Differences in circulating alpha-calcitonin gene-related peptide levels in inflammatory bowel disease and its relation to migraine comorbidity: A cross-sectional study.

OBJECTIVE: To analyze the specificity of calcitonin gene-related peptide (CGRP) levels, we measured alpha-CGRP circulating levels in a large series of patients with a recent diagnosis of inflammatory bowel disease (IBD) who were interviewed regarding comorbid headache. BACKGROUND: Several studies have found an association between migraine and IBD. METHODS: In this cross-sectional study performed in an IBD clinic, morning serum alpha-CGRP levels were measured by enzyme-linked immunosorbent assay in 96 patients who were recently diagnosed with IBD and compared to those from 50 similar patients with chronic migraine (CM) and 50 healthy controls (HC). RESULTS: Alpha-CGRP levels were higher in patients with IBD (median [interquartile range] 56.9 [35.6-73.9] pg/mL) and patients with CM (53.0 [36.7-73.9] pg/mL) compared to HC (37.2 [30.0-51.8] pg/mL; p = 0.003; p = 0.019, respectively). Regarding IBD diagnostic subtypes, alpha-CGRP levels for ulcerative colitis (67.2 ± 49.3 pg/mL; 57.0 [35.6-73.4] pg/mL) and Crohn's disease (54.9 ± 27.5 pg/mL; 57.7 [29.1-76.1] pg/mL) were significantly higher than those of HC (p = 0.013, p = 0.040, respectively). Alpha-CGRP levels were further different in patients with IBD with migraine (70.9 [51.8-88.7] pg/mL) compared to HC (p < 0.001), patients with IBD without headache (57.5 [33.3-73.8] pg/mL; p = 0.049), and patients with IBD with tension-type headache but without migraine (41.7 [28.5-66.9] pg/mL; p = 0.004), though alpha-CGRP levels in patients with IBD without migraine (53.7 [32.9-73.5] pg/mL) remained different over HC (p = 0.028). CONCLUSION: Together with CM, circulating alpha-CGRP levels are different in patients with IBD, perhaps reflecting a chronic inflammatory state. IBD is an example of how alpha-CGRP levels are not a totally specific migraine biomarker. However, alpha-CGRP levels were further increased in patients with IBD who have a history of migraine, which reinforces its role as a biomarker in migraine patients, always bearing in mind their comorbidities.

Long-term safety of OnabotulinumtoxinA treatment in chronic migraine patients: a five-year retrospective study.

Background: Real-world studies have shown the sustained therapeutic effect and favourable safety profile of OnabotulinumtoxinA (BoNTA) in the long term and up to 4 years of treatment in chronic migraine (CM). This study aims to assess the safety profile and efficacy of BoNTA in CM after 5 years of treatment in a real-life setting. Methods: We performed a retrospective chart review of patients with CM in relation to BoNTA treatment for more than 5 years in 19 Spanish headache clinics. We excluded patients who discontinued treatment due to lack of efficacy or poor tolerability. Results: 489 patients were included [mean age 49, 82.8% women]. The mean age of onset of migraine was 21.8 years; patients had CM with a mean of 6.4 years (20.8% fulfilled the aura criteria). At baseline, patients reported a mean of 24.7 monthly headache days (MHDs) and 15.7 monthly migraine days (MMDs). In relation to effectiveness, the responder rate was 59.1% and the mean reduction in MMDs was 9.4 days (15.7 to 6.3 days; p < 0.001). The MHDs were also reduced by 14.9 days (24.7 to 9.8 days; p < 0.001). Regarding the side effects, 17.5% experienced neck pain, 17.3% headache, 8.5% eyelid ptosis, 7.5% temporal muscle atrophy and 3.2% trapezius muscle atrophy. Furthermore, after longer-term exposure exceeding 5 years, there were no serious adverse events (AE) or treatment discontinuation because of safety or tolerability issues. Conclusion: Treatment with BoNTA led to sustained reductions in migraine frequency, even after long-term exposure exceeding 5 years, with no evidence of new safety concerns.

Metastases Affecting Cranial Nervous Structures in Male Breast Cancer: Two Case Reports.

