Migraine with aura is not linked to the FHM gene CACNA1A or the chromosomal region, 19p13

Two microsatellite markers, tightly linked to CACNA1A, were genotyped in migraine with aura (MA) families to determine if this gene, which underlies the 19p13 linked forms of familial hemiplegic migraine, is also linked to MA. Two-point parametric lod and nonparametric linkage scores did not support linkage. Transmission disequilibrium testing provided no evidence for linkage of MA to CACNA1A. In a large dataset of 64 Canadian MA families, the authors did not find evidence to support an MA susceptibility gene in the region of 19p13.     

Is the CACNA1A gene involved in familial migraine with aura?

The discovery of mutations in the neural calcium channel (CACNA1A) gene in familial hemiplegic migraine (FHM), variant of migraine with aura, led to the suggestion that this gene might be involved in familial migraine with aura (FMA). We investigated whether the mutations in FHM are present in FMA patients, analyzing genomic DNA by PCR, single stranded conformation polymorphism, sequencing and restriction enzyme. No mutations were found. A known polymorphism (5682–14C>T) was found in exon 36. These findings suggest that the mutations found in FHM and the other known mutations of the CACNA1A gene are not the genetic basis of FMA. Genetic alterations in FMA patients may be localized on chromosome 19 but not in the CACNA1A exons we investigated. Received: 25 January 2002 / Accepted in revised form: 25 February 2002     

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.     

Sporadic hemiplegic migraine and epilepsy associated with CACNA1A gene mutation

Familial hemiplegic migraine (FHM) is a clinically and genetically heterogeneous disease most commonly linked to CACNA1A gene mutation. Epilepsy rarely occurs in FHM and is seen predominantly with specific CACNA1A gene mutations. Here we report a sporadic case of FHM1 linked to S218L CACNA1A gene mutation with the triad of prolonged hemiplegic migraine, cerebellar symptoms, and epileptic seizures. Epilepsy in this syndrome follows the pattern of isolated unprovoked seizures occurring only during childhood and hemiplegic migraine-provoked seizures occurring during adulthood. Clinical and electrographic status epilepticus can occur during prolonged migraine attacks. We suggest that patients with seizures, ataxia, and hemiplegic migraine be genetically tested for FHM. Patients with prolonged hemiplegic migraine attacks and confusion should be tested with continuous EEG recording to ascertain whether electrographic status is occurring, as intensive antiepileptic treatment not only resolves status but immediately stops hemiplegic migraine and improves associated neurological deficits.     

Precipitating factors of migraine attacks in patients with migraine without aura

To study the distribution of triggers of migraine in a selected population, 100 patients who fulfilled the diagnostic criteria for migraine without aura as proposed by the International Headache Society were evaluated by means of a personal interview. Stress was the most cited trigger, triggering migraine in 76%. Afterwards, in descending order of frequency, were cited sensorial stimuli (75%), sleep deprivation (49%), hunger (48%), environmental factors (47%), food (46%), menses (39%), fatigue (35%), alcohol (28%), sleep excess (27%), caffeine (22%), physical exertion (20%), head trauma (20%), trips (4%), sexual activity (3%), medications (2%), neck movements (2%), smoking (1%) and the use of a low pillow (1%). It is concluded that certain factors seem to play an important role in the triggering of migraine.     

Oestrogen and attacks of migraine with and without aura

During women's reproductive years, migraine is three times more common than in men of a similar age. Although this female preponderance is commonly assumed to be associated with the additional trigger of fluctuating sex hormones of the menstrual cycle, few studies have been done to confirm or refute this. This review is confined to the relation between oestrogen and attacks of migraine. The evidence for an association between oestrogen "withdrawal" and attacks of migraine without aura is presented, as well as evidence for an association between high oestrogen states and attacks of migraine with aura. Only clinical data are presented here.     

Lamotrigine reduces migraine aura and migraine attacks in patients with migraine with aura

This study examined the efficacy of lamotrigine in the prevention of migraine aura. Fifty nine patients suffering from migraine with aura received lamotrigine in a controlled three year prospective open study. Treatment response was defined as a reduction of aura frequency each month by at least 50%. Primary endpoint was reached by three quarters of the patients. Lamotrigine significantly reduced both frequency of migraine aura (mean, 1.5 (SD, 0.6) each month before v 0.4 (0.7) after treatment; p < 0.001) and aura duration (mean, 27 (SD, 11) minutes before v 8 (14) after treatment; p < 0.001). Furthermore, more than three quarters of those patients with a reduction of aura symptoms experienced a significant reduction of frequency of migraine attacks (mean, 2.1 (SD, 1.0) each month before v 1.2 (1.1) after treatment; p < 0.001). Lamotrigine was highly effective in reducing migraine aura and migraine attacks. The strong correlation between reduction of aura symptoms and migraine attacks stresses the potential role of aura-like events and possibly cortical spreading depression as a trigger for trigeminal vascular activation, and subsequently the development of migraine headaches.     

