Canalopatías autoinmunes del sistema nervioso central

[spa] Esta tesis plantea por primera vez la existencia de canalopatías autoinmunes en el sistema nervioso central, aportando los resultados obtenidos de dos trabajos importantes. Se conocía la existencia de autoanticuerpos contra canales iónicos dependientes de voltaje en síndromes neurológicos periféricos. Dada la asociación entre síndromes que afectan al SNP y síndromes neurológicos centrales, se quiso estudiar si los autoanticuerpos contra canales iónicos dependientes de voltaje presentes en los síndromes neurológicos periféricos, podían estar presentes en síndromes neurológicos centrales. Esto se quiso estudiar en los anticuerpos contra canales de calcio dependientes de voltaje (VGCC) presentes en el síndrome miasténico de Eaton-Lambert (SMEL). Dada la conocida asociación entre el SMEL y la degeneración cerebelosa paraneoplásica subaguda (DCP), quedaba por determinar si la DCP podía estar asociada o no los anticuerpos anti-VGCC. Posteriormente, se amplió el estudio de los anticuerpos antineuronales contra canales iónicos en asociación con síndromes neurológicos del SNC, a los canales de potasio dependientes de voltaje (VGKC). Se conocía la presencia de anticuerpos anti-VGKC en la neuromiotonía. Surgió la posibilidad de una asociación entre la encefalitis límbica y otros anticuerpos o trastornos. Además, un 40% de los pacientes con encefalitis límbica quedaban por determinar séricamente, por la ausencia de anticuerpos (seronegativos) o la presencia de anticuerpos no caracterizados. Se estudió de la presencia de anticuerpos anti-VGKC en pacientes con una encefalitis límbica, de origen paraneoplásico o idiopático.Con los trabajos realizados, se ha abierto la posibilidad a la existencia de canalopatías autoinmunes en el SNC, como la ataxia causada por la degeneración cerebelosa asociada al cáncer de pulmón de célula pequeña y la encefalitis límbica. La relación causal del anticuerpo con el síndrome neurológico no se ha dilucidado, dado que es difícil demostrar si los anticuerpos son capaces de cruzar la barrera hematoencefálica o si son sintetizados en el propio SNC, causando la posterior disfunción neuronal.Los anticuerpos descritos hasta ahora en el SNC eran utilizados como marcadores de síndromes paraneoplásicos y por lo tanto, no eran patogénicos y su diana era intracelular. En cambio, los anticuerpos que se han descrito en esta tesis como causantes de las canalopatías autoinmunes son patogénicos y en principio tienen dianas extracelulares: los canales iónicos neuronales. Esta diferencia plantea interesantes preguntas sobre la relación entre el SNC y el sistema inmune. Aunque a nivel práctico, nos permite tener una herramienta diagnóstico-terapéutica frente a pacientes que presenten estos síndromes, pues aquellos pacientes que presentan anticuerpos, especialmente si tienen una encefalitis límbica, responden muy bien a tratamiento inmunosupresor. Por lo tanto, los anticuerpos descritos en esta tesis permiten ser utilizados como un marcador diagnóstico y de control de mejoría clínico-inmunológica. Esto es un avance para manejo de estos pacientes neurológicos

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

Chronic migraine; Episodic migraine; Preventive treatmentMigraña crónica; Migraña episódica; Tratamiento preventivoMigranya crònica; Migranya episòdica; Tractament preventiuEptinezumab, 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.The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. Medical writing was funded by Lundbeck Spain in accordance with Good Publication Practice (GPP3) guidelines. Lundbeck Spain was not involved in the study design, collection, analysis, interpretation of data, or the decision to submit it for publication

The impact of epigenetic mechanisms in migraine: Current knowledge and future directions

DNA methylation; Biomarkers; EpigeneticsMetilació de l'ADN; Biomarcadors; EpigenèticaMetilación del ADN; Biomarcadores; EpigenéticaBackground Epigenetic mechanisms, including DNA methylation, microRNAs and histone modifications, may modulate the genetic expression in migraine and its interaction with internal and external factors, such as lifestyle and environmental changes. Objective To summarize, contextualize and critically analyze the published literature on the current state of epigenetic mechanisms in migraine in a narrative review. Findings The studies published to date have used different approaches and methodologies to determine the role of epigenetic mechanisms in migraine. Epigenetic changes seem to be involved in migraine and are increasing our knowledge of the disease. Conclusions Changes in DNA methylation, microRNA expression and histone modifications could be utilized as biomarkers that would be highly valuable for patient stratification, molecular diagnosis, and precision medicine in migraine.The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: MV-P was supported by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie IF grant agreement No. 101023175

