[Rho kinase inhibitors as new local therapy option in primary open angle glaucoma]. / Rho-Kinase-Hemmer als neue lokale Therapieoption beim primären Offenwinkelglaukom.

BACKGROUND: In 2014 in Japan and 2017 in the USA, the Rho-kinase inhibitors were approved as a new antiglaucomatous substance group and will now be launched in Europe. OBJECTIVE: On this occasion the current state of knowledge on Rho-kinase inhibitors is presented. METHODS: In intensive search in PubMed the relevant experimental and clinical literature on the Rho-kinase inhibitors ripasudil and netarsudil and the combination of netarsudil and latanoprost were selected and compiled for this review. RESULTS: The intraocular pressure lowering efficacy of ripasudil and netarsudil is in the range of the beta blocker timolol and the prostaglandin analogue latanoprost. In the fixed combination netarsudil/latanoprost the intraocular pressure reduction is greater than that of the single components and reaches a target pressure of below 15 mm Hg in 32%. Conjunctival hyperemia with 53-65% is the most common local side effect. Systemic side effects are very rare and so far there are no contraindications. CONCLUSION: The Rho-kinase inhibitors are an interesting new introduction for glaucoma therapy, as each new pressure-lowering therapy represents an additional chance to reach the individually defined target pressure level in a glaucoma patient with local therapy; however, many of the pleiotropic effects associated with Rho-kinase inhibitors have so far only been found experimentally and will require clinical confirmation in the future.

Age dependence of plasma endothelin levels in glaucoma patients.

The aim of the study was to investigate the endothelin-1 (ET-1) plasma level and its age dependence in patients with normal tension glaucoma (NTG), high tension glaucoma (HTG), and healthy controls. In blood samples from 35 NTG patients, 34 HTG patients, and 36 controls, ET-1 plasma levels were determined by enzyme-linked immunosorbent assay (ELISA). After adjustment for age and gender, the mean ET-1 levels were found to be similar in all three study groups. The age dependency however was highest in NTGs and significantly different from that of the controls. For the HTGs, this dependence was weaker and not significantly different from that of the controls. Our findings suggest that age had a significantly greater influence on ET plasma level in the NTG patients than in the HTG patients and controls. This supports previous reports indicating that ET plays a role in the pathogenesis of glaucoma, and in particular normal NTG.

[Phenomenology and Clinical Relevance of the Flammer Syndrome]. / Phänomenologie und klinische Bedeutung des Flammer-Syndroms.

The Flammer syndrome (FS) describes the phenotype of people with a predisposition for an altered reaction of the blood vessels to stimuli like coldness, emotional stress or high altitude. Frequent symptoms are: cold hands and/or feet, low blood pressure, prolonged sleep onset time, reduced feeling of thirst, increased sensitivity to odour, pain, vibration and certain drugs. SF subjects are often ambitious and successful but also perfectionistic and sometimes brooding. Frequent signs are: altered gene expression, prolonged blood flow cessation in nailfold capillaroscopy after cold provocation, reduced autoregulation of ocular blood flow, and reduced vasodilation after stimulation with flickering light. Retinal venous pressure is on the average higher and retinal astrocytes are more often activated. FS occurs more often in females than in males, in thin than in obese subjects, in young than in old people, in graduates than in blue collar workers, in subjects with indoor than outdoor jobs. Associated diseases are: normal tension glaucoma, occlusion of ocular vessels, retinitis pigmentosa, multiple sclerosis, tinnitus or even sudden hearing loss.

Preserved functional and structural integrity of the papillomacular area correlates with better visual acuity in retinitis pigmentosa.

PurposeLinking multifocal electroretinography (mfERG) and optical coherence tomography (OCT) findings with visual acuity in retinitis pigmentosa (RP) patients.DesignProspective, cross-sectional, nonintervention study.SubjectsPatients with typical RP and age-matched controls, who underwent SD-OCT (spectral domain OCT) and mfERG, were included.MethodsMfERG responses were averaged in three zones (zone 1 (0°-3°), zone 2 (3°-8°), and zone 3 (8°-15°)). Baseline-to-trough- (N1) and trough-to-peak amplitudes (N1P1) of the mfERG were compared with corresponding areas of the OCT. The papillomacular area (PMA) was analyzed separately. Correlations between best-corrected visual acuity (BCVA, logMAR) and each parameter were determined.Main outcome measuresComparing structural (OCT) and functional (mfERG) measures with the BCVA.ResultsIn RP patients, the N1 and N1P1 responses showed positive association with the central retinal thickness outside zone 1 (P≤0.002), while the central N1 and the N1P1 responses in zones 1, 2, and 3-with the BCVA (P≤0.007). The integrity of the IS/OS line on OCT showed also a positive association with the BCVA (P<0.001). Isolated analysis of the PMA strengthened further the structure-function association with the BCVA (P≤0.037). Interactions between the BCVA and the OCT, respectively, the mfERG parameters were more pronounced in the RP subgroup without macular edema (P≤0.020).ConclusionIn RP patients, preserved structure-function of PMA, measured by mfERG amplitude and OCT retinal thickness, correlated well with the remaining BCVA. The subgroup analyses revealed stronger links between the examined parameters, in the RP subgroup without appearance of macular edema.

