Changes in innate immunity in chronic migraine. Role of Toll-like receptors 2 and 4 as key players in migraine chronification and potential therapeutic targets

Migraine is a complex disorder that involves several physiopathological mechanisms. Toll-like receptors (TLRs) are involved in neuroinflammation, but their role in migraine is not completely understood. This translational study investigates whether expression of Toll-like receptors 2 and 4 (TLR2 and TLR4) is increased in chronic migraine (CM) patients, and if TLR4 is involved in the vascular response to CSD. With this aim, we designed a clinical cross-sectional study measuring peripheral blood expression of TLR2 and TLR4 and a experimental study based on an animal model of cortical spreading depolarization (CSD). CM patients showed increased expression of TLR4 and TLR2 in peripheral blood. TLR4 KO mice had a different response to CSD stimulation that was reproduced after pharmacological blockade of TLR4. Our results suggest that TLR2 and TLR4 may have a role in migraine pathophysiology, providing a potential novel strategy for treatment

Hospital-associated deconditioning:Not only physical, but also cognitive

INTRODUCTION: Hospital‐associated deconditioning (HAD) or post‐hospital syndrome is well recognized as reduced functional performance after an acute hospitalization. Recommendations for the management of HAD are still lacking, partly due to a poor understanding of the underlying processes. We aimed to review existing data on risk factors, pathophysiology, measurement tools, and potential interventions. MATERIALS AND METHODS: We conducted a systematic review from bibliographical databases in English, Spanish and French with keywords such as ‘post‐hospitalization syndrome’ or ‘deconditioning’. We selected studies that included people aged 60 years or older. Three researchers independently selected articles and assessed their quality. RESULTS: From 4421 articles initially retrieved, we included 94 studies. Most were related to risk factors, trajectories and measures, and focused on the physical aspects of deconditioning. Risk factors for HAD included age, nutritional status, mobility, and pre‐admission functional status, but also cognitive impairment and depression. Regarding interventions, almost all studies were devoted to physical rehabilitation and environmental modifications. Only one study focused on cognitive stimulation. DISCUSSION: In the last decade, studies on HAD have mostly focused on the physical domain. However, neurological changes may also play a role in the pathophysiology of HAD. Beyond physical interventions, cognitive rehabilitation and neurological interventions should also be evaluated to improve deconditioning prevention and treatment in the hospital setting

Pentraxin 3 (PTX3): A Molecular Marker of Endothelial Dysfunction in Chronic Migraine

Even though endothelial dysfunction is known to play a role in migraine pathophysiology, studies regarding levels of endothelial biomarkers in migraine have controversial results. Our aim was to evaluate the role of pentraxin 3 (PTX3) and soluble tumour necrosis factor-like weak inducer of apoptosis (sTWEAK) as potential biomarkers of endothelial dysfunction in chronic migraine (CM). We performed a case-control study including 102 CM patients and 28 control subjects and measured serum levels of markers of endothelial dysfunction (PTX3 and sTWEAK) and inflammation [high-sensitivity C-reactive protein (hs-CRP)] as well as brachial artery flow-mediated dilation (FMD) during interictal periods. Interictal serum levels of PTX3 and sTWEAK were higher in CM patients than in controls (1350.6 ± 54.8 versus 476.1 ± 49.4 pg/mL, p < 0.001 and 255.7 ± 21.1 versus 26.4 ± 2.6 pg/mL, p < 0.0001; respectively). FMD was diminished in CM patients compared to controls (9.6 ± 0.6 versus 15.2 ± 0.9%, p < 0.001). Both PTX3 and sTWEAK were negatively correlated with FMD (r = −0.508, p < 0.001 and r = −0.188, p = 0.033; respectively). After adjustment of confounders, PTX3 remained significantly correlated to FMD (r = −0.250, p = 0.013). Diagnosis of CM was 68.4 times more likely in an individual with levels of PTX3 ≥ 832.5 pg/mL, suggesting that PTX3 could be a novel biomarker of endothelial dysfunction in CMThis research was funded by Spanish Ministry of Economy and Competitiveness—Institute of Health Carlos III, Grant/Award Numbers: PI15/01578S

Mild systemic inflammation enhances response to OnabotulinumtoxinA in chronic migraineurs