INTRODUCTION: Breast cancer in males is a very rare entity, and survival is mainly influenced by the stage at diagnosis. The lack of early detection tools in men results in a diagnostic delay of about 5-10 years and a higher percentage of metastatic disease at diagnosis. However, the characteristics of head metastases are not well defined. CASE REPORTS: We present 2 cases of male breast cancer with metastases affecting cranial nervous structures and we provide imaging and histologic data. Both were middle-aged patients with ductal-type, HER-2- negative, and androgen receptor-positive primary tumors. CONCLUSION: Although central nervous system involvement is uncommon, this entity should be considered in middle-aged males with focal neurologic symptoms. More cases would be necessary to better understand the biology of this condition in order to establish an adequate diagnosis and treatment.

Untangling the mess of CGRP levels as a migraine biomarker: an in-depth literature review and analysis of our experimental experience.

BACKGROUND: Calcitonin gene-related peptide (CGRP) is the most promising candidate to become the first migraine biomarker. However, literature shows clashing results and suggests a methodological source for such discrepancies. We aimed to investigate some of these methodological factors to evaluate the actual role of CGRP as biomarker. METHODS: Previous to the experimental part, we performed a literature review of articles measuring CGRP in migraine patients. Using our 399 bio-bank sera samples, we performed a series of experiments to test the validity of different ELISA kits employed, time of sample processing, long-term storage, sampling in rest or after moderate exercise. Analysis of in-house data was performed to analyse average levels of the peptide and the effect of sex and age. RESULTS: Literature review shows the high variability in terms of study design, determination methods, results and conclusions obtained by studies including CGRP determinations in migraine patients. CGRP measurements depends on the method and specific kit employed, also on the isoform detected, showing completely different ranges of concentrations. Alpha-CGRP and beta-CGRP had median with IQR levels of 37.5 (28.2-54.4) and 4.6 (2.4-6.4)pg/mL, respectively. CGRP content is preserved in serum within the 24 first hours when samples are stored at 4°C after clotting and immediate centrifugation. Storages at -80°C of more than 6 months result in a decrease in CGRP levels. Moderate exercise prior to blood extraction does not modulate the concentration of the peptide. Age positively correlates with beta-CGRP content and men have higher alpha-CGRP levels than women. CONCLUSIONS: We present valuable information for CGRP measurements in serum. ELISA kit suitability should be tested prior to the experiments. Alpha and beta-CGRP levels should be analysed separately as they can show different behaviours even within the same condition. Samples can be processed in a 24-h window if they have been kept in 4°C and should not be stored for more than 6 months at -80°C before assayed. Patients do not need to rest before the blood extraction unless they have performed a high-endurance exercise. For comparative studies, sex and age should be accounted for as these parameters can impact CGRP concentrations.

CandeSpartan Study: Candesartan Spanish Response-prediction and Tolerability study in migraine.

INTRODUCTION: Effectiveness of candesartan in migraine prevention is supported by two randomized controlled trials. We aimed to assess the effectiveness, tolerability, and response predictors of candesartan in the preventive treatment of migraine. METHODS: Observational, multicenter, prospective cohort study. The 50%, 75% and 30% responder rates, between weeks 8-12 and 20-24, were compared with the baseline. Treatment emergent adverse effects were systematically evaluated. Response predictors were estimated by multivariate regression models. RESULTS: Eighty-six patients were included, 79.1% females, aged 39.5 (inter-quartile range [IQR] 26.3-50.3), with chronic migraine (43.0%), medication overuse headache (55.8%) and a median of two (inter-quartile range: 0.75-3) prior preventive treatments. At baseline patients had 14 (10-24) headache and 8 (5-11) migraine days per month. The 30%, 50% and 75% responder rates were 40%, 34.9% and 15.1% between weeks 8-12, and 48.8%, 36%, and 18.6% between weeks 20-24. Adverse effects were reported by 30 (34.9%) and 13 (15.1%) patients between weeks 0-12 and 12-24, leading to discontinuation in 15 (17.4%) patients. Chronic migraine, depression, headache days per month, medication overuse headache, and daily headache at baseline predicted the response between weeks 20-24. CONCLUSION: Candesartan effectiveness and tolerability in migraine prevention was in line with the clinical trials' efficacy.Trial registration: The study protocol is registered in ClinicalTrials.gov (NCT04138316).

Increased prevalence of migraine in women with inflammatory bowel disease: A cross-sectional study.

