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.

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.

Serum CGRP, VIP, and PACAP usefulness in migraine: a case-control study in chronic migraine patients in real clinical practice.

Calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypetide-38 (PACAP-38) have relevant roles in migraine pathophysiology. Their serum levels have been proposed as biomarkers for migraine. Our aim was to assess their diagnostic value in real clinical practice in a cohort of chronic migraine (CM), episodic migraine (EM) and healthy controls (HC). We recruited subjects with CM, EM and HC at two medical centers. Blood samples were drawn under fasting conditions in the interictal period, immediately centrifuged and stored at - 80 ºC. Serum levels were determined by ELISA. Neuropeptide levels, the effect of preventatives, correlations with clinical and demographic variables, and their diagnostic value were studied among clinical categories. 296 age- and sex-matched subjects (101 CM, 98 EM and 97 HC) were included. All three neuropeptide serum levels were higher in CM [median and IQ for CGRP = 18.023 pg/ml (14.4-24.7); VIP = 121.732 pg/ml (48.72-186.72) and PACAP = 204.931 pg/ml (101.08-597.64)] vs EM [CGRP = 14.659 pg/ml (10.29-17.45); VIP = 75.603 pg/ml (28.722-107.10); and PACAP = 94.992 pg/ml (65.77-128.48)] and vs HC [CGRP = 13.988 pg/ml (10.095-17.87); VIP = 84.685 pg/ml (35.32-99.79), and PACAP = 103.142 pg/ml (59.42-123.97)]. Using multinomial modeling, only VIP (OR 1.011, 95% CI 1.003-1.018, p = 0.005) and PACAP (OR 1.003, 95% CI 1.001-1.005, p = 0.002) increased the risk for CM, but not for EM. CGRP did not predict CM or EM. This model could correctly classify only 62/101 (61.38%) of CM, 75/98 (76.53%) of EM, and 5/97 (4.12%) of HC [globally 147/296 (49.8%)]. Individually, PACAP performed the best for classifying clinical categories [global accuracy 150/296 (50.67%)]. In CM, neuropeptide levels were higher in those OnaBT-treated than in no-treated patients. Although interictal serum CGRP and VIP were higher in CM than both EM or HC, their utility to discriminate migraine categories was low. Contrary to other studies, PACAP serum levels were also higher in CM than in EM or HC and had more discriminative capability to distinguish CM from EM and HC. Further investigation is needed for determination technique standardization.

Peripheral, Interictal Serum S100B Levels are Not Increased in Chronic Migraine Patients.

BACKGROUND: The trigemino-vascular system (TVS) plays a key role in migraine pathophysiology. Glial cells are abundant in the TVS system and mainly in the trigeminal ganglion. S100B protein is a calcium-binding protein, found in the cytoplasm of glial cells in the central nervous system, which is released in response to inflammatory stimuli. Previous works analyzing S100B in migraineurs have offered contradictory results. OBJECTIVE: In this case-control study, we analyzed serum levels of S100B as a possible biomarker of the glial TVS activation in chronic migraine (CM). PATIENTS AND METHODS: The study group consisted of patients attending our clinic with CM and, as control groups, patients with episodic migraine (EM), cluster headache (CH) outside of a bout and healthy volunteers (HV) with no headache history. S100B levels were determined interictally in peripheral blood samples by ELISA. RESULTS: We assessed serum samples from 43 patients with CM, 19 with EM, 29 HV (mostly women), and 22 with (CH). S100B levels in CM (mean 22.9 ± 9.8 pg/mL) were not different (P = .727) when compared to EM patients (21.2 ± 9.3 pg/mL), difference of 1.7 (95% CI -5.7 to 8.9), CH patients (22.4 ± 7.8 pg/mL), difference of 0.5 (-5.7 to 6.7), and HV (20.6 ± 8.3 pg/mL), difference of 2.3 (-3.7 to 8.3). CONCLUSION: In contrast to other neuropeptides such as calcitonin gene-related-peptide and vasoactive intestinal peptide, which are increased in CM, interictal serum S100B levels are not elevated in these patients. According to our results, S100B levels do not seem to be a useful peripheral biomarker of the glial TVS activation in CM.

Chronic Migraine With Apparent Loss of Response to Onabotulinum Toxin Type A Due to Local Nitroglycerin Treatment for an Anal Fissure: A Case Report.

Many patients with chronic migraine are difficult to treat. We present a patient with chronic migraine with good response to onabotulinum toxin type A whose headaches worsened in clear temporal relationship to local treatment with glyceryl trinitrate for an anal fissure. Our case shows that the use, even at distance, of nitric oxide donors can be a precipitating factor for migraineurs and should be always inquired in chronic migraine patients. In addition, the presence of frequent headaches should always be ruled out before prescribing such medications.

Isolated De Novo Headache as the Presenting Symptom of Listeria Meningitis: A Report of 2 Cases.

BACKGROUND: Headache is a frequent symptom at the onset of Listeria meningitis, accompanied by others such as fever, altered mental status and meningeal signs, but never reported so far as an isolated symptom. METHODS AND RESULTS: Two immunocompetent males, with no history of primary headaches, went to the emergency department because of headache. The first after a sudden severe, holocranial headache without other associated symptoms, and the second after a subacute, moderate oppressive headache in temples, which 8 days later added a mild left hemiparesis. None of them had fever or meningeal signs. The initial cranial CT was unremarkable in both cases. Lumbar puncture was diagnostic for Listeria meningitis serotype IVb. CONCLUSIONS: Listeria meningitis may present as an isolated headache, with different clinical patterns, which should be taken into account when evaluating de novo unclassified headaches according to the ICHD-3 criteria.

The increasing importance of environmental conditions in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons (MNs). Although a small percentage of ALS has a familial origin, the vast majority of cases are sporadic in which genetic factors and environment interact with each other leading to disease onset in genetically predisposed individuals. In the current model of the disease, each individual has a determined genetic load, some degree of cell degeneration related to age and several risky environmental exposures. In this scenario, MN degeneration would occur when the sum of these factors reach a certain threshold. To date, an extensive list of environmental factors has been associated to ALS, including different categories, such as exposure to heavy metals and other toxicants, cyanotoxins or infectious agents. In addition, in recent years, lifestyle and other demographic parameters are gaining relevance in the genesis of the disease. Among them, physical activity, nutrition, body mass index, cardiovascular risk factors, autoimmune diseases and cancer are some of the conditions which have been related to the disease. In this review, we will discuss the potential mechanisms of environmental conditions in motor neuron degeneration. Understanding the role of each one of these factors as well as their interactions appears as a crucial step in order to develop new preventive, diagnostic and therapeutic approaches for ALS patients.