The anti-inflammatory effect of OnabotulinumtoxinA (OnabotA) has been a matter of discussion for many years. In chronic migraine, however, increased pro-inflammatory state is associated with good response to OnabotA. We aimed to investigate whether a mild systemic inflammatory state elicited by a common oral infection (periodontitis) could enhance treatment response to OnabotA. In this study, we included 61 chronic migraineurs otherwise healthy treated with OnabotA of which 7 were poor responders and 54 good responders. Before receiving OnabotA therapy, all participants underwent a full-mouth periodontal examination and blood samples were collected to determine serum levels of calcitonin gene-related peptide (CGRP), interleukin 6 (IL-6), IL-10 and high sensitivity C-reactive protein (hs-CRP). Periodontitis was present in 70.4% of responders and 28.6% of non-responders (P = 0.042). Responders showed greater levels of inflammation than non-responders (IL-6: 15.3 ± 8.7 vs. 9.2 ± 4.7 ng/mL, P = 0.016; CGRP: 18.8 ± 7.6 vs. 13.0 ± 3.1 pg/mL, P = 0.002; and hs-CRP: 3.9 ± 6.6 vs. 0.9 ± 0.8 mg/L, P = 0.003). A linear positive correlation was found between the amount of periodontal tissue inflamed in the oral cavity and markers of inflammation (IL-6: r = 0.270, P = 0.035; CGRP: r = 0.325, P = 0.011; and hs-CRP: r = 0.370, P = 0.003). This report shows that in presence of elevated systemic inflammatory markers related to periodontitis, OnabotA seems to reduce migraine attacks. The changes of scheduled inflammatory parameters after treatment and subsequent assessment during an adequate period still need to be doneThis study was partially supported by a grant from the Spanish Ministry of Economy and Competitiveness—Institute of Health Carlos III (PI15/01578). YL holds a Senior Clinical Research Fellowship supported by the UCL Biomedical Research Centre who receives funding from the NIHR (NIHR-INF-0387) and a research contract with Fundación Instituto de Investigación Sanitaria de Santiago de Compostela (fIDIS). TS (CPII17/00027) and FC (CP14/00154) are recipients of research contracts from Miguel Servet Program of Institute of Health Carlos IIIS

Iron Deposits in Periaqueductal Gray Matter Are Associated with Poor Response to OnabotulinumtoxinA in Chronic Migraine

Previous studies have reported increased brain deposits of iron in patients with chronic migraine (CM). This study aims to determine the relation between iron deposits and outcome after treatment with OnabotulinumtoxinA (OnabotA). Demographic and clinical data were collected for this study through a prospective cohort study including 62 CM patients treated with OnabotA in the Hospital Clínico Universitario de Santiago de Compostela (Spain). Demographic and clinical variables were registered. Selected biomarkers in plasma during interictal periods (calcitonin gene-related peptide (CGRP) and pentraxin-3 (PTX3)) and neuroimaging changes (iron deposits in the red nucleus (RN), substantia nigra (SN), globus pallidus (GP), and periaqueductal gray matter (PAG), and white matter lesions (WML)) were determined. Subjects were classified in responders (≥50% reduction in headache days) or non-responders (<50%). Responders to treatment were younger (mean age difference = 12.2; 95% confidence interval (CI): 5.4–18.9, p = 0.001), showed higher serum levels of CGRP (≥50 ng/mL) and PTX3 (≥1000 pg/mL) and smaller iron deposits in the GP and PAG (mean difference = 805.0; 95% CI: 37.9–1572.1 μL, p = 0.040 and mean difference = 69.8; 95% CI: 31.0–108.6 μL, p = 0.008; respectively). Differences in PAG iron deposits remained significant after adjusting for age (mean difference = 65.7; 95% CI: 22.8–108.6 μL, p = 0.003) and were associated with poor response to OnabotA after adjustment for clinical and biochemical variables (odds ratio (OR) = 0.963; 95% CI: 0.927–0.997, p = 0.041). We conclude that larger PAG iron deposits are associated with poor response to OnabotA in CMSpanish Ministry of Economy and Competitiveness—Institute of Health Carlos III, grant/award number PI15/01578S