NEUROINFLAMMATION MECHANISMS, CLINICAL IMPLICATIONS, AND THERAPEUTIC APPROACHES

neuroinflamationkapak

HEADACHE AND INFLAMMATION: CAUSE OR ASSOCIATION?

Güldeniz Çetin Erci1
Uğur Uygunoğlu2

1University of Health Sciences, Hamidiye Faculty of Medicine, SancaktepeŞehit Prof. Dr. İlhan Varank Training and Research Hospital, Department of Neurology, İstanbul, Türkiye
2İstanbul University-Cerrahpaşa, Cerrahpaşa Faculty of Medicine, Department of Neurology, İstanbul, Türkiye

Çetin Erci G, Uygunoğlu U. Headache and İnflammation: Cause or Association?. In: Şahin Ş editor. Neuroinflammation. 1st ed. Ankara: Türkiye Klinikleri; 2025. p.65-76.

ABSTRACT

Understanding the role of neuroinflammation in headaches is of critical importance for both improving diagnostic evaluations and developing treatment approaches. In neurological practice, headaches are categorized into two subgroups: primary and secondary. In the literature, studies related to inflammation are predominantly conducted in the field of primary headaches. However, the association between secondary headaches and neuroinflammation is more pronounced compared to primary headaches. Nevertheless, the clinical features of secondary headaches are generally defined in terms of primary headaches.

Keywords: Primary headaches; Secondary headaches; Inflammation; Neurogenic inflammation

ÖZET

Nöroinflamasyonun baş ağrılarındaki rolünü anlamak hem tanısal değerlendirmelerin iyileştirilmesi hem de tedavi yaklaşımlarının geliştirilmesi açısından kritik öneme sahiptir. Nöroloji pratiğinde baş ağrıları, primer ve sekonder olmak üzere iki alt grupta değerlendirilmektedir. Literatürde inflamasyonla ilgili çalışmalar çoğunlukla primer baş ağrıları alanında yapılmaktadır. Ancak sekonder baş ağrılarının nöroinflamasyonla ilişkisi primer baş ağrılarına göre daha belirgindir. Bununla birlikte sekonder baş ağrılarının klinik özellikleri genellikle primer baş ağrıları üzerinden tanımlanmaktadır.

Anahtar Kelimeler: Primer baş ağrıları; Sekonder baş ağrıları; İnflamasyon; Nöroinflamasyon

