Eptinezumab for the preventive treatment of episodic and chronic migraine: a narrative review.

Eptinezumab, a monoclonal antibody that targets calcitonin gene-related peptide (CGRP), was recently approved in Europe for the prophylactic treatment of migraine in adults who have at least four migraine days a month. Eptinezumab is administered by intravenous infusion every 12 weeks. During recent months, a considerable amount of evidence from eptinezumab trials has been published. The aim of this review is to describe the existing evidence on the tolerability, safety and efficacy of eptinezumab in patients with migraine. Data from randomized (PROMISE-1, PROMISE-2, RELIEF and DELIVER) and open-label (PREVAIL) phase 3 clinical trials have demonstrated the favorable effect of eptinezumab in migraine symptoms from first day of treatment. These studies showed that eptinezumab results in an overall reduction in mean monthly migraine days (MMDs), increases in the ≥50% and ≥ 75% migraine responder rates (MRRs) and improvements in patient-reported outcome measures in both patients with episodic migraine (EM) and with chronic migraine (CM), including patients who failed previous preventive treatments. The RELIEF trial also showed that eptinezumab, within 2 h of administration, reduced headache pain, migraine-associated symptoms and acute medication use when administered during a migraine attack. Eptinezumab benefits manifested as early as day 1 after dosing and with the subsequent doses lasted up to at least 2 years. Treatment-emergent adverse events reported by ≥2% of patients included upper respiratory tract infection and fatigue. Current evidence demonstrates that eptinezumab has a potent, fast-acting, sustained migraine preventive effect in patients with EM and CM. Eptinezumab has also shown to be well tolerated, supporting its use in the treatment of patients with migraine and inclusion in the current migraine therapeutic options.

Periodontal inflammation is associated with increased circulating levels of endothelial progenitor cells: a retrospective cohort study in a high vascular risk population.

Background: One of the main biological mechanisms behind the link between periodontitis and atherosclerotic vascular diseases is vascular endothelial dysfunction. Particularly, circulating endothelial progenitor cells (EPCs) have been considered a biomarker of altered vascular endothelial function. Objectives: The aim of this study was to investigate relationship between periodontal inflammation and increased number of circulating EPCs. Design: This is retrospective cohort study. Methods: In this study, 85 elderly patients with a previous history of hypertension were followed up to 12 months. A baseline full-mouth periodontal assessment was carried out, and the amount of periodontal tissue inflamed per subject was calculated as a proxy of periodontal inflammation [periodontal inflamed surface area (PISA)]. The number of circulating EPCs (CD34+/CD133+/KDR+) was determined by flow cytometry from peripheral blood samples collected at baseline and 12 months. Results: Mean concentrations of CD34+/CD133+/KDR+ progenitor cells were higher in periodontitis patients than in those without periodontitis at baseline [55.4, 95% confidence interval (CI) = 20.8 to 90.0 versus 27.2, 95% CI = 13.6 to 40.8, p = 0.008] and 12 months (114.6, 95% CI = 53.5 to 175.7 versus 19.1, 95% CI = 10.8 to 27.4, p = 0.003). A significant increase over the follow-up was noticed in the group of subjects with periodontitis (p = 0.049) but not in the nonperiodontitis group (p = 0.819). PISA was independently associated with CD34+/CD133+/KDR+ EPCs at baseline (B coefficient = 0.031, 95% CI = 0.005 to 0.058; p = 0.021). The relationship between PISA and CD34+/CD133+/KDR+ EPCs at 12 months was confounded by increased baseline body mass index (B coefficient = 0.064, 95% CI = -0.005 to 0.132; p = 0.066). Conclusion: Periodontal inflammation is associated with high number of CD34+/CD133+/KDR+ EPCs, thus supporting a potential link between periodontitis and endothelial dysfunction.

Association between periodontitis and peripheral markers of innate immunity activation and inflammation.

