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.

Keywords: Flammer syndrome; Glaucoma; Multiple sclerosis; Prediction of health problems; Primary vascular dysregulation; Retinitis pigmentosa; Vasospasm.

Fig. 1

Long-term follow-up of glaucoma patients with Goldmann perimetry (a) revealed that both the increase of scotomas (b) and the diffuse reduction (c) of the differential light sensitivity were highly related to IOP fluctuations

Fig. 2

Perimetry. (a) Octopus instrument of the first generation. (b) The tests were done with the help of the program G1, and the results were presented with the Bebie curve (c). Patients with vasospastic syndrome had slight diffuse depressions of the light sensitivity at baseline; these depressions reversibly increased after cold provocation (c) and were reversed after treatment with acetazolamide or low dose of a calcium channel blocker (modified after ref. [205])

Fig. 3

Quantification of aspects of ocular blood flow. With time, new methods were introduced step by step and contributed to the understanding of the Flammer syndrome. Capillary microscopy with cold provocation (a), 24-h blood pressure monitoring (b), colour Doppler imaging (CDI) of the retroocular vessels (c), static and dynamic analyses of the diameter of retinal arteries and veins at baseline and after flicker light stimulation (d) and quantification of retinal venous pressure (e, f)

Fig. 4

Physiological and pharmacological ex vivo testing of ocular vessels, with the help of a myograph system (a) and the help of a perfused eye model (b) (modified after ref. [141])

Fig. 5

The blood-retina barrier prevents a direct access of circulating molecules (such as a vasoconstrictor endothelin (ET)) to the smooth muscle cells of the retinal vessels. These molecules can however diffuse form the choroid into the optic nerve head (ONH), bypassing this barrier (blue arrow in a) (modified after ref. [204]). ET can also be produced by the neighbouring hypoxic tissue (red arrow in a) or diffuse from diseased arteries to adjacent veins (c) (modified after ref. [259]). These can potentially increase retinal venous pressure and finally contribute to the pathogenesis of retinal vein occlusion (b) (modified after ref. [221]) but also to the pathogenesis of haemorrhages (d) (modified after ref. [175])

Fig. 6

The pathogenetic concept of glaucomatous optic neuropathy (GON). Beside an increased intraocular pressure, a disturbed vascular dysregulation as demonstrated with thermography of the hands and the eyes (a) plays an important role (modified after ref. [205]) This leads to an increased oxidative stress as demonstrated with the comet analysis (b) (modified after [288]). The activated astrocytes change their gene expression, but also morphology. This increases the backscatter as demonstrated in red-free photos (c, left) (modified after ref. [225]). This also reduces the transport of oxygen from the blood vessels to the neurons (c, right). The oxygen tension in the axons decreases and in the retinal veins increases. The entire concept is summarised in d (modified after ref. [250])

Fig. 7

The two extremes in terms of body weight, blood pressure, etc., lead to different types of vascular dysfunctions. Interestingly, both types of dysfunction can lead to very similar end points as exemplified on the development of glaucomatous damage. The Flammer syndrome increases the risk for normal-tension glaucoma (NTG) and the arteriosclerosis (and its risk factors) for high-tension glaucoma (HTG) (modified after ref. [323])

Fig. 8

Illustrations of frequent, but not compulsory, symptoms of subjects with Flammer syndrome (modified after ref. [3])