Patricia Pozo-Rosich

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.

SNP variants within the vanilloid TRPV1 and TRPV3 receptor genes are associated with migraine in the Spanish population.

The transient receptor potential (TRP) superfamily of non‐selective cationic channels are involved in several processes plausibly relevant to migraine pathophysiology, including multimodal sensory and pain perception, central and peripheral sensitization, and regulation of calcium homeostasis. With the aim of identifying single nucleotide polymorphisms (SNPs) in TRP genes that may confer increased genetic susceptibility to migraine, we carried out a case–control genetic association study with replication, including a total of 1,040 cases and 1,037 controls. We genotyped 149 SNPs covering 14 TRP genes with known brain expression. The two‐stage study comprised samples of 555 and 485 Spanish, Caucasian patients, selected according to the ICHD‐II criteria for the diagnosis of migraine without aura (MO) or migraine with aura (MA). In the discovery sample, 19 SNPs in ten TRP genes showed nominal association (P < 0.05) with MO, MA, or overall migraine. In the replication sample, nominal association was confirmed for TRPV3 rs7217270 in MA and TRPV1 rs222741 in the overall migraine group. Risk haplotypes were identified for seven of the genes showing nominal association in the discovery set, but none of them was replicated. The present findings suggest that members of the vanilloid TRPV subfamily of receptors contribute to the genetic susceptibility to migraine in the Spanish population.

Replication study of previous migraine genome-wide association study findings in a Spanish sample of migraine with aura

Background Migraine is a common disabling condition that affects approximately 15% of the population. Several genome-wide association studies have attempted to identify susceptibility variants involved in migraine, reporting several candidate loci for the disorder. Methods In order to replicate findings from previous genome-wide association studies, a case–control association study was performed. Twelve single nucleotide polymorphisms were genotyped in a Spanish sample of 512 migraine with aura patients and 535 migraine-free controls. Results Nominal associations were found for single nucleotide polymorphisms rs2651899 (within the PRDM16 gene), rs10166942 (near TRPM8), rs12134493 (close to TSPAN2) and rs10504861 (near MMP16) in our migraine with aura sample. Conclusions Our study provides suggestive replication, in a Spanish migraine with aura sample, of four genome-wide association study findings previously reported in common migraine. However, larger sample sets should be explored to confirm our results.

A replication study of a GWAS finding in migraine does not identify association in a Spanish case-control sample.

Background: Migraine is a prevalent neurological disorder with a complex genetic background characterized by recurrent episodes of headache. The disease is subclassified into migraine with aura (MA) and migraine without aura (MO). Many association studies have been performed to date to identify genetic risk variants for common migraine, most of them focusing on selected candidate genes, with variable and often inconsistent results. Recently, a clinic-based genome-wide association study for migraine reported a functionally relevant risk variant (SNP rs1835740), involved in glutamate homeostasis, which showed a significant association with MA. We aimed to replicate this finding in a clinic-based study of a Spanish cohort with MA and MO patients. Methods: We genotyped SNP rs1835740 in a Spanish sample of 1521 patients and 1379 screened controls and performed a case-control association study. Conclusion: No association was found between the assayed SNP and any of the clinical groups considered.

Candidate-gene association study searching for genetic factors involved in migraine chronification

Introduction Chronic migraine (CM) is at the severe end of the clinical migraine spectrum, but its genetic background is unknown. Our study searched for evidence that genetic factors are involved in the chronification process. Methods We initially selected 144 single-nucleotide polymorphisms (SNPs) from 48 candidate genes, which we tested for association in two stages: The first stage encompassed 262 CM patients, the second investigated 226 patients with high-frequency migraine (HFM). Subsequently, SNPs with p values < 0.05 were forwarded to the replication stage containing 531 patients with CM or HFM. Results Eight SNPs were significantly associated with CM and HFM in the two-stage phase. None survived replication in the third stage. Discussion We present the first comprehensive genetic association study for migraine chronification. There were no significant findings. Future studies may benefit from larger, genome-wide data sets or should use other genetic approaches to identify genetic factors involved in migraine chronification.

OnabotulinumtoxinA in chronic migraine: predictors of response. A prospective multicentre descriptive study

OnabotulinumtoxinA is a treatment specifically approved for the prophylaxis of chronic migraine in adults. The aim of this study was to assess the effectiveness of OnabotulinumtoxinA in chronic migraine after 1 year of treatment in a real‐life setting and to identify clinical predictors of outcome.

