A. Heinze

Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 × 10−9, odds ratio = 1.23, 95% CI 1.150–1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 × 10−11 (odds ratio = 1.18, 95% CI 1.127–1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 × 10−5, permuted threshold for genome-wide significance 7.7 × 10−5). To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

Genome-wide meta-analysis identifies new susceptibility loci for migraine

Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P < 5 × 10−8). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B.

Genome-wide association analysis identifies susceptibility loci for migraine without aura

Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 × 10−5 for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 × 10−4; combined P = 7.06 × 10−11) and at 3p24 (near TGFBR2; replication P = 1.0 × 10−4; combined P = 1.17 × 10−9). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 × 10−8 and P = 0.02; combined P = 3.86 × 10−8, respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.

Efficacy and safety of a single botulinum type A toxin complex treatment (Dysport®) for the relief of upper back myofascial pain syndrome: Results from a randomized double-blind placebo-controlled multicentre study

&NA; Botulinum type A toxin (BoNT‐A) has antinociceptive and muscle‐relaxant properties and may help relieve the symptoms of myofascial pain syndrome. In this study we evaluated the efficacy and tolerability of BoNT‐A (Dysport®) in patients with myofascial pain syndrome of the upper back. We conducted a prospective, randomized, double‐blind, placebo‐controlled, 12‐week, multicentre study. Patients with moderate‐to‐severe myofascial pain syndrome affecting cervical and/or shoulder muscles (≥10 trigger points, disease duration 6–24 months) were randomized to Dysport® or saline. Injections were made into the 10 most tender trigger points (40 units per site). The primary outcome was the proportion of patients with mild or no pain at week 5. Secondary outcomes included changes in pain intensity and the number of pain‐free days per week. Tolerability and safety were also assessed. At week 5, significantly more patients in the Dysport® group reported mild or no pain (51%), compared with the patients in the placebo group (26%; p = 0.002). Compared with placebo, Dysport® resulted in a significantly greater change from baseline in pain intensity during weeks 5–8 (p < 0.05), and significantly fewer days per week without pain between weeks 5 and 12 (p = 0.036). Treatment was well tolerated, with most side effects resolving within 8 weeks. In conclusion, in patients with upper back myofascial pain syndrome, injections of 400 Ipsen units of Dysport® at 10 individualised trigger points significantly improved pain levels 4–6 weeks after treatment. Injections were well tolerated.

Botulinum toxin A in the treatment of headache syndromes and pericranial pain syndromes

For 20 years, botulinum toxin A has been used for treating a variety of disorders characterized by pathologically increased muscle contraction. Current research efforts focus on new areas of application for botulinum toxin A in speci®c pain therapy, particularly in primary headache syndromes and in myofascial pain syndromes of the neck, shoulder girdle and back. This opens up new options for patients with hitherto therapy-resistant chronic pain syndromes. From a scienti®c view, it offers new perspectives for basic research and clinical analyses of these syndromes. There is also a need to rethink and analyze the modes of action of botulinum toxin A. The use of botulinum toxin A in pain therapy, however, calls for a detailed knowledge of functional anatomy and for expertise in practical applications.

Effectiveness of Oleum menthae piperitae and paracetamol in therapy of headache of the tension type

