Baseline tear fluid CGRP is elevated in active cluster headache patients as long as they have not taken attack abortive medication

Background Calcitonin gene-related peptide plays a key role in cluster headache pathophysiology. It is released from the trigeminal nerve, which also innervates the eye. In this study, we tested if tear fluid calcitonin gene-related peptide measurement detects elevated calcitonin gene-related peptide levels in cluster headache patients compared to controls. Methods Calcitonin gene-related peptide concentration in tear fluid and plasma of 16 active episodic and 11 chronic cluster headache patients (all outside acute attacks) and 60 controls were assessed using ELISA. Results Cluster headache patients without use of attack abortive medication in the last 48 h showed significantly elevated tear fluid calcitonin gene-related peptide levels (1.78 ± 1.57 ng/ml, n = 17) compared to healthy controls (0.79 ± 0.74 ng/ml, p = 0.003) and compared to cluster headache patients who had used attack abortive medication in the last 48 h (0.84 ± 1.40 ng/ml, n = 10, p = 0.022). High calcitonin gene-related peptide levels in cluster headache patients were independent of the occurrence of a cluster headache attack in the last 48 hours (no attack: 1.95 ± 1.65 ng/ml, n = 8; attack: 1.63 ± 1.59 ng/ml, n = 9, p = 0.82) as long as no acute medication was used. No significant difference in tear fluid calcitonin gene-related peptide levels between episodic (1.48 ± 1.34 ng/ml) and chronic cluster headache patients (2.21 ± 1.88 ng/ml, p = 0.364) was detected. In contrast to these results in tear fluid, there were no significant group differences in plasma calcitonin gene-related peptide levels. Conclusion This study shows that active cluster headache patients have increased calcitonin gene-related peptide levels in tear fluid compared to healthy subjects, which are reduced to control levels after intake of attack abortive medication. Calcitonin gene-related peptide measurement in tear fluid is non-invasive, and has the advantage of allowing direct access to calcitonin gene-related peptide released from the trigeminal nerve.

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Effect of calcitonin gene-related peptide (-receptor) antibodies in chronic cluster headache: Results from a retrospective case series support individual treatment attempts

Cephalalgia ◽

10.1177/0333102420949866 ◽

2020 ◽

Vol 40 (14) ◽

pp. 1574-1584 ◽

Cited By ~ 1

Author(s):

Ruth Ruscheweyh ◽

Gregor Broessner ◽

Gudrun Goßrau ◽

Katja Heinze-Kuhn ◽

Tim P Jürgens ◽

...

Keyword(s):

Cluster Headache ◽

Calcitonin Gene Related Peptide ◽

Chronic Cluster Headache ◽

Individual Treatment ◽

Attack Frequency ◽

Peptide Receptor ◽

Related Peptide ◽

Calcitonin Gene ◽

Receptor Antibodies ◽

Headache Patients

Objective To assess the efficacy of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor in chronic cluster headache (CCH) treatment under real world conditions. Background Calcitonin gene-related peptide has an important pathophysiological role in cluster headache. Although the randomised controlled trial with the calcitonin gene-related peptide antibody galcanezumab was negative, chronic cluster headache patients with insufficient response to other preventive treatments have been receiving individual off-label treatment attempts with calcitonin gene-related peptide-(receptor) antibodies. Methods Data from 22 chronic cluster headache patients who received at least one dose of a calcitonin gene-related peptide(-receptor) antibody and recorded attack frequency in a headache diary were retrospectively collected at eight headache centres. Results The number of previous preventive therapies was 6.5 ± 2.4 (mean ± standard deviation, range: 2–11). The average number of attacks per week was 23.3 ± 16.4 at baseline and significantly decreased by −9.2 ± 9.7 in the first month of treatment with a calcitonin gene-related peptide(-receptor) antibody ( p < 0.001). Fifty-five percent of the patients were 50% responders and 36% were 75% responders with respect to attack frequency. Significant reduction of attack frequency started at week 1 (−6.8 ± 2.8 attacks, p < 0.01). Results were corroborated by significant decreases in weekly uses of acute headache medication (−9.8 ± 7.6, p < 0.001) and pain intensity during attacks (−1.2 ± 2.0, numerical rating scale (NRS) [0–10], p < 0.01) in the first month. In months 2 (n = 14) and 3 (n = 10), reduction of attack frequency from baseline was −8.0 ± 8.4 ( p = 0.004) and −9.1 ± 10.0 ( p = 0.024), respectively. Conclusion Under real-world conditions, individual treatment with calcitonin gene-related peptide(-receptor) antibodies was effective in 55% of our chronic cluster headache patients. This finding supports individual off-label treatment attempts with calcitonin gene-related peptide-(receptor) antibodies in chronic cluster headache patients insufficiently responding to other therapies.