The impact of onabotulinumtoxinA on severe headache days: PREEMPT 56-week pooled analysis

BackgroundOnabotulinumtoxinA has been shown to reduce headache-days among patients with chronic migraine (CM). The objective of this analysis was to determine whether onabotulinumtoxinA has an impact on headache-day severity in patients with CM among those patients who were deemed non-responders based on reduction in the frequency of headache days alone.MethodsData from the Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical trial program (a 24-week, 2-treatment cycle, double-blind, randomized, placebo-controlled, parallel-group phase, followed by a 32-week, 3-treatment cycle, open-label phase) were pooled for analysis. Patients kept a daily diary to record headache severity on a 4-point scale (from none to severe), and a 6-domain Headache Impact Test (HIT-6) was used to determine the clinical impact of headaches. Analysis was undertaken to assess whether the subset of patients that were headache-day frequency non-responders at week 24 (patients with <50% reduction in headache-day frequency) experienced a reduction in headache severity whilst receiving onabotulinumtoxinA.ResultsFor headache-day frequency non-responders, significant reductions in the number of severe headache days, average daily headache severity, pooled percentage of severe headache days and headache severity score were observed at week 24 for patients who had received onabotulinumtoxinA compared with those who had received placebo. The between-group differences were reduced and non-significant at week 56. Similarly, headache-day frequency non-responders receiving onabotulinumtoxinA were found to have an improvement in the clinical impact of headaches using results from the HIT-6.ConclusionsThese results suggest that even those patients with CM who are deemed non-responders based on analysis of headache frequency alone experience clinically meaningful relief from headache intensity following treatment with onabotulinumtoxinA.

When does chronic migraine strike? A clinical comparison of migraine according to the headache days suffered per month:

Introduction According to the IHCD-3β classification, chronic migraine (CM) is headache occurring on 15 or more days/month. Episodic migraine (EM) can be divided into low frequency (LFEM) and high frequency (HFEM) depending on the headache days suffered per month. Methods We performed a clinical comparison of migraine characteristics according to monthly headache days suffered. Patients were divided into three groups: LFEM (1–9 headache days/month), HFEM (10–14 headache days/month) and CM (≥15 headache days/month). Results The analysis included 1109 patients. Previously reported differences between EM and CM were replicated. However, there were three times more clinical differences between LFEM and HFEM than between HFEM and CM (15 vs. 6). A new model that takes 10 headache days as a cut-off value for CM would have a minimally higher predictive capacity (72.8%) and no statistical differences (71.8%) when comparing it to the current classification. Conclusions HFEM patients have few clinical differences compared with CM patients. This includes the poor outcomes regarding headache-related disability and impact on daily life. According to these findings, neurologists and headache specialists should consider that the emotional and functional impact in HFEM patients could be as disabling as in those with CM.

Guidelines of the International Headache Society for controlled trials of preventive treatment of chronic migraine in adults

Background Quality clinical trials form an essential part of the evidence base for the treatment of headache disorders. In 1991, the International Headache Society Clinical Trials Standing Committee developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Migraine. In 2008, the Committee published the first specific guidelines on chronic migraine. Subsequent advances in drug, device, and biologicals development, as well as novel trial designs, have created a need for a revision of the chronic migraine guidelines. Objective The present update is intended to optimize the design of controlled trials of preventive treatment of chronic migraine in adults, and its recommendations do not apply to trials in children or adolescents.

Normal Hypocretin-1 (Orexin A) Levels in Cerebrospinal Fluid in Patients with Idiopathic Intracranial Hypertension

AIM Low levels of hypocretin-1 (HC-1) have been associated with hypersomnia, obesity, depression, and chronic headaches. These conditions are frequently present in patients with idiopathic intracranial hypertension (IIH) and may be associated with abnormalities of the hypocretin system. The aim of this study was to determine HC-1 concentrations in cerebrospinal fluid (CSF) in a series of patients with IIH and to compare these concentrations with those in a control group with no neurological alterations. PATIENTS AND METHODS This prospective study included a cohort of 26 consecutive patients with IIH who were mostly women (25 vs. 1) with a mean age of 42.5 ± 13.2. CSF samples were obtained from a lumbar puncture performed between 08:00 and 10:00 a.m. HC-1 was determined by a competitive radioimmunoassay (RIA) using I(125) as the isotope. Samples of normal CSF were obtained during spinal anesthesia for urological, general or vascular surgery from 40 patients (10 women and 30 men with a mean age of 63.7 ± 14.8) with no previous neurological or psychiatric history, a normal neurological examination, and MMSE scores of ≥ 24. RESULTS No statistically significant differences were found between HC-1 levels in the CSF of patients with IIH (119.61 ± 21.63 pg/mL) and those of the control group (119.07 ± 20.30 pg/mL; p = 0.918). CONCLUSIONS HC-1 is not associated with the clinical symptoms present in patients with IIH.