BACKGROUND: Some studies have suggested an association between migraine and inflammatory bowel disease. We determined migraine prevalence in a cohort of patients with inflammatory bowel disease. METHODS: Patients with inflammatory bowel disease aged 18-65 years were interviewed using an ad hoc headache questionnaire. Those who admitted a history of headache in the last year answered the three questions of the ID-Migraine questionnaire. Those who answered "yes" to the three of them were classified as "definite" and those who answered "yes" to two were classified as "probable" migraine. RESULTS: We interviewed 283 patients with inflammatory bowel disease. Of these, 176 (62.2%) had headache. Fifty-nine (20.8%; 95% CI 16.3-26.0%) met migraine criteria either definite (n = 33; 11.7%; 95% CI 8.2-16.0%) or probable (n = 26; 9.2%; 95% CI 6.1-13.2). When divided by gender, 12 men (9.6%; 95% CI 5.1-16.2%) and 47 women (29.8%; 95% CI 22.8-37.5%) met migraine criteria. The prevalence of migraine was increased in inflammatory bowel disease patients from the current cohort (20.8%) versus that reported for our general population for the same age group (12.6%; p < 0.0001). These differences remained significant in female inflammatory bowel disease patients (29.8% versus 17.2% in our general population; p < 0.0001), but not in males (9.6% in inflammatory bowel disease vs 8.0%; p = 0.30). Seventeen patients with inflammatory bowel disease (6.0%; 95% CI 3.54-9.44%) fulfilled chronic migraine criteria. There were no differences in migraine prevalence by inflammatory bowel disease subtypes. CONCLUSION: Migraine prevalence, including chronic migraine, seems to be increased in patients with inflammatory bowel disease. The fact that this association was stronger for women suggests an influence of sex-related factors.

OnabotulinumtoxinA: Discussion of the evidence for effectiveness of OnabotulinumA and its place in chronic migraine treatment.

OnabotulinumtoxinA is a potent inhibitor of muscle contraction that acts by preventing the release of acetylcholine at the neuromuscular junction. In pain states such as migraine, its mechanism of action is not yet fully elucidated and probably relates to the phenomena of central and peripheral sensitization within the trigeminal system. Migraine is a prevalent and disabling disorder and, especially in its variant of chronic migraine (CM), is associated with relevant symptomatic and socioeconomic burden, the objective of preventive treatment being to reduce the frequency, duration, or severity of migraine attacks. OnabotulinumtoxinA, administered by intramuscular injection, is approved for the prevention of CM and is among the most utilized preventive treatments in CM and fundamental to clinical practice. The efficacy and safety of OnabotulinumtoxinA in the treatment of CM have been verified by the PREEMPT 1 and 2 studies and confirmed by the real-world studies that followed, including the COMPEL, REPOSE, and CM PASS. OnabotulinumtoxinA not only reduces headache days but also leads to improvement in functioning and quality of life, thereby reducing migraine impact. Data about its pathophysiology, efficacy, and its place in CM treatment in the era of CGRP monoclonal antibodies are reviewed and discussed here.

Serum Alpha and Beta-CGRP Levels in Chronic Migraine Patients Before and After Monoclonal Antibodies Against CGRP or its Receptor.

OBJECTIVE: The objective of this study was to analyze the evolution of alpha and beta-CGRP circulating levels throughout CGRP monoclonal antibodies (mAbs) treatment in patients with chronic migraine (CM). METHODS: We recruited patients with CM beginning mAbs along with sex and age paired healthy controls (HCs). Blood was extracted before, 2 weeks (M0.5) and 3 months (M3) after the first dose of mAbs, always in free-migraine periods, and once for HCs. Alpha and beta-CGRP serum levels were measured using enzyme-linked immunosorbent assays (ELISAs) specific for each isoform. RESULTS: Baseline alpha-CGRP levels were significantly elevated in 103 patients with CM (median = 50.3, 95% confidence interval [CI] = 40.5-57.0 pg/ml) compared to 78 HCs (median = 37.5, 95% CI = 33.9-45.0 pg/ml; 95% CI of differences = 2.85-17.08 pg/ml) and significantly decreased (n = 96) over the course of mAb treatment (M0.5: median = 40.4, 95% CI = 35.6-48.2 pg/ml; and M3: median = 40.9, 95% CI = 36.3-45.9 pg/ml). Absolute decrease of alpha-CGRP throughout the treatment positively correlated with the decrease in MMDs. Negative modulation of alpha-CGRP significantly associated with positive scores at the Patient Global Impression of Change scale and with analgesic overuse reversal. Beta-CGRP did not differ at baseline between patients with CM (median = 4.2, 95% CI = 3.0-4.8 pg/ml) and HCs (median = 4.4, 95% CI = 3.4-5.6 pg/ml; -1.09 to 0.60) nor was modulated by mAb treatment (n = 96; M0.5: median = 4.5, 95% CI = 3.5-5.2 pg/ml; and M3: median = 4.6, 95% CI = 3.7-5.2 pg/ml). INTERPRETATION: Treatment with mAbs, regardless of its target, is able to progressively normalize basally increased alpha-CGRP levels in CM and this effect correlates with efficacy measures, which supports a role of this neuropeptide as the first CM biomarker. ANN NEUROL 2023;94:285-294.

