[Glaucoma Patient with Suspected Flammer Syndrome: Diagnostic Procedures and Therapeutic Implications]. / Glaukompatient mit Verdacht auf Flammer-Syndrom: diagnostische Schritte und therapeutische Konsequenzen.

If glaucoma damage develops despite normal intraocular pressure or if the damage progresses despite well-controlled intraocular pressure, we usually find other risk factors. One important group are the vascular factors. We should focus not only on the classical risk factors of atherosclerosis, such as arterial hypertension or dyslipidaemia, but also on dysregulation of blood flow, especially on primary vascular dysregulation (PVD). Low blood pressure, either current or in adolescence, low body mass index or frequently cold hands and feet may provide important hints. Very often PVD is coupled with a number of other symptoms and signs, and we then speak of a Flammer Syndrome (FS). If there is any indication of FS, we take a targeted patient history, undertake 24 h blood pressure monitoring, measure retinal venous pressure, and perform a dynamic retinal vessel analysis or nail fold capillary microscopy. This is especially recommended if the patient is relatively young or the damage is progressing rapidly. If the suspicion is confirmed, we then try to reduce the drops in blood pressure, lower the retinal venous pressure, improve the regulation of blood flow and reduce the oxidative stress in the mitochondria.

Role of ocular blood flow in normal tension glaucoma.

Background: Normal tension glaucoma (NTG) is a multifactorial disease in the pathogenesis of which intraocular pressure (IOP)-independent factors play a key role. Main text: There is considerable evidence that impairment of the ocular blood flow (OBF) is involved both in the onset and progression of this disease. With the development of the hypothesis of OBF in NTG, various imaging techniques have been developed to evaluate the OBF and blood vessels. Moreover, vascular dysregulation, which is a main factor in Flammer syndrome, was frequently observed in NTG patients. Disturbed OBF leads to increased oxidative stress, which plays an important role in the pathogenesis of glaucomatous optic neuropathy. These results suggested that IOP-independent management may provide alternative treatment options for NTG patients. Conclusions: In this review, we mainly focus on the mechanisms of the abnormal OBF in NTG.

Treatment of Glaucoma Patients with Flammer Syndrome.

Flammer syndrome (FS) describes a phenotype characterized by the presence of primary vascular dysregulation along with a number of symptoms and signs. Although most people with FS are healthy, FS favors the occurrence of certain diseases, such as normal tension glaucoma. This is because disturbed autoregulation makes the eye more sensitive to intraocular pressure (IOP) spikes or blood pressure drops. Treatment of FS is generally appropriate when patients either suffer greatly from their symptoms or if we can assume that it has contributed to a disease. In glaucoma, this may be the case if the glaucoma damage progresses despite well-controlled IOP. Both the still sparse scientific studies and our long clinical experience suggest that FS-targeted therapy not only relieves the symptoms of FS but also slows the progression of glaucoma damage in selected cases. This description is intended not only to help affected patients but to also motivate clinicians and researchers to conduct therapy studies to confirm or refute our observations.

Retinal venous pressure is decreased after anti-VEGF therapy in patients with retinal vein occlusion-related macular edema.

PURPOSE: The pathomechanism leading to retinal vein occlusion (RVO) is unclear. Mechanical compression, thrombosis, and functional contractions of veins are discussed as the reasons for the increased resistance of venous outflow. We evaluated changes in the retinal venous pressure (RVP) following intravitreal injection of anti-vascular endothelial growth factor (VEGF) agent to determine the effect on RVO-related macular edema. METHODS: Twenty-six patients with RVO-related macular edema (16 branch RVOs [BRVOs] and 10 central RVOs [CRVOs], age 72.5 ± 8.8 years) who visited our hospital were included in this prospective study. Visual acuity (VA), intraocular pressure (IOP), central retinal thickness (CRT) determined by macular optical coherence tomography, and RVP measured using an ophthalmodynamometer were obtained before intravitreal injection of ranibizumab (IVR) and 1 month later. RESULTS: Comparison of the BRVOs and CRVOs showed that VA was significantly improved by a single injection in BRVOs (P < 0.0001; P = 0.1087 for CRVOs), but CRT and RVP were significantly decreased without significant difference in IOP after the treatment in both groups (P < 0.0001). CONCLUSION: The anti-VEGF treatment resulted in a significant decrease in the RVP, but the RVP remained significantly higher than the IOP. An increased RVP plays a decisive role in the formation of macula edema, and reducing it is desirable.