Evaluation of placebo use in migraine without aura, migraine with aura and episodic tension-type headache acute attacks

This study presents an evaluation of placebo response in the acute treatment of migraine with or without aura and episodic tension type headache. We studied patients admitted between March 1st,1997 and November 31st,1999 in two Emergency Room Units. Three groups had been defined, each one with 30 participants: migraine without aura (MWOA), migraine with aura (MWA) and episodic tension-type headache (ETTH). Patients were participating of a randomized study to evaluate efficacy of 4 different drugs; those randomized to receive placebo were included. We evaluated pain and associated symptoms. After one hour of placebo administration, 50% of MWOA patients, 23.3% of MWA and 26.7% of ETTH had presented pain relief. The mean of this relief, evaluated by the numerical pain scale, was 41.6%, 23.1% and 36%, respectively. Use of placebo is essential in evaluating the therapeutic role of drugs used in the treatment of acute headache.     

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.     

A study of symptomatic drug use in migraine without aura

We assessed the attack drugs taken by 200 migraine without aura patients (International Headache Society criteria, 1988) between 1989 and 1991. A detailed pharmacological history regarding the acute attack therapy adopted up until our initial visit was gathered, including the type of drug used, dosage, administration route, the time of starting therapy, treatment efficacy, and the frequency and types of undesirable effects, all of which were subsequently compared with the guidelines (1993) of the Italian Society for the Study of Headache (SISC). The most commonly used are non steroidal anti-inflammatory drugs (NSAIDs). We observed a similar high frequency in the use of combinations, particularly prophyphenazone and barbituric acid. The pirazolones, such as noramidopyrine and prophyphenazone, are also widely used as single agents, even though they are not considered by the guidelines. Our study underlines the fact that current drug use differs in several respects from the guidelines.

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Sommario Abbiamo esaminato il trattamento farmacologico dell'attacco acuto, usato da 200 pazienti sofferenti di emicrania senza aura (criteri IHS 1988), visitati nel periodo 1989–1991. È stata raccolta una dettagliata analisi farmacologica sulle terapie d'attacco usate dai pazienti nel corso della loro storia cefalalgica precedentemente alla prima visita presso il nostro ambulatorio. Sono state studiate le seguenti variabili: tipo di farmaco usato, dosaggio e via di somministrazione, efficacia del trattamento, frequenza e tipo degli effetti indesiderati; questi parametri sono stati confrontati con le linee guida della Società Italiana per lo Studio delle Cefalee (SISC, 1993). I farmaci più comunemente usati sono gli antiinfiammatori non steroidei; abbiamo osservato un analogo uso delle associazioni, in particolare propifenazone ed acido barbiturico. I pirazolonici propifenazone ed amidopirina, non consigliati nelle linee guida, sono anch'essi largamente usati. Il nostro studio evidenzia il fatto che l'utilizzo corrente dei farmaci differisce in molti aspetti da quello suggerito dalle linee guida.

     

Identification of a susceptibility locus for migraine with and without aura on 6p12.2-p21.1

Migraine is the most common type of chronic episodic headache. To find novel susceptibility genes for familial migraine with and without aura, a genomewide screen was performed in a large family from northern Sweden. Evidence of linkage was obtained on chromosome 6p12.2-p21.1, with a maximum two-point lod score of 5.41 for marker D6S452. The patients with migraine shared a common haplotype of 10 Mb between markers D6S1650 and D6S1960.     

无先兆偏头痛的神经影像学研究进展

无先兆偏头痛是常见原发性头痛,不断的反复发作可能增加心、脑血管疾病患病的风险, 或增加某些脑区细微病变的风险,并有可能导致某些大脑区域的神经功能损伤,对患者的生活质量造 成严重影响,现对无先兆偏头痛的神经影像学研究进展进行阐述,旨在为无先兆偏头痛的临床诊断提 供影像学的帮助。     

A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia.

OBJECTIVE: To search for mutations in the calcium channel gene CACNA1A and to study the genotype-phenotype correlation in a family with a severe familial hemiplegic migraine (FHM) phenotype and a slowly progressive cerebellar ataxia. BACKGROUND: CACNA1A gene mutations on chromosome 19 are involved in approximately 50% of FHM families. The association of FHM and cerebellar ataxia has been reported in a small number of FHM families, all linked to chromosome 19. METHODS: The proband, in addition to typical hemiplegic migraine attacks, experienced severe episodes during which hemiplegia was associated with acutely altered consciousness and fever lasting several days. She, as well as her affected sister, developed a permanent, late-onset cerebellar ataxia and cerebellar atrophy evident on MRI. Linkage analysis was performed and the whole CACNA1A gene, 47 exon-intron boundaries, was analyzed by double gradient-denaturing gradient gel electrophoresis (DG-DGGE). RESULTS: Genetic studies suggested linkage to chromosome 19p13, and DG-DGGE analysis detected a heteroduplex fragment in exon 13 of the CACNA1A gene. By direct sequencing, a G-to-A substitution resulting in an arginine to glutamine change at codon 583 in the second putative voltage sensor domain of the channel alpha1A-subunit, was identified, possibly representing the disease-causing mutation. The proband and her affected sister were treated with acetazolamide, reporting freedom from new FHM attacks but no benefit in the progression of ataxia. CONCLUSIONS: The combination of episodic dysfunction and permanent deficit could depend on the variety of functions of calcium channels and their distribution in the nervous system.     