OnabotulinumtoxinA: An Effective Tool in the Therapeutic Arsenal for Chronic Migraine With Medication Overuse

Objective: To evaluate the early response of onabotulinumtoxinA as a treatment tool in patients with chronic migraine (CM) and medication overuse (MO).Patients and Methods: This is a retrospective study in patients with CM and MO who received two cycles of onabotulinumtoxinA infiltrations following PREEMPT protocol. We evaluated the efficacy of onabotulinumtoxinA in MO resolution, defined as less than 10 days/month of acute medication intake (triptans, opioids, and combinations) or 15 days/month (non-steroidal anti-inflammatory drugs - and simple analgesics). In addition, we analyzed changes in headache frequency, pain intensity, and headache-related disability (MIDAS scale). A multivariate analysis was carried out to identify factors independently related to MO resolution.Results: We included 139 consecutive patients with CM and MO. After 2 cycles of onabotulinumtoxinA, 73.4% had ≥50% reduction in acute medication intake and 57.6% achieved MO resolution. 7.9% of patients did not use any acute medication after treatment. Even though both MO-ongoing group and MO-resolution group improve in headache frequency, the reduction was significantly higher for the group which discontinued the use of acute medication after onabotulinumtoxinA treatment (p < 0.001). In this group, 73.0% reduced headache frequency ≥50%. Daily headache changed from 71.2 to 23.2% (p < 0.001). Both groups showed an improvement in pain intensity and in MIDAS score (p < 0.05). In the multivariate analysis we observed that MO resolution had an inverse association with medication intake at baseline (OR:0.294, p < 0.05) and a direct association with frequency (OR:20.455, p < 0.001) and MIDAS score (OR: 6.465, p < 0.05) improvements.Conclusion: OnabotulinumtoxinA has an early beneficial effect on the discontinuation of acute medication in a substantial proportion of patients with CM and MO. Therefore, onabotulinumtoxinA might be considered a therapeutic tool in CM with MO

Non-invasive neuromodulation for migraine and cluster headache : a systematic review of clinical trials

Non-invasive neuromodulation therapies for migraine and cluster headache are a practical and safe alternative to pharmacologics. Comparisons of these therapies are difficult because of the heterogeneity in study designs. In this systematic review of clinical trials, the scientific rigour and clinical relevance of the available data were assessed to inform clinical decisions about non-invasive neuromodulation. PubMed, Cochrane Library and ClinicalTrials.gov databases and the WHO's International Clinical Trials Registry Platform were searched for relevant clinical studies of non-invasive neuromodulation devices for migraine and cluster headache (1 January 1990 to 31 January 2018), and 71 were identified. This analysis compared study designs using recommendations of the International Headache Society for pharmacological clinical trials, the only available guidelines for migraine and cluster headache. Non-invasive vagus nerve stimulation (nVNS), single-transcranial magnetic stimulation and external trigeminal nerve stimulation (all with regulatory clearance) were well studied compared with the other devices, for which studies frequently lacked proper blinding, sham controls and sufficient population sizes. nVNS studies demonstrated the most consistent adherence to available guidelines. Studies of all neuromodulation devices should strive to achieve the same high level of scientific rigour to allow for proper comparison across devices. Device-specific guidelines for migraine and cluster headache will be soon available, but adherence to current guidelines for pharmacological trials will remain a key consideration for investigators and clinicians

Epidemiology, burden and clinical spectrum of cluster headache: a global update

Disability; Economic and job-related burdens; Quality of lifeDiscapacidad; Cargas económicas y laborales; Calidad de vidaDiscapacitat; Càrregues econòmiques i laborals; Qualitat de vidaBackground This narrative review aims to broaden our understanding of the epidemiology, burden and clinical spectrum of cluster headache based on updated findings with a global perspective. Methods We conducted a literature search on the following topics: (a) epidemiology; (b) burden: quality of life, disability, economic burden, job-related burden and suicidality; and (c) clinical spectrum: male predominance and its changes, age, pre-cluster and pre-attack symptoms, aura, post-drome, attack characteristics (location, severity, duration and associated symptoms), bout characteristics (attack frequency, bout duration and bout frequency), circadian and seasonal rhythmicity and disease course. Results New large-scale population-based reports have suggested a lower prevalence than previous estimations. The impact of cluster headache creates a significant burden in terms of the quality of life, disability, economic and job-related burdens and suicidality. Several studies have reported decreasing male-to-female ratios and a wide age range at disease onset. The non-headache phases of cluster headache, including pre-cluster, pre-attack and postictal symptoms, have recently been revisited. The latest data regarding attack characteristics, bout characteristics, and circadian and seasonal rhythmicity from different countries have shown variability among bouts, attacks, individuals and ethnicities. Studies on the disease course of cluster headache have shown typical characteristics of attacks or bouts that decrease with time. Conclusions Cluster headache may be more than a “trigeminal autonomic headache” because it involves complex central nervous system phenomena. The spectrum of attacks and bouts is wider than previously recognised. Cluster headache is a dynamic disorder that evolves or regresses over time.This study was supported by the New Faculty Start-up Fund of Seoul National University and National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIP; No. 2020R1A2B5B01001826)