Referanslar

  1. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211. [Crossref]  [PubMed]
  2. May A, Burstein R. Hypothalamic regulation of headache and migraine. Cephalalgia. 2019;39(13):1710-1719. [Crossref]  [PubMed]  [PMC]
  3. Bruno PP, Carpino F, Carpino G, Zicari A. An overview on immune system and migraine. Eur Rev Med Pharmacol Sci. 2007;11(4):245-248.
  4. Edvinsson L, Haanes KA, Warfvinge K. Does inflammation have a role in migraine? Nature Reviews. Neurology, 2019;15(8):483-490. [Crossref]  [PubMed]
  5. Urbach A, Bruehl C, Witte OW. Microarray-based longterm detection of genes differentially expressed after cortical spreading depression. The European Journal of Neuroscience. 2006;24(3):841-856. [Crossref]  [PubMed]
  6. Karatas H, Erdener SE, Gursoy Ozdemir Y, Lule S, Eren Koçak E, Sen ZD, Dalkara T. Spreading Depression Triggers Headache by Activating Neuronal Panx1 Channels. Science. 2013;339:1092-1095. [Crossref]  [PubMed]
  7. Gursoy Ozdemir Y, Qiu J, Matsuoka N, Bolay H, Bermpohl D, Jin H, Wang X, Rosenberg GA, Lo EH, Moskowitz MA. Cortical spreading depression activates and upregulates MMP-9. The Journal of Clinical Investigation. 2004;113(10):1447-1455. [Crossref]  [PubMed]
  8. Jansson D, Rustenhoven J, Feng S, Hurley D, Oldfield RL, Bergin PS, Mee EW, Faull RLM, Dragunow M. (2014). A role for human brain pericytes in neuroinflammation. Journal of Neuroinflammation. 2014;11(104). [Crossref]  [PubMed]  [PMC]
  9. Biscetti L, De Vanna G, Cresta E, Bellotti A, Corbelli I, Letizia Cupini M, Calabresi P, Sarchielli P. Immunological find ings in patients with migraine and other primary headaches: a narrative review. Clin Exp Immunol. 2022 Jan 28;207(1):11-26. [Crossref]  [PubMed]  [PMC]
  10. Della Vedova C, Cathcart S, Dohnalek A, et al. Peripheral interleukin-1ß levels are elevated in chronic tension-type head ache patients. Pain Res Manag 2013;18:301-6. [Crossref]  [PubMed]  [PMC]
  11. Domingues RB, Duarte H, Rocha NP, Teixeira AL. Increased serum levels of interleukin-8 in patients with tension-type head ache. Cephalalgia. 2015;35:801-6. [Crossref]  [PubMed]
  12. Leone M, Giustiniani A, Cecchini AP. Cluster headache: present and future therapy. Neurol Sci. 2017;38(Suppl 1):45-50. [Crossref]  [PubMed]
  13. Hoffmann J, May A. Diagnosis, pathophysiology, and management of cluster headache. Lancet Neurol. 2018;17(1):75-83. [Crossref]  [PubMed]
  14. Bree D, Levy D. Intact mast cell content during mild head injury is required for development of latent pain sensitization: implications for mechanisms underlying post-traumatic headache. Pain. 2019;160:1050-1058. [Crossref]  [PubMed]  [PMC]
  15. Fischer M, Wille G, Klien S, et al. Brain-derived neurotrophic factor in primary headaches. J Headache Pain. 2012;13(6):469-475. [Crossref]  [PubMed]  [PMC]
  16. Olesen J. International Classification of Headache Disorders. Lancet Neurol. 2018;17(5):396-397. [Crossref]  [PubMed]
  17. Ameer MA, Vaqar S, Khazaeni B. Giant Cell Arteritis (Temporal Arteritis). StatPearls. 2024. [Crossref]  [PubMed]
  18. Younger DS. Systemic vasculitis and headache. Current Opinion in Neurology. 2023;36(6):631-646. [Crossref]  [PubMed]  [PMC]
  19. Demir T, Onan HB, Balal M, Aksungur E, Bicakci S. Clin ical features and risk factors of angiography headache and evaluation of its relationship to primary headaches. Neurol Neurochir Pol. 2019;53(6):442-448. [Crossref]  [PubMed]
  20. Szymanowicz O, Korczowska-Łącka I, Słowikowski B, et al. Headache and NOTCH3 Gene Variants in Patients with CADASIL [published correction appears in Neurol Int. 2024 May 06;16(3):518-521. [Crossref]  [PubMed]  [PMC]
  21. Pia S, Lui F. Melas Syndrome. [Updated 2024 Jan 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan. [Crossref]  [PubMed]