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Calcitonin gene-related peptide and disease activity in cluster headache

Cephalalgia ◽

10.1177/0333102419837154 ◽

2019 ◽

Vol 39 (5) ◽

pp. 575-584 ◽

Cited By ~ 15

Author(s):

Agneta Snoer ◽

Anne Luise H Vollesen ◽

Rasmus P Beske ◽

Song Guo ◽

Jan Hoffmann ◽

...

Keyword(s):

Cluster Headache ◽

Vasoactive Intestinal Polypeptide ◽

Active Phase ◽

Calcitonin Gene Related Peptide ◽

Chronic Cluster Headache ◽

Related Peptide ◽

Episodic Cluster Headache ◽

Calcitonin Gene ◽

Headache Patients ◽

Intestinal Polypeptide

Objective To investigate the role of calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide in cluster headache, we measured these vasoactive peptides interictally and during experimentally induced cluster headache attacks. Methods We included patients with episodic cluster headache in an active phase (n = 9), episodic cluster headache patients in remission (n = 9) and patients with chronic cluster headache (n = 13). Cluster headache attacks were induced by infusion of calcitonin gene-related peptide (1.5 µg/min) in a randomized, double-blind, placebo controlled, two-way cross-over study. At baseline, we collected interictal blood samples from all patients and during 11 calcitonin gene-related peptide-induced cluster headache attacks. Results At baseline, episodic cluster headache patients in remission had higher plasma levels of calcitonin gene-related peptide, 100.6 ± 36.3 pmol/l, compared to chronic cluster headache patients, 65.9 ± 30.5 pmol/l, ( p = 0.011). Episodic cluster headache patients in active phase had higher PACAP38 levels, 4.0 ± 0.8 pmol/l, compared to chronic cluster headache patients, 3.3 ± 0.7 pmol/l, ( p = 0.033). Baseline levels of vasoactive intestinal polypeptide did not differ between cluster headache groups. We found no attack-related increase in calcitonin gene-related peptide, PACAP38 or vasoactive intestinal polypeptide levels during calcitonin gene-related peptide-induced cluster headache attacks. Conclusions This study suggests that cluster headache disease activity is associated with alterations of calcitonin gene-related peptide expression. Future studies should investigate the potential of using calcitonin gene-related peptide measurements in monitoring of disease state and predicting response to preventive treatments, including response to anti-calcitonin gene-related peptide monoclonal antibodies.

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Calcitonin gene-related peptide levels in tear fluid are elevated in migraine patients compared to healthy controls

Cephalalgia ◽

10.1177/0333102419856640 ◽

2019 ◽

Vol 39 (12) ◽

pp. 1535-1543 ◽

Cited By ~ 6

Author(s):

Katharina Kamm ◽

Andreas Straube ◽

Ruth Ruscheweyh

Keyword(s):

