Top

Published in:

Open Access 17-01-2024 | Headache | Original Communication

Serum calcitonin gene-related peptide in patients with persistent post-concussion symptoms, including headache: a cohort study

Authors: Peter Preben Eggertsen, Johan Palmfeldt, Henrik Winther Schytz, Debbie Hay, Rikke Katrine Jentoft Olsen, Jørgen Feldbæk Nielsen

Published in: Journal of Neurology | Issue 5/2024

Abstract

Background

Calcitonin gene-related peptide (CGRP) plays an important role in migraine pathophysiology, and post-traumatic headache (PTH) frequently presents with migraine-like features. Despite several clinical similarities, few studies have explored CGRP in PTH and concussion. This study investigates serum CGRP levels in patients with persistent post-concussion symptoms (PPCS), including PTH.

Methods

This cohort study was based on serum samples from individuals aged 18–30 years with PPCS who participated in a previously published randomized controlled trial of a non-pharmacological intervention. The primary outcome was serum CGRP concentrations, determined at baseline before randomization and at follow-up 7 months later, using an enzyme-linked immunosorbent assay (ELISA). CGRP levels at baseline were compared with healthy anonymous blood donors in the same age group.

Results

Baseline serum samples were collected from 86 participants with PPCS. The participants were most often female (78%) and migraine-like headache was the most frequent headache phenotype (74%). Serum CGRP levels were higher in participants with PPCS than in 120 healthy individuals (median: 158.5 pg/mL vs. 76.3 pg/mL, p = 0.050). A stratified analysis revealed that females with PPCS had a fivefold higher median than healthy females (166.3 pg/mL vs. 32.1 pg/mL, p = 0.0006), while no differences were observed in males (p = 0.83). At follow-up, CGRP levels decreased with a median change of – 1.3 pg/mL (95% confidence interval: – 17.6–0, p = 0.024).

Discussion

Elevated serum levels of CGRP in patients with PPCS and a decrease over time suggest an involvement of CGRP in PTH/PPCS. If confirmed in other studies, it could pave the way for CGRP-targeted therapies, which could have clinical significance.

Available only for authorised users

Peeters W, Van Den Brande R, Polinder S, Brazinova A, Steyerberg EW, Lingsma HF et al (2015) Epidemiology of traumatic brain injury in Europe. Acta Neurochir 157(10):1683–1696. https://doi.org/10.1007/s00701-015-2512-7CrossRefPubMed

Silverberg ND, Iverson GL, Cogan A, Dams OCK, Delmonico R, Graf MJP et al (2023) The American congress of rehabilitation medicine diagnostic criteria for mild traumatic brain injury. Arch Phys Med Rehabil 104(8):1343–1355. https://doi.org/10.1016/j.apmr.2023.03.036CrossRefPubMed

Brazinova A, Rehorcikova V, Taylor MS, Buckova V, Majdan M, Psota M et al (2021) Epidemiology of traumatic brain injury in europe: a living systematic review [supplementary data; living update 5, search January 2019]. J Neurotrauma 38(10):1411–1440. https://doi.org/10.1089/neu.2015.4126CrossRefPubMedPubMedCentral

Feigin VL, Theadom A, Barker-Collo S, Starkey NJ, McPherson K, Kahan M et al (2013) Incidence of traumatic brain injury in New Zealand: a population-based study. Lancet Neurol 12(1):53–64. https://doi.org/10.1016/S1474-4422(12)70262-4CrossRefPubMed

Dewan MC, Rattani A, Gupta S, Baticulon RE, Hung Y-C, Punchak M et al (2019) Estimating the global incidence of traumatic brain injury. J Neurosurg 130(4):1080–1097. https://doi.org/10.3171/2017.10.jns17352CrossRef

Cancelliere C, Verville L, Stubbs JL, Yu H, Hincapié CA, Cassidy JD et al (2023) Post-concussion symptoms and disability in adults with mild traumatic brain injury: a systematic review and meta-analysis. J Neurotrauma 40(11–12):1045–1059. https://doi.org/10.1089/neu.2022.0185CrossRefPubMed

Lumba-Brown A, Teramoto M, Bloom OJ, Brody D, Chesnutt J, Clugston JR et al (2020) Concussion guidelines step 2: evidence for subtype classification. Neurosurgery 86(1):2–13. https://doi.org/10.1093/neuros/nyz332CrossRefPubMed

Larsen EL, Ashina H, Iljazi A, Al-Khazali HM, Seem K, Ashina M et al (2019) Acute and preventive pharmacological treatment of post-traumatic headache: a systematic review. J Headache Pain. https://doi.org/10.1186/s10194-019-1051-7CrossRefPubMedPubMedCentral

Ashina H, Eigenbrodt AK, Seifert T, Sinclair AJ, Scher AI, Schytz HW et al (2021) Post-traumatic headache attributed to traumatic brain injury: classification, clinical characteristics, and treatment. Lancet Neurol 20(6):460–469. https://doi.org/10.1016/s1474-4422(21)00094-6CrossRefPubMed

10.