Impact of monthly headache days on migraine-related quality of life: Results from the Chronic Migraine Epidemiology and Outcomes (CaMEO) study

Allodynia; Anxiety; DepressionAl·lodínia; Ansietat; DepressióAlodinia; Ansiedad; DepresiónObjective To characterize the direct impact of monthly headache days (MHDs) on health-related quality of life (HRQoL) in people with migraine and the potential mediating effects of anxiety, depression, and allodynia. Background Although the general relationship between increased migraine frequency (i.e., MHDs) and reduced HRQoL is well established, the degree to which reduced HRQoL is due to a direct effect of increased MHDs or attributable to mediating factors remains uncertain. Methods Cross-sectional baseline data from participants with migraine who completed the Core and Comorbidities/Endophenotypes modules in the 2012–2013 US Chronic Migraine Epidemiology and Outcomes (CaMEO) study, a longitudinal web-based survey study, were analyzed. The potential contribution of depression, anxiety, and/or allodynia to the observed effects of MHDs on HRQoL as measured by the Migraine-Specific Quality-of-Life Questionnaire version 2.1 (MSQ) was evaluated. Results A total of 12,715 respondents were included in the analyses. The MSQ domain scores demonstrated progressive declines with increasing MHD categories (B = −1.23 to −0.60; p < 0.001). The observed HRQoL decrements associated with increasing MHDs were partially mediated by the presence of depression, anxiety, and allodynia. The MHD values predicted 24.0%–32.4% of the observed variation in the MSQ domains. Depression mediated 15.2%–24.3%, allodynia mediated 9.6%–16.1%, and anxiety mediated 2.3%–6.0% of the observed MHD effects on the MSQ. Conclusions Increased MHD values were associated with lower MSQ scores; the impact of MHDs on the MSQ domain scores was partially mediated by the presence of depression, anxiety, and allodynia. MHDs remain the predominant driver of the MSQ variation; moreover, most of the variation in the MSQ remains unexplained by the variables we analyzed. Future longitudinal analyses and studies may help clarify the contribution of MHDs, comorbidities, and other factors to changes in HRQoL

Anti-CGRP monoclonal antibodies in chronic migraine with medication overuse: real-life effectiveness and predictors of response at 6 months

Erenumab; Migranya; Anticossos monoclonalsErenumab; Migraña; Anticuerpos monoclonicosErenumab; Migraine; Monoclonal antibodiesBackground In daily practice, anti-CGRP monoclonal antibodies (MAbs) may be useful in chronic migraine (CM) with medication overuse (MO), but data is limited. We evaluated their effectiveness in a real-life clinical cohort. Methods This is a prospective study conducted in CM patients with and without medication overuse treated with monthly MAbs during 6 months (erenumab/galcanezumab). We collected headache characteristics, including acute medication intake, through an electronic diary. We compared patients (1) with and without MO at baseline, (2) with and without ongoing MO after treatment, defining MO resolution as < 10 or 15 days/month of acute medication intake, according to analgesic type, during the 6-month treatment. Results Of 139 CM patients completing 6-month treatment with anti-CGRP MAbs, 71.2% (99/139) had MO at baseline. After 6 months, patients with and without MO at baseline had significant and similar proportions of ≥50% reduction in migraine days/month (MO: 63.6% vs. non-MO: 57.5%, p = 0.500). 60.6% (60/99) no longer satisfied MO definition. Reduction in headache frequency compared to baseline occurred in both MO-ongoing and MO-resolution group, although those who stopped overusing had a greater improvement (headache days/month: − 13.4 ± 7.6 vs. -7.8 ± 7.2, p < 0.0001). No differences in MO resolution were observed according to the MAbs used. Baseline lower pain severity was associated with MO resolution (OR [95%]:0.236[0.054–0.975]; p = 0.049). Conclusions In real-life anti-CGRP MAbs are as effective in CM patients with MO as in patients without it and facilitate MO cessation. Reduction in headache frequency and acute medication days/month occurs regardless of whether patients stop overusing or not.No funding was received for this study