Chronic Migraine ◽

Trigeminal Nerve ◽

Plasma Concentrations ◽

Calcitonin Gene Related Peptide ◽

Tear Fluid ◽

Direct Access ◽

Healthy Controls ◽

Significant Group ◽

Related Peptide ◽

Calcitonin Gene

Background Calcitonin gene-related peptide (CGRP) released from trigeminal nerve fibres indicates trigeminal activation and has a key role in migraine pathophysiology. The trigeminal nerve directly innervates the eye. Therefore, in this study, we compared Calcitonin gene-related peptide in tear fluid of migraine patients and healthy controls. Methods Calcitonin gene-related peptide concentrations in tear fluid and plasma of 48 episodic and 45 chronic migraine patients and 48 controls were assessed using ELISA. Results Calcitonin gene-related peptide levels in tear fluid (0.94 ± 1.11 ng/ml) were ∼140 times higher than plasma concentrations (6.81 ± 4.12 pg/ml). Tear fluid CGRP concentrations were elevated in interictal migraine patients (1.10 ± 1.27 ng/ml, n = 49) compared to controls (0.75 ± 0.80 ng/ml, p = 0.022). There was no difference in tear fluid CGRP levels between interictal episodic and chronic migraine patients (episodic: 1.09 ± 1.47 ng/ml, n = 30 and chronic: 1.10 ± 0.89 ng/ml, n = 19) and no correlation of tear fluid CGRP levels with headache frequency in interictal patients (rho = 0.062, p = 0.674). Unmedicated ictal migraine patients had even more elevated tear fluid CGRP levels than interictal migraine patients (1.92 ± 1.84 ng/ml, n = 13, p = 0.102), while medicated ictal migraine patients had lower levels (0.56 ± 0.47 ng/ml, n = 25, p = 0.011 compared to interictal patients), which were undistinguishable from controls ( p = 0.609). In contrast to tear fluid, no significant group differences were found in plasma CGRP levels. Conclusion To the best of our knowledge, this study shows, for the first time, increased CGRP tear fluid levels in migraine patients compared to healthy subjects. Detection of calcitonin gene-related peptide in tear fluid is non-invasive, and likely allows a more direct access to CGRP released from the trigeminal nerve than plasma sampling.

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PACAP38- and VIP-induced cluster headache attacks are not associated with changes of plasma CGRP or markers of mast cell activation

Cephalalgia ◽

10.1177/03331024211056248 ◽

2021 ◽

pp. 033310242110562

Author(s):

Lanfranco Pellesi ◽

Basit Ali Chaudhry ◽

Anne Luise Haulund Vollesen ◽

Agneta Henriette Snoer ◽

Katrine Baumann ◽

...

Keyword(s):

Mast Cell ◽

Cluster Headache ◽

Vasoactive Intestinal Polypeptide ◽

Plasma Levels ◽

Cell Activation ◽

Calcitonin Gene Related Peptide ◽

Mast Cell Activation ◽

Related Peptide ◽

Calcitonin Gene ◽

Headache Patients

Background Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide can provoke cluster headache attacks in up to half of cluster headache patients in their active phase. At present, it is unknown whether provoked attacks are mediated via calcitonin gene-related peptide or mast cell activation. Methods All enrolled patients with cluster headache were randomly allocated to receive a continuous infusion of either PACAP38 (10 pmol/kg/min) or vasoactive intestinal polypeptide (8 pmol/kg/min) over 20 min. We collected clinical data and measured plasma levels of calcitonin gene-related peptide and markers of mast cell activation (tryptase and histamine) at fixed time points: at baseline (T0), at the end of the infusion (T20), 10 min after the infusion (T30), and 70 min after the infusion (T90). Results Blood was collected from episodic cluster headache patients in active phase (n = 14), episodic cluster headache patients in remission (n = 15), and chronic cluster headache patients (n = 15). At baseline, plasma levels of calcitonin gene-related peptide, tryptase, and histamine were not different among the three study groups. Plasma levels of calcitonin gene-related peptide ( p = 0.7074), tryptase ( p = 0.6673), or histamine ( p = 0.4792) remained unchanged during provoked attacks compared to attack-free patients. Conclusion Cluster headache attacks provoked by either PACAP38 or vasoactive intestinal polypeptide were not accompanied by alterations of plasma calcitonin gene-related peptide, tryptase or histamine. The provoked attacks may not be mediated by calcitonin gene-related peptide or mast cell activation. Trial Registration: The study is registered at ClinicalTrials.gov (NCT03814226).

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Erenumab for chronic cluster headache: A case report

Cephalalgia Reports ◽

10.1177/2515816320947713 ◽

2020 ◽

Vol 3 ◽

pp. 251581632094771

Author(s):

Franz Riederer ◽

Allyson M Wenner

Keyword(s):

Cluster Headache ◽

Preventive Treatment ◽

Calcitonin Gene Related Peptide ◽

Chronic Cluster Headache ◽

Attack Frequency ◽

Related Peptide ◽

Episodic Cluster Headache ◽

Calcitonin Gene ◽

Repeated Doses ◽

Randomized Control

The preventive treatment for cluster headache is often limited by a lack of efficacy or side effects. Calcitonin gene-related peptide (CGRP) has been implicated in the pathophysiology of cluster headache. Galcanezumab, a monoclonal antibody against calcitonin gene-related peptide (CGRP), significantly reduced the frequency of episodic cluster headache attacks. We report the case of a 38-year-old woman with chronic refractory cluster headache and comorbid migraine who received erenumab in 4 repeated doses of 70 mg subcutaneously over 25 weeks. Attack frequency decreased from three attacks per day to several attacks per week. Erenumab seemed to be highly effective in the prevention of cluster headache attacks in this patient. We suggest that randomized control trials should be performed.