Serum alpha-CGRP levels are increased in COVID-19 patients with headache indicating an activation of the trigeminal system.

BACKGROUND: Headache is among the most frequent symptoms of acute COVID-19 infection. Its mechanisms remain obscure, but due to its migraine-like characteristics, the activation of the trigeminal system could account for its underlying pathophysiology. METHODS: Our aim was to compare the serum levels of CGRP, as a theoretical marker of trigemino-vascular activation, in 25 COVID-19 inpatients with lung involvement experiencing headache, against 15 COVID-19 inpatients without headache and with those of 25 matched healthy controls with no headache history. RESULTS: Morning serum alpha-CGRP levels, as measured by ELISA (Abbexa, UK), were increased in COVID-19 patients with headache (55.2±34.3 pg/mL) vs. controls (33.9±14.0 pg/mL) (p < 0.01). Alpha-CGRP levels in COVID-19 patients without headache were also significantly increased (43.3 ± 12.8 pg/mL; p = 0.05) versus healthy controls, but were numerically lower (-28.2%; p = 0.36) as compared to COVID-19 patients with headache. CONCLUSION: CGRP levels are increased in COVID-19 patients experiencing headache in the acute phase of this disease, which could explain why headache frequently occurs in COVID-19 and strongly supports a role for trigeminal activation in the pathophysiology of headache in this viral infection.

Update on headaches associated with physical exertion.

BACKGROUND: Headaches associated with physical exertion include headache precipitated by coughing or other Valsalva maneuvers, headache brought on by prolonged physical exercise, sexual headaches and cardiac cephalalgia. OBJECTIVE: To review and update the clinical characteristics, etiologies, pathophysiology and management of these headaches related to exertion. METHODS: In depth review of the publications, both in PubMed and in the main textbooks, of the different headaches induced by physical exercise. RESULTS: Cough, exercise and sexual headaches can be primary or secondary; therefore, complementary studies are mandatory to rule out structural lesions. However, clinical characteristics, such as an old age and response to indomethacin for cough headache or being a young male and response to beta-blockers for exercise and sexual headaches, plus a normal examination are suggestive of a primary etiology. Etiology for secondary varieties, as posterior fossa lesions for cough headache or vascular malformations for exercise and sexual headaches, are also different. Finally, headache as a distant manifestation of myocardial ischemia, also known as "cardiac cephalalgia", appears at exertion in around two-thirds of cases and typically lasts less than 30 minutes and is relieved by nitroglycerine. CONCLUSIONS: Primary and secondary cough headache can usually be suspected based on clinical characteristics and separated from exercise and sexual headaches, which share many aspects. Cardiac cephalalgia is not necessarily an exertional headache and should be considered in adult patients with short lasting headaches and patent vascular risk factors.

Serum Calcitonin Gene-Related Peptide α and ß Levels are Increased in COVID-19 Inpatients.