BACKGROUND: Immune response leading to increased systemic inflammation is one of the mechanisms linking periodontitis to chronic inflammatory diseases. The aim of this study was to compare the expression of toll-like receptors 2 and 4 in monocytes and neutrophils (TLR2M, TLR2N, TLR4M, and TLR4N) and its endogenous ligands (cellular fibronectin [cFN] and heat shock protein 60 [HSP60]) in patients with and without periodontitis. Additionally, the relationship between cFN and HSP60 expression with innate immunity activation and systemic inflammatory response (interleukin 6 [IL-6]) was also evaluated. METHODS: A case-controlled study was designed in which 30 patients with periodontitis (cases) and 30 age- and sex-matched participants without periodontitis (controls) were included. Fasting blood samples were collected to determine: (1) expression of TLR2N, TLR2M, TLR4N, and TLR4M by flow cytometry; and (2) serum concentrations of cFN, HSP60, and IL-6 by ELISA technique. RESULTS: Expression of TLR2M (411.5 [314.2, 460.0] vs. 236.5 [204.0, 333.0] AFU), TLR2N (387.0 [332.0, 545.5] vs 230.0 [166.2, 277.7] AFU), TLR4M (2478.5 [1762.2, 2828.0] vs 1705.0 [1274.5, 1951.2] AFU), and TLR4N (2791.0 [2306.7, 3226.2] vs. 1866.0 [1547.5, 2687.2] AFU) as well as serum levels of cFN (301.1 [222.2, 410.9] vs. 156.4 [115.3, 194.0] ng/ml) and IL-6 (10.4 [6.5, 11.5] vs. 3.5 [2.6, 4.9] pg/ml) were significantly higher in periodontitis patients than those without periodontitis. A positive association was found between periodontitis and cFN (odds ratio [OR] = 1.028, p < 0.001), TLR2N (OR = 1.026, p < 0.001), TLR4M (OR = 1.001, p = 0.002), and IL-6 (OR = 1.774, p < 0.001). CONCLUSIONS: Periodontitis patients exhibited high expression of TLRs, cFN, and IL-6.

The impact of a digital platform on migraine patient-centered outcome research. Evaluation of midolordecabeza.org, a headache website in Spanish.

OBJECTIVE: This internet survey aimed to analyze the activity of midolordecabeza.org, a specialized website for headache stakeholders. BACKGROUND: eHealth tools, such as websites, can be educational for stakeholders of a specific disease, such as patients. This is particularly helpful in chronic disorders such as migraine. eHealth also enhances patient-centered outcome research. The website midolordecabeza.org has the stated aim of organizing key information on headache making it accessible and useful for all stakeholders, and, eventually promoting patient participation. METHODS: We analyzed Google Analytics (GA) data to study the web's activity, traffic source, geographical distribution of access, registered-user behavior, electronic device performance, and temporary references with greater web activity. RESULTS: From January 2015 until December 2020, the website registered 1,121,585 visitors, 1,775,953 sessions, and a total of 3,833,144 views with an average time per session of nearly 2 min. Higher data traffic has been registered in Spanish-speaking countries such as Spain (33.3%; 591,256/1,775,953), where Spain's regions with higher views were statistically significantly correlated with the nationwide migraine prevalence (ρ = 0.505; p = 0.039). In regard to social behavior, returning users were statistically significantly associated with being a woman (84.0%; 5696/6781), and they predominantly acceded from organic searches (50.6%; 3434/6781). When answering available open surveys, 72.5% (1827/2520) described their migraine as a disabling disease with high impact on their daily tasks and 64.4% (14,016/21,764) were unaware of what their headache diagnosis is. CONCLUSIONS: Spanish-speaking patients with migraine around the world increasingly visited the headache-specialized website midolordecabeza.org using different electronic devices, showing great interest in their disease. This website allowed them to get updated information on their disease, share clinical data with physicians, and finally express their concerns.

MAB-MIG: registry of the spanish neurological society of erenumab for migraine prevention.