ZusammenfassungIn einer randomisierten, placebokontrollierten Doppelblindstudie im Cross-over-Design wurde erstmalig die analgetische Wirksamkeit und Verträglichkeit einer lokal applizierten Pfefferminzölpräparation bei klinischem Kopfschmerz vom Spannungstyp bestimmt. Die Prüfung erfolgte sowohl gegen die Vergleichssubstanz Paracetamol als auch gegen Placebo. Die Applikation des Öls erfolgte großflächig auf Stirn und Schläfen und war 2mal (nach 15 und 30 min) zu wiederholen. Als Ergebnis fand sich, daß im Vergleich zu der Gabe von Placebo 10 %iges Pfefferminzöl in ethanolischer Lösung bereits nach 15 min in der Lage war, eine signifikante Reduktion der klinischen Kopfschmerzintensität im Vergleich zur Placebotherapie zu erzielen. Die signifikante klinische Reduktion der Schmerzintensität setzte sich im Verlauf der Beobachtungszeit von 1 h weiter fort. Auch Paracetamol erwies sich als signifikant gegenüber Placebo wirksam. Zwischen der Wirksamkeit von 1 g Paracetamol und 10 %igem Pfefferminzöl in ethanolischer Lösung bestand kein signifikanter Unterschied. Bei gleichzeitiger Gabe von 1 g Paracetamol plus 10 %igem Pfefferminzöl in ethanolischer Lösung ließ sich ein additiver Effekt feststellen, der jedoch die Signifikanzgrenze nicht überschritt. Unerwünschte Arzneimittelwirkungen wurden von den Patienten nicht berichtet. Pfefferminzöl stellt eine verträgliche und kostengünstige Alternative zu den bisherigen therapeutischen Möglichkeiten dar und ist hinsichtlich der Wirksamkeit und Verträglichkeit der Standardmedikation Paracetamol ebenbürtig.SummaryThe effect of a locally applied peppermint oil preparation on tension-type headache was examined in the design of a randomized, placebo-controlled double-blind crossover study for the first time. The preparation was tested against both the reference substance acetaminophen and to the corresponding placebo. The liquid test preparation contained 10 g of peppermint oil and ethanol (90 %) ad 100 (test preparation LI 170, Lichtwer Pharma, Berlin); the placebo was a 90 % ethanol solution to which traces of peppermint oil were added for blinding purposes. The reference preparation contained 500 mg acetaminophen; the placebo tablet was identical to the verum in size and appearance. The study included the analysis of 164 headache attacks of 41 patients of both sexes ranging between 18 and 65 years of age, suffering from tension-type headache in accordance with the IHS classification. Four headache episodes per patient were treated in a double-blind, randomized crossover design. Each headache attack was treated by the application of 2 capsules of the oral medication (1000 mg of acetaminophen or placebo) and the cutaneous application of the oil preparation (peppermint oil or placebo solution). The oil was spread largely across forehead and temples which was repeated after 15 and 30 minutes. Using a headache diary, the headache parameters were assessed after 15, 30, 45 and 60 minutes. Compared to the application of placebo, a 10 % peppermint oil in ethanol solution significantly reduced the clinical headache intensity already after 15 minutes (p < 0.01). This significant clinical reduction of the pain intensity continued over the one hour observation period. Acetaminophen, too, proved to be efficient compared to placebo (p < 0.01). There was no significant difference between the efficacy of 1000 mg of acetaminophen and 10 % peppermint oil in ethanol solution. Simultaneous application of 1000 mg of acetaminophen and 10 % peppermint oil in ethanol solution leads to an additive effect which remains below the significance threshold, however. The patients reported no adverse events. This controlled study showed for the first time that a 10 % peppermint oil in ethanol solution efficiently alleviates tension-type headache. Peppermint oil thus proves to be a well-tolerated and cost-effective alternative to usual therapies.

Percutaneous closure of patent foramen ovale in migraine with aura, a randomized controlled trial

AIMS Migraine with aura and patent foramen ovale (PFO) are associated. The Percutaneous Closure of PFO in Migraine with Aura (PRIMA) trial is a multicentre, randomized trial to investigate the effect of percutaneous PFO closure in patients refractory to medical treatment. METHODS Migraine with aura patients and PFO who were unresponsive to preventive medications were randomized to PFO closure or medical treatment. Both groups were given acetylsalicylic acid 75-100 mg/day for 6 months and clopidogrel 75 mg/day for 3 months. The primary endpoint was reduction in monthly migraine days during months 9-12 after randomization compared with a 3-month baseline phase before randomization. The committee reviewing the headache diaries were blinded to treatment assignment. RESULTS One hundred and seven patients were randomly allocated to treatment with an Amplatzer PFO Occluder (N = 53) or control with medical management (N = 54). The trial was terminated prematurely because of slow enrolment. Eighty-three patients (40 occluder, 43 control) completed 12-month follow-up. Mean migraine days at baseline were 8 (±4.7 SD) in the closure group and 8.3 (±2.4) in controls. The primary endpoint was negative with -2.9 days after PFO closure vs. -1.7 days in control group (P = 0.17). Patent foramen ovale closure caused five adverse events without permanent sequelae. CONCLUSION In patients with refractory migraine with aura and PFO, PFO closure did not reduce overall monthly migraine days.