BACKGROUND: Vasoactive peptides play an important role in a wide range of physiological and pathological conditions. Due to its known functions, the calcitonin gene-related peptide (CGRP) has been suggested as a possible modulator of the hyperimmune response in COVID-19 and thus, blocking its action may lessen the pulmonary effects of COVID-19. AIM OF THE STUDY: To compare the circulating levels of CGRPα and CGRPß in healthy controls compared to hospitalized COVID-19 patients. The study also analyzed how different comorbidities and treatments may affect these concentrations in cases of COVID-19 infection with pulmonary involvement METHODS: Serum samples were collected from the antecubital vein of 51 control subjects (mean age = 55 ± 14 years; range = 26-77; 56.9% female) and 52 patients hospitalized with COVID-19 infection (mean age = 55 ± 13; range = 23-77; 55.8% female) from December 2020 to May 2021. Enzyme-linked immunosorbent assays (ELISAs) were used for CGRPα (Abbexa, UK) and CGRPß (CUSABIO, China) measurements. Comorbidities, symptoms, and treatments of infection were listed. RESULTS: The results showed that the serum levels of both isoforms of CGRP were significantly higher in patients with COVID-19 (α: 57.9 ± 35.8 pg/mL; ß: 6.1 ± 2.6 pg/mL) compared to controls (α: 41.8 ± 25.4 pg/mL; ß: 4.5 ± 2.4 pg/mL) (p <0.01). Also, the presence of arterial hypertension (HT), obesity, or corticosteroid treatment significantly alter the serum concentration of CGRPα in the subgroups compared to controls. CONCLUSION: The elevated serum CGRP levels found in our COVID-19 group compared to controls may suggest that CGRP plays a role in the pathophysiology of the disease, more specifically, in the cytokine storm and in the pulmonary involvement. Future studies should focus on the source of this CGRP elevation.

De novo headache in ischemic stroke patients treated with thrombectomy: a prospective study.

BACKGROUND AND AIM: Headache attributed to intracranial endovascular procedures is described in the ICHD-3. Our aim was to study the frequency and characteristics of headache specifically related to thrombectomy in patients with ischemic stroke. METHODS: Prospective evaluation of clinical features of headache after thrombectomy using an ad hoc questionnaire. RESULTS: One hundred seventeen patients were included (52.1% females). Most had an anterior circulation artery occlusion (91.5%). 93 (79.5%) received general anaesthesia. 111 (94.9%) required stent retriever, 21 (24.4%) angioplasty and 19 (16.2%) aspiration thrombectomy. 31 (26.5%; 95% CI 18.8-35.5%) had headache related to thrombectomy, and it was associated with a history of primary headache (p = 0.004). No differences about sex, initial NIHSS score, or the type or complexity of the procedure were observed. Headache was usually moderate and oppressive, ipsilateral to the artery occlusion and usually lasted less than 48 hours. CONCLUSIONS: Almost one-third of patients with ischemic stroke who undergo endovascular thrombectomy experience headache in the first 24 hours, occurring more frequently in patients who had a previous history of headaches regardless of the procedure complexity.

Is conventional brain MRI useful for the diagnosis of cluster headache in patients who meet ICHD-3 criteria? Experience in three hospitals in Spain.

OBJECTIVE: To assess the frequency of symptomatic structural lesions and the diagnostic yield of conventional brain MRI in cluster headache (CH). BACKGROUND: In contrast to migraine, brain MRI is recommended in patients with CH to exclude potential mimics. The prevalence of symptomatic CH is not known. METHODS: We retrospectively analysed in detail the brain MRIs of patients diagnosed as CH in 3 Neurology Services in Spain and reviewed their clinical history. Clinical diagnoses were reassessed based on the ICHD-3 criteria. RESULTS: We included 130 patients: 113 (86.9%) were male; mean age at diagnosis being 41.4 years (range 7-82). Forty-nine (37.7%) showed some abnormal MRI finding. Only in two cases potential symptomatic lesions were found: one trigeminal schwannoma and one craneopharyngioma, but both presented atypical features (facial hypoesthesia on examination and episodes of prolonged duration that had progressed to continuous refractory pain without specific pattern, respectively) and therefore did not fulfil the ICHD-3 CH criteria. The remaining abnormal MRI findings were: white matter lesions (24 patients; 18.4%), sinus inflammatory changes (13; 10.0%), small arachnoid cysts (5; 3.8%), empty sella turca (3; 2.3%), and other unspecific findings (8; 6.2%). All of them were not symptomatic based on neuroimaging characteristics, clinical course and response to treatment. CONCLUSIONS: Brain MRI in patients who meet ICHD-3 CH criteria, with no atypical clinical features, does not show any clinically-relevant findings, suggesting that these criteria are highly predictive of its primary origin and that systematic MRI is not useful for the diagnosis of typical CH.

