Retinal venous pressure measurements in patients with Flammer syndrome and metabolic syndrome.

BACKGROUND: The purpose of this research is to analyze retinal venous pressure (RVP) of both eyes of patients who visited a Swiss ophthalmic practice and compare values among the following groups of patients with primary open-angle glaucoma (POAG), Flammer syndrome (FS), and metabolic syndrome (MetS). METHODS: RVP was measured in both eyes of all patients who visited a Swiss ophthalmic practice during March 2016 till November 2016, and the results were analyzed retrospectively. All measurements were performed by one physician by means of ophthalmodynamometry. Ophthalmodynamometry is done by applying an increasing pressure on the eye via a contact lens. The minimum force required to induce a venous pulsation is called ophthalmodynamometric force (ODF). The RVP is defined and calculated as the sum of ODF and intraocular pressure (IOP) [RVP = ODF + IOP]. RESULTS: Spontaneous central retinal venous pulsation was present in the majority of the patients (192 out of 357, 53.8%). Spontaneous RVP rate was significantly negatively correlated with age (r = -0.348, p < 0.001). A significantly increased RVP was noted in FS, MetS, and POAG patients, particularly those POAG patients who also suffered from FS (p < 0.005). CONCLUSIONS: Although most patients had a spontaneous RVP, those with FS, POAG, and MetS had increased RVP. Measuring RVP by means of ophthalmodynamometry provides predictive information about certain ocular diseases and aids in instituting adequate preventive measures.

Nutritional recommendations for individuals with Flammer syndrome.

The Flammer syndrome (FS) describes the phenotype of people with a predisposition for an altered reaction of the blood vessels to stimuli like coldness or emotional stress. The question whether such people should be treated is often discussed. On the one hand, most of these subjects are healthy; on the other hand, FS seems to predispose to certain eye diseases such as normal tension glaucoma or retinitis pigmentosa or systemic diseases such as multiple sclerosis or tinnitus. A compromise between doing nothing and a drug treatment is the adaption of nutrition. But what do we mean by healthy food consumption for subjects with FS? The adaption of nutrition depends on the health condition. Whereas patients with e.g. a metabolic syndrome should reduce their calorie intake, this can be counterproductive for subjects with FS, as most subjects with FS have already a low body mass index (BMI) and the lower the BMI the stronger the FS symptoms. Accordingly, while fasting is healthy e.g. for subjects with metabolic syndrome, fasting can even dangerously aggravate the vascular dysregulation, as it has been nicely demonstrated by the loss of retinal vascular regulation during fasting. To give another example, while reducing salt intake is recommended for subjects with systemic hypertensions, such a salt restriction can aggravate systemic hypotension and thereby indirectly also the vascular regulation in subjects with FS. This clearly demonstrates that such a preventive adaption of nutrition needs to be personalized.

Comet assay as an indirect measure of systemic oxidative stress.

Higher eukaryotic organisms cannot live without oxygen; yet, paradoxically, oxygen can be harmful to them. The oxygen molecule is chemically relatively inert because it has two unpaired electrons located in different pi * anti-bonding orbitals. These two electrons have parallel spins, meaning they rotate in the same direction about their own axes. This is why the oxygen molecule is not very reactive. Activation of oxygen may occur by two different mechanisms; either through reduction via one electron at a time (monovalent reduction), or through the absorption of sufficient energy to reverse the spin of one of the unpaired electrons. This results in the production of reactive oxidative species (ROS). There are a number of ways in which the human body eliminates ROS in its physiological state. If ROS production exceeds the repair capacity, oxidative stress results and damages different molecules. There are many different methods by which oxidative stress can be measured. This manuscript focuses on one of the methods named cell gel electrophoresis, also known as "comet assay" which allows measurement of DNA breaks. If all factors known to cause DNA damage, other than oxidative stress are kept constant, the amount of DNA damage measured by comet assay is a good parameter of oxidative stress. The principle is simple and relies upon the fact that DNA molecules are negatively charged. An intact DNA molecule has such a large size that it does not migrate during electrophoresis. DNA breaks, however, if present result in smaller fragments which move in the electrical field towards the anode. Smaller fragments migrate faster. As the fragments have different sizes the final result of the electrophoresis is not a distinct line but rather a continuum with the shape of a comet. The system allows a quantification of the resulting "comet" and thus of the DNA breaks in the cell.

Retinal venous pressure in chronic smokers.