Mavroudis I, Ciobica A, Luca AC, Balmus IM (2023) Post-traumatic headache: a review of prevalence, clinical features, risk factors, and treatment strategies. J Clin Med. https://doi.org/10.3390/jcm12134233CrossRefPubMedPubMedCentral

11.

Goadsby PJ, Edvinsson L, Ekman R (1990) Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 28(2):183–187. https://doi.org/10.1002/ana.410280213CrossRefPubMed

12.

Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J (2002) CGRP may play a causative role in migraine. Cephalalgia 22(1):54–61. https://doi.org/10.1046/j.1468-2982.2002.00310.xCrossRefPubMed

13.

Russo AF, Hay DL (2023) CGRP physiology, pharmacology, and therapeutic targets: migraine and beyond. Physiol Rev 103(2):1565–1644. https://doi.org/10.1152/physrev.00059.2021CrossRefPubMed

14.

Ashina H, Al-Khazali HM, Iljazi A, Ashina S, Jørgensen NR, Amin FM et al (2020) Low plasma levels of calcitonin gene-related peptide in persistent post-traumatic headache attributed to mild traumatic brain injury. Cephalalgia 40(12):1276–1282. https://doi.org/10.1177/0333102420941115CrossRefPubMed

15.

Thastum MM, Rask CU, Næss-Schmidt ET, Tuborgh A, Jensen JS, Svendsen SW et al (2019) Novel interdisciplinary intervention, GAIN, vs. enhanced usual care to reduce high levels of post-concussion symptoms in adolescents and young adults 2–6 months post-injury: A randomised trial. EClinicalMedicine. 17:100214. https://doi.org/10.1016/j.eclinm.2019.11.007CrossRefPubMedPubMedCentral

16.

Holm L, Cassidy JD, Carroll LJ, Borg J (2005) Summary of the WHO collaborating centre for neurotrauma task force on mild traumatic brain injury. J Rehabil Med 37(3):137–141. https://doi.org/10.1080/16501970510027321CrossRefPubMed

17.

King NS, Crawford S, Wenden FJ, Moss NE, Wade DT (1995) The Rivermead post concussion symptoms questionnaire: a measure of symptoms commonly experienced after head injury and its reliability. J Neurol 242(9):587–592. https://doi.org/10.1007/bf00868811CrossRefPubMed

18.

Thastum MM, Rask CU, Naess-Schmidt ET, Jensen JS, Frederiksen OV, Tuborgh A et al (2018) Design of an early intervention for persistent post-concussion symptoms in adolescents and young adults: a feasibility study. NeuroRehabilitation 43(2):155–167. https://doi.org/10.3233/nre-172391CrossRefPubMed

19.

Kothari SF, Eggertsen PP, Frederiksen OV, Thastum MM, Svendsen SW, Tuborgh A et al (2022) Characterization of persistent post-traumatic headache and management strategies in adolescents and young adults following mild traumatic brain injury. Sci Rep 12(1):2209. https://doi.org/10.1038/s41598-022-05187-xCrossRefPubMedPubMedCentral

20.

Kosinski M, Bayliss MS, Bjorner JB, Ware JE Jr, Garber WH, Batenhorst A et al (2003) A six-item short-form survey for measuring headache impact: the HIT-6. Qual Life Res 12(8):963–974. https://doi.org/10.1023/a:1026119331193CrossRefPubMed

21.

Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition (2018) Cephalalgia. 38(1):1–211. https://doi.org/10.1177/0333102417738202

22.

Ware JE, Sherbourne CD (1992) The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 30(6):473–83CrossRefPubMed

23.

Budtz-Lilly A, Fink P, Ørnbøl E, Vestergaard M, Moth G, Christensen KS et al (2015) A new questionnaire to identify bodily distress in primary care: The ‘BDS checklist.’ J Psychosom Res 78(6):536–545. https://doi.org/10.1016/j.jpsychores.2015.03.006CrossRefPubMed

24.

Carstensen TBW, Ørnbøl E, Fink P, Pedersen MM, Jørgensen T, Dantoft TM et al (2020) Detection of illness worry in the general population: a specific item on illness rumination improves the Whiteley Index. J Psychosom Res 138:110245. https://doi.org/10.1016/j.jpsychores.2020.110245CrossRefPubMed

25.

