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Botulinum toxin A (BTA) is widely used as treatment of chronic migraine. Efficacy in studies, however, was only modest and likely influenced by unblinding due to BTA-induced removal of forehead wrinkles. Moreover, most study participants were overusing acute headache medications and might have benefitted from withdrawal. We assessed in a double blind, placebo-controlled, randomized clinical trial whether add-on therapy with BTA enhances efficacy of acute withdrawal. Participants were enrolled between December 2012 and February 2015, with follow-up to January 2016, in a single academic hospital in the Netherlands. A total of 179 participants, male and female, aged 18-65, diagnosed with chronic migraine and overuse of acute headache medication were included. All participants were instructed to withdraw acutely from all medication for a 12-week period, in an outpatient setting. In addition, they were randomly assigned (1:1) to 31 injections with BTA (155 units) or placebo (saline); to prevent unblinding, placebo-treated participants received low doses of BTA (17.5 units in total) in the forehead, along with saline injections outside the forehead region. Primary endpoint was percentage change in monthly headache days from baseline to the last 4 weeks of double-blind treatment (Weeks 9-12). Among 179 randomized patients, 90 received BTA and 89 received placebo, and 175 (98%) completed the double-blind phase. All 179 patients were included in the intention-to-treat analyses. BTA did not reduce monthly headache days versus placebo (-26.9% versus -20.5%; difference -6.4%; 95% confidence interval: -15.2 to 2.4; P = 0.15). Absolute changes in migraine days at 12 weeks for BTA versus placebo were -6.2 versus -7.0 (difference: 0.8; 95% confidence interval: -1.0 to 2.7; P = 0.38). Other secondary endpoints, including measures for disability and quality of life, did also not differ. Withdrawal was well tolerated and blinding was successful. Thus, in patients with chronic migraine and medication overuse, BTA does not afford any additional benefit over acute withdrawal alone. Acute withdrawal should be tried first before initiating more expensive treatment with BTA., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Cortical hyperexcitability due to enhanced glutamatergic activity has been implicated in migraine pathophysiology but direct evidence is lacking. Here we assessed glutamate levels and intracellular mobility of glutamate in the visual cortex of migraineurs in-between attacks. We included 50 migraineurs (23 with aura and 27 without aura) and 24 age- and gender-matched non-headache controls. We used proton magnetic resonance spectroscopy (1H-MRS) and diffusion weighted spectroscopy at 7 T with a single volume of interest (2 × 2 × 3 cm) located in the primary and secondary visual cortex. For 1H-MRS we used a semi-LASER sequence with water referencing for absolute quantification. For diffusion weighted spectroscopy we used an adapted PRESS sequence with gradients applied in three directions and two different gradient amplitudes. Between-group differences were evaluated using analysis of covariance with the grey matter fraction in the volume of interest as covariate and post hoc comparisons with Bonferroni correction. Glutamate concentrations differed between groups (P = 0.047) and were higher in migraineurs without aura (mean ± standard deviation: 7.02 ± 0.50 mM) compared to controls (mean ± standard deviation: 6.40 ± 0.78 mM, P = 0.042). The apparent diffusion coefficient of glutamate was similar among groups (P = 0.129) suggesting similar inter- and intracellular mobility of glutamate in all three study groups. No differences were observed for concentrations and diffusion constants of other metabolites. The present study suggests that interictal glutamate levels are increased in the visual cortex of migraineurs without aura, supporting the hypothesis of cortical hyperexcitability in migraine., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Motivation: Predicting disease phenotypes from genotypes is a key challenge in medical applications in the postgenomic era. Large training datasets of patients that have been both genotyped and phenotyped are the key requisite when aiming for high prediction accuracy. With current genotyping projects producing genetic data for hundreds of thousands of patients, large-scale phenotyping has become the bottleneck in disease phenotype prediction., Results: Here we present an approach for imputing missing disease phenotypes given the genotype of a patient. Our approach is based on co-training, which predicts the phenotype of unlabeled patients based on a second class of information, e.g. clinical health record information. Augmenting training datasets by this type of in silico phenotyping can lead to significant improvements in prediction accuracy. We demonstrate this on a dataset of patients with two diagnostic types of migraine, termed migraine with aura and migraine without aura, from the International Headache Genetics Consortium., Conclusions: Imputing missing disease phenotypes for patients via co-training leads to larger training datasets and improved prediction accuracy in phenotype prediction., Availability and Implementation: The code can be obtained at: http://www.bsse.ethz.ch/mlcb/research/bioinformatics-and-computational-biology/co-training.html, (© The Author 2015. Published by Oxford University Press.)

