The Prevalence of Migraine in Children Diagnosed with Familial Mediterranean Fever

Yiğithan Güzin; Safa Mete Dağdaş; Gamze Sarıkaya Uzan; Mügen Baykan; Pınar Gençpınar; Figen Baydan; Berk Özyılmaz; Gizem Doğan; Belde Kasap Demir; Nihal Olgaç Dündar

doi:10.1055/a-2509-0278

Neuropediatrics, Table of Contents

Neuropediatrics 2025; 56(03): 194-199
DOI: 10.1055/a-2509-0278

Original Article

The Prevalence of Migraine in Children Diagnosed with Familial Mediterranean Fever

Authors

Yiğithan Güzin

¹Department of Pediatric Neurology, Tepecik Training and Research Hospital, University of Health Sciences, Izmir, Türkiye
Safa Mete Dağdaş

¹Department of Pediatric Neurology, Tepecik Training and Research Hospital, University of Health Sciences, Izmir, Türkiye
Gamze Sarıkaya Uzan

¹Department of Pediatric Neurology, Tepecik Training and Research Hospital, University of Health Sciences, Izmir, Türkiye
Mügen Baykan

¹Department of Pediatric Neurology, Tepecik Training and Research Hospital, University of Health Sciences, Izmir, Türkiye
Pınar Gençpınar

²Department of Pediatric Neurology, Izmir Katip Celebi University, Tepecik Training and Research Hospital, Izmir, Türkiye

³Neuroscience Research Center, İzmir Katip Çelebi University, Izmir, Türkiye
Figen Baydan

¹Department of Pediatric Neurology, Tepecik Training and Research Hospital, University of Health Sciences, Izmir, Türkiye
Berk Özyılmaz

⁵Department of Genetic Diseases Evaluation Center, University of Health Sciences, Tepecik Training and Research Hospital, Izmir, Türkiye
Gizem Doğan

¹Department of Pediatric Neurology, Tepecik Training and Research Hospital, University of Health Sciences, Izmir, Türkiye
Belde Kasap Demir

⁴Department of Pediatric Rheumatology and Nephrology, İzmir Katip Çelebi University, Izmir, Türkiye
Nihal Olgaç Dündar

²Department of Pediatric Neurology, Izmir Katip Celebi University, Tepecik Training and Research Hospital, Izmir, Türkiye

³Neuroscience Research Center, İzmir Katip Çelebi University, Izmir, Türkiye

Abstract

Purpose Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent episodes of fever and serositis, caused by mutations in the MEFV gene. Inflammatory pathways associated with FMF are linked to increased proinflammatory cytokines, which may be related to primary headaches, including migraine. The aim of this study was to evaluate the frequency of migraine and other primary headaches in FMF patients.

Methods In this retrospective study, the medical records of FMF patients were analyzed. Demographic data, MEFV gene mutations, and headache histories were collected. The frequency of migraine was compared among patients with these mutations, and statistical analyses were conducted.

Results The study included 148 FMF patients, comprising 56.1% females and 43.9% males, with a mean age of 11.3 ± 3.7 years. A family history of FMF was reported in 77.7% of patients, and 35.8% had a family history of migraine. Headaches were reported in 52.7% of patients: 24.3% non-specific, 15.5% tension-type, and 12.8% migraine. Of those with migraine, 8.1% had migraine with aura, and 4.7% without aura. Headaches were more frequently frontal in patients under 12 years of age and temporal in those aged ≥12 years (p = 0.011). The most common genetic mutations were M694V heterozygous and homozygous, with M694V and E148Q mutations linked to more frequent migraines, although not statistically significant.

Conclusion FMF patients should be screened for primary headaches, particularly migraine. The high frequency of migraine observed in this study suggests that clinicians should particularly consider migraine as a diagnosis in headache episodes experienced by FMF patients.

Keywords

familial mediterranean fever - migraine - primary headaches - MEFV gene mutations

