Treating migraine with contraceptives

At least 18% of women suffers from migraine. Clinically, there are two main forms of migraine: migraine with aura (MA) and migraine without aura (MO) and more than 50% of MO is strongly correlated to the menstrual cycle. The high prevalence of migraine in females, its correlation with the menstrual cycle and with the use of combined hormonal contraceptives (CHCs) suggest that the estrogen drop is implicated in the pathogenesis of the attacks. Although CHCs may trigger or worsen migraine, their correct use may even prevent or reduce some forms of migraine, like estrogen withdrawal headache. Evidence suggested that stable estrogen levels have a positive effect, minimising or eliminating the estrogenic drop. Several contraceptive strategies may act in this way: extended-cycle CHCs, CHCs with shortened hormone-free interval (HFI), progestogen-only contraceptives, CHCs containing new generation estrogens and estrogen supplementation during the HFI.     

Circannual periodicity of migraine?

Seasonal rhythm of migraine attacks may support a role of the suprachiasmatic nucleus of the hypothalamus in the pathophysiology of migraine. The objective of this study was to provide evidence for seasonal variation in migraine. Eighty-nine female migraineurs volunteered to record every migraine attack in detail for 12 consecutive months. Attacks associated with sleep complaints were defined as insomnia-related. By using Edwards' model for recognition and estimation of cyclic trends, time-series analysis was made. Fifty-eight patients, of which 26 had migraine without aura (MO) and 32 had migraine with aura (MA), completed the study. A total of 1840 attacks were recorded. The mean age ± SD was 36.9 ± 6.0. Patients with a lifetime history of MA showed marked seasonal fluctuation with more attacks in the light season compared to the dark. Time of peak was May 21. Peak/low ratio was 1.30 (95% CI: 1.08–1.55). When insomnia-related attacks ( n  = 312) were removed the seasonal variation became insignificant. There is a seasonal trend with more migraine attacks in the light season compared to the dark season in females with MA, but not MO, living in an arctic area. This is caused by the seasonal variation of insomnia-related attacks in patients with MA.     

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.     

Validation of the deCODE Migraine Questionnaire (DMQ3) for use in genetic studies

We assessed the reliability of the diagnosis of migraine with aura (MA) and migraine without aura (MO) based on the third edition of the deCODE Migraine Questionnaire (DMQ3) using a physician-conducted interview as an empirical index of validity. Amongst Danish migraine families recruited from specialist practice we selected 200 cases diagnosed according to the International Classification of Headache Disorders 2nd Edition in a validated physician-conducted telephone interview: 50 patients with exclusively MA, 50 with both MA and MO, 50 with exclusively MO and 50 controls. A written copy of the DMQ3 was mailed to the participant. The DMQ3-based diagnosis was compared with the interview-based diagnosis. Overall, the DMQ3 diagnosed migraine (MA, MO or both) with a sensitivity of 99% (109/110), a specificity of 86% (32/37) and a kappa statistic of 0.89. The most reliable subtype of migraine was MA (with or without co-occurring attacks of MO) which was diagnosed with a sensitivity of 92% (71/77), a specificity of 93% (65/70) and a kappa statistic of 0.85. Exclusively MO was diagnosed with a sensitivity of 91% (30/33), a specificity of 93% (106/114) and a kappa statistic of 0.80. Weakest was the diagnosis of both MO and MA which was diagnosed with a sensitivity of 63% (24/38), a specificity of 92% (100/109) and a kappa statistic of 0.57. In conclusion, the DMQ3 is a valid tool for diagnosing patients with migraine for genetic studies.     

Abnormal visual processing in migraine with aura: a study of steady-state visual evoked potentials

BACKGROUND: Although a number of studies reported different interictal findings between migraine with aura (MA) and migraine without aura (MO), the pathophysiology of the visual aura in migraine remains unclear. OBJECTIVE: To investigate the visual processing in patients who experience MA between attacks using steady-state visual evoked potentials (SSVEPs). METHODS: SSVEPs to high (98%) and low (29%) contrast black and white checkerboard gratings with two spatial frequencies (0.5 and 2.0 cpd) at 5 and 10 Hz (10 and 20 reversal/s) were recorded binocularly from 10 patients with MA, 10 patients with MO between attacks and 20 healthy controls (HC). The SSVEPs were Fourier analyzed to obtain the amplitude and phase of the second (2F) and fourth (4F) harmonic response. RESULTS: In the amplitude of 2F, at 0.5 cpd, there was significant increased amplitude in both MA and MO in comparison to HC at 5 Hz in high and low contrast. However, no significant differences were detected at 2.0 cpd in both 5 and 10 Hz in high and low contrast. In the amplitude of 4F, at 2.0 cpd, there was significant increased amplitude in MA in comparison to MO and HC at 10 Hz in high contrast. However, there were no significant differences at 0.5 cpd at both 5 and 10 Hz in high and low contrast. There were no significant phase differences between MA, MO, and HC. CONCLUSION: The high amplitude of the SSVEPs suggests that interictally migraine patients have abnormal excitability in the primary visual cortex, and this change in excitability may exist, at least partially, in the visual association cortex in MA.     

