[Is there a relationship between white matter lesions associated with migraine and patent foramen ovale? Analysis of a series of patients with chronic migraine]. / ¿Existe relación entre las lesiones de la sustancia blanca asociadas a migraña y el foramen oval permeable? Análisis de una serie de pacientes con migraña crónica.

INTRODUCTION: White matter lesions are more prevalent in migraine patients than in the general population, especially those with a high frequency of attacks. A patent foramen ovale has been described as a possible link between migraine and white matter lesions. AIM: To determine the existence of a possible relationship between a patent foramen ovale and white matter lesions in a series of patients with chronic migraine. PATIENTS AND METHODS: Observational, single-centre, case-control study. Eighty-nine women with chronic migraine were selected. The persistence and characteristics of the patent foramen ovale were assessed by means of a transcranial Doppler study. The patent foramen ovale was classified as small, moderate or massive. Those detected at rest were considered permanent, and the others were classified as latent. The MRI protocol included T1-enhanced sagittal images, FLAIR-T2-enhanced axial images, and a proton density and T2-FSE combined sequence. The white matter lesions were classified as deep, periventricular or both. RESULTS: The prevalence of patent foramen ovale (53.6% versus 48.5%; p = 0.80) and the proportion of massive, permanent patent foramen ovale were similar among patients with and without white matter lesions. Neither was there any difference in the prevalence (55.6% versus 52.6%; p = 1.00) or the characteristics of the patent foramen ovale as a function of the distribution of white matter lesions. CONCLUSION: The results do not suggest that a patent foramen ovale intervenes in the pathophysiology of the white matter lesions observed in patients with migraine.

TITLE: ¿Existe relación entre las lesiones de la sustancia blanca asociadas a migraña y el foramen oval permeable? Análisis de una serie de pacientes con migraña crónica.Introducción. Las lesiones de la sustancia blanca son más prevalentes en los pacientes migrañosos que en la población general, especialmente en los que tienen una alta frecuencia de ataques. El foramen oval permeable se ha descrito como posible nexo de unión entre la migraña y las lesiones de la sustancia blanca. Objetivo. Determinar la existencia de una posible relación entre el foramen oval permeable y las lesiones de la sustancia blanca en una serie de pacientes con migraña crónica. Pacientes y métodos. Estudio observacional, unicéntrico, de casos y controles. Se seleccionó a 89 mujeres con migraña crónica. La persistencia y las características del foramen oval permeable se evaluaron mediante un estudio Doppler transcraneal. El foramen oval permeable se clasificó como pequeño, moderado o masivo. Se consideraron permanentes los detectados en reposo, y latentes, el resto. El protocolo de resonancia magnética incluyó imágenes sagitales potenciadas en T1, axiales potenciadas en FLAIR-T2 y secuencia combinada de densidad protónica y T2-FSE. Las lesiones de la sustancia blanca se clasificaron como profundas, periventriculares o ambas. Resultados. La prevalencia de foramen oval permeable (53,6% frente a 48,5%; p = 0,80) y la proporción de foramen oval permeable masivo y permanente fueron similares entre los pacientes con y sin lesiones de la sustancia blanca. Tampoco se encontraron diferencias en la prevalencia (55,6% frente a 52,6%; p = 1,00) o las características del foramen oval permeable en función de la distribución de las lesiones de la sustancia blanca. Conclusión. Los resultados no sugieren la intervención del foramen oval permeable en la fisiopatología de las lesiones de la sustancia blanca observadas en pacientes migrañosos.

No association between migraine frequency, white matter lesions and silent brain infarctions: a study in a series of women with chronic migraine.