Restless legs-like syndrome as an emergent adverse event of CGRP monoclonal antibodies: A report of two cases.

BACKGROUND: One of the advantages of CGRP monoclonal antibodies is their excellent safety and tolerability. However, postmarketing surveillance, is essential to detect potential rare emergent adverse events. OBJECTIVES: To report two patients who developed restless legs syndrome symptoms after treatment with CGRP antibodies. METHODS AND RESULTS: Two women with chronic refractory migraine, with no significant medical antecedents, developed typical restless legs syndrome symptoms 1.5 and 4 months after starting erenumab 140 mg, respectively. In case 1 symptoms resolved when erenumab was stopped for two months but reappeared on galcanezumab. In both patients migraine attacks had dramatically decreased and no iron deficiency was found. CONCLUSIONS: Even though caution is needed before establishing a causal relationship, these cases suggest that restless legs-like symptoms might be an emergent adverse event of CGRP antibodies, regardless of the mechanism of action. We propose that plastic changes in CGRP sensory fibers, which are very abundant in legs, induced by CGRP monoclonal antibodies could be the reason for restless legs syndrome development.

El sistema glinfático y su implicación en las enfermedades del sistema nervioso / The glymphatic system and its involvement in disorders of the nervous system

Se pensaba que el sistema nervioso central no contaba con sistema linfático. Recientemente se ha demostrado la existencia de un auténtico sistema linfático cerebral, denominado sistema glinfático, constituido por los espacios paravasculares arteriales y venosos y linfáticos durales, encargado de limpiar el espacio intersticial cerebral. La proteína acuaporina-4, localizada en los pies astrocitarios opuestos a los espacios paravasculares, juega un papel crucial en la eliminación de moléculas de desecho, tales como la proteína beta-amiloide o la tau. El sistema glinfático se activa durante el sueño, sobre todo durante la fase de ondas lentas y si se duerme de lado, con el ejercicio físico y se deteriora con el envejecimiento. Aunque disponemos de datos preliminares, probablemente el sistema glinfático interviene de forma decisiva en la fisiopatología de enfermedades neurológicas tales como enfermedades neurodegenerativas, desmielinizantes, hidrocefalia a presión normal, ictus o determinadas cefaleas. La descripción de este sistema debería conllevar nuevas posibilidades de tratamiento para estas enfermedades. (AU)

The central nervous system was thought to be devoid of lymphatics. Recently, the existence of an authentic brain lymphatic system, known as the glymphatic system, composed of paravascular channels penetrating arterial and venous brain vessels and dural lymphatics cleaning the interstitial space, has been demonstrated. Aquaporin-4, located in astrocyte feet attached to the paravascular spaces, plays a key role in the clearance of waste molecules, such as beta-amyloid or tau proteins. The activity of this system is increased during sleep, mainly in the slow wave phase and while sleeping on one side, and with exercise, and is reduced with aging. Even though data are still preliminary, the glymphatic system could be decisively involved in the pathophysiology of neurological disorders such as neurodegenerative and demyelinating diseases, normal pressure hydrocephalus, stroke or certain headaches. The discovery of this system should provide new opportunities for the treatment of these neurological disorders. (AU)

[The glymphatic system and its involvement in disorders of the nervous system]. / El sistema glinfático y su implicación en las enfermedades del sistema nervioso.

The central nervous system was thought to be devoid of lymphatics. Recently, the existence of an authentic brain lymphatic system, known as the glymphatic system, composed of paravascular channels penetrating arterial and venous brain vessels and dural lymphatics cleaning the interstitial space, has been demonstrated. Aquaporin-4, located in astrocyte feet attached to the paravascular spaces, plays a key role in the clearance of waste molecules, such as beta-amyloid or tau proteins. The activity of this system is increased during sleep, mainly in the slow wave phase and while sleeping on one side, and with exercise, and is reduced with aging. Even though data are still preliminary, the glymphatic system could be decisively involved in the pathophysiology of neurological disorders such as neurodegenerative and demyelinating diseases, normal pressure hydrocephalus, stroke or certain headaches. The discovery of this system should provide new opportunities for the treatment of these neurological disorders.