BACKGROUND: Erenumab was approved in Europe for migraine prevention in patients with ≥ 4 monthly migraine days (MMDs). In Spain, Novartis started a personalized managed access program, which allowed free access to erenumab before official reimbursement. The Spanish Neurological Society started a prospective registry to evaluate real-world effectiveness and tolerability, and all Spanish headache experts were invited to participate. We present their first results. METHODS: Patients fulfilled the ICHD-3 criteria for migraine and had ≥ 4 MMDs. Sociodemographic and clinical data were registered as well as MMDs, monthly headache days, MHDs, prior and concomitant preventive treatment, medication overuse headache (MOH), migraine evolution, adverse events, and patient-reported outcomes (PROs): headache impact test (HIT-6), migraine disability assessment questionnaire (MIDAS), and patient global improvement change (PGIC). A > 50% reduction of MMDs after 12 weeks was considered as a response. RESULTS: We included 210 patients (female 86.7%, mean age 46.4 years old) from 22 Spanish hospitals from February 2019 to June 2020. Most patients (89.5%) suffered from chronic migraine with a mean evolution of 8.6 years. MOH was present in 70% of patients, and 17.1% had migraine with aura. Patients had failed a mean of 7.8 preventive treatments at baseline (botulinum toxin type A-BoNT/A-had been used by 95.2% of patients). Most patients (67.6%) started with erenumab 70 mg. Sixty-one percent of patients were also simultaneously taking oral preventive drugs and 27.6% were getting simultaneous BoNT/A. Responder rate was 37.1% and the mean reduction of MMDs and MHDs was -6.28 and -8.6, respectively. Changes in PROs were: MIDAS: -35 points, HIT-6: -11.6 points, PIGC: 4.7 points. Predictors of good response were prior HIT-6 score < 80 points (p = 0.01), ≤ 5 prior preventive treatment failures (p = 0.026), absence of MOH (p = 0.039), and simultaneous BoNT/A treatment (p < 0.001). Twenty percent of patients had an adverse event, but only two of them were severe (0.9%), which led to treatment discontinuation. Mild constipation was the most frequent adverse event (8.1%). CONCLUSIONS: In real-life, in a personalized managed access program, erenumab shows a good effectiveness profile and an excellent tolerability in migraine prevention in our cohort of refractory patients.

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 done.

Interictal amylin levels in chronic migraine patients: A case-control study.

BACKGROUND: Recently, amylin and its receptors were found in different structures involved in migraine pathophysiology. Here, we evaluate interictal concentrations of amylin and calcitonin gene-related peptide in peripheral blood as biomarkers for chronic migraine. METHODS: We prospectively recruited patients with episodic migraine, chronic migraine and healthy controls. Interictal amylin and calcitonin gene-related peptide levels were assessed in blood samples using enzyme linked immunosorbent assay. RESULTS: We assessed plasma samples from 58 patients with episodic migraine (mean age 37.71 ± 10.47, 87.9% female), 191 with chronic migraine (mean age 46.03 ± 11.93, 95% female), and on 68 healthy controls (mean age 43.58 ± 11.08 years, 86% female). Body mass index was 25.94 ± 4.53 kg/m2 for migraine patients and 25.13 ± 4.92 kg/m2 for healthy controls (p = 0.0683). Interictal plasma amylin levels were higher in chronic migraine patients (47.1 pg/mL) than in the episodic migraine patients (28.84 pg/mL, p < 0.0001) and healthy controls (24.74 pg/mL, p < 0.0001). Plasma calcitonin gene-related peptide levels were increased (20.01 pg/mL) in chronic migraine patients when compared to healthy controls (11.37 pg/mL, p = 0.0016), but not to episodic migraine patients (18.89 pg/mL, p = 0.4369). Applying a cut-off concentration of 39.68 pg/mL plasma amylin, the sensitivity to differentiate chronic migraine from healthy controls was 57.6% and the specificity was 88.2%. Variables such as age, analgesic overuse, depression, allodynia, use of preventive medication or a history of aura did not influence the plasma concentrations of amylin or calcitonin gene-related peptide. CONCLUSION: Interictal plasma amylin levels are higher in patients with chronic migraine and may serve as a diagnostic biomarker for chronic migraine.