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.     

Pyridoxine,folate and cobalamin for migraine: A systematic review

There is a possible relationship between migraine and hypercoagulability inducing factors, such as hyperhomocysteinemia. In this context, homocysteine (Hcy)-lowering vitamins (B6-folate-B12) may prove beneficial in the management—prophylaxis of migraine. We performed a systematic literature search in order to retrieve studies assessing the supplementation of B6, folate and B12 (alone or as adjunctive therapies) to migraine patients, as well as patients suffering from other primary headache disorders. MEDLINE, EMBASE, CENTRAL, Google Scholar, trial registries and OpenGrey were searched. Twelve relevant articles were retrieved. The management of acute migraine attacks with Hcy-lowering vitamins has not provided promising results (one randomized controlled trial—RCT—and one prospective uncontrolled trial). On the contrary, significant benefits were registered for the use of B6 alone, in combination with folate and in combination with folate and B12 in the prophylaxis of migraine with aura (MA) in adults compared to placebo (five RCTs, only one did not obtain significant results). Folate supplementation alone was not more efficacious than placebo (one RCT). Limited data for the prophylaxis of migraine without aura (MO) in children (two prospective uncontrolled trials) and adults (two prospective uncontrolled trials involving both MA and MO participants) impede the extraction of safe conclusions. An overall attractive safety profile was exhibited with gastrointestinal adverse events being the most common. Overall, a potential beneficial effect regarding the administration of B6, folate and/or B12 in the prophylaxis of MA in adults was indicated. Additional high-quality RCTs that will investigate MO in adults as well as MO and MA in children are warranted.     

Investigation of an LDLR gene polymorphism (19p13.2) in susceptibility to migraine without aura

We performed a genetic association study with the LDL receptor gene (LDLR) on chromosome 19p13.2 in 360 migraine patients, 220 with migraine without aura (MO) and 140 with migraine with aura (MA), and 200 controls, by analysing two polymorphic markers, a G142A transition in exon 10 and a triallelic (TA)n repeat in exon 18. The allelic distribution of the (TA)n polymorphism was significantly different between migraine without aura (MO) and both controls and migraine with aura (MA). We suggest a possible predisposition to MO in the studied population through this polymorphism or another polymorphism in linkage disequilibrium with (TA)n.     

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.     

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.     

Auditory cognitive event-related potentials in migraine with and without aura in children and adolescents

BACKGROUND AND PURPOSE: Cognitive Event-Related Potentials (CERP) reflect sensory information processing: cognitive function and early memory. Studies of CERP in adult migraneurs yielded contradictory results. The aim of our study was to evaluate CERP in children and adolescents with migraine with and without aura during the interictal period. MATERIAL AND METHODS: The study was carried out on 111 children aged 7-18 years (mean 12.92 (2.78) with idiopathic attack headaches. In this group migraine with aura (MA) was diagnosed in 27 patients, migraine without aura (MO) in 36 children and episodic tension-type (TH) headaches in 48 patients. RESULTS: The latencies N2 and P3 were significantly longer (p < 0.05 and p < 0.01, respectively) in the group of all migraneurs (MA + MO, n = 63) as compared with the TH group. In the MO group not only N2 and P3 latency, but also P2 latency (p < 0.05) were longer, if particular types of migraine were compared with tension-type headaches. There were no statistically significant differences between mean latencies in MA and TH groups. Analyzing CERP amplitudes, the N1/P2 amplitude was significantly higher in MO patients than in the TH group only. We found longer P2, N2 and P3 latencies and higher N1/P2 amplitude in MO patients in comparison with MA patients. We found correlation between P3 latency and the age of patients with migraine. There were no statistically significant correlations for either headache type between CERP parameters and illness duration, sex of patients and unilateral localisation of headache. CONCLUSIONS: The CERP parameter changes in children with migraine point out the disturbances of cognitive functions also for auditory modalities. It suggests generalized dysfunction of cortical information processing in the interictal period of migraine.     