Unexpected Effect of Calcium Channel Blockers on the Optic Nerve Compartment Syndrome.

BACKGROUND: The optic nerve compartment syndrome is a pathological condition in which cerebrospinal fluid of the subarachnoid space surrounding the optic nerve is partly or totally segregated from the cerebrospinal fluid of the intracranial subarachnoid space, leading - inter alia - to an increase in the diameter of the optic nerve sheath. The pathogenesis of this condition remains unclear. We have observed clinically that optic nerve compartment syndrome often occurs in normal tension glaucoma patients with Flammer syndrome. To treat Flammer syndrome, some glaucoma patients received a low dose of a calcium channel blocker and we analysed whether this treatment also had an effect on the optic nerve compartment syndrome. PATIENTS AND METHODS: We retrospectively analysed the data of 10 eyes of seven patients suffering from a combination of primary open angle glaucoma, optic nerve compartment syndrome, and Flammer syndrome. We included subjects who had eye socket echography before and after a few months of therapy with a calcium channel blocker. THERAPY AND RESULTS: All patients received a low dose of a calcium channel blocker (nifedipine or amlodipine) to treat Flammer syndrome. As expected, the symptoms of Flammer syndrome were mitigated. To our surprise, the optic nerve compartment syndrome also improved in eight of the 10 eyes (80 %), but remained unchanged in the remainder. CONCLUSIONS: To some extent, the optic nerve compartment syndrome is related to the combination of primary open angle glaucoma and Flammer syndrome. On the basis of our results, we hypothesise that treatment of Flammer syndrome may also improve the optic nerve compartment syndrome.

Increased Prevalence of Flammer Syndrome in Patients with Retinitis Pigmentosa.

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.

Endothelin-1 Plasma Levels in Patients with both Retinitis Pigmentosa and Flammer Syndrome.

BACKGROUND: Endothelin-1 is a strong endogenous vasoconstrictor and is also an agent reducing the ocular blood flow. Patients with retinitis pigmentosa are known to have reduced ocular blood flow. This can be secondary to retinal atrophy, but may also partially result from an additional condition, such as a Flammer syndrome. The aim of the study was to investigate whether the endothelin-1 plasma levels in retinitis pigmentosa patients with and without Flammer syndrome are different. PATIENTS AND METHODS: In the study we included patients with clinical signs and symptoms of retinitis pigmentosa, confirmed by electrophysiological findings. Blood samples were obtained from 6 retinitis pigmentosa patients with and 4 without Flammer syndrome. The results were related to 30 age- and sex-matched control subjects. Endothelin-1 plasma levels were determined by specific radioimmunoassay. RESULTS: The endothelin-1 plasma levels in retinitis pigmentosa patients with Flammer syndrome were significantly higher than those without Flammer syndrome. The mean (±SD) endothelin-1 levels (pg/mL) in retinitis pigmentosa patients with Flammer syndrome were 4.95 (±1.74), range: (2.37-6.76), whereas in patients without Flammer syndrome they were 1.10 (±0.08), range: 1.00-1.20. Our own normal values are: 1.56 (±0.30), range: (0.90-2.13). All retinitis pigmentosa patients with increased endothelin-1 plasma levels had signs and symptoms related to a Flammer syndrome, such as cold extremities, low blood pressure, reduced feeling of thirst, increased sensitivity in general, e.g., increased sensitivity to certain drugs, increased pain sensitivity and increased sense of smell. CONCLUSION: Endothelin-1 plasma levels were increased in retinitis pigmentosa patients with but not in patients without Flammer syndrome. Many questions remain open: Why so many retinitis pigmentosa patients suffer from Flammer syndrome, why is the endothelin-1 level in such patients higher than in healthy subjects with Flammer syndrome, how much of the ocular blood flow reduction is due to retinal degeneration and how much to the Flammer syndrome? We hypothesise that Flammer syndrome leads to an additional increase of the endothelin-1 level and an additional decrease of ocular blood flow in retinitis pigmentosa patients. Further studies are needed to analyse the causal relationship between retinitis pigmentosa and Flammer syndrome and evaluate potential therapeutic implications.