BACKGROUND: The overall aim of this study was to determine retinal venous pressure (RVP) in healthy chronic smokers and compare values to those of healthy non-smokers. METHODS: Both eyes of 25 healthy chronic smokers and 41 healthy non-smokers were included. Measurements of RVP were performed by means of contact lens ophthalmodynamometry. Ophthalmodynamometry is done by applying increasing force on the eye via a contact lens. If a spontaneous venous pulsation was present, it was noted. If not, the compressive force was increased until the first venous pulsation was detected, and the measurement value was fixed and read. RVP was calculated as the sum of pressure increase induced by the instrument and intraocular pressure. RESULTS: Smokers had a significantly higher frequency of spontaneous venous pulsations than non-smokers (p < 0.001). Mean values of RVP were slightly lower in smokers than in non-smokers: 15.3 and 15.5 (smokers) versus 15.9 and 16.2 (non-smokers) for the right and left eye, respectively; however, the difference in RVP between the two groups did not reach significance. There was no significant difference in blood pressure between the two groups, but heart rate was significantly higher in smokers (p = 0.043). CONCLUSIONS: RVP values may differ in healthy smokers than in non-smokers. Therefore, smoking habits should be considered when interpreting RVP results.

The effect of nifedipine on retinal venous pressure of glaucoma patients with the Flammer-Syndrome.

PURPOSE: The purpose was to measure the retinal venous pressure (RVP) in both eyes of primary open-angle glaucoma (POAG) patients before and 3 weeks after treatment with low-dosed Nifedipine. METHODS: This retrospective study included 20 POAG patients who were treated with Nifedipine (5 mg daily) and 20 untreated control POAG patients. In both the treated and untreated control group, a distinction was made between those patients who had the Flammer-Syndrome (FS) and those who did not. The RVP was measured in all patients bilaterally at baseline and 3 weeks later by means of contact lens ophthalmodynamometry and the RVP measurements of the treated POAG patients were compared to the RVPs of the untreated POAG controls. Ophthalmodynamometry is done by applying an increasing force on the eye via a contact lens. The minimum force required to induce a venous pulsation is called the ophthalmodynamometric force (ODF). The RVP is defined and calculated as the sum of ODF and intraocular pressure (IOP) [RVP = ODF + IOP]. RESULTS: The RVP decreased significantly after 3 weeks in both eyes of patients treated with low-dosed Nifedipine compared to the untreated group (mean decrease of 12.5 mmHg (SD 12.5), P < 0.001). A larger response to therapy was found in patients with the FS compared to patients lacking the FS (mean decrease of 16.07 vs. 7.28 mmHg, confidence Interval (CI): 5.2 to 9.3 vs. 12.3 to 19.7; P < 0.001). No significant differences were accounted for in the IOP's of the patients after treatment. In the untreated control group, no significant differences were accounted for either in the RVP or the IOP after 3 weeks. CONCLUSIONS: Treatment with low-dosed Nifedipine decreases RVP in both eyes of glaucoma patients, particularly in those with the Flammer-Syndrome. This effect may be due to the partial inhibition of Endothelin-1 (ET-1) by Nifedipine.

The effect of flammer-syndrome on retinal venous pressure.

BACKGROUND: The purpose of the study was to measure the retinal venous pressure (RVP) in the eyes of primary open-angle glaucoma (POAG) patients and healthy subjects with and without a Flammer-Syndrome (FS). METHODS: RVP was measured in the following four groups of patients and age- and sex-matched healthy controls: (a) 15 patients with a POAG and a FS (POAG/FS+); (b) 15 patients with a POAG but without a FS (POAG/FS-); (c) 14 healthy subjects with a FS (healthy/FS+) and (d) 16 healthy subjects without a FS (healthy/FS-). RVP was measured in all participants bilaterally by means of contact lens ophthalmodynamometry. Ophthalmodynamometry is done by applying increasing pressure on the eye via a contact lens. The minimum force required to induce a venous pulsation is called ophthalmodynamometric force (ODF). The RVP is defined and calculated as the sum of ODF and intraocular pressure (IOP) [RVP = ODF + IOP]. RESULTS: The participants with a FS (whether patients with POAG or healthy subjects), had a significantly higher RVP compared to subjects without a FS (p = 0.0103). Patients with a POAG and FS (POAG/FS+) had a significantly higher RVP compared to patients without a FS (POAG/FS-) (p = 0.0301). There was a notable trend for a higher RVP in the healthy/FS + group compared to the healthy/FS - group, which did not reach statistical significance (p = 0.0898). CONCLUSIONS: RVP is higher in subjects with a FS, particularly in glaucoma patients. The causal relationship needs to be further evaluated.