BACKGROUND AND PURPOSE: It has been suggested that silent infarctions (SIs) and hyperintense white matter lesions (WMLs) are related to migraine frequency. We studied their prevalence and anatomical distribution in patients with chronic migraine (CM). METHODS: A total of 96 women with CM [mean age 43 (range 16-65) years] and 29 women with episodic migraine (EM) [mean age 36 (range 16-58) years] underwent 1.5-T magnetic resonance imaging following the CAMERA protocol. The number, size and location of SIs and deep WMLs were recorded and a modified Fazekas scale was applied to assess periventricular WMLs. RESULTS: White matter lesions were found in 59 (61.5%) women with CM and 17 (58.6%) women with EM (odds ratio, 1.13; 95% confidence intervals, 0.48-2.62; P = 0.784). The majority (63% CM and 71% EM) were small deep WMLs. Exclusive periventricular WMLs were exceptional. Of the 739 WMLs seen in patients with CM, 734 (99.3%) were hemispheric and mostly frontal (81%). Posterior fossa WMLs were seen in only five (5.2%) women with CM (always in the pons) and two (6.9%) women with EM. Age >45 years was the only vascular risk factor associated with a higher WML number (median: 0 < 45 years and 3 > 45 years; P = 0.004). We found seven SIs in six women with CM (6.3%). CONCLUSIONS: As compared with the expected prevalence at this age, this study confirms that the prevalence of WMLs, in most cases small, deep and frontal, was increased in CM and EM. However, our results do not support an association of WMLs or SIs with a higher frequency of attacks, but with the presence of vascular risk factors and mainly age >45 years.

CALCA and TRPV1 genes polymorphisms are related to a good outcome in female chronic migraine patients treated with OnabotulinumtoxinA.

BACKGROUND: Some variables have been proposed as predictors of efficacy of OnabotulinumtoxinA in chronic migraine patients, but data available are inconclusive. We aimed to analyse the influence of single nucleotide polymorphisms in the response to OnabotulinumtoxinA. METHODS: We included 156 female patients treated with OnabotulinumtoxinA accordingly to PREEMPT paradigm in three headache units. OnabotulinumtoxinA was offered to patients that had not responded to topiramate and at least one other preventative. Age at first procedure was 43.7 ± 11.8 years (16-74). Patients with a reduction of at least 50% in the number of migraine days after two OnabotulinumtoxinA procedures were considered as responders. We analysed 25 polymorphisms selected for their relevance regarding migraine pathophysiology and their association with migraine according to previously published genome-wide association studies. Genotyping was performed using KASP probes and a LightCycler-480 (Roche-Diagnostics). Allelic, genotypic frequencies and dominance/recesivity hypothesis of the allelic variants were compared between responders and non-responders by Fisher's exact test. RESULTS: Response to treatment with OnabotulinumtoxinA was achieved in 120 patients (76,9%). Two polymorphisms showed differences: CALCA rs3781719, where allele C represents 26.9% in responders and 40.9% in non-responders (p = 0.007, OR = 3.11 (1.33-7.26)); and TRPV1 rs222749, where allele A represents 4.17% in responders and 12.5% in non-responders (p = 0.013, OR = 3.29 (1.28-8.43)). No significant differences in rest of polymorphisms or clinical or demographic variables were found. CONCLUSIONS: Polymorphic variations of CALCA and TRPV1 genes might play a role as prognostic markers of efficacy of OnabotulinumtoxinA in chronic migraine female patients in our population.

Relationship between serum levels of VIP, but not of CGRP, and cranial autonomic parasympathetic symptoms: A study in chronic migraine patients.

Background Cranial autonomic parasympathetic symptoms (CAPS) appear in at least half of migraine patients theoretically as a result of the release of peptides by the trigemino-vascular system (TVS). Cranial pain pathways become sensitised by repeated episodes of TVS activation, leading to migraine chronification. Objective The objective of this article is to correlate the presence of CAPS with serum levels of vasoactive intestinal peptides (VIP) and calcitonin gene-related peptide (CGRP). Patients and methods Patients with chronic migraine (CM) were asked about the presence - during migraine attacks - of five CAPS, which were scored from 0 to 10 by using a quantitative scale. Serum VIP and CGRP levels were determined by ELISA. Results We interviewed 87 CM patients (82 females; mean age 44.7 ± 10.6 years). Seventeen had no CAPS, while 70 reported at least one CAPS. VIP levels ranged from 20.8 to 668.2 pg/ml (mean 154.5 ± 123.2). There was a significant positive correlation between scores in the CAPS scale and VIP levels (Spearman correlation coefficient = 0.227; p = 0.035). VIP levels were significantly higher in CM patients by at least one point in the scale vs those with 0 points ( p = 0.002). Analysing symptoms individually, VIP levels were numerically higher in those patients with symptoms, though they were significantly higher only in those patients with lacrimation vs those without it ( p = 0.013). There was no significant correlation between CGRP levels and the score in the CAPS scale. Conclusions Serum VIP, but not CGRP, levels seem to reflect the rate of activation of the parasympathetic arm of the TVS in migraine.

