Increased Prevalence of Flammer Syndrome in Patients with Retinitis Pigmentosa

Abstract

Background: “Retinitis pigmentosa” refers to a group of degenerative eye diseases with a genetic background. Flammer syndrome encompasses a set of symptoms and signs, mainly but not exclusively related to dysregulation of blood vessels. The purpose of the present study was to determine, with the help of a questionnaire, whether symptoms of Flammer syndrome occur more often in patients with retinitis pigmentosa than in controls. Methods: 76 patients with retinitis pigmentosa (members of the Swiss patient organization for retinitis pigmentosa) and 274 control subjects answered a questionnaire (Flammer Syndrome Questionnaire) on 15 symptoms and signs of Flammer syndrome. Results: Seven of 15 symptoms and signs of Flammer syndrome were significantly more often positive in retinitis pigmentosa patients than in controls. Six additional symptoms and signs occurred non-significantly more often and 2 non-significantly less often in patients with retinitis pigmentosa. Conclusion: Retinitis pigmentosa patients suffer significantly more often from symptoms and signs of the Flammer syndrome than control subjects. This includes low body mass index, low blood pressure, feeling cold, migraine, increased smell perception and perfectionism. The reason for this association between retinitis pigmentosa and Flammer syndrome and the potential implications need to be determined.

Zusammenfassung

Hintergrund: Retinitis pigmentosa umfasst eine Gruppe genetisch bedingter, degenerativer Augenerkrankungen. Das Flammer-Syndrom umfasst die primäre vaskuläre Dysregulation zusammen mit weiteren vaskulären und nicht-vaskulären Symptomen und Zeichen. Das Ziel dieser Studie war es, mit Hilfe eines Fragebogens zu prüfen, ob die Symptome des Flammer-Syndroms bei Patienten mit Retinitis pigmentosa häufiger oder seltener sind, als bei Kontroll-Personen. Methode: 76 Patienten mit Retinitis pigmentosa und 274 Kontroll-Personen füllten einen Multiple-Choice Fragebogen (Flammer-Syndrom Fragebogen) aus. Es wurde nach 15 Symptomen und Zeichen des Flammer-Syndroms gefragt. Ergebnisse: 7 von 15 Symptomen oder Zeichen des Flammer-Syndroms waren signifikant und 6 weitere nicht signifikant häufiger bei Patienten mit Retinitis pigmentosa als bei Kontroll-Personen. 2 Symptomen oder Zeichen waren nicht signifikant seltener bei Patienten mit Retinitis pigmentosa. Schlussfolgerungen: Patienten mit Retinitis pigmentosa haben Symptome und Zeichen des Flammer-Syndroms häufiger als Kontroll-Personen. Signifikant häufiger sind ein tiefer BMI, tiefer Blutdruck, schnelles Frieren, Migräne, erhöhte Empfindlichkeit auf Gerüche und Perfektionismus. Der Grund dieser Zusammenhänge ist noch unklar und potentielle Folgen sind Gegenstand zukünftiger Untersuchungen.

Key words

Retinitis pigmentosa - Flammer syndrome - endothelin - ocular blood flow - vascular dysregulation

Schlüsselwörter

Retinitis pigmentosa - Flammer-Syndrom - Endothelin - Augendurchblutung - vaskuläre Dysregulation