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 CM.

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 CM.

Prolonged Migraine Stuttering Aura: Structural, Functional, and Video Neuroimaging Study of an Atypical Migraine Aura. A Case Report.

BACKGROUND: Stuttering is a disorder in the rhythm of speech characterized by an involuntary repetition, prolongation, and cessation of sounds. Neurogenic acquired stuttering is a very rare disorder which could result from different conditions with the involvement of several brain locations. CASE REPORT: A 16-year-old male presented to our Hospital with headache associated with blurred vision followed by right-sided facial and upper limb tingling, clumsiness of right arm, and a complete inability to formulate language which evolved in the next minutes into an intense speech disorder characterized by persistent stuttering. Urgent brain magnetic resonance imaging showed a prominence of venous vasculature in left hemisphere in susceptibility weighted imaging sequence. A fluorodeoxyglucose-positron emission tomography revealed a bilateral occipital, temporal, and parietal hypometabolism. With the suspicion of migraine aura, analgesic treatment was administered. Symptoms progressively resolved inside 10 hours. Five months later he experienced a similar episode. CONCLUSION: This case report represents a diagnostic challenge and suggests the inclusion of stuttering within the neurological manifestations of higher cortical dysfunction that can be found as a result of migraine aura.

Severe periodontitis is linked with increased peripheral levels of sTWEAK and PTX3 in chronic migraineurs.

OBJECTIVES: Periodontitis (PD) and chronic migraine (CM) have been recently linked, and inflammatory processes and vascular endothelial changes are hypothesized as potential mediators of this relationship. The aim of this cross-sectional analysis was to investigate the potential association of PD with vascular systemic inflammation and complement activation in patients with CM. MATERIALS AND METHODS: Ninety-four chronic migraineurs underwent a full-mouth periodontal evaluation and a measure of PD activity and severity, namely the periodontal inflamed surface area (PISA) was calculated for each patient. We divided CM patients according to their periodontal status: mild PD (N = 14), moderate PD (N = 22), severe PD (N = 19), and non-PD (N = 39). Serum levels of C-reactive protein (CRP), pentraxin 3 (PTX3), soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK), and complements C3 and C4 were measured outside of migraine attacks. RESULTS: We found that severe periodontal patients had significantly higher circulating levels of PTX3 and sTWEAK compared with those without PD (2475.3 ± 1646.8 pg/mL vs. 516.6 ± 1193.8 pg/mL, P < 0.0001 and 672.4 ± 118.2 pg/mL vs. 485.7 ± 112.2 pg/mL, P < 0.0001; respectively). For the remaining biomarkers, no significant differences were found between groups. Severe PD was independently associated with higher levels of PTX3 (ß = 1997.6, P < 0.0001) and sTWEAK (ß = 187.1, P < 0.0001) but not with CRP, C3, and C4. PISA positively correlated to PTX3 (r = 0.475, P < 0.0001) and sTWEAK (r = 0.386, P < 0.0001). CONCLUSIONS: Based on these preliminary results, severe PD was linked with vascular systemic inflammation in patients with CM. However, further longitudinal studies should be performed to confirm these findings. CLINICAL RELEVANCE: sTWEAK and PTX3 measured in serum could be used as biomarkers in the PD-CM link.

Periodontal inflammation is related to increased serum calcitonin gene-related peptide levels in patients with chronic migraine.