Retinal venous pressure in the non-affected eye of patients with retinal vein occlusions.

BACKGROUND: To measure the retinal venous pressure (RVP) in both eyes of patients with unilateral central retinal vein occlusions and to compare these values to controls. METHODS: The study included 31 patients with unilateral central retinal vein occlusions (CRVO) and 31 controls who were matched by age, sex, and systemic disease. RVP was measured in all patients bilaterally by means of contact lens ophthalmodynamometry, and the RVP measurements of the affected and unaffected eyes of patients were compared to the RVPs of controls. Ophthalmodynamometry is done by applying an increasing pressure on the eye via a contact lens. The minimum force required to induce a venous pulsation is called ophthalmodynamometric force (ODF). The RVP is defined and calculated as the sum of ODF and intraocular pressure (IOP) [RVP = ODF + IOP]. RESULTS: The RVP group means ± SD were as follows: patient's affected eyes (45.0 ± 11.6 mmHg), patient's unaffected eyes (38.0 ± 11.1 mmHg) ,and (17.7 ± 6.7 mmHg) in the eyes of controls. The values of RVP, even in the patients unaffected eyes, were significantly higher than in the eyes of controls (P < 0.001). CONCLUSIONS: In patients with CRVO, the RVP is increased in both the affected as well as in the unaffected contralateral eye.

New insights in the pathogenesis and treatment of normal tension glaucoma.

Increased intraocular pressure (IOP) is a major risk factor for glaucomatous damage and reducing IOP improves prognosis. Nevertheless, there is little doubt that other risk factors besides IOP such as unstable ocular perfusion are involved. Blood flow is unstable if either the IOP fluctuates at a high level (or blood pressure fluctuates at a low level) or if the autoregulation of blood flow disturbed. A common cause for a disturbed OBF autoregulation is a primary vascular dysregulation (PVD) frequently observed in normal tension glaucoma patients. An unstable blood flow leads to recurrent mild reperfusion injury (chronic oxidative stress) affecting particularly the mitochondria of the optic nerve head. OBF regulation can be improved by magnesium, calcium channel blockers as well as with carbonic anhydrase inhibitors.

Effect of avosentan (SPP-301) in porcine ciliary arteries.

PURPOSE: To investigate the vasoactive effect of ET(A)-endothelin receptor antagonists avosentan (SPP-301) and BQ-123 in isolated porcine ciliary arteries with and without endothelium. To investigate the effect of avosentan on the endothelin-1 induced contractions in comparison with BQ-123 and BQ-788 (ET(B)-endothelin receptor antagonist) in isolated porcine ciliary arteries with and without endothelium. METHODS: Vessels were placed in a myograph system to measure isometric forces. In a first set of experiments, quiescent vessels were exposed, cumulatively, to increasing concentrations of avosentan and BQ-123 (10(-9) M-3 × 10(-6) M). In a second set of experiments, quiescent vessels were first incubated with avosentan (10(-6) M and 10(-8) M), BQ-123 (10(-6) M), and BQ-788 (10(-6) M), respectively. Then the vessels were exposed, cumulatively, to increasing concentrations of endothelin-1 (10(-12) M-3 × 10(-8) M). Each set of experiments was conducted in the vessels with and without endothelium. RESULTS: Cumulative concentrations of avosentan and BQ-123 had no vasoactive effect in quiescent vessels. Avosentan had a strong inhibitory effect on the endothelin-1-induced contractions. The inhibitory effect of 10(-6) M avosentan was significantly stronger than the effect of 10(-8) M avosentan. The effect of avosentan (10(-6) M) tended to be stronger than the effect of BQ-123 (10(-6) M). To a lesser extent, BQ-788 also had an inhibitory effect on the endothelin-1-induced contractions. CONCLUSIONS: Avosentan has a strong inhibitory effect on the endothelin-1-induced contractions. Blockade of ET receptors is potentially an attractive target in many eye diseases including glaucoma. Further studies are needed to evaluate the usefulness of endothelin blockers in ophthalmology.

Half a pack of cigarettes a day more than doubles DNA breaks in circulating leukocytes.