Effects of the Glaucoma Drugs Latanoprost and Brimonidine on Corneal Temperature.

PURPOSE: The aim of this study was to investigate the effects of the glaucoma drugs latanoprost, brimonidine, and the combination of both on the central corneal temperature (CT) of healthy subjects by means of infrared thermography. Changes of the central CT may reflect changes of ocular blood flow. METHODS: Before application and during 2 hours after the application of latanoprost, brimonidine, or the combination of both in one eye, the CT in both eyes of 40 healthy subjects was measured repeatedly. RESULTS: Brimonidine reduced CT by approximately 0.5°C. This effect was statistically significant (P < 0.0001). Latanoprost, however, had a very small and insignificant influence (P = 0.47). Accordingly, the combination of brimonidine and latanoprost also reduced CT up to 0.5°C, and this effect was statistically significant (P < 0.0001). CONCLUSIONS: Brimonidine, but not latanoprost, had a significant effect on central CT. This cooling effect of brimonidine is most probably due to a drug-induced reduction of blood circulation in the ciliary body and iris and to a certain extent also to a reduction of blood flow in the fundus of the eye. TRANSLATIONAL RELEVANCE: This study shows evidence that thermography of the cornea provides indirect information on the influence of drugs on the blood flow to the anterior segment of the patient's eye.

Transient visual field impairment after cold provocation in glaucoma patients with Flammer syndrome.

BACKGROUND: It is still debatable whether visual field defects in glaucoma have a reversible component and to what extent a temporary loss can be provoked. OBJECTIVE: To investigate the response of the visual function to a cold provocation in glaucoma patients, particularly to test whether subjects with Flammer syndrome (FS) behaved differently from subjects without FS. METHODS: Ten (10) primary open-angle glaucoma (POAG) patients with FS, 7 POAG patients without FS, and 11 healthy controls were tested with program G2 on the Octopus 101 perimeter before and after putting one hand in cold water (4°C) for 2 min. The mean sensitivity (MS) of each visual field was included in the statistical analysis. RESULTS: In glaucoma patients with FS, the mean MS significantly decreased after cold provocation (delta MS = -0.91 dB, CI = -1.43 to -0.39, p = 0.0014). In contrast, the mean MS in glaucoma patients without FS did not change significantly (delta MS = 0.17 dB, CI = -0.43 to 0.78, p = 0.56). Likewise, the mean MS did not change significantly in the healthy controls (delta MS = 0.23 dB, CI = -0.27 to 0.72, p = 0.36). CONCLUSIONS: Cold provocation induced a transient visual field deterioration in the glaucoma patients with FS but not in the glaucoma patients without FS or in the healthy controls. We assume this effect to be the result of a transient reduction of ocular blood flow.

In glaucoma patients, low blood pressure is accompanied by vascular dysregulation.

BACKGROUND: There are many risk factors contributing to glaucomatous optic neuropathy. Beside increased intraocular pressure, vascular factors play a prominent role, particularly low blood pressure (BP), and vascular dysregulation. Both of them are essential components of the Flammer syndrome. The aim of this retrospective study was to evaluate whether in glaucoma patients there is a relationship between vascular dysregulation and the BP. METHODS: Medical records of 57 unselected glaucoma patients were retrospectively studied. RESULTS: Based on the outcome of the capillaroscopy, patients were divided in a group of patients with vascular dysregulation, also called long-stoppers (flow cessation for 13 s or more), and a group of patients with normal vascular regulation, also called short-stoppers (flow cessation for 12 s or less). BP was significantly lower in the group of long-stoppers than in the group of short-stoppers. This applies for both systolic (p = 0.028) and diastolic BP (p = 0.036). The regression analysis revealed also a significant inverse relationship between the duration of blood flow cessation and the systolic (p = 0.025) and diastolic BP (p = 0.016). After adjustment for age, gender, use of antihypertensive therapy, and excluding patients taking calcium channel blockers, the relationship was still significant for systolic (p = 0.025) and diastolic BP (p = 0.003). CONCLUSIONS: In glaucoma patients, vascular dysregulation (as defined by response in the nailfold capillaroscopy to a cold provocation) and low BP are statistically related. This is in line with the observation that Flammer syndrome subjects have both primary vascular dysregulation and low BP and that Flammer syndrome is a risk factor for glaucomatous optic neuropathy, at least in normal tension glaucoma patients. The detection of vascular factors in glaucoma patients may lead to a more efficient treatment, better tailored to the individual patient.