  22. Bradshaw MJ, Pawate S, Koth LL, Cho TA, Gelfand JM. Neurosarcoidosis: Pathophysiology, Diagnosis, and Treatment. Neurol Neuroimmunol Neuroinflamm. 2021;8(6):e1084. Published 2021 Oct 4. [Crossref]  [PubMed]  [PMC]
  23. Ungprasert P, Ryu JH, Matteson EL. Clinical Manifestations, Diagnosis, and Treatment of Sarcoidosis. Mayo Clinic Proceedings. Innovations, Quality & Outcomes. 2019;3(3):358-375. [Crossref]  [PubMed]  [PMC]
  24. Vannemreddy PS, Nanda A, Reddy PK, Gonzalez E. Primary cerebral sarcoid granuloma: the importance of definitive diagnosis in the high-risk patient population. Clin Neurol Neurosurg. 2002;104(4):289-292. [Crossref]  [PubMed]
  25. Katz JM, Bruno MK, Winterkorn JM, Nealon N. The pathogenesis and treatment of optic disc swelling in neurosarcoidosis: a unique therapeutic response to infliximab. Arch Neurol. 2003;60(3):426-430. [Crossref]  [PubMed]
  26. Loor RG, van Tongeren J, Derks W. Multiple cranial nerve dysfunction caused by neurosarcoidosis. Am J Otolaryngol. 2012;33(4):484-486. [Crossref]  [PubMed]
  27. Tana C, Azorin DG, Cinetto F, et al. Common Clinical and Molecular Pathways between Migraine and Sarcoidosis. Int J Mol Sci. 2023;24(9):8304. Published 2023 May5. [Crossref]  [PubMed]  [PMC]
  28. Berntsson SG, Elmgren A, Gudjonsson O, Grabowska A, Landtblom AM, Moraes-Fontes MF. A comprehensive diagnostic approach in suspected neurosarcoidosis. Sci Rep. 2023;13(1):6539. Published 2023 Apr 21. [Crossref]  [PubMed]  [PMC]
  29. Vlad B, Neidhart S, Hilty M, Ziegler M, Jelcic I. Differentiating neurosarcoidosis from multiple sclerosis using combined analysis of basic CSF parameters and MRZ reaction. Front Neurol. 2023;14:1135392. Published 2023 Mar 24. [Crossref]  [PubMed]  [PMC]
  30. Voortman M, Drent M, Baughman RP. Management of neurosarcoidosis: a clinical challenge. Curr Opin Neurol. 2019;32(3):475-483. [Crossref]  [PubMed]  [PMC]
  31. Kaur H, Betances EM, Perera TB. Aseptic Meningitis. In: StatPearls. Treasure Island (FL): StatPearls Publishing; February 26, 2024. [Crossref]  [PubMed]
  32. Kumar R. Aseptic meningitis: diagnosis and management. Indian J Pediatr. 2005;72(1):57-63. [Crossref]  [PubMed]
  33. Tattevin P, Tchamgoué S, Belem A, Bénézit F, Pronier C, Revest M. Aseptic meningitis. Rev Neurol (Paris). 2019;175(7-8):475-480. [Crossref]  [PubMed]
  34. Orbach R, Schneebaum Sender N, Lubetzky R, Fattal-Valevski A. Increased Intracranial Pressure in Acute Disseminated Encephalomyelitis. J Child Neurol. 2019;34(2):99-103. [Crossref]  [PubMed]
  35. Husain F, Pardo G, Rabadi M. Headache and Its Management in Patients With Multiple Sclerosis. Curr Treat Options Neurol. 2018;20(4):10. Published 2018 Mar 24. [Crossref]  [PubMed]
  36. Schwarz S, Mohr A, Knauth M, Wildemann B, Storch-Hagenlocher B. Acute disseminated encephalomyelitis: a follow-up study of 40 adult patients. Neurology. 2001;56(10):13131318. [Crossref]  [PubMed]
  37. Ciçek A, De Temmerman L, De Weweire M, De Backer H, Buyle M, Clement F. Thunderclap headache as a first manifestation of acute disseminated encephalomyelitis: case report and literature review. BMC Neurol. 2024;24(1):315. Published 2024 Sep 4. [Crossref]  [PubMed]  [PMC]
  38. Williams BJ, Skinner HJ, Maria BL. Increased intracranial pressure in a case of pediatric multiple sclerosis. J Child Neurol. 2008;23(6):699-702. [Crossref]  [PubMed]
  39. Borhani-Haghighi A, Kardeh B, Banerjee S, et al. Neuro-Behcet’s disease: An update on diagnosis, differential diagnoses, and treatment. Mult Scler Relat Disord. 2020;39:101906. [Crossref]  [PubMed]
  40. Zhang L, Wang X, Liu F, Zhang Z. Neuro-Behcet disease. Arch Med Sci. 2021;17(2):569-573. Published 2021 Feb 26. [Crossref]  [PubMed]  [PMC]
  41. Mousa AE, Okasha M, Isaacs JD, et al. Brain pseudotumour secondary to Behçet’s disease. Ann R Coll Surg Engl. 2019;101(8):e164-e168. [Crossref]  [PubMed]  [PMC]
