The discovery of the Flammer syndrome: a historical and personal perspective

Abstract

This review describes the clinical and basic research that led to the description of Flammer syndrome. It is narrated from a personal perspective. This research was initiated by the observation of an increased long-term fluctuation of visual fields in a subgroup of glaucoma patients. As these patients had strikingly cold hands, peripheral blood flow was tested with a capillary microscopy, and vasospastic syndrome (VS) was diagnosed. Further studies on these patients revealed frequently weakened autoregulation of ocular blood flow and increased flow resistivity in retroocular vessels. Their retinal vessels were more rigid and irregular and responded less to flickering light. Holistic investigation demonstrated low blood pressure, silent myocardial ischaemia, altered beat-to-beat variation, altered gene expression in the lymphocytes, slightly increased plasma endothelin level and increased systemic oxidative stress. This combination of signs and symptoms was better described by the term primary vascular dysregulation (PVD) than by VS. Subsequent studies showed additional symptoms frequently related to PVD, such as low body mass index, cold extremities combined with slightly increased core temperature, prolonged sleep onset time, reduced feelings of thirst, increased sensitivity to smell and also for certain drugs and increased retinal venous pressure. To better characterise this entire syndrome, the term Flammer syndrome (FS) was introduced. Most subjects with FS were healthy. Nevertheless, FS seemed to increase the risk for certain eye diseases, particularly in younger patients. This included normal-tension glaucoma, anterior ischaemic optic neuropathy, retinal vein occlusions, Susac syndrome and central serous chorioretinopathy. Hereditary diseases, such as Leber’s optic neuropathy or retinitis pigmentosa, were also associated with FS, and FS symptoms and sings occurred more frequent in patients with multiple sclerosis or with acute hearing loss. Further research should lead to a more concise definition of FS, a precise diagnosis and tools for recognizing people at risk for associated diseases. This may ultimately lead to more efficient and more personalised treatment.

Elevated Intraocular Pressure Causes Abnormal Reactivity of Mouse Retinal Arterioles

“…Previous studies that examined the role of vascular function in glaucoma pathophysiology suggested that vasospasm, systemic hypotension, angiographic vascular perfusion defects, and alterations in blood flow parameters may result in or be a result of reduced vascular perfusion in the optic nerve head and/or retina consequently leading or at least contributing to glaucoma onset and progression [4,[28][29][30][31]. Some authors even regard normal tension glaucoma as an ocular manifestation of a systemic vascular dysfunction, as reflected in the so called Flammer syndrome [32,33]. Other research groups found retinal vascular abnormalities in normal-tension and high-tension glaucoma patients, which include narrowing of retinal blood vessels, optic disc hemorrhage, and reduction of blood vessel density [12,34,35].…”

Personality and stress influence vision restoration and recovery in glaucoma and optic neuropathy following alternating current stimulation: implications for personalized neuromodulation and rehabilitation

“…A basic demographic questionnaire probed the age, gender, education level, working status, living conditions, and economic status. We selected physiological questions from the (non-standardized) FS checklist to count FS signs and symptoms which are believed to be associated with primary VD (courtesy of Dr. Flammer and Dr. Konieczka, University Eye Clinic Basel, Switzerland, 51) such as cold hands and cold feet, low blood pressure, and reduced thirst [24].…”

“…One possibility is endotheliopathy of local microvessels due to vascular dysregulation (VD), which reduces (but not stop) oxygen delivery [23][24][25][26][27][28] to levels which are sufficient for cell survival, but insufficient for sustained firing of action potentials. VD is a problem not only for the eye (e.g., in normal tension glaucoma [23,24]) but also for the brain and other organs, leading to a cluster of symptoms and signs such as cold hands or feet, hypotension, diffuse visual field defects, and/or elevated oxidative stress, collectively described by the "Flammer syndrome" (FS) [29][30][31][32][33][34][35]. Furthermore, there are additional FS signs at different levels, including the hormonal (increased cortisol and endothelin-1), physiological (increased sensitivity to pain and drugs, lack of thirst, slim body shape), and psychological levels.…”

Stellenwert von Endothelin-1 beim Glaukom – ein kurzer Überblick

“…Diesbezüglich hat die Forschungsgruppe in Basel (Schweiz) um Josef Flammer die Vorreiterrolle gehabt [26 -31]; bald danach jedoch haben andere Forschungsgruppen ebenfalls einen wesentlichen Beitrag auf dem Feld geleistet [32,33]. Endothelin stellt ein wesentliches Puzzleteil der Pathophysiologie des Flammer-Syndroms dar [34,35].…”