Data on the involvement of endothelin-1 (ET-1) in the dysregulation of retinal veins.

Retinal vein occlusion (RVO) is a common vascular disease of the retina; however, the pathogenesis of RVO is still unclear. Branch RVO (BRVO) commonly occurs at the arteriovenous crossing and it was formerly believed that the diseased artery mechanically compresses the vein. However, it has been reported that the retinal vein runs deep beneath the artery at the arteriovenous crossing in eyes with an arterial overcrossing, and the venous lumen often appears to be preserved, even at the arteriovenous crossing, as shown by optical coherence tomography. Paques et al. [1] found venous nicking without arteriovenous contact using adaptive optics imaging. Thus, we investigated the potential role of a dysregulation of the retinal vein. While the pathogenesis of retinal vein occlusion (RVO) is still unclear, systemic hypertension and increased level of endothelin-1 (ET-1) are known risk factors (Flammer and Konieczka, 2015) [2]. We focused on the behavior of retinal veins in spontaneous hypertensive rats (SHR). Then, one of the retinal veins became exceptionally constricted and was nearly occluded (Fig. 1), and the chorioretinal blood flow significantly decreased in the retinas of SHRs following the intravenous injection of ET-1. In addition, immunoreactivity to ET-A receptor was higher in SHR retinas than in control (WKY; Wistar Kyoto rat) retinas (Fig. 2). The protein levels of ET-A receptor and HIF-1 were also significantly higher in SHR retinas than in WKY retinas (Fig. 3). We observed vasoactivity of retinal veins; a retinal venous constriction (Kida et al., 2018) [3]. This supports the hypothesis that ET-1 can constrict retinal veins, thus increasing retinal venous pressure, and that ET-1 may even contribute to the pathogenesis of RVO.

Vasoactivity of retinal veins: A potential involvement of endothelin-1 (ET-1) in the pathogenesis of retinal vein occlusion (RVO).

PURPOSE: Whilst the pathogenesis of retinal vein occlusion (RVO) is still unclear, systemic hypertension and increased level of endothelin-1 (ET-1) are known risk factors. Therefore, we studied the influence of ET-1 on the retinal veins in hypertensive rats. METHODS: We focused on the behavior of retinal veins in spontaneous hypertensive rats (SHR). To determine whether ET-1 was associated with the blood flow in eyes of SHRs, the chorioretinal blood flow in the rats was assessed using laser speckle flowgraphy (LSFG-Micro, Softcare, Fukuoka, Japan) before and after an intravenous injection of ET-1 under general anesthesia. In addition, retinas from SHRs and age-matched normotensive Wistar-Kyoto rats (WKYs) were removed, and retinal sections were immunostained for the ET-A and ET-B receptors. The protein levels of both ET-1 receptors and hypoxia-inducible factor 1 (HIF-1) in the retinal tissues were also determined by western blot analysis. RESULTS: One of the retinal veins became exceptionally constricted and was nearly occluded, and the chorioretinal blood flow significantly decreased in the retinas of SHRs following the injection of ET-1. Immunoreactivity to ET-A receptor was higher in SHR retinas than in WKY retinas. The protein levels of ET-A receptor and HIF-1 were also significantly higher in SHR retinas than in WKY retinas. CONCLUSIONS: An increase of ET-1 in circulating blood leads to the local constriction of retinal veins and this effect is accentuated in hypertensive rats by an upregulation of ET-A receptor. It is plausible that such a constriction of retinal veins increases retinal venous pressure, and may even contribute to the pathogenesis of RVO.