  42. Uygunoğlu U, Siva A. Behçet’s Syndrome and Nervous System Involvement. Curr Neurol Neurosci Rep. 2018;18(7):35. Published 2018 May 23. [Crossref]  [PubMed]
  43. Saip S, Siva A, Altintas A, et al. Headache in Behçet’s syndrome. Headache. 2005;45(7):911-919. [Crossref]  [PubMed]
  44. Foley PL, Vesterinen HM, Laird BJ, et al. Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis. Pain. 2013;154(5):632642. [Crossref]  [PubMed]
  45. Sîrbu CA, Rotaru AR, Antochi FA, Plesa A, Manole AM, Roceanu AM. Headache and Other Pain Syndromes in Multiple Sclerosis: A Narrative Review. Life (Basel). 2024;14(1):87. Published 2024 Jan 5. [Crossref]  [PubMed]  [PMC]
  46. Adamczyk B, Morawiec N, Boczek S, et al. Headache in Multiple Sclerosis: A Narrative Review. Medicina (Kaunas). 2024;60(4):572. Published 2024 Mar 30. [Crossref]  [PubMed]  [PMC]
  47. Rościszewska-Żukowska I, Galiniak S, Bartosik-Psujek H. Clinical Characteristics of Headache in Multiple Sclerosis Patients: A Cross-Sectional Study. J Clin Med. 2023;12(10):3518. Published 2023 May 17. [Crossref]  [PubMed]  [PMC]
  48. Biscetti L, De Vanna G, Cresta E, et al. Headache and immunological/autoimmune disorders: a comprehensive review of available epidemiological evidence with insights on potential underlying mechanisms. J Neuroinflammation. 2021;18(1):259. Published 2021 Nov 8. [Crossref]  [PubMed]  [PMC]
  49. Mohammadi M, Kankam SB, Salehi S, et al. The association between multiple sclerosis and migraine: A meta-analysis. Mult Scler Relat Disord. 2023;79:104954. [Crossref]  [PubMed]
  50. Wang L, Zhang J, Deng ZR, Zu MD, Wang Y. The epidemiology of primary headaches in patients with multiple sclerosis. Brain Behav. 2021;11(1):e01830. [Crossref]  [PubMed]  [PMC]
  51. Beckmann Y, Türe S. Headache characteristics in multiple sclerosis. Mult Scler Relat Disord. 2019;27:112-116. [Crossref]  [PubMed]
  52. Husain F, Pardo G, Rabadi M. Headache and Its Management in Patients With Multiple Sclerosis. Curr Treat Options Neurol. 2018;20(4):10. Published 2018 Mar 24. [Crossref]  [PubMed]
  53. Kania K, Ambrosius W, Dyczkowska K, Kozubski W, Kalinowska-Lyszczarz A. Prevalence and prognostic value of prodromal symptoms in relapsing-remitting multiple sclerosis. Neurol Neurochir Pol. 2023;57(3):289-296. [Crossref]  [PubMed]
  54. Arzani M, Jahromi SR, Ghorbani Z, et al. Gut-brain Axis and migraine headache: a comprehensive review. J Headache Pain. 2020;21(1):15. Published 2020 Feb 13. [Crossref]  [PubMed]  [PMC]
  55. Mavridis T, Papagiannakis N, Breza M, et al. B-Cell Targeted Therapies in Patients with Multiple Sclerosis and Incidence of Headache: A Systematic Review and Meta-Analysis. J Pers Med. 2022;12(9):1474. Published 2022 Sep 8. [Crossref]  [PubMed]  [PMC]
  56. Fragoso YD, Adoni T, Gomes S, et al. Persistent headache in patients with multiple sclerosis starting treatment with fingolimod. Headache. 2015;55(4):578-579. [Crossref]  [PubMed]
  57. Joshi MN, Whitelaw BC, Carroll PV. MECHANISMS IN ENDOCRINOLOGY: Hypophysitis: diagnosis and treatment. Eur J Endocrinol. 2018;179(3):R151-R163. [Crossref]  [PubMed]
  58. Angelousi A, Alexandraki K, Tsoli M, Kaltsas G, Kassi E. Hypophysitis (Including IgG4 and Immunotherapy). Neuroendocrinology. 2020;110(9-10):822-835. [Crossref]  [PubMed]
  59. Friedman DI, Gordon LK, Quiros PA. Headache attributable to disorders of the eye. Curr Pain Headache Rep. 2010;14(1):62-72. [Crossref]  [PubMed]
  60. Caronna E, Alpuente A, Torres-Ferrus M, Pozo-Rosich P. Toward a better understanding of persistent headache after mild COVID-19: Three migraine-like yet distinct scenarios. Headache. 2021;61(8):1277-1280. [Crossref]  [PubMed]  [PMC]
  61. Afrin LB, Weinstock LB, Molderings GJ. Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome. Int J Infect Dis. 2020;100:327-332. [Crossref]  [PubMed]  [PMC]