Effect of Atogepant for Preventive Migraine Treatment on Patient-Reported Outcomes in the Randomized, Double-blind, Phase 3 ADVANCE Trial

Atogepant; Preventive treatment; MigraineAtogepant; Tractament preventiu; MigranyaAtogepant; Tratamiento preventivo; MigrañaBackground and Objectives The oral calcitonin gene–related peptide receptor antagonist atogepant is indicated for the preventive treatment of episodic migraine. We evaluated changes in patient-reported outcomes with atogepant in adults with migraine. Methods In this phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (ADVANCE), adults with 4–14 migraine days per month received atogepant (10, 30, or 60 mg) once daily or placebo. Secondary endpoints included changes from baseline in Migraine-Specific Quality-of-Life Questionnaire (MSQ) version 2.1 Role Function–Restrictive (RFR) domain at week 12 and mean monthly Activity Impairment in Migraine–Diary (AIM-D) Performance of Daily Activities (PDA) and Physical Impairment (PI) domains across the 12-week treatment period. Exploratory endpoints included change in MSQ Role Function–Preventive (RFP) and Emotional Function (EF) domains; AIM-D total scores; and change in Headache Impact Test (HIT)–6 scores. Results Of 910 participants randomized, 873 comprised the modified intent-to-treat population (atogepant: 10 mg [n = 214]; 30 mg [n = 223]; and 60 mg [n = 222]; placebo [n = 214]). All atogepant groups demonstrated significantly greater improvements vs placebo in MSQ RFR that exceeded minimum clinically meaningful between-group difference (3.2 points) at week 12 (least-square mean difference [LSMD] vs placebo: 10 mg [9.9]; 30 mg [10.1]; 60 mg [10.8]; all p < 0.0001). LSMDs in monthly AIM-D PDA and PI scores across the 12-week treatment period improved significantly for the atogepant 30 (PDA: −2.54; p = 0.0003; PI: −1.99; and p = 0.0011) and 60 mg groups (PDA: −3.32; p < 0.0001; PI: −2.46; p < 0.0001), but not for the 10 mg group (PDA: −1.19; p = 0.086; PI: −1.08; p = 0.074). In exploratory analyses, atogepant 30 and 60 mg were associated with nominal improvements in MSQ RFP and EF domains, other AIM-D outcomes, and HIT-6 scores at the earliest time point (week 4) and throughout the 12-week treatment period. Results varied for atogepant 10 mg. Discussion Atogepant 30 and 60 mg produced significant improvements in key patient-reported outcomes including MSQ-RFR scores and both AIM-D domains. Nominal improvements also occurred for other MSQ domains and HIT-6, reinforcing the beneficial effects of atogepant as a new treatment for migraine prevention.Allergan, now AbbVie, sponsored the study

Migraine-attributed burden, impact and disability, and migraine-impacted quality of life: Expert consensus on definitions from a Delphi process

Delphi; Migraine; DisabilityDelphi; Migraña; DiscapacidadDelphi; Migranya; DiscapacitatBackground Migraine-attributed burden, impact, disability and migraine-impacted quality of life are important concepts in clinical management, clinical and epidemiological research, and health policy, requiring clear and agreed definitions. We aimed to formulate concise and precise definitions of these concepts by expert consensus. Methods We searched the terms migraine-attributed burden, impact, disability and migraine-impacted quality of life in Embase and Medline from 1974 and 1946 respectively. We followed a Delphi process to reach consensus on definitions. Results We found widespread conflation of concepts and inconsistent terminology within publications. Following three Delphi rounds, we defined migraine-attributed burden as “the summation of all negative consequences of the disease or its diagnosis”; migraine-attributed impact as “the effect of the disease, or its diagnosis, on a specified aspect of life, health or wellbeing”; migraine-attributed disability as “physical, cognitive and mental incapacities imposed by the disease”; and migraine-impacted quality of life as “the subjective assessment by a person with the disease of their general wellbeing, position and prospects in life”. We complemented each definition with a detailed description. Conclusion These definitions and descriptions should foster consistency and encourage more appropriate use of currently available quantifying instruments and aid the future development of others.The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded by Eli Lilly and Company