Spence M, Moss-Morris R, Chalder T (2005) The Behavioural Responses to Illness Questionnaire (BRIQ): a new predictive measure of medically unexplained symptoms following acute infection. Psychol Med 35(4):583–593. https://doi.org/10.1017/s0033291704003484CrossRefPubMed

26.

Broadbent E, Petrie KJ, Main J, Weinman J (2006) The brief illness perception questionnaire. J Psychosom Res 60(6):631–637. https://doi.org/10.1016/j.jpsychores.2005.10.020CrossRefPubMed

27.

Søgaard HJ, Bech P (2009) Psychometric analysis of common mental disorders – Screening Questionnaire (CMD-SQ) in long-term sickness absence. Scand J Public Health 37(8):855–863. https://doi.org/10.1177/1403494809344653CrossRefPubMed

28.

Eskildsen A, Dalgaard VL, Nielsen KJ, Andersen JH, Zachariae R, Olsen LR et al (2015) Cross-cultural adaptation and validation of the Danish consensus version of the 10-item Perceived Stress Scale. Scand J Work Environ Health 41(5):486–490. https://doi.org/10.5271/sjweh.3510CrossRefPubMed

29.

Frobert Y, Nevers MC, Amadesi S, Volland H, Brune P, Geppetti P et al (1999) A sensitive sandwich enzyme immunoassay for calcitonin gene-related peptide (CGRP): characterization and application. Peptides 20(2):275–284. https://doi.org/10.1016/s0196-9781(98)00172-7CrossRefPubMed

30.

Bioanalytical Method Validation Guidance for Industry - Food and Drug Administration (FDA). https://www.fda.gov/media/70858/download (2018). Accessed 21–11–2023

31.

Kamm K (2022) CGRP and migraine: what have we learned from measuring CGRP in migraine patients so far? Front Neurol 13:930383. https://doi.org/10.3389/fneur.2022.930383CrossRefPubMedPubMedCentral

32.

Ashina H, Iljazi A, Al-Khazali HM, Do TP, Eigenbrodt AK, Larsen EL et al (2022) CGRP-induced migraine-like headache in persistent post-traumatic headache attributed to mild traumatic brain injury. J Headache Pain 23(1):135. https://doi.org/10.1186/s10194-022-01499-5CrossRefPubMedPubMedCentral

33.

Ashina H, Iljazi A, Al-Khazali HM, Eigenbrodt AK, Larsen EL, Andersen AM et al (2020) Efficacy, tolerability, and safety of erenumab for the preventive treatment of persistent post-traumatic headache attributed to mild traumatic brain injury: an open-label study. J Headache Pain 21(1):62. https://doi.org/10.1186/s10194-020-01136-zCrossRefPubMedPubMedCentral

34.

Bree D, Mackenzie K, Stratton J, Levy D (2020) Enhanced post-traumatic headache-like behaviors and diminished contribution of peripheral CGRP in female rats following a mild closed head injury. Cephalalgia 40(7):748–760. https://doi.org/10.1177/0333102420907597CrossRefPubMedPubMedCentral

35.

Skandsen T, Stenberg J, Follestad T, Karaliute M, Saksvik SB, Einarsen CE et al (2021) Personal factors associated with postconcussion symptoms 3 months after mild traumatic brain injury. Arch Phys Med Rehabil 102(6):1102–1112. https://doi.org/10.1016/j.apmr.2020.10.106CrossRefPubMed

36.

Labastida-Ramírez A, Rubio-Beltrán E, Villalón CM, MaassenVanDenBrink A (2019) Gender aspects of CGRP in migraine. Cephalalgia 39(3):435–444. https://doi.org/10.1177/0333102417739584CrossRefPubMed

37.

Schou WS, Ashina S, Amin FM, Goadsby PJ, Ashina M (2017) Calcitonin gene-related peptide and pain: a systematic review. J Headache Pain 18(1):34. https://doi.org/10.1186/s10194-017-0741-2CrossRefPubMedPubMedCentral

38.

Scher AI, McGinley JS, VanDam LR, Campbell AM, Chai X, Collins B et al (2023) Plasma calcitonin gene-related peptide and nerve growth factor as headache and pain biomarkers in recently deployed soldiers with and without a recent concussion. Headache. https://doi.org/10.1111/head.14635CrossRefPubMed

39.

Donnerer J, Amann R, Schuligoi R, Skofitsch G (1996) Complete recovery by nerve growth factor of neuropeptide content and function in capsaicin-impaired sensory neurons. Brain Res 741(1–2):103–108. https://doi.org/10.1016/s0006-8993(96)00905-5CrossRefPubMed

40.

Wattiez AS, Wang M, Russo AF (2019) CGRP in animal models of migraine. Handb Exp Pharmacol 255:85–107. https://doi.org/10.1007/164_2018_187CrossRefPubMedPubMedCentral

41.