Full Text

References

References
1 Abu-Arafeh I, Razak S, Sivaraman B, Graham C. Prevalence of headache and migraine in children and adolescents: a systematic review of population-based studies. Dev Med Child Neurol 2010; 52 (12) 1088-1097
2 Parisi P, Papetti L, Spalice A, Nicita F, Ursitti F, Villa MP. Tension-type headache in paediatric age. Acta Paediatr 2011; 100 (04) 491-495
3 Zwart J-A, Dyb G, Holmen TL, Stovner LJ, Sand T. The prevalence of migraine and tension-type headaches among adolescents in Norway. The Nord-Trøndelag Health Study (Head-HUNT-Youth), a large population-based epidemiological study. Cephalalgia 2004; 24 (05) 373-379
4 Ducros A, Tournier-Lasserve E, Bousser M-G. The genetics of migraine. Lancet Neurol 2002; 1 (05) 285-293
5 Ashina M. Migraine. N Engl J Med 2020; 383 (19) 1866-1876
6 Noseda R, Kainz V, Borsook D, Burstein R. Neurochemical pathways that converge on thalamic trigeminovascular neurons: potential substrate for modulation of migraine by sleep, food intake, stress and anxiety. PLoS One 2014; 9 (08) e103929
7 Eising E, A Datson N, van den Maagdenberg AM, Ferrari MD. Epigenetic mechanisms in migraine: a promising avenue?. BMC Med 2013; 11: 26
8 Theoharides TC, Donelan J, Kandere-Grzybowska K, Konstantinidou A. The role of mast cells in migraine pathophysiology. Brain Res Brain Res Rev 2005; 49 (01) 65-76
9 Chae JJ, Cho Y-H, Lee G-S. et al. Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1β activation and severe autoinflammation in mice. Immunity 2011; 34 (05) 755-768
10 Coşkun S, Varol S, Özdemir HH. et al. Association between sequence variations of the Mediterranean fever gene and the risk of migraine: a case-control study. Neuropsychiatr Dis Treat 2016; 12: 2225-2232
11 Papin S, Cuenin S, Agostini L. et al. The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1beta processing. Cell Death Differ 2007; 14 (08) 1457-1466
12 Inal A, Yilmaz M, Kendirli SG, Altintas DU, Karakoc GB. The clinical and genetical features of 124 children with Familial Mediterranean fever: experience of a single tertiary center. Rheumatol Int 2009; 29 (11) 1279-1285
13 Çomak E, Tüfekçi Ö, Kılıçbay F. et al. Febrile seizures in children with familial Mediterranean fever: coincidence or association?. Eur J Paediatr Neurol 2015; 19 (05) 572-576
14 Uluduz D, Tavsanli ME, Uygunoğlu U. et al. Primary headaches in pediatric patients with chronic rheumatic disease. Brain Dev 2014; 36 (10) 884-891
15 Yalçinkaya F, Ozen S, Ozçakar ZB. et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford) 2009; 48 (04) 395-398
16 Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018; 38 (01) 1-211
17 Dodick DW. Clinical practice. Chronic daily headache. N Engl J Med 2006; 354 (02) 158-165
18 Onen F. Familial Mediterranean fever. Rheumatol Int 2006; 26 (06) 489-496
19 GBD 2016 Headache Collaborators. Global, regional, and national burden of migraine and tension-type headache, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2018; 17 (11) 954-976
20 Canpolat M, Gumus H, Gunduz Z. et al. Neurological manifestations in Familial Mediterranean fever: results of 22 children from a reference center in Kayseri, an Urban Area in Central Anatolia, Turkey. Neuropediatrics 2017; 48 (02) 79-85
21 Kalyoncu U, Eker A, Oguz KK. et al. Familial Mediterranean fever and central nervous system involvement: a case series. Medicine (Baltimore) 2010; 89 (02) 75-84
22 Bektaş PC, Kavas Tufan A, Çetin N, Yarar C, Carman KB. Neurological face of familial Mediterranean fever. Turk Arch Pediatr 2022; 57 (05) 511-515
23 Grangeon L, Lange KS, Waliszewska-Prosół M. et al; European Headache Federation School of Advanced Studies (EHF-SAS). Genetics of migraine: where are we now?. J Headache Pain 2023; 24 (01) 12
24 Polderman TJC, Benyamin B, de Leeuw CA. et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat Genet 2015; 47 (07) 702-709
25 Al Khalili Y, Asuncion RMDCP. Migraine Headache in Childhood. Treasure Island: StatPearls; 2024. , pp. 1–14. Accessed January 6, 2025 at: https://www.ncbi.nlm.nih.gov/books/NBK557813/
26 Rao R, Hershey AD. An update on acute and preventive treatments for migraine in children and adolescents. Expert Rev Neurother 2020; 20 (10) 1017-1027
27 Karaaslan Z, Uygunoğlu U, Şaşmaz T. et al. The prevalence of headache disorders in children and adolescents in Istanbul: a school-based study. Pediatr Neurol 2023; 149: 100-107
28 Wöber C, Wöber-Bingöl Ç, Uluduz D. et al. Undifferentiated headache: broadening the approach to headache in children and adolescents, with supporting evidence from a nationwide school-based cross-sectional survey in Turkey. J Headache Pain 2018; 19 (01) 18
29 Albers L, Straube A, Landgraf MN, Heinen F, von Kries R. High diagnostic stability of confirmed migraine and confirmed tension-type headache according to the ICHD-3 beta in adolescents. J Headache Pain 2014; 15 (01) 36
30 Barnes NP. Migraine headache in children. Clin Evid 2015; 2015: 0318
31 Lancieri M, Bustaffa M, Palmeri S. et al. An update on familial Mediterranean fever. Int J Mol Sci 2023; 24 (11) 9584
32 Lidar M, Doron A, Barzilai A. et al. Erysipelas-like erythema as the presenting feature of familial Mediterranean fever. J Eur Acad Dermatol Venereol 2013; 27 (07) 912-915
33 Avar-Aydın PÖ, Ozcakar ZB, Aydın F, Karakaş HD, Çakar N, Yalçınkaya F. Erysipelas-like erythema: a manifestation of severe disease phenotype in pediatric patients with familial Mediterranean fever. Turk Arch Pediatr 2022; 57 (06) 599-602
34 Shohat M. Familial mediterranean fever. In: Adam MP, Feldman J, Mirzaa GM. eds. GeneReviews® [Internet]. Seattle, WA: University of Washington; 2000. :1993-2025. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1227/
35 Papadopoulos VP, Giaglis S, Mitroulis I, Ritis K. The population genetics of familial mediterranean fever: a meta-analysis study. Ann Hum Genet 2008; 72 (Pt 6): 752-761
36 Güneş-Yılmaz S, Kasap-Demir B, Soyaltın E. et al. Prediction of more severe MEFV gene mutations in childhood. Turk Arch Pediatr 2021; 56 (06) 610-617
37 Ben-Chetrit E, Lerer I, Malamud E, Domingo C, Abeliovich D. The E148Q mutation in the MEFV gene: is it a disease-causing mutation or a sequence variant?. Hum Mutat 2000; 15 (04) 385-386