BACKGROUND: Recently, a relationship was found between periodontitis and chronic migraine. Calcitonin gene-related peptide (CGRP) is a key element in migraine pathophysiology. However, no information exists of the potential association between periodontal inflammation and CGRP in chronic migraine. The aim of the study was, therefore, to investigate whether there is a link between periodontitis and peripheral levels of CGRP in a cohort of patients with chronic migraine. METHODS: We included 102 chronic migraineurs and 77 age- and sex-matched individuals free of headache/migraine. Full-mouth periodontal parameters were recorded and the periodontal inflamed surface area (PISA) was calculated to quantify the periodontal inflammatory status for each participant. Sociodemographic data and comorbidities were assessed by means of a standard questionnaire. We collected blood samples and serum concentrations were done for CGRP, interleukin (IL)-6 and IL-10. RESULTS: In the chronic migraine group, patients with periodontitis had greater levels of serum CGRP (19.7 ± 6.5 versus 15.3 ± 6.2 pg/mL, P < 0.0001) and IL-6 (15.1 ± 9.2 versus 9.6 ± 6.3 pg/mL, P < 0.0001) while non-significant differences were observed with IL-10 (2.0 ± 1.0 versus 2.8 ± 1.5 pg/mL, P = 0.675) concentrations than those without periodontitis. PISA was independently associated with CGRP in patients with chronic migraine (ß = 0.003; 95% confidence interval: 0.001 to 0.006, P = 0.031). PISA correlated positively with CGRP (r = 0.236; P = 0.017) and IL-6 (r = 0.262; P = 0.008) in chronic migraine. CONCLUSIONS: Periodontal inflammation is associated with increased circulating levels of CGRP in chronic migraineurs. Elucidating the exact mechanisms through which periodontitis and CGRP are linked in these patients deserves further investigation.

Self-reported periodontitis and migraine: results from a multicenter, cross-sectional survey in Spain.

The aim of this study was to evaluate self-reported periodontitis (PD) prevalence in migraineurs as well as to investigate the association between both diseases. A cross-sectional survey was carried out including patients diagnosed with migraine attending 12 Spanish Headache Units. We determined diagnosis of PD administering a validated self-reported questionnaire. Socio-demographic, clinical and medical information, comorbidities, daily habits, migraine characteristics and medication were collected using a questionnaire. Of the 651 consecutive migraineurs included in the study, 393 suffered from chronic migraine (CM). Self-reported PD was detected in 327 patients with migraine (50.2%). Migraineurs with self-reported PD were significantly older and had a previous history of fibromyalgia, stress, anxiety, depression, and allodynia (all P < 0.001). Additionally, this group of patients consumed more topiramate (P = 0.008) and simple analgesics (P < 0.001) than patients with migraine and without self-reported PD. Also, they were less active physically and belonged to a low education level (both P < 0.001). Prevalence of self-reported PD was significantly higher in chronic migraineurs compared to those diagnosed with episodic migraine (EM) (53.9% vs. 44.6%, P = 0.019). Logistic regression analyses showed that self-reported PD was associated with CM (OR 1.456; 95% CI 1.062-1.997, P = 0.020). However, after adjusting for significant confounders, the association was attenuated (OR 1.100; 95% CI 0.784-1.543, P = 0.581). We concluded that self-reported PD was significantly more frequent in CM compared to EM. Self-reported PD was associated with the presence of CM, although some comorbidities shared by both diseases could have an effect on this association.

Iron deposition in periaqueductal gray matter as a potential biomarker for chronic migraine.