• References

• 1 Kajiwara K, Berson EL, Dryja TP. Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. Science 1994; 264: 1604-1608
• 2 Mansergh FC, Millington-Ward S, Kennan A et al. Retinitis pigmentosa and progressive sensorineural hearing loss caused by a C12258A mutation in the mitochondrial MTTS2 gene. Am J Hum Genet 1999; 64: 971-985
• 3 Ferrari S, Di Iorio E, Barbaro V et al. Retinitis pigmentosa: genes and disease mechanisms. Curr Genomics 2011; 12: 238-249
• 4 Grunwald JE, Maguire AM, Dupont J. Retinal hemodynamics in retinitis pigmentosa. Am J Ophthalmol 1996; 122: 502-508
• 5 Falsini B, Anselmi GM, Marangoni D et al. Subfoveal choroidal blood flow and central retinal function in retinitis pigmentosa. Invest Ophthalmol Vis Sci 2011; 52: 1064-1069
• 6 Cellini M, Strobbe E, Gizzi C et al. ET-1 plasma levels and ocular blood flow in retinitis pigmentosa. Can J Physiol Pharmacol 2010; 88: 630-635
• 7 Polak K, Petternel V, Luksch A et al. Effect of endothelin and BQ123 on ocular blood flow parameters in healthy subjects. Invest Ophthalmol Vis Sci 2001; 42: 2949-2956
• 8 Cellini M, Santiago L, Versura P et al. Plasma levels of endothelin-1 in retinitis pigmentosa. Ophthalmologica 2002; 216: 265-268
• 9 Vingolo EM, Lupo S, Grenga PL et al. Endothelin-1 plasma concentrations in patients with retinitis pigmentosa. Regul Pept 2010; 160: 64-67
• 10 Finzi A, Cellini M, Strobbe E et al. ET-1 plasma levels, choroidal thickness and multifocal electroretinogram in retinitis pigmentosa. Life Sci 2014; 118: 386-390
• 11 Todorova MG, Josifova T, Konieczka K. Endothelin-1 Plasma Levels in Patients with both Retinitis Pigmentosa and Flammer Syndrome. Klin Monbl Augenheilkd 2015; 232: 514-518
• 12 Ohguro H, Mashima Y, Nakazawa M. Low levels of plasma endothelin-1 in patients with retinitis pigmentosa. Clin Ophthalmol 2010; 4: 569-573
• 13 Strobbe E, Cellini M, Fresina M et al. ET-1 Plasma Levels, Aqueous Flare, and Choroidal Thickness in Patients with Retinitis Pigmentosa. J Ophthalmol 2015; 2015: 292615
• 14 Nakazawa M, Ohguro H, Takeuchi K et al. Effect of nilvadipine on central visual field in retinitis pigmentosa: a 30-month clinical trial. Ophthalmologica 2011; 225: 120-126
• 15 Liang SY, Lee LR. Retinitis pigmentosa associated with hypomagnesaemia. Clin Experiment Ophthalmol 2010; 38: 645-647
• 16 Meyer P, Lang MG, Flammer J et al. Effects of calcium channel blockers on the response to endothelin-1, bradykinin and sodium nitroprusside in porcine ciliary arteries. Exp Eye Res 1995; 60: 505-510
• 17 Dettmann ES, Luscher TF, Flammer J et al. Modulation of endothelin-1-induced contractions by magnesium/calcium in porcine ciliary arteries. Graefes Arch Clin Exp Ophthalmol 1998; 236: 47-51
• 18 Konieczka K, Flammer AJ, Todorova M et al. Retinitis pigmentosa and ocular blood flow. EPMA J 2012; 3: 17
• 19 Sorrentino FS, Bonifazzi C, Perri P. The Role of the Endothelin System in the Vascular Dysregulation Involved in Retinitis Pigmentosa. J Ophthalmol 2015; 2015: 405234
• 20 Konieczka K, Ritch R, Traverso CE et al. Flammer syndrome. EPMA J 2014; 5: 11
• 21 Flammer J, Konieczka K, Flammer AJ. The primary vascular dysregulation syndrome: implications for eye diseases. EPMA J 2013; 4: 14
• 22 Flammer J, Konieczka K, Bruno RM et al. The eye and the heart. Eur Heart J 2013; 34: 1270-1278
• 23 Saner H, Wurbel H, Mahler F et al. Microvasculatory evaluation of vasospastic syndromes. Adv Exp Med Biol 1987; 220: 215-218
• 24 Guthauser U, Flammer J, Mahler F. The relationship between digital and ocular vasospasm. Graefes Arch Clin Exp Ophthalmol 1988; 226: 224-226
• 25 Mozaffarieh M, Fontana Gasio P, Schotzau A et al. Thermal discomfort with cold extremities in relation to age, gender, and body mass index in a random sample of a Swiss urban population. Popul Health Metr 2010; 8: 17
• 26 Kavroulaki D, Gugleta K, Kochkorov A et al. Relation of body mass index and blood pressure to subjective and objective acral temperature. Klin Monbl Augenheilkd 2009; 226: 328-331
• 27 Gasser P, Stumpfig D, Schotzau A et al. Body mass index in glaucoma. J Glaucoma 1999; 8: 8-11
• 28 Flammer J. Glaucoma. 3rd. edn. Bern: Hogrefe & Huber; 2006
• 29 Emre M, Orgul S, Gugleta K et al. Ocular blood flow alteration in glaucoma is related to systemic vascular dysregulation. Br J Ophthalmol 2004; 88: 662-666
• 30 Kochkorov A, Gugleta K, Zawinka C et al. Short-term retinal vessel diameter variability in relation to the history of cold extremities. Invest Ophthalmol Vis Sci 2006; 47: 4026-4033
