presence of PFO was found in 33/61 (54%) patients with MA(+) compared to 15/60 (25%) without aura and 16/65 (25%) control subjects. The difference between MA(+) patients and MA(-) patients and the difference between MA(+) patients and control group was statistically significant (P < .05). There was no association between type of migraine aura and PFO, as well as we found no association between PFO and frequency of attacks, familial occurrence, sex and age of patients and PFO. CONCLUSIONS: Our findings suggest possible association of migraine with aura and PFO. It seems that PFO does not influence the type of aura and frequency of attacks of migraine as well as it is not associated with familial occurrence of migraine.     

Osmophobia in primary headaches

This study evaluates osmophobia (defined as an unpleasant perception, during a headache attack, of odours that are non–aversive or even pleasurable outside the attacks) in connection with the diagnosis of primary headaches. We recruited 775 patients from our Headache Centre (566 females, 209 males; age 38±12 years), of whom 477 were migraineurs without aura (MO), 92 with aura (MA), 135 had episodic tension–type headache (ETTH), 44 episodic cluster headache (ECH), 2 chronic paroxysmal hemicrania (CPH) and 25 other primary headaches (OPHs: 12 primary stabbing headaches, 2 primary cough headaches, 3 primary exertional headaches, 2 primary headaches associated with sexual activity, 3 hypnic headaches, 2 primary thunderclap headaches and 1 hemicrania continua). Among them, 43% with MO (205/477), 39% with MA (36/92), and 7% with CH (3/44) reported osmophobia during the attacks; none of the 135 ETTH and 25 OPH patients suffered this symptom. We conclude that osmophobia is a very specific marker to discriminate adequately between migraine (MO and MA) and ETTH; moreover, from this limited series it seems to be a good discriminant also for OPHs, and for CH patients not sharing neurovegetative symptoms with migraine. Therefore, osmophobia should be considered a good candidate as a new criterion for the diagnosis of migraine.