OBJECTIVE: To study iron deposition in red nucleus (RN), globus pallidus (GP), and periaqueductal gray matter (PAG) as a potential biomarker of chronic migraine (CM) and its association with levels of biomarkers related to migraine pathophysiology. METHODS: This case-control study included 112 patients with migraine (55 CM, 57 episodic migraine [EM]) and 25 headache-free controls. We analyzed iron deposition using 3T MRI and the NIH software platform ImageJ; we analyzed serum levels of markers of inflammation, endothelial dysfunction, and blood-brain barrier (BBB) disruption by ELISA in peripheral blood during interictal periods. RESULTS: Patients with CM showed larger iron grounds volume in RN compared to patients with EM (70.2 ± 6.8 vs 25.5 ± 7.3 µL, p < 0.001) and controls (70.2 ± 6.8 vs 15.1 ± 10.8 µL, p < 0.001), as well as larger iron deposits in PAG compared to patients with EM (360.3 ± 6.5 vs 249.7 ± 6.9 µL, p < 0.001) and controls (360.3 ± 6.5 vs 168.6 ± 10.3 µL, p < 0.001). In PAG, differences were also significant between patients with EM and controls. No significant differences were obtained for GP. Receiver operating characteristic curves showed that the optimal threshold for iron volume was 15 µL in RN (80% sensitivity, 71% specificity) and 240 µL in PAG (93% sensitivity, 97% specificity). Iron grounds volume in PAG was correlated with higher plasma levels of soluble tumor necrosis factor-like WEAK (r = 0.395, p = 0.005) and cellular fibronectin (r = 0.294, p = 0.040). CONCLUSIONS: Patients with CM showed increased iron deposition in RN and PAG compared to patients with EM and controls. Iron grounds volume in PAG identified correctly patients with CM and was associated with elevated biomarkers of endothelial dysfunction and BBB disruption.

Association between periodontitis and chronic migraine: a case-control study.

The aim of this investigation was to examine whether chronic periodontitis (CP) is a risk indicator of chronic migraine (CM). We performed a case-control study consisted of 102 cases (patients diagnosed with CM) and 91 controls (non-CM individuals) matched by age and gender. Full-mouth periodontal charts, demographic, medical, clinical, as well as neurological data were obtained. In addition, high sensitive C-reactive protein serum levels were determined from blood samples of both cases (taken during migraine interictal period) and controls. The prevalence of CP was significantly higher in patients with CM compared to those without CM (58.8 vs. 30.8%, p < 0.0001). Logistic regression analysis showed that CP was significantly associated with the presence of CM, independently of well-known chronifying factors of migraine (OR 2.4; 95% CI 1.2-4.7; p = 0.012). Based on our results, CP could be considered as a risk indicator of CM. However, more evidence is necessary to investigate if this relationship is causal or not.

High serum procalcitonin levels in patients with periodontitis and chronic migraine.

BACKGROUND: To evaluate the contribution of chronic periodontitis (CP) to serum procalcitonin (proCT) levels in chronic migraine (CM) patients in a cross-sectional study. METHODS: We included 138 subjects divided into 4 groups based on clinical features of CM and periodontal parameters: systemically and periodontally healthy individuals (n = 37), systemically healthy and CP patients (n = 19), CM and periodontally healthy patients (n = 34), and CM+CP patients (n = 48). Demographic, neurological, clinical data as well as full-mouth periodontal records were obtained. ProCT and high sensitive C-reactive protein (hs-CRP) serum levels were determined from blood samples taken during migraine interictal period. RESULTS: Patients from the CP+CM group (0.056±0.006 ng/mL) had significantly higher serum proCT levels in comparison with the systemically and periodontally healthy group (0.029±0.019 ng/mL), CM group (0.041±0.002 ng/mL), or CP group (0.034±0.014 ng/mL) (p < 0.001). There were no significant differences in hs-CRP between groups (p = 0.081). Multiple linear regression analysis showed that CP was associated with increased proCT levels in CM patients (R2  = 0.293, p < 0.001). CONCLUSIONS: CP independently contributes to elevated serum proCT levels in CM patients. These findings suggest that CP could play a role in migraine chronification.

CGRP and PTX3 as Predictors of Efficacy of Onabotulinumtoxin Type A in Chronic Migraine: An Observational Study.