Chen LX, Zhang WF, Wang M, Jia PF (2018) Relationship of calcitonin gene-related peptide with disease progression and prognosis of patients with severe traumatic brain injury. Neural Regen Res 13(10):1782–1786. https://doi.org/10.4103/1673-5374.238619CrossRefPubMedPubMedCentral

42.

Toth CC, Willis D, Twiss JL, Walsh S, Martinez JA, Liu WQ et al (2009) Locally synthesized calcitonin gene-related Peptide has a critical role in peripheral nerve regeneration. J Neuropathol Exp Neurol 68(3):326–337. https://doi.org/10.1097/NEN.0b013e31819ac71bCrossRefPubMed

43.

Valdemarsson S, Edvinsson L, Hedner P, Ekman R (1990) Hormonal influence on calcitonin gene-related peptide in man: effects of sex difference and contraceptive pills. Scand J Clin Lab Invest 50(4):385–388. https://doi.org/10.3109/00365519009091595CrossRefPubMed

44.

Frederiksen SD, Bekker-Nielsen Dunbar M, Snoer AH, Deen M, Edvinsson L (2020) Serotonin and neuropeptides in blood from episodic and chronic migraine and cluster headache patients in case-control and case-crossover settings: a systematic review and meta-analysis. Headache J Head Face Pain. 60(6):1132–64. https://doi.org/10.1111/head.13802CrossRef

45.

Messlinger K, Vogler B, Kuhn A, Sertel-Nakajima J, Frank F, Broessner G (2021) CGRP measurements in human plasma - a methodological study. Cephalalgia 41(13):1359–1373. https://doi.org/10.1177/03331024211024161CrossRefPubMedPubMedCentral

46.

Schifter S (1991) Circulating concentrations of calcitonin gene-related peptide (CGRP) in normal man determined with a new, highly sensitive radioimmunoassay. Peptides 12(2):365–369. https://doi.org/10.1016/0196-9781(91)90027-mCrossRefPubMed

47.

Brodersen T, Rostgaard K, Lau CJ, Juel K, Erikstrup C, Nielsen KR et al (2023) The healthy donor effect and survey participation, becoming a donor and donor career. Transfusion 63(1):143–155. https://doi.org/10.1111/trf.17190CrossRefPubMed

48.

Schifter S, Krusell LR, Sehested J (1991) Normal serum levels of Calcitonin Gene-Related Peptide (CGRP) in Mild to moderate essential hypertension. Am J Hypertens 4(7_Pt_1):565–9. https://doi.org/10.1093/ajh/4.7.565CrossRefPubMed

49.

Tarperi C, Sanchis-Gomar F, Montagnana M, Danese E, Salvagno GL, Gelati M et al (2020) Effects of endurance exercise on serum concentration of calcitonin gene-related peptide (CGRP): a potential link between exercise intensity and headache. Clin Chem Lab Med 58(10):1707–1712. https://doi.org/10.1515/cclm-2019-1337CrossRefPubMed

50.

Transfusionsmedicinske Standarder - Dansk Selskab for Klinisk Immunologi. https://dski.dk/wp-content/uploads/2023/01/tms-5.4-final.pdf (2023). Accessed 21–11–2023

Title: Serum calcitonin gene-related peptide in patients with persistent post-concussion symptoms, including headache: a cohort study
Authors: Peter Preben Eggertsen
Johan Palmfeldt
Henrik Winther Schytz
Debbie Hay
Rikke Katrine Jentoft Olsen
Jørgen Feldbæk Nielsen
Publication date: 17-01-2024
Publisher: Springer Berlin Heidelberg
Keywords: Headache
Migraine
Central Nervous System Trauma
Published in: Journal of Neurology / Issue 5/2024
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-024-12181-y

At a glance: The STEP trials

Springer Medicine

Serum calcitonin gene-related peptide in patients with persistent post-concussion symptoms, including headache: a cohort study

Abstract

Background

Methods

Results

Discussion

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Discussion

Please log in to get access to this content

Other articles of this Issue 5/2024

A randomized controlled trial of oral antipyretic treatment to reduce overheating during exercise in adults with multiple sclerosis

Real-word application of the AT(N) classification and disease-modifying treatment eligibility in a hospital-based cohort

Assessing the synergistic effectiveness of intermittent theta burst stimulation and the vestibular ocular reflex rehabilitation protocol in the treatment of Mal de Debarquement Syndrome: a randomised controlled trial

Endovascular thrombectomy for DAWN- and DEFUSE-3 ineligible acute ischemic stroke patients: a systematic review and meta-analysis

Genome-wide DNA methylation analysis related to ALS patient progression and survival

Utility of genetic testing in the pre-surgical evaluation of children with drug-resistant epilepsy