BACKGROUND: The mechanisms by which smoking induces damage is not known for all diseases. One mechanism believed to play a role is oxidative stress. Oxidative stress leads to cellular damage including DNA damage, particularly DNA breaks. We conducted this study to test the hypothesis that smokers have increased DNA breaks in their circulating leukocytes. METHODS: A comparative quantification of single-stranded DNA breaks was performed by comet assay analysis in the circulating leukocytes of ten healthy smokers (average smoking rate: half a pack a day, range: 9-12 cigarettes a day) and ten age and sex matched healthy non-smokers. DNA breaks lead to smaller pieces of DNA, which migrate out of the nucleus forming a tail during gel-electrophoresis. Damage of an individual cell was quantified by the parameters tail moment and olive moment. RESULTS: Smoking had a clear effect on both study parameters (tail and olive moment). Smokers had more than double the amount of ss-DNA breaks in their circulating leukocytes than non-smokers [tail moment: 0·75 AU [smokers] compared to 0·2 AU [non-smokers]; olive moment: 0·85 AU [smokers] compared to 0·3 AU [non-smokers]; both p < 0·001]. CONCLUSION: Smoking half a pack a day interferes with DNA integrity. One potential explanation for the enhanced DNA breaks in smokers is oxidative stress.

Thermal discomfort with cold extremities in relation to age, gender, and body mass index in a random sample of a Swiss urban population.

BACKGROUND: The aim of this epidemiological study was to investigate the relationship of thermal discomfort with cold extremities (TDCE) to age, gender, and body mass index (BMI) in a Swiss urban population. METHODS: In a random population sample of Basel city, 2,800 subjects aged 20-40 years were asked to complete a questionnaire evaluating the extent of cold extremities. Values of cold extremities were based on questionnaire-derived scores. The correlation of age, gender, and BMI to TDCE was analyzed using multiple regression analysis. RESULTS: A total of 1,001 women (72.3% response rate) and 809 men (60% response rate) returned a completed questionnaire. Statistical analyses revealed the following findings: Younger subjects suffered more intensely from cold extremities than the elderly, and women suffered more than men (particularly younger women). Slimmer subjects suffered significantly more often from cold extremities than subjects with higher BMIs. CONCLUSIONS: Thermal discomfort with cold extremities (a relevant symptom of primary vascular dysregulation) occurs at highest intensity in younger, slimmer women and at lowest intensity in elderly, stouter men.

Smell perception in normal tension glaucoma patients.

PURPOSE: The aim of this study was to quantify the ability to identify odors in normal tension glaucoma (NTG) patients and healthy subjects with and without a primary vascular dysregulation (PVD). METHODS: Both self-assessment of smell perception and evaluation of odor identification by means of the 12-item odor identification test ("Sniffin' Sticks") were performed in the following groups of subjects: 1) 18 NTG patients with PVD (G+), 2) 18 NTG patients without PVD (G-), 3) 18 healthy subjects with PVD (H(+)) and 4) 18 healthy subjects without PVD (H-). The subjects self-assessment of smell perception was evaluated before the Sniffin' Sticks test by asking them to judge their ability to identify odors as either "average," "better than average," or "worse than average." RESULTS: Subjects with a PVD (G+ and H(+)) can identify odors significantly better than those without a PVD (G- and H-; in a score scale of 1-12 the score point difference=2.64, 95% CI=1.88-3.40, p<0.001). No significant differences in odor identification was found between NTG (groups G+ and G-) and healthy subjects (groups H(+) and H-; score point difference=-0.14, 95% CI=-0.9-0.62, p=0.72). CONCLUSIONS: Subjects with a PVD can identify odors significantly better than those without a PVD.

Retinal vein occlusions: The potential impact of a dysregulation of the retinal veins.

A retinal vein occlusion (RVO) is a sight threatening disease. It can be divided into central vein occlusion and branch retinal vein occlusion. The pathogenesis of the condition remains to be solved. Mechanical compression of the vessel wall or thrombotic occlusion of the vessel lumen, sometimes combined with rheological disorders, are often assumed pathomechanisms. Accordingly, the therapy relies either on mechanical decompression, lyses of thrombi or improvement of rheology. A number of observations however, such as the relationship of RVO to atherosclerotic risk factors, spontaneous reversibility particularly in young patients, rest flow observed in angiography, occlusion despite anticoagulation or thrombocytopenia and finally the positive effect of anti-VEGF therapy are not explained by the present pathogenetic concept. As a new concept we propose a local venous constriction induced by vasoconstrictive molecules diffusing from neighbouring diseased arteries and/or from other neighbouring (hypoxic) tissues. Recognizing these postulated conditions might lead to an earlier identification of impending vein occlusions as well as to a treatment more tailored to the risk factor constellation of the particular patient.