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Calcitonin gene-related peptide antagonism and cluster headache: an emerging new treatment

Neurological Sciences ◽

10.1007/s10072-017-3101-8 ◽

2017 ◽

Vol 38 (12) ◽

pp. 2089-2093 ◽

Cited By ~ 10

Author(s):

Håkan Ashina ◽

Lawrence Newman ◽

Sait Ashina

Keyword(s):

Cluster Headache ◽

Calcitonin Gene Related Peptide ◽

Related Peptide ◽

Calcitonin Gene ◽

New Treatment

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Calcitonin gene-related peptide in blood: is it increased in the external jugular vein during migraine and cluster headache? A review

The Journal of Headache and Pain ◽

10.1007/s10194-009-0112-8 ◽

2009 ◽

Vol 10 (3) ◽

pp. 137-143 ◽

Cited By ~ 38

Author(s):

Peer Tfelt-Hansen ◽

Han Le

Keyword(s):

Cluster Headache ◽

Jugular Vein ◽

Calcitonin Gene Related Peptide ◽

External Jugular Vein ◽

Related Peptide ◽

Calcitonin Gene

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Calcitonin gene-related peptide and nitric oxide in the trigeminal ganglion: Cerebral vasodilatation from trigeminal nerve stimulation involves mainly calcitonin gene-related peptide

Journal of the Autonomic Nervous System ◽

10.1016/s0165-1838(98)00033-2 ◽

1998 ◽

Vol 70 (1-2) ◽

pp. 15-22 ◽

Cited By ~ 75

Author(s):

Lars Edvinsson ◽

Hindrik Mulder ◽

Peter J Goadsby ◽

Rolf Uddman

Keyword(s):

Nitric Oxide ◽

Trigeminal Ganglion ◽

Trigeminal Nerve ◽

Nerve Stimulation ◽

Calcitonin Gene Related Peptide ◽

Related Peptide ◽

Trigeminal Nerve Stimulation ◽

Calcitonin Gene ◽

Cerebral Vasodilatation

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Plasma Changes of Calcitonin Gene-Related Peptide and Substance P in Patients with Dialysis Headache

Cephalalgia ◽

10.1111/j.1468-2982.2006.01217.x ◽

2006 ◽

Vol 26 (11) ◽

pp. 1287-1293 ◽

Cited By ~ 20

Author(s):

M Alessandri ◽

L Massanti ◽

P Geppetti ◽

G Bellucci ◽

M Cipriani ◽

...

Keyword(s):

Substance P ◽

Plasma Concentrations ◽

Calcitonin Gene Related Peptide ◽

Related Peptide ◽

Calcitonin Gene ◽

Biochemical Factor ◽

Before And After ◽

Basal Plasma ◽

Headache Patients

Little is known of mechanism of dialysis headache (DH). As suggested for migraine, a role for neuropeptides has been investigated. Twenty-four patients under haemodialysis were studied. Twelve of them suffered from DH. The remaining patients were headache free. Blood samples for radioimmunoassay of calcitonin gene-related peptide (CGRP) and substance P (SP) were collected from the arteriovenous fistula before and after dialysis treatment. Basal plasma concentrations of CGRP were found to be higher in headache patients. Dialysis significantly decreased CGRP concentrations in both groups. No difference in basal plasma concentrations of SP was observed between groups. At the end of the treatment plasma SP concentrations were reduced in headache-free patients but increased in headache patients. Elevated plasma concentrations of CGRP in patients with DH could represent a biochemical factor contributing to susceptibility to headache. Because of the disputable role of SP in migraine, the significance of the increase of the peptide in plasma during DH remains to be elucidated.

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