Cornea Thermography: Optimal Evaluation of the Outcome and the Resulting Reproducibility.

PURPOSE: The aim of the study was to establish a standardized quantitative evaluation of corneal temperature (CT) that includes anchoring reference points in the topography and minimization of artifacts. We further investigated the distribution and the short- and long-term reproducibility of the CT values, as well as the influence of the core temperatures. METHODS: The CT values in both eyes of 40 healthy subjects were measured through thermography. These examinations took place over the course of four visits within 2 consecutive weeks. At each visit, the CTs were measured twice in both eyes with intervals of 15 minutes between measurements. RESULTS: CT values were not significantly different between the right and left eyes and their distribution was nearly normal. The CTs increased slightly when measured twice over the 15-minute intervals (short-term reproducibility) but remained stable over a period of 2 weeks (long-term reproducibility). In addition, the CT values depended on the core temperatures. CONCLUSIONS: Ocular surface thermography is a fast and noninvasive examination. The methods of optimized and standardized evaluation of the CT values facilitate comparisons and follow-ups. TRANSLATIONAL RELEVANCE: Thermography can be used clinically and scientifically only if both the measurement and its evaluation are efficient and standardized and if the outcomes are highly reproducible.

[Mitochondrial Dysfunctions and Role of Coenzyme Q10 in Patients with Glaucoma]. / Mitochondriale Dysfunktion und Bedeutung von Coenzym Q10 beim Glaukom.

Mitochondrial function is closely linked to numerous aspects of eye health. Imbalance between the creation of energy and the development of reactive oxygen species (ROS) seems to be the cause of the development of mitochondrial dysfunctions. As a result of this energy deficit, the level of oxidative stress in the eye tissues increases, leading to numerous ophthalmic impairments. It is important to distinguish between primary mitochondrial eye diseases and secondary mitochondrial changes. Primary mitochondrial eye diseases, for example Leber's hereditary optic atrophy (LHON), retinitis pigmentosa and chronic progressive external ophthalmoplegia are caused by direct damage to mitochondrial function induced by defective genes, either located on mitochondrial DNA (mtDNA) or the DNA of the nucleus (nDNA). In contrast, secondary mitochondrial dysfunctions are caused by environmental factors. In recent years, there has been growing evidence that mitochondrial dysfunctions play an important role in many common eye diseases, such as glaucoma, dry eye, diabetic retinopathy, cataract and age-related macular degeneration (AMD). This article summarises current knowledge of mitochondrial dysfunctions and the role of coenzyme Q10 (CoQ10) as a possible treatment option - with a special focus on glaucoma.

Diseases potentially related to Flammer syndrome.

Flammer syndrome (FS) is a prevalent and mostly benign condition. Subjects with FS seem to have a good life expectancy. Nevertheless, FS subjects are at increased risk for certain diseases, mainly when they are challenged by psychological stress or other stimuli such as coldness. FS is related to ocular diseases, such as normal-tension glaucoma, retinitis pigmentosa, central serous chorioretinopathy, optic nerve compartment syndrome, Leber's hereditary optic neuropathy, arterial or venous occlusions in the retina, and choroid and optic nerve head, despite the absence of classical vascular risk factors. FS is also related to some non-ocular diseases, such as multiple sclerosis, breast cancer, and altitude sickness. The role of FS in other diseases such as tinnitus, sudden hearing loss, Ménière's disease, anorexia nervosa, and thyroid dysfunction is currently under investigation. The exact relationship of FS to related diseases however still needs to be established. This may hopefully lead to more targeted diagnostics and personalized treatments.

Breast cancer and Flammer syndrome: any symptoms in common for prediction, prevention and personalised medical approach?