Frequency of symptoms and signs of primary vascular dysregulation in Swiss and Korean populations.

BACKGROUND: Primary vascular dysregulation syndrome (also called Flammer syndrome) is related to certain eye diseases, particularly normal tension glaucoma. Primary vascular dysregulation is characterized by a number of symptoms and signs (e.g., cold hands and/or feet, low blood pressure), that occur more frequently in subjects with primary vascular dysregulation compared to the general population. The aim of the present study was to test and compare the relative frequency of symptoms and signs related to primary vascular dysregulation in unselected populations in Switzerland and Korea. SUBJECTS AND METHODS: Swiss (n=259) and Korean (n=1116) subjects filled out our questionnaire containing 15 questions related to symptoms and signs of primary vascular dysregulation. RESULTS: In the populations studied, seven of 15 symptoms and signs of primary vascular dysregulation (increased smell perception, increased pain sensation, increased response to certain drugs, low body mass index, feeling cold, cold hands and/or feet, and headaches) occurred significantly more often in the Swiss population than in the Korean population, whereas five symptoms and signs (reversible skin blotches, tendency toward perfectionism, long sleep onset time, tinnitus, and dizziness) occurred significantly more often in the Korean population. CONCLUSION: The relative frequency of these symptoms and signs of primary vascular dysregulation in an unselected average population differs between Switzerland and Korea. Therefore, if a diagnosis of primary vascular dysregulation is based on the self-reported symptoms and signs of the patient, they must be compared with the frequency of symptoms and signs in the corresponding local population.

Retinal vessel oxygen saturation in giant cell arteritis patients without ocular symptoms.

BACKGROUND: The aim of this study was to determine subclinical ocular ischemia related to giant cell arteritis (GCA) by means of retinal oximetry (RO) measurements. PATIENTS AND METHODS: Four test-retest RO images per eye were taken with the retinal vessel analyser (IMEDOS Systems UG, Jena). RO measurements in arterial (A-SO2) and venous (V-SO2) retinal vessels and their difference (A-V SO2) were calculated in GCA patients and compared to those of age-matched controls. RESULTS: GCA biopsy and duplex sonography positive patients (n=8, 13 eyes) from the Basler Riesenzellarteriitis Kohorte study (BARK) were recruited. In controls (n=6, 10 eyes), the mean (± SD) A-SO2 and V-SO2 were measured at 93.89% (± 3.0) and at 55.60% (± 3.4), respectively. In the GCAs, a reduction in the A-SO2 to 93.37% (± 3.3) and an increase in V-SO2 to 61.13% (± 3.6) were found. The A-V SO2 difference was reduced in the GCAs to 32.24% (± 3.8) whereas in the controls the difference was 38.31% (± 2.8). CONCLUSIONS: Oxygen metabolism is affected in cases with GCA. Thus, RO may provide additional data in the diagnosis of GCA, even when no ophthalmic symptoms have been reported.

Unstable oxygen supply and glaucoma.

The pathogenesis of the glaucomatous optic neuropathy (GON) is an ongoing bone of contention. While the role of intraocular pressure (IOP) is well known, it is also clear that a variety of other factors, particularly those of a vascular nature, are involved as well. In contrast to other eye diseases, it is an unstable oxygen supply, as opposed to chronic hypoxia, that contributes to GON. The major cause of fluctuations in the local oxygen tension is an unstable ocular blood flow (OBF). OBF, in turn, fluctuates if the IOP spikes, blood pressure drops, or OBF autoregulation is defective. The main reason for disturbed autoregulation is a primary vascular dysregulation (PVD), particularly in the context of the so-called Flammer syndrome. Unstable oxygen tension leads to local oxidative stress with many detrimental effects, such as the activation of glial cells, which alters their morphology and gene expression. As a consequence, the local concentrations of nitric oxide and the metalloproteinases increase. The metalloproteinases digest extracellular matrix and thereby contribute to tissue remodelling. The short-lived nitric oxide easily diffuses into the neighbouring neuronal axons, allowing a fusion with the superoxide anion and thereby generating the cell-damaging peroxynitrite. Both this tissue remodelling and damage of the axons contribute to the development and progression of GON.