OBJECTIVE: The aim of this study is to find a relation between several biomarkers in peripheral blood and outcome after treatment with onabotulinumtoxin A (OnabotA). BACKGROUND: OnabotA is an effective treatment in chronic migraine (CM). Different studies have tried to find predictors of response to treatment, either with clinical characteristics, neuroimaging features, or molecular biomarkers; however, it is still not possible to predict the individual outcome. METHODS: We measured serum levels of biomarkers of inflammation (IL-6, IL-10, TNF-α, and hs-CRP), endothelial dysfunction (PTX3 and sTWEAK), blood-brain barrier disruption (cFN), brain damage (S100b, NSE), and trigemino-vascular activation (CGRP) by ELISA in a group of CM patients treated with OnabotA and healthy controls. After 24 weeks, patients were classified in two groups according to their outcome considering variations in headache frequency: nonresponders (nonimprovement or improvement <50%) and responders (improvement >50%). We compared baseline levels of biomarkers between these groups. RESULTS: Sixty-two patients diagnosed with CM (IHS 2013 criteria) who fulfilled criteria for treatment with OnabotA and 24 healthy controls were included. Fifteen patients did not respond to treatment (24.2%) and 47 were responders (75.8%). Pentraxin 3 (PTX3) serum levels (1455.4 ± 487.5 pg/mL versus 720.3 ± 334.1 pg/mL, P < .0001) and calcitonin gene-related peptide (CGRP) serum levels (133.1 ± 86.6 ng/mL versus 58.2 ± 91.7 ng/mL, P = .004) were significantly higher in responders than nonresponders. Serum basal levels of PTX3 >1000 pg/mL (AUC 0.908; 95% CI: 0.827-0.990) and CGRP >50 ng/mL (AUC 0.800; 95% CI: 0.652-0.947) were associated with good response to OnabotA treatment. CONCLUSIONS: These results show that molecular markers of trigeminovascular activation (CGRP) and endothelial dysfunction (PTX3) are associated with response to OnabotA and may act as new biomarkers for the selection of treatment in chronic migraineurs.

Role of adipocytokines in the pathophysiology of migraine: A cross-sectional study.

Background Obesity is a risk factor for migraine and headache chronification. Adipocytokines may be involved in this correlation. Objective To relate serum adipocytokine levels to clinical and biochemical parameters associated with migraine. Methods We measured levels of leptin, adiponectin and other inflammatory (interleukin 6, interleukin 10, tumor necrosis factor α, high sensitivity C-reactive protein) and endothelial (pentraxin 3, soluble TNF-like weak inducer of apoptosis) molecules potentially related to migraine pathophysiology in a group of migraine patients (IHS 2013) and healthy controls. Results One hundred and eleven patients (mean age 39.7 years, 93% female) and 24 healthy controls (mean age 35.9 years, 90% female) were included. Fifty-six patients were diagnosed with episodic migraine (mean age 35.1 years, 98.2% female) and 55 patients with chronic migraine (mean age 44.4 years, 89.5% female). Leptin serum levels (15.2 ng/mL, SD = 10.5 vs . 3.1 ng/mL, SD = 0.9; p < 0.001) and adiponectin serum levels (72.3 µg/mL, SD = 38.5 vs . 37.7 µg/mL, SD = 16.9; p < 0.001) were significantly increased in migraine patients. Leptin serum levels (15.5 ng/mL, SD = 9.7 vs . 10.8 ng/mL, SD = 6.0; p < 0.001) and adiponectin serum levels (65.8 µg/mL, SD = 42.9 vs . 33.2 µg/mL, SD = 31.0; p < 0.001) were significantly higher in chronic compared to episodic migraine patients. We found a positive correlation between leptin levels and inflammatory biomarkers: IL6 (r = 0.498; p < 0.001), TNF-α (r = 0.389; p < 0.001), and hs-CRP (r = 0.422; p < 0.001). Conclusions Leptin and adiponectin are increased in migraineurs. There is a correlation between adipocytokine levels and other inflammation-related molecules. This suggests a potential role of adipocytokines in migraine pathophysiology and chronification.