• 31 Oettli A, Gugleta K, Kochkorov A et al. Rigidity of retinal vessel in untreated eyes of normal tension primary open-angle glaucoma patients. J Glaucoma 2011; 20: 303-306
• 32 Gugleta K, Zawinka C, Rickenbacher I et al. Analysis of retinal vasodilation after flicker light stimulation in relation to vasospastic propensity. Invest Ophthalmol Vis Sci 2006; 47: 4034-4041
• 33 Gugleta K, Kochkorov A, Waldmann N et al. Dynamics of retinal vessel response to flicker light in glaucoma patients and ocular hypertensives. Graefes Arch Clin Exp Ophthalmol 2012; 250: 589-594
• 34 Fang L, Baertschi M, Mozaffarieh M. The effect of flammer-syndrome on retinal venous pressure. BMC Ophthalmol 2014; 14: 121
• 35 Flammer J, Orgul S, Costa VP et al. The impact of ocular blood flow in glaucoma. Prog Retin Eye Res 2002; 21: 359-393
• 36 Konieczka K, Frankl S, Todorova MG et al. Unstable oxygen supply and glaucoma. Klin Monbl Augenheilkd 2014; 231: 121-126
• 37 Yeghiazaryan K, Flammer J, Orgul S et al. Vasospastic individuals demonstrate significant similarity to glaucoma patients as revealed by gene expression profiling in circulating leukocytes. Mol Vis 2009; 15: 2339-2348
• 38 Konieczka K, Choi HJ, Koch S et al. Frequency of symptoms and signs of primary vascular dysregulation in Swiss and Korean populations. Klin Monbl Augenheilkd 2014; 231: 344-347
• 39 Team RDC. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2012
• 40 Heckenlively JR, Yoser SL, Friedman LH et al. Clinical findings and common symptoms in retinitis pigmentosa. Am J Ophthalmol 1988; 105: 504-511
• 41 Iwasaki S, Maruyama Y, Hotta Y et al. Survey in to the prevalence of hearing loss in patients diagnosed with retinitis pigmentosa. Int Ophthalmol 2004; 25: 277-282
• 42 Mozaffarieh M, Schoetzau A, Sauter M et al. Comet assay analysis of single-stranded DNA breaks in circulating leukocytes of glaucoma patients. Mol Vis 2008; 14: 1584-1588
• 43 Komeima K, Rogers BS, Lu L et al. Antioxidants reduce cone cell death in a model of retinitis pigmentosa. Proc Natl Acad Sci U S A 2006; 103: 11300-11305
• 44 Martinez-Fernandez de la Camara C, Salom D, Sequedo MD et al. Altered antioxidant-oxidant status in the aqueous humor and peripheral blood of patients with retinitis pigmentosa. PLoS One 2013; 8: e74223
• 45 Gaspar AZ, Gasser P, Flammer J. The influence of magnesium on visual field and peripheral vasospasm in glaucoma. Ophthalmologica 1995; 209: 11-13
• 46 Strenn K, Matulla B, Wolzt M et al. Reversal of endothelin-1-induced ocular hemodynamic effects by low-dose nifedipine in humans. Clin Pharmacol Ther 1998; 63: 54-63
• 47 Nyby MD, Hori MT, Ormsby B et al. Eicosapentaenoic acid inhibits Ca2+ mobilization and PKC activity in vascular smooth muscle cells. Am J Hypertens 2003; 16: 708-714
• 48 Shirao S, Fujisawa H, Kudo A et al. Inhibitory effects of eicosapentaenoic acid on chronic cerebral vasospasm after subarachnoid hemorrhage: possible involvement of a sphingosylphosphorylcholine-rho-kinase pathway. Cerebrovasc Dis 2008; 26: 30-37
• 49 Teuchner B, Orgul S, Ulmer H et al. Reduced thirst in patients with a vasospastic syndrome. Acta Ophthalmol Scand 2004; 82: 738-740
• 50 Gherghel D, Orgul S, Gugleta K et al. Retrobulbar blood flow in glaucoma patients with nocturnal over-dipping in systemic blood pressure. Am J Ophthalmol 2001; 132: 641-647
• 51 Wunderlich K, Zimmerman C, Gutmann H et al. Vasospastic persons exhibit differential expression of ABC-transport proteins. Mol Vis 2003; 9: 756-761
• 52 Gasser P, Meienberg O. Finger microcirculation in classical migraine. A video-microscopic study of nailfold capillaries. Eur Neurol 1991; 31: 168-171
• 53 Palmer KT, Griffin MJ, Syddall HE et al. Raynaudʼs phenomenon, vibration induced white finger, and difficulties in hearing. Occup Environ Med 2002; 59: 640-642
• 54 Krauchi K, Deboer T. The interrelationship between sleep regulation and thermoregulation. Front Biosci 2010; 15: 604-625
• 55 Pache M, Krauchi K, Cajochen C et al. Cold feet and prolonged sleep-onset latency in vasospastic syndrome. Lancet 2001; 358: 125-126
• 56 Mozaffarieh M, Hauenstein D, Schoetzau A et al. Smell perception in normal tension glaucoma patients. Mol Vis 2010; 16: 506-510
• 57 Pache M, Ochs J, Genth E et al. Increased plasma endothelin-1 levels in fibromyalgia syndrome. Rheumatology (Oxford) 2003; 42: 493-494