Cutaneous allodynia is a common feature accompanying migraine attacks and considered a clinical marker for central sensitization. In a longitudinal study, we wanted to investigate if allodynia in migraine patients is a predictor of increasing frequency of migraine days. We included 3029 well-defined, web-based migraine patients (86% female, mean age 42.8 ± 11.4 years, 61% migraine without aura). Questionnaires on migraine characteristics (including allodynia), depression and demographic factors were applied. The number of migraine days was measured twice. Multivariate regression models were used, with correction for other factors that are involved in the relation between allodynia and the number of migraine attacks or migraine days, with specific focus on depression. Of all 2331 eligible migraine patients, 1624 (70%) had allodynia. Lifetime depression was an independent risk factor for allodynia (odds ratio 1.52, 95% confidence interval 1.26-1.84), as well as female gender, low age at onset, and high migraine attack frequency. Analysis of the longitudinal data (in migraineurs with a follow-up period of >6 months) showed that, apart from the known risk factors (low age at onset, high baseline number of migraine days, and depression), allodynia was an independent predictor for increase in number of migraine days over a mean follow-up period of 93 ± 30 weeks (median 103 weeks, range 26-160 weeks). Cutaneous allodynia is a risk factor for migraine chronification and may warrant preventive treatment strategies.

Migraine headache is widely believed to be associated with cerebral or meningeal vasodilatation. Human evidence for this hypothesis is lacking. 3 Tesla magnetic resonance angiography (3T MRA) allows for repetitive, non-invasive, sensitive assessment of intracranial vasodilatation and blood flow. Nitroglycerine (NTG) can faithfully induce migraine attacks facilitating pathophysiological studies in migraine. Migraineurs (n = 32) randomly received NTG (IV 0.5 microg/kg/min for 20 min; n = 27) or placebo (n = 5; for blinding reasons). Using 3T MRA, we measured: (i) blood flow in the basilar (BA) and internal carotid arteries (ICA) and (ii) diameters of the middle meningeal, external carotid, ICA, middle cerebral, BA and posterior cerebral arteries at three timepoints: (a) at baseline, outside an attack; (b) during infusion of NTG or placebo and (c) during a provoked attack or, if no attack had occurred, at 6 h after infusion. Migraine headache was provoked in 20/27 (74%) migraineurs who received NTG, but in none of the five patients who received placebo. The headache occurred between 1.5 h and 5.5 h after infusion and was unilateral in 18/20 (90%) responders. During NTG (but not placebo) infusion, there was a transient 6.7-30.3% vasodilatation (P < 0.01) of all blood vessels. During migraine, blood vessel diameters were no different from baseline, nor between headache and non-headache sides. There were no changes in BA and ICA blood flow during either NTG infusion or migraine. In contrast to widespread belief, migraine attacks are not associated with vasodilatation of cerebral or meningeal blood vessels. Future anti-migraine drugs may not require vasoconstrictor action.

We describe an extended Dutch family with a new hereditary disorder: autosomal dominant vascular retinopathy, migraine and Raynaud's phenomenon. Information was obtained on 289 family members (151 males, 138 females), of whom 198 were personally interviewed. Retinopathy was found in 20 (6.9%) of the family members, migraine in 65 (22.5%) and Raynaud's phenomenon in 50 (17.3%). A combination of all three symptoms was found in 11 subjects. In a genetic linkage analysis we firstly excluded several candidate loci. Subsequently, 75% of the autosomal genome was excluded in a genome-wide search. The following conclusions were drawn. First, genetic factors are involved in Raynaud's phenomenon. Secondly, the genetic linkage of migraine with vascular retinopathy and Raynaud's phenomenon supports a vascular aetiology of this disorder. Finding the gene for this family may help to elucidate the genetic background of migraine and of vascular disorders in general.