The G-308A promoter variant of the tumor necrosis factor-alpha gene is associated with migraine without aura

Migraine is considered to be a polygenic multifactorial disease with various environmental and genetic etiologies. Tumor necrosis factor-alpha (TNF-alpha), a potent immunomodulator and pro-inflammatory cytokine, has been implicated in many pathological processes in brain. The hypothesis of this study was that migraine without aura (MWA) might be associated with TNF-alpha (-308) polymorphism, resulting in increased TNF-alpha production. Genotyping was performed on DNA extracted from peripheral leukocytes by PCR-SSP method in 221 patients with WMA and 183 healthy control subjects from Iranian population. The results showed that the frequency of -308 A variant allele was higher in MWA than in the control group (40.6% versus 22.3%, OR 3.73, 95% CI 2.4-5.82, p<0.0001). TNF-alpha GA heterozygous genotype, high producer, was significantly more prevalent in patients with MWA than controls (74% versus 44.7%, p<0.0001) whilst the low producer GG homozygous genotype was less frequent in patients compared with controls (22.4% versus 55.3%, p<0.0001). The logistic regression analysis showed a significant association for TNF-alpha (-308A) female allele carriers with MWA at reproductive ages (OR 2.56; 95% CI, 1.57-4.16, p<0.0001) when compared with their matched control subjects.In conclusion, this study demonstrates an association of tumor necrosis factor-alpha (-308A) carriage with MWA, suggesting that carrying a high responder TNF-alpha-308A allele may be a genetic factor in increasing the susceptibility to develop MWA.     

Family-based association analysis of functional VNTR polymorphisms in the dopamine transporter gene in migraine with and without aura

Because of the role of dopamine in triggering migraine attacks, genes of the dopamine system are candidates for involvement in migraine. We examined three VNTR polymorphisms in the dopamine transporter, the 5'UTR VNTR, the intron 8 VNTR and the intron 14 VNTR, in a sample of 205 family trios. We used the transmission disequilibirium test (TDT) to examine the transmission of these three markers and their haplotypes to offspring affected by migraine. We found no significant transmission distortion of any marker. Likewise haplotypes of the three markers did not show significant overall or individual association with migraine. Finally we examined migraine with and without aura, and likewise found no association between dopamine transporter VNTRs or their haplotypes and either classification of the disease. We conclude that functional genetic variation in the dopamine transporter does not act as a significant risk factor for migraine.     

Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine

BACKGROUND: Familial hemiplegic migraine is a rare autosomal dominant subtype of migraine with aura that in half of the families is caused by mutations in the CACNA1A gene on chromosome 19p13. In sporadic hemiplegic migraine (SHM), that is, hemiplegic migraine without affected family members, the contribution of the CACNA1A gene is unknown. OBJECTIVE: To investigate the involvement of the CACNA1A calcium channel subunit gene in SHM. METHODS: We screened 27 patients with SHM for mutations in the CACNA1A gene by a combination of single-strand conformational polymorphism analysis and sequence analysis. RESULTS: One patient with SHM also had ataxia, nystagmus, and cerebellar atrophy on computed tomography and carried a T666M mutation. Another patient with SHM who had no cerebellar signs carried an R583Q mutation. No mutations or interictal neurological abnormalities were found in the remaining 25 patients with SHM. CONCLUSIONS: Most patients with SHM do not have a CACNA1A mutation. The results of this study, combined with the findings reported in the literature, show that the presence of cerebellar symptoms in addition to the hemiplegic attacks increases the chance of finding a CACNA1A mutation. In addition, to our knowledge, we have found a first patient with SHM without cerebellar signs with a mutation.     

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.     

A functional serotonin transporter gene polymorphism is associated with migraine with aura

An association study was performed in 197 migraineurs with regard to a functional serotonin (5-HT) transporter (5-HTT) gene promoter polymorphism that leads to low or high 5-HT uptake activity. The frequency of the less active short allele was increased in migraineurs with aura but not in migraineurs without aura in comparison with the control population (p < 0.001). This indicates that the 5-HTT may be involved in the polygenic etiology of migraine with aura.