Restless legs syndrome is not associated with migraine with aura: a clinical study

Based on recent data about the association between restless legs syndrome (RLS) and migraine, we performed an observational study on the occurrence of RLS in patients affected by “pure” migraine with aura (pMA). We recruited 63 patients (33 females and 30 males) affected by MA without other types of primary headache among all patients referred in five Italian headache centers in a 1-year period. The prevalence of RLS in pMA patients (9.5%) is similar to that observed in Italian headache-free subjects (8.3%). No significant differences were found between pMA patients with and without RLS about clinical features of MA attacks and systemic and psychiatric diseases were investigated. Moreover, no association appeared between RLS and familial cases of MA. Differently from migraine without aura, our data do not confirm the existence of an association between RLS and MA, not even when a genetic factor is involved.

     

Sleep-related migraine occurrence increases with aging

A preferential occurrence of attacks at night-time or during early morning is documented in migraine without aura, suggesting a relationship between migraine and sleep and an impairment of circadian rhythms. The objective of this study was to verify the occurrence of sleep-related migraine in a large sample of migraineurs divided in different age groups and to evaluate the possible role of physiological variables (i.e., aging, gender) and comorbidities (i.e., psychiatric diseases). 734 patients (519 women and 215 males), aged 21-70?years, fulfilling IHS criteria (2004) for migraine without aura, were enrolled. The population was divided into five groups according to decades of life and it was evaluated the percentage of sleep-related migraine (at least 75% migraine attacks occurring during night sleep and/or upon awakening) in the different age groups. Headache clinical diary, Pittsburgh Sleep Quality Index and Beck Depression Inventory were also used. The preferential emergence of attacks during night sleep and/or upon awakening progressively increased with aging, without gender predilection; the percentage of patients with sleep-related migraine was: 16% between 20 and 30?years, 27% between 31 and 40?years, 38% between 41 and 50?years, 45% between 51 and 60?years, and 58% between 61 and 70?years, respectively. Poor sleep quality and depression did not account for night-time and/or awakening migraine collocation. These data suggest the main role of aging in order to favor nocturnal/early morning emergence of migraine without aura and support the hypothesis of an involvement of impaired chronobiological mechanisms and sleep regulation.     

Comparison of visual and auditory evoked cortical potentials in migraine patients between attacks.

OBJECTIVE: As both habituation of pattern reversal visual evoked potentials (PR-VEP) (Schoenen J, Wang W, Albert A, Delwaide PJ. Potentiation instead of habituation characterizes visual evoked potentials in migraine patients between attacks. Eur J Neurol 1995;2:115-122) and intensity dependence of auditory evoked cortical potentials (IDAP) (Wang W, Timsit-Berthier M, Schoenen J. Intensity dependence of auditory evoked potentials in migraine: an indication of cortical potentiation and low serotonergic neurotransmission? Neurology 1996;46:1404-1409) were found abnormal in migraine between attacks, we have searched for intraindividual correlations between both tests in 59 migraine patients (22 with aura [MA], 37 without aura [MO]) and in 23 healthy volunteers (HV). METHODS: Amplitude change of the PR-VEP N1-P1 was measured between the 1st and 5th block of 50 sequential averagings during continuous stimulation at 3.1 Hz. IDAP was computed from N1-P2 amplitudes of 100 averagings during stimulations at 40, 50, 60 and 70 dB SL. Amplitude-stimulus intensity function (ASF) slopes and amplitude changes between 40 and 70 dB were calculated. MO and MA differed from HV in PR-VEP amplitude change (P=0.007) and IDAP slope (P = 0.0004). RESULTS: There was no significant correlation between VEP amplitude changes and IDAP slopes, nor between the latter two and attack frequency or disease duration. A negative correlation was found between the amplitude of the first block of averaged responses and potentiation of VEP in all subject groups (P = 0.03) as well as between the amplitude of the auditory evoked potential, at 40 dB, and the percentage of amplitude increase between 40 and 70 dB in MO (P = 0.004) and MA (P = 0.007). ASF slopes and 40 dB amplitudes were significantly correlated only in the MA group (P = 0.002). These results confirm the interictal deficit of habituation in cortical processing of repetitive visual and auditory information in migraine. Since there is no intraindividual correlation between the cortical responses to these sensory modalities they are complementary tools for the study of migraine and may help to identify subgroups of patients with distinct pathophysiological mechanisms. CONCLUSIONS: The strong negative correlation between the initial amplitude of evoked potentials and their amplitude increase during subsequent averaging confirms that the response potentiation in migraine is likely to be due to a reduced preactivation level of sensory cortices.     