An epidemic scale of the breast cancer (BC) prevalence is actually recognised as the reality of the early twenty-first century. Particularly alarming is that the sporadic BC (about 90% of all patients) creates currently unpredictable subpopulations in terms of disease predisposition, development and progression. Despite broad discussions run since years in BC area, no any plausible approach has been suggested so far to get the overall situation better controlled in the populations. Here, we present highly innovative concepts considering investigation of specific syndromes and symptoms underestimated till now in relationship with BC predisposition and development. Consequently, the purpose of our pilot project was to evaluate the prevalence of Flammer Syndrome (FS) in BC patient cohort. The results achieved here support the main hypothesis of the project clearly demonstrating the tendency of BC patients to the increased prevalence of FS symptoms compared to the disease-free individuals. Our study strongly indicates the relevance of FS symptoms for BC pathology such as feeling inadequately cold, deficient thermoregulation, altered sensitivity to different stimuli, potential dehydration, altered sleep patterns, tendency towards headache, migraine attacks and dizziness. Moreover, the symptoms' appearance is specifically linked to the individual BC subtypes. Potential mechanisms interconnecting FS with BC pathology are discussed.

Postmenopausal breast cancer: European challenge and innovative concepts.

Breast cancer (BC) epidemic is recognised now worldwide as the reality of the early twenty-first century. Increasing trends in the postmenopausal BC prevalence, even for the European countries earlier demonstrating relatively stable incidence rates of the disease, are highly alarming for the healthcare givers. This new actuality requires a substantial revision of the paradigm currently applied to the BC management and creation of highly innovative concepts. Current multi-centred study highlights new complex mechanisms of the development and progression of the postmenopausal BC. Innovative concepts are presented which argue for more effective predictive and preventive approaches well justified in view of the clusters of the symptoms analysed here and demonstrated as highly prevalent in the postmenopausal breast cancer versus BC-free individuals. Another conceptual novelty presented here is a new interpretation of the "Seed and Soil" theory of metastasis in BC. According to the new concept, the "pre-metastatic niches" ("Soil") are created by a systemic hypoxia a long time before the breast malignancy is clinically manifested.

Relationship between normal tension glaucoma and Flammer syndrome.

BACKGROUND: Besides intraocular pressure, vascular factors play a role in the pathogenesis of glaucomatous optic neuropathy. One of these potential vascular factors is Flammer syndrome. The purpose of the present study was to determine in a Korean population whether signs and symptoms of Flammer syndrome occur more often in normal tension glaucoma patients than in control subjects. METHODS: Two hundred forty-six normal tension glaucoma patients and 1116 control subjects responded to a multiple-choice questionnaire asking about 15 signs and symptoms of Flammer syndrome. RESULTS: Seven of the 15 signs and symptoms of Flammer syndrome (increased drug sensitivity, good smell perception, reversible skin blotches, tinnitus, long sleep onset time, tendency to perfectionism, and cold hands/feet) were significantly more often positive in normal tension glaucoma patients than in controls. Six additional signs and symptoms (migraines, low blood pressure, headaches, dizziness, increased pain sensation, and feeling cold) also occurred more often, but did not reach statistical significance. Only two items (low body weight and reduced feeling of thirst) were more frequently (not significant) positive in the controls. CONCLUSION: There is an association between normal tension glaucoma and Flammer syndrome. If future studies confirm this relationship, treatment of Flammer syndrome may help to prevent normal tension glaucoma or to slow down its progression.

"Pre-metastatic niches" in breast cancer: are they created by or prior to the tumour onset? "Flammer Syndrome" relevance to address the question.