Relationship between optic nerve head and finger blood flow.

PURPOSE: To examine the relationship between optic nerve head (ONH) and finger blood flow in subjects with and without a primary vascular dysregulation (PVD). METHODS: ONH blood flow and finger blood flow was measured in 15 subjects with PVD and in 24 subjects without PVD. PVD was defined as being present if it was detected in patient history as well as by nailfold capillaromicroscopy. PVD was defined as being absent if the patient history for PVD was negative and the results of nailfold capillaromicroscopy were negative. Scanning laser Doppler flowmetry (LDF) was used to measure ONH and finger blood flow. Finger temperature was measured in all subjects using a contact sensor. RESULTS: ONH blood flow is significantly related to finger blood flow in subjects with PVD (p<0.01), but not in subjects without a PVD. Subjects with PVD had a significantly lower finger skin temperature in comparison to those without PVD (p<0.01) CONCLUSIONS: The present study indicates a relationship between ONH and finger blood flow in subjects with PVD. This might be an indirect sign of a disturbed autoregulation of ocular blood flow in PVD subjects.

Targeted preventive measures and advanced approaches in personalised treatment of glaucoma neuropathy.

Glaucoma is a major cause of vision loss worldwide with nearly 8 million people bilaterally blind from the disease. This number is estimated to increase over the next 10 years. The key to preventing blindness from glaucoma is effective diagnosis and treatment. The classical glaucoma treatment focuses on intraocular pressure (IOP) reduction. Better knowledge of the pathogenesis has opened up additional therapeutical approaches often called non-IOP lowering treatment. Whilst most of these new avenues of treatment are still in the experimental phase, others are already used by some physicians. These new therapeutic approaches allow a more personalised patient treatment. Non-IOP lowering treatment includes improvements of ocular blood flow, particularly blood flow regulation. This can be achieved by improving the regulation of ocular blood flow (improving autoregulation) by drugs such as carbonic anhydrase inhibitors, magnesium or calcium channel blockers. It can also be improved by decreasing blood pressure over-dips. Blood pressure can be increased by an increase in salt intake or in rare cases by treatment with fludrocortisone. Experimentally, glaucomatous optic neuropathy can be prevented by inhibition of astrocyte activation, either by blockage of epidermal growth factor receptor or by counteracting Endothelin. Glaucomatous optic neuropathy can also be prevented by nitric oxide-2 synthase inhibition. Suppression of matrix metalloproteinase-9 inhibits apoptosis of retinal ganglion cells and tissue remodelling. Upregulation of heat shock proteins protects the retinal ganglion cells and the optic nerve head. Reduction of oxidative stress especially at the level of mitochondria also seems to be protective. This can be achieved by gingko, dark chocolate, polyphenolic flavonoids occurring in tea, coffee or red wine and anthocyanosides found in bilberries as well as by ubiquinone and melatonin. This review describes the individual mechanisms which may be targeted by non-IOP lowering treatment based on our pathogenic scheme.

Second eye cataract surgery in the diabetes patient? Quality of life gains and speed of visual and functional rehabilitation.

PURPOSE: To assess gains in quality of life (QOL) and visual acuity (VA), and to evaluate speed of visual and functional rehabilitation in diabetes patients with different stages of retinopathy (DR) after phacoemulsification in either one or both eyes. METHODS: This prospective longitudinal study comprised 102 patients having either (1) first eye, or (2) first and subsequent second eye cataract surgery. One surgeon performed all surgeries. In both groups, the following subset of patients was compared: those with no apparent retinopathy (no DR), those with mild nonproliferative DR (NPDR), those with severe NPDR, and those with proliferative DR. VA and questionnaire (VF-14) responses were recorded prior to and 1, 3, 6, 8 and 12 months after surgery. RESULTS: Patients with no DR and mild NPDR showed a significantly more rapid speed of visual and functional rehabilitation compared to patients with severe NPDR and proliferative DR. Maximum visual and functional results for these patients were observed 1 month after surgery, and values were significantly higher in comparison to other patients (p values <0.0001). Patients with no DR and mild NPDR who had second eye surgery demonstrated significant improvements (VA, QOL) and sustainment of the improved functional status achieved after first eye surgery (p<0.001). CONCLUSIONS: Patients with no DR and mild NPDR show greater significant improvements in QOL and VA, and a more rapid speed of visual and functional rehabilitation in comparison to patients with more advanced DR. Functional gains are sustained at 1 year after surgery, if second eye surgery is performed.

