Abstract
Background
Flammer syndrome (FS) occurs from well-described signs and symptoms. The syndrome itself is not a disease, but it may be a directive marker for advancing therapeutic approaches by predictive and preventive measures as well as for personalization of treatments. The syndrome is related to many diseases, but FS has been rarely studied in multiple sclerosis (MS). The study aimed to determine whether FS signs and symptoms occur more often in people with MS than in healthy controls, and in order to personalize the treatment, we investigated the possible effect of current therapies on FS signs and symptoms.
Methods
Two hundred twenty-two MS patients and 203 healthy controls answered the questionnaire consisting of 15 signs and symptoms of FS.
Results
MS patients had significantly more complaints in 9 items of FS signs and symptoms (cold hands or/and feet, the reduced feeling of thirst, dizziness, drug side effects, other headaches (tension-type, medication overuse), weight loss, feeling cold, long sleep-onset time, and skin blotches) compared to healthy controls. Six items (low blood pressure, tinnitus, increased odor sensitivity, low pain threshold, and perfectionism) were similar between the two groups. The treatment agents currently used did not have any effect on the signs and symptoms of FS.
Conclusion
This study showed that FS might be associated with MS. Injectable or oral agents are not related to the signs and symptoms of FS. Further studies are needed to validate this association.
Relevance of the article for predictive, preventive, and personalized medicine
FS is common among MS patients. Being aware of this incidence that might impair the life quality of MS patients is useful to predict the comorbidity and develop preventive strategies and applying personalized treatment options and procedures.
Similar content being viewed by others
References
Dobson R, Giovanni G. Multiple sclerosis: a review. Eur J Neurol. 2018;26:27–40. https://doi.org/10.1111/ene.13819.
Krieger SC, Cook K, De Nino S, Fletcher M. The topographical model of multiple sclerosis: a dynamic visualization of disease course. Neurol Neuroimmunol Neuroinflamm. 2016;3:e279. https://doi.org/10.1212/NXI.0000000000000279.
Pawlitzki M, Neumann J, Kaufmann J, Heidel j SE, Sweeney-Reed C, Sailer M, et al. Loss of corticospinal tract integrity in early MS disease stages. Neurol Neuroimmunol Neuroinflamm. 2017;4:e399. https://doi.org/10.1212/NXI.0000000000000399.
Hemond CC, Healy BC, Tauhid S, Mazzola MA, Quintana FJ, Gandhi R, et al. MRI phenotypes in MS: longitudinal changes and miRNA signatures. Neurol Neuroimmunol Neuroinflamm. 2019;6:e530. https://doi.org/10.1212/NXI.0000000000000530.
Spanò B, Giulietti G, Pisani V, Morreale M, Tuzzi E, Nocentini U, et al. Disruption of neurite morphology parallels MS progression. Neurol Neuroimmunol Neuroinflamm. 2018;5:e502. https://doi.org/10.1212/NXI.0000000000000502.
Kemenyova P, Siarnik P, Sutovsky S, Blaho A, Turcani P, Kolar B. Impairment of endothelial function in patients with multiple sclerosis. Neuro Endocrinol Lett. 2015;36:67–71.
Marrie RA, Reider N, Cohen J, Stuve O, Trojano M, Cutter G, et al. A systematic review of the incidence and prevalence of cardiac, cerebrovascular, and peripheral vascular disease in multiple sclerosis. Multipl Scler. 2015;21:318–21. https://doi.org/10.1177/1352458514564485.
Konieczka K, Ritch R, Traverso CE, Kim DM, Kook MS, Gallino A, et al. Flammer syndrome. EPMA J. 2014;5:11. https://doi.org/10.1186/1878-5085-5-11.
Bae KH, Go HY, Park KH, Ahn I, Yoon Y, Lee S. The association between cold hypersensitivity in the hands and feet and chronic disease: results of a multicentre study. BMC Complement Altern Med. 2018;18(1):40. https://doi.org/10.1186/s12906-018-2082-3.
Konieczka K, Koch S, Binggeli T, Schoetzau A, Kesselring J. Multiple sclerosis and primary vascular dysregulation (Flammer syndrome). EPMA J. 2016;15:7–13. https://doi.org/10.1186/s13167-016-0062-6.
Flammer J, Konieczka K, Flammer AJ. The primary vascular dysregulation syndrome: implications for eye diseases. EPMA J. 2013;4(14). https://doi.org/10.1186/1878-5085-4-14.
Haider L. Inflammation, iron, energy failure, and oxidative stress in the pathogenesis of multiple sclerosis. Oxidative Med Cell Longev. 2015;2015(725370):1–10. https://doi.org/10.1155/2015/725370.