Haplotype-based systematic association studies of ATP1A2 in migraine with aura

Mutations in ATP1A2 cause familial hemiplegic migraine (FHM) type 2, a rare monogenic form of migraine with aura (MA). Moreover, rare ATP1A2 missense variants are found in familial clustering of common forms of migraine in single pedigrees. To determine whether also common ATP1A2 polymorphisms contribute to MA pathogenesis, we performed systematic case‐control association studies in 284 MA cases and 241 control individuals. By direct sequencing of the 23 coding exons and adjacent intronic regions in 45 MA patients, 16 polymorphisms (12 SNPs, 3 small indels, 1 microsatellite marker) were identified. The sequencing results were used to estimate seven common ATP1A2 haplotypes (with a frequency >5%) covering about 97% of total haplotype diversity for this region. Subsequently, six haplotype‐tagging SNPs/polymorphisms were genotyped in 95 individuals with a family history of MA, in 189 individuals with sporadic MA, and in a gender‐matched control sample. A haplotype analysis was performed using the program FAMHAP. No significant differences in the ATP1A2 haplotype distribution could be detected between MA patients (or patient subgroups) and the control group. In a single‐marker analysis the allele and genotype frequencies of ATP1A2 polymorphisms between cases and controls were compared. Neither the six ht‐SNPs nor a single allele of the microsatellite marker were significantly associated with MA. In summary, we found no evidence for a common contribution of ATP1A2 to the pathogenesis of complex inherited MA.

Genetic association studies of the chromosome 15 GABA‐A receptor cluster in migraine with aura

Recently, a novel susceptibility locus for migraine with aura (MA) on chromosome 15q containing three GABA‐A receptor subunits has been identified by linkage analysis in several large pedigrees. To further study the role of this locus in MA etiology we genotyped 56 SNPs capturing the known common haplotype variations of these three candidate genes in a sample comprising 270 MA patients and 273 matched controls. In a single marker analysis, four SNPs displayed nominally significant (P < 0.05) association with MA. However, after permutation‐based correction for the number of tests performed, the P‐values of these SNPs were non‐significant. Furthermore, a replication study of two of these SNPs in a second independent sample of 379 MA patients and 379 controls did not result in a significant finding. We also compared haplotype estimates based on case–control genotypes. Again we could not demonstrate a significant association with the phenotype after correction for multiple testing. In summary, we found no convincing evidence for an involvement of common SNPs at the GABA‐A receptor cluster on 15q11‐q12 in the pathophysiology of MA.

Efficacy and Tolerability of Rizatriptan 10 mg in Migraine: Experience With 70 527 Patient Episodes

As patients who suffer from migraine need long‐term treatment, the safety and consistent efficacy of such therapy is very important. Concurrent illness and additional medication can interfere with the treatment chosen for the attacks of migraine. The objective of this open‐label study was to investigate the efficacy and tolerability of rizatriptan, in the treatment of up to three attacks of migraine, in the clinical setting. From October 1998 to July 1999, 6 174 doctors enrolled 33 147 patients into the study (26 644 women, 650 men). The mean age was 42.7 years. We were able to examine standardized migraine diaries relating to 25 501 patients and 70 537 migrainous episodes. Rizatriptan scored consistently high on efficacy and showed a consistently rapid onset. There was no evidence of tolerance to repeated use. An effect was reported within 1 hour of ingestion in 79% of attacks treated. In 27.8% of attacks, remission of headache was complete at 1 hour. Two hours after ingestion, 74% of attacks had subsided completely.