Differential effects of immunosuppressive drugs on T-cell motility.

The best-characterized mechanism of the action of immunosuppressive drugs is to prevent T-cell clonal expansion, thus containing the magnitude of the ensuing immune response. As T-cell recruitment to the inflammatory site is another key step in the development of T-cell-mediated inflammation, we analyzed and compared the effects of two commonly used immunosuppressants, cyclosporin A (CsA) and the rapamycin-related compound SDZ-RAD, on the motility of human CD4+ T cells. We show that CsA, but not SDZ-RAD, inhibits T-cell transendothelial migration in vitro. CsA selectively impaired chemokine-induced T-cell chemotaxis while integrin-mediated migration was unaffected. The inhibition of T-cell chemotaxis correlated with reduced AKT/PKB but not ERK activation following exposure to the chemokine CXCL-12/SDF-1. In addition, CsA, but not SDZ-RAD, prevents some T-cell receptor-mediated effects on T-cell motility. Finally, we show that CsA, but not SDZ-RAD inhibits tissue infiltration by T cells in vivo. Our data suggest a prominent antiinflammatory role for CsA in T-cell-mediated tissue damage, by inhibiting T-cell trafficking into tissues in addition to containing clonal expansion.

15-Deoxy-Delta 12,14-prostaglandin J2 inhibition of NF-kappaB-DNA binding through covalent modification of the p50 subunit.

Cyclopentenone prostaglandins display anti-inflammatory activities and interfere with the signaling pathway that leads to activation of transcription factor NF-kappaB. Here we explore the possibility that the NF-kappaB subunit p50 may be a target for the cyclopentenone 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)). This prostaglandin inhibited the DNA binding ability of recombinant p50 in a dose-dependent manner. The inhibition required the cyclopentenone moiety and could be prevented but not reverted by glutathione and dithiothreitol. Moreover, a p50 mutant with a C62S mutation was resistant to inhibition, indicating that the effect of 15d-PGJ(2) was probably due to its interaction with cysteine 62 in p50. The covalent modification of p50 by 15d-PGJ(2) was demonstrated by reverse-phase high pressure liquid chromatography and mass spectrometry analysis that showed an increase in retention time and in the molecular mass of 15d-PGJ(2)-treated p50, respectively. The interaction between p50 and 15d-PGJ(2) was relevant in intact cells. 15d-PGJ(2) effectively inhibited cytokine-elicited NF-kappaB activity in HeLa without reducing IkappaBalpha degradation or nuclear translocation of NF-kappaB subunits. 15d-PGJ(2) reduced NF-kappaB DNA binding activity in isolated nuclear extracts, suggesting a direct effect on NF-kappaB proteins. Finally, treatment of HeLa with biotinylated-15d-PGJ(2) resulted in the formation of a 15d-PGJ(2)-p50 adduct as demonstrated by neutravidin binding and immunoprecipitation. These results clearly show that p50 is a target for covalent modification by 15d-PGJ(2) that results in inhibition of DNA binding.

Posttranscriptional regulation of human iNOS by the NO/cGMP pathway.

Nitric oxide (NO) and cGMP may exert positive or negative effects on inducible NO synthase (iNOS) expression. We have explored the influence of the NO/cGMP pathway on iNOS levels in human mesangial cells. Inhibition of NOS activity during an 8-h stimulation with IL-1beta plus tumor necrosis factor (TNF)-alpha reduced iNOS levels, while NO donors amplified iNOS induction threefold. However, time-course studies revealed a subsequent inhibitory effect of NO donors on iNOS protein and mRNA levels. This suggests that NO may contribute both to iNOS induction and downregulation. Soluble guanylyl cyclase (sGC) activation may be involved in these effects. Inhibition of sGC attenuated IL-1beta/TNF-alpha-elicited iNOS induction and reduced NO-driven amplification. Interestingly, cGMP analogs also modulated iNOS protein and mRNA levels in a biphasic manner. Inhibition of transcription unveiled a negative posttranscriptional modulation of the iNOS transcript by NO and cGMP at late times of induction. Supplementation with 8-bromo-cGMP (8-BrcGMP) reduced iNOS mRNA stability by 50%. These observations evidence a complex feedback regulation of iNOS expression, in which posttranscriptional mechanisms may play an important role.