Flammer J, Konieczka K. The discovery of the Flammer syndrome: a historical and personal perspective. EPMA J. 2017;8:75–92. https://doi.org/10.1007/s13167-017-0090-x.
Lucas RM, Rodney Harris RM. On the nature of evidence and ‘proving’ causality: smoking and lung cancer vs. sun exposure, vitamin D and multiple sclerosis. Int J Environ Res Public Health. 2018;12, 15(8). https://doi.org/10.3390/ijerph15081726.
Rocha NP, Colpo GD, Bravo-Alegria J, Lincoln JA, Wolinsky JS, Lindsey JW, et al. Exploring the relationship between Endothelin-1 and peripheral inflammation in multiple sclerosis. J Neuroimmunol. 2018;326:45–8. https://doi.org/10.1016/j.jneuroim.2018.11.007.
Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292–302. https://doi.org/10.1002/ana.22366.
Konieczka K, Choi HJ, Koch S, Fankhauser F, Schoetzau A, Kim DM. Relationship between normal tension glaucoma and Flammer syndrome. EPMA J. 2017;8:111–7. https://doi.org/10.1007/s13167-017-0097-3.
Barin L, Salmen A, Disanto G, Babačić H, Calabrese P, Chan A, et al. The disease burden of multiple sclerosis from the individual and population perspective: which symptoms matter most? Multipl Scler Relat Disord. 2018;25:112–21. https://doi.org/10.1016/j.msard.2018.07.013.
Filingeri D, Chaseling G, Hoang P, Barnett M, Davis SL, Jay O. Afferent thermosensory function in relapsing-remitting multiple sclerosis following exercise-induced increases in body temperature. Exper Physiol. 2017;107:887–93. https://doi.org/10.1113/EP086320.
Davis SL, Jay O, Wilson TE. Thermoregulatory dysfunction in multiple sclerosis. Handb Clin Neurol. 2018;157:701–14. https://doi.org/10.1016/B978-0-444-64074-1.00042-2.
Keller DM, Fadel PJ, Hamsberger MA, Remington GM, Frohman EM, Davis SL. Reduced spontaneous sympathetic nerve activity in multiple sclerosis patients. J Neurol Sci. 2014;344:210–4. https://doi.org/10.1016/j.jns.2014.06.053.
Speciale L, Sarasella M, Ruzzante S, Caputo D, Mancuso R, Calvo MG. Endothelin and nitric oxide levels in cerebrospinal fluid of patients with multiple sclerosis. J Neuro-Oncol. 2006;2:62–6.
Haufschild T, Shaw SG, Kesselring J, Flammer J. Increased endothelin-1 plasma levels in patients with multiple sclerosis. J Neuroophthalmol. 2001;21:37–8.
Vargas DL, Tyor WR. Update on disease-modifying therapies for multiple sclerosis. J Investig Med. 2017;65:883–91. https://doi.org/10.1136/jim-2016-000339.
Auricchio F, Scavone C, Cimmaruta D, Di Mauro G, Capuano A, Sportiello L, et al. Drugs approved for the treatment of multiple sclerosis: review of their safety profile. Expert Opin Drug Saf. 2017;16:1359–71. https://doi.org/10.1080/14740338.2017.1388371.
Putzki N, Katsarava Z. Headache in multiple sclerosis. Curr Pain Headache Rep. 2010;14:316–20. https://doi.org/10.1007/s11916-010-0126-6.
Kister I, Caminero AB, Herbert J, Lipton RB. Tension-type headache and migraine in multiple sclerosis. Curr Pain Headache Rep. 2010;14:441–8. https://doi.org/10.1007/s11916-010-0143-5.
Beckmann Y, Türe S. Headache characteristics in multiple sclerosis. Mult Scler Relat Disord. 2018;27:112–6. https://doi.org/10.1016/j.msard.2018.09.022.
Husain F, Pardo G, Rabadi M. Headache and its management in patients with multiple sclerosis. Curr Treat Options Neurol. 2018;20(4):10. https://doi.org/10.1007/s11940-018-0495-4.
Gustavsen MW, Celius EG, Winsvold BS, Moen SM, Nygaard GO, Berg-Hansen P, et al. Migraine and frequent tension-type headache are not associated with multiple sclerosis in a Norwegian case-control study. Multipl Scler J Exp Transl Clin. 2016;12(2):20. https://doi.org/10.1177/2055217316682976.
Langer-Gould A, Brara SM, Beaber BE, Koebnick C. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology. 2013;80:548–52. https://doi.org/10.1212/WNL.0b013e31828154f3.