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。     

Migraine with aura and brain magnetic resonance imaging abnormalities in patients with CADASIL

BACKGROUND: Migraine with aura (MA) is one of the clinical hallmarks of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a small vessel disease of the brain caused by mutations in the NOTCH3 gene, but its exact mechanisms are unknown. OBJECTIVES: To describe the patterns of MA in CADASIL and to compare brain magnetic resonance signal abnormalities between CADASIL patients with and without MA. DESIGN: Comparison of brain magnetic resonance signal abnormalities between cases and controls. SETTING: Patients with CADASIL seen at Lariboisière Hospital. PATIENTS: Forty-one CADASIL patients with MA and 31 age-matched CADASIL controls without MA. RESULTS: The mean age at onset of MA was significantly younger in women compared with men and occurred a mean of 15 years prior to stroke onset. A majority of patients (56%) reported at least 1 migraine attack with atypical aura. All CADASIL patients either with or without MA had white matter signal abnormalities on T2-weighted imaging. There was no difference in the frequency and distribution of brain signal abnormalities between CADASIL patients with and without MA. CONCLUSIONS: In CADASIL, MA is characterized by an unusually high frequency of attacks of migraine with atypical aura. The distribution and extent of magnetic resonance signal abnormalities did not differ according to migraine phenotype.     

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

Objective

White 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.

Chromosome 1p36 in migraine with aura: association study of the 5HT(1D) locus

Migraine with aura (MA) may share some but not all risk factors with other forms of migraine. As common migraine without aura (MO) has been associated with the chromosome 1p36 locus, we tested its involvement in MA by using two-point parametric linkage analysis to analyze 64 multiplex MA families. A logarithm of the odds score of 1.9 was suggestive of chromosome 1p36 linkage to MA. The transmission disequilibrium test analysis was then performed in 79 nuclear families with one MA parent and one MA offspring. We identified the presence of genetic association at chromosome 1p36 with MA (P=0.045, Bonferroni corrected): the locus encoding the 5HT(1D) receptor gene. Although these data suggest that the 1p36 locus may protect against MA, consistent with the role of the 5HT(1D) receptor in migraine treatment with triptan drugs, the study is subject to the limitations associated with studying a small number of affected families. As a result, we contrast evidence suggesting that the chromosome 1p36 locus is strongly MO associated with our finding that 1p36 has a more limited contribution to MA in the families we analyzed. Further work using a genome-wide association study approach in familial typical migraine, consisting of those affected by MO or MA, will serve to further distinguish how and why MA differs from MO.     

Migraine genetics

Migraine with aura (MA) and migraine without aura (MO) are primary headaches prevalent in the general population that carry a substantial familial liability. Based on the model of migraine as a complex disease, a multifactorial type of inheritance has been suggested, but familial hemiplegic migraine (FHM), classified as a subtype of MA, shows an autosomal dominant transmission pattern and is due to mutations in three genes encoding for neural channel subunits. These FHM mutations, however, account for a minority of the FHM families and are not usually found in sporadic HM or in the typical migraines MA/MO. This implies that the genetic predisposition to the typical migraines may be different and that FHM could be better classified as a type of syndromic migraine rather than a MA subtype. Linkage and genome-wide scans have disclosed several chromosomal liability loci in selected families with MA/MO. It is likely that typical migraine genes will be discovered in the future. Epigenetic mechanisms, especially those acting in the early stages of neural development, are here proposed to be involved in the genetics of the typical migraines, especially if the typical migraines are modeled as evolutionarily conserved behaviors (sickness behavior) enacted out of a genetic repertoire.     

Monoamine oxidases A and B gene polymorphisms in migraine patients

Abnormal cortical activity and brainstem functioning are considered the possible etiopathogenetic factors of migraine. Monoamine oxidase A and B (MAO-A and -B) regulate the levels of monoamine neurotransmitters, so changes in their activity could participate in migraine pathogenesis. We have investigated the possible association of MAO-A and -B alleles and haplotypes with two common types of migraine, i.e. migraine without aura (MO) and migraine with aura (MA), on the sample of 110 migraineours (80 MO and 30 MA) and 150 controls. MAO-A promoter and MAO-B intron 13 polymorphisms were genotyped by the PCR-based methods. In addition, we have reevaluated the reported association between MAO-B intron 13 polymorphism and platelet MAO-B activity. The platelet MAO-B activity was determined fluorimetrically using kynuramine as a substrate. We have found a tendency toward association of the shorter variant of MAO-A gene promoter with migraine without aura in male subjects. Regarding investigated MAO-B polymorphism, no association with migraine or with platelet MAO-B activity was found. The suggestive association of the variant in MAO-A gene with migraine is considered worthy of independent replication. On the other hand, further studies on MAO-B polymorphism in migraine do not seem promising.