Breast cancer (BC) epidemic in the twenty-first century is characterised by around half a million deaths and 1.7 million new cases registered annually worldwide. Metastatic disease is the major cause of death in BC patient cohorts. Current statistics are much alarming from the viewpoint of the early mortality amongst BC patients with de novo metastatic disease. A new paradigm of so-called "pre-metastatic niches" may sufficiently promote our knowledge regarding potential pathomechanisms, individual predisposition and prognosis in development and progression of the metastatic disease. However, the crucial question remains unaddressed, whether hypoxic pre-metastatic niches in BC are created by or prior to the tumour onset. So far, the current interpretation of the "Seed and Soil" theory of metastasis proposing that the pre-metastatic niches are formed by primary tumours which "induce and guide" the process is incomplete, since it does not provide satisfactory explanations towards several facts overviewed in the article. The overall results of this study clearly support the working hypothesis presented by the authors proposing that the epi/genetic predisposition of individuals at risk to form the systemic hypoxic pre-metastatic niches can be established a long time before breast malignancy is clinically manifested. "Flammer Syndrome" (FS) phenotype may strongly contribute to particularly poor outcomes of metastatic breast cancer. Significance and relevance of individual FS symptoms for breast cancer metastatic disease are discussed in extenso.

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

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.

Choroidal infarction in a glaucoma patient with Flammer syndrome: a case report with a long term follow-up.

BACKGROUND: We present a long term follow-up of a young female patient with choroidal infarction, primary open angle glaucoma and Flammer syndrome. The patient had no classical risk factors for vascular occlusions, except for the presence of Flammer syndrome. The essential feature of this syndrome is primary vascular dysregulation, sometimes including vasospasm. The vessels of affected people respond more intensely to a number of stimuli, such as coldness or emotional stress. Any organ can be involved, including parts of the eye. The dense autonomic innervation of the choroidal vessels predisposes them particularly to vasospasms. CASE PRESENTATION: The patient was originally referred to our centre because of a deep unilateral paracentral scotoma with the presumptive diagnosis of a normal tension glaucoma. The discrepancy between the visual field defect and the optic nerve head morphology, however, led us to a vascular evaluation by a simultaneous fluorescein/indocyanine green angiography. This revealed an antecedent choroidal infarction that explained the visual field scotoma and the retinal nerve fibre layer defect in the corresponding area. During the follow-up period of 11 years, the patient also developed bilateral glaucomatous optic neuropathy despite a well-controlled intraocular pressure. CONCLUSIONS: We hypothesise that in the patient presented here, the Flammer syndrome contributed to both the acute unilateral choroidal infarction and to the chronic development of bilateral glaucomatous optic neuropathy.

Suppressed endothelin-1 by anti-VEGF therapy is important for patients with BRVO-related macular edema to improve their vision.

BACKGROUND: Branch retinal vein occlusion (BRVO) commonly occurs at the arteriovenous crossing in the unilateral eye, and cardiovascular diseases can be risk factors of BRVO. However, the pathomechanism leading to BRVO is not yet clear. In addition to mechanical compression, the vein might locally constrict due to an altered biochemical environment, such as an increase in the concentration of endothelin-1 (ET-1). We evaluated changes in ET-1 following injection of intravitreal bevacizumab (IVB), which is the anti-vascular endothelial growth factor (VEGF) agent with the longest serum half-life, to determine the effect on BRVO-related macular edema. METHODS: Twenty consecutive patients with BRVO-related macular edema (10 males, 10 females; age range 56-83 years) who visited our hospital were included in this prospective study. Visual acuity (VA); central retinal thickness (CRT), determined by macular optical coherence tomography (OCT); and plasma ET-1 levels were obtained before IVB treatment and 1 month later. RESULTS: Patients had hypertension (80 %), dyslipidemia (50 %), diabetes mellitus (35 %), or collagen disease (5 %). Mean CRT was significantly decreased from 673.0 ± 327.8 to 388.2 ± 155.0 µm (P = 0.0007), and mean VA was significantly improved after IVB (P = 0.0239). Mean plasma ET-1 was significantly decreased from 1.272 ± 0.451 to 1.095 ± 0.316 pg/mL (P = 0.0238); however, the plasma ET-1 level was increased in all five patients who did not show improved VA after IVB. CONCLUSIONS: In patients with BRVO-related macular edema, anti-VEGF therapy leads to an expected reduction in ET-1 levels; however, the ET-1 level was found to increase in some patients; this is clearly related to less improvement of VA after anti-VEGF therapy. TRIAL REGISTRATION: University hospital Medical Information Network (UMIN) Center UMIN000013236. Registered 10 October, 2012.