Munger KL, Bentzen J, Laursen B, Stenager E, Koch-Henriksen N, Sørensen TIA, et al. Childhood body mass index and multiple sclerosis risk: a long-term cohort study. Mult Scler. 2013;19:1323–9. https://doi.org/10.1177/1352458513483889.
Marrie RA, Elliott L, Marriott J, Cossoy M, Blanchard J, Leung S, et al. Effect of comorbidity on mortality in multiple sclerosis. Neurology. 2015;85:240–7. https://doi.org/10.1212/WNL.0000000000001718.
Marrie RA, Elliot L, Marriott J, Cossoy M, Tennakoon A, Yu N. Comorbidity increases the risk of hospitalizations in multiple sclerosis. Neurology. 2015;84:350–8. https://doi.org/10.1212/WNL.0000000000001187.
Mowry EM, Azevedo CJ, McCulloch CE, Okuda DT, Lincoln RR, Waubant E, et al. Body mass index, but not vitamin D status, is associated with brain volume change in MS. Neurology. 2018;91:e2256–64. https://doi.org/10.1212/WNL.0000000000006644.
Payne C, Wiffen PJ, Martin S. WITHDRAWN: interventions for fatigue and weight loss in adults with advanced progressive illness. Cochrane Database Syst Rev. 2017;4:CD008427. https://doi.org/10.1002/14651858.CD008427.pub3.
Braley TJ. Overview: a framework for the discussion of sleep in multiple sclerosis. Curr Sleep Med Rep. 2017;3:263–71.
Veauthier C, Hasselmann H, Gold SM, Paul F. The Berlin Treatment Algorithm: recommendations for tailored innovative therapeutic strategies for multiple sclerosis-related fatigue. EPMA J. 2016;7:25. https://doi.org/10.1186/s13167-016-0073-3.
Braley TJ, Boudreau EA. Sleep disorders in multiple sclerosis. Curr Neurol Neurosci Rep. 2016;16:50. https://doi.org/10.1007/s11910-016-0649-2.
Veauthier C, Gaede G, Radbruch H, Wernecke KD, Paul F. Sleep disorders reduce health-related quality of life in multiple sclerosis (Nottingham Health Profile Data in Patients with Multiple Sclerosis). Int J Mol Sci. 2015;16:16514–28. https://doi.org/10.3390/ijms160716514.
Veauthier C, Paul F. Sleep disorders in multiple sclerosis and their relationship to fatigue. Sleep Med. 2014;15:5–14. https://doi.org/10.1016/j.sleep.2013.08.791.
Sahraian MA, Rezaali S, Hosseiny M, Doosti R, Tajik A, Naser Moghadasi A. Sleep disorder as a triggering factor for relapse in multiple sclerosis. Eur Neurol. 2017;77:258–61. https://doi.org/10.1159/000470904.
Amtmann D, Askew RL, Kim J, Chung H, Ehde DM, Bombardier CH, et al. Pain affects depression through anxiety, fatigue, and sleep in multiple sclerosis. Rehabil Psychol. 2015;60:81–90. https://doi.org/10.1037/rep0000027.
Maurelli M, Bergamaschi R, Antonini A, Fargnoli MC, Puma E, Mallucci G, et al. Interferon-beta injection site reactions in patients with multiple sclerosis. J Dermatalog Treat. 2018;29:831–4. https://doi.org/10.1080/09546634.2018.1467539.
Sejbaek T, Nybo M, Petersen T, Illes Z. Real-life persistence and tolerability with dimethyl fumarate. Mult Scler Relat Disord. 2018;24:42–6. https://doi.org/10.1016/j.msard.2018.05.007.
Golubnitschaja O, Flammer J. Individualised patient profile: clinical utility of Flammer syndrome phenotype and general lessons for predictive, preventive and personalised medicine. EPMA J. 2018;9:15–20. https://doi.org/10.1007/s13167-018-0127-9.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
All the patient investigations conformed to the principles outlined in the Declaration of Helsinki and have been performed with the permission of the Ethics Committee of İzmir Katip Çelebi University. The study was approved by the Ethics Committee of İzmir Katip Çelebi University. All the patients were informed about the purposes of the study and have signed their “consent of the patient.” This article does not contain any studies with animals performed by any of the authors.
Competing interests
The authors declare that they have no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Uzunköprü, C., Beckmann, Y. Flammer syndrome in multiple sclerosis: diagnostics, prediction, and personalization of treatments. EPMA Journal 10, 437–444 (2019). https://doi.org/10.1007/s13167-019-00179-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13167-019-00179-w