Subretinal hemorrhages secondary to age-related macular degeneration: psychological and vision-related functional perspectives.

PURPOSE: To assess psychological, visual and functional aspects associated with subretinal hemorrhages secondary to age-related macular degeneration (AMD). METHOD: In this prospective, comparative, longitudinal study, 90 eyes of 90 patients with a subretinal hemorrhage, secondary to AMD, of at least 1 disk diameter were treated with recombinant tissue plasminogen activator (rTPA) and gas, and compared to 25 eyes of 25 controls. Outcome measures were: (1) visual acuity, (2) self-reported vision-related quality of life (Visual Function 14-item questionnaire) and (3)Hospital Anxiety and Depression (HAD) scores. Visual acuity and questionnaire responses were recorded prior to as well as 2 weeks and 4 months after treatment. RESULTS: Improvements across objective visual acuity and vision-related functional measures, assessed at 2 weeks and 4 months, were significantly higher in patients who had rTPA and gas injections than in controls (p < 0.01). Patients were significantly more distressed at their 2-week follow-up in comparison to controls (HAD scores p < 0.01). Comparisons to controls showed no significant difference in psychological scores at the 4-month follow-up (p > 0.32). CONCLUSIONS: Patients with subretinal hemorrhages secondary to AMD are psychologically distressed as a result of acute loss of vision. More attention should be given to strategies that teach patients to cope with acute vision loss and thereby psychological disorder.

Autoregulation, a balancing act between supply and demand.

Regulation of blood flow is necessary to adapt to different conditions. Regulation of ocular blood flow (OBF) compensates for varying perfusion pressures (autoregulation), adapts to the retinal activity (neurovascular coupling), and keeps the back of the eye at constant temperature (thermoregulation). While all vessels are under the control of the vascular endothelial cells, the retinal vessels are additionally under the control of the neural and glial cells, and the choroidal vessels are influenced by the autonomic nervous system. The optic nerve head is additionally controlled by circulating hormones. If the regulation does not occur according to the needs of the tissue, it is referred to as vascular dysregulation. Such a dysregulation can be secondary in nature, as, for example, in multiple sclerosis, in which the high level of endothelin reduces OBF. Dysregulation, however, can also occur without any underlying disease and is characterized by an inborn tendency to respond differently to various stimuli, such as cold temperatures or mechanical or emotional stress. The constellation of these features is known as primary vascular dysregulation (PVD). Subjects with PVD have disturbed autoregulation leading to an unstable OBF. This instability, in turn, induces a repeated mild reperfusion injury. The resulting oxidative stress contributes to the pathogenesis of glaucomatous optic neuropathy.

Oxygen and blood flow: players in the pathogenesis of glaucoma.

UNLABELLED: The increase of IOP in POAG is due an increased resistance of aqueous outflow through the trabecular meshwork (TM). The exact mechanisms leading to the corresponding changes in the TM are not yet known. We know, however, that all risk factors for arteriosclerosis are also risk factors for an increase in IOP. RESULTS: The association between IOP increase and these factors is relatively weak but nevertheless significant. Similar to the pathogenesis of arteriosclerosis, oxidative stress plays a role in the development of TM damage. Even less is known about the pathogenesis of glaucomatous optic neuropathy (GON). Obviously the risk factors for arteriosclerosis play a role via increasing the IOP. When corrected for IOP, however, these factors only play a minor role. In contrast, factors associated with disturbed autoregulation, in particular a systemic primary vascular dysregulation (PVD), increase the risk for GON. This is best observed in normal tension glaucoma patients. An insufficient autoregulation increases the chance for an unstable ocular perfusion and thereby an unstable oxygen supply. This, in turn, leads to oxidative stress. The concentration of superoxide (O(2)(-)) within the axons of the optic nerve head increases. If neighboring astrocytes are activated, either by mechanical or by ischemic stress, in excess produced nitric oxide (NO) molecules diffuse also into the axons and fuse with oxygen. The resulting peroxynitrat (ONOO(-)) diffuses within the axons towards the retina and the lateral geniculate nucleus and induces apoptosis.