[Structural endpoints for glaucoma studies]. / Strukturelle Endpunkte für Glaukomstudien.

BACKGROUND: Structural endpoints have been discussed as surrogate endpoints for the approval of neuroprotective drugs in glaucoma. OBJECTIVE: Is the evidence strong enough to establish structural endpoints as surrogate endpoints? MATERIAL AND METHODS: Review of current understanding between structure and function in glaucoma. RESULTS: The introduction of optical coherence tomography has revolutionized imaging in glaucoma patients. Clinically either the nerve fiber layer thickness can be measured along a circle centered in the optic nerve head or the ganglion cell layer thickness can be assessed in the macular region, the latter being quantified in combination with other inner retinal layers. On a microscopic level there is a strong correlation between structural and functional loss but this relation can only partially be described with currently available clinical methods. This is particularly true for longitudinal course of the disease in glaucoma patients. Novel imaging techniques that are not yet used clinically may have the potential to increase our understanding between structure and function in glaucoma but further research in this field is required. CONCLUSION: The current evidence does not allow the establishment of structural endpoints as surrogate endpoints for phase 3 studies in glaucoma. Neuroprotective drugs have to be approved on the basis of visual field data because this is the patient-relevant endpoint. Structural endpoints can, however, play an important role in phase 2 and proof of concept studies.

[News in Retinal Imaging]. / Neuerungen in der retinalen Bildgebung.

New developments in retinal imaging have revolutionised ophthalmology in recent years. In particular, optical coherence tomography (OCT) provides highly resolved and well reproducible images and has rung in a new era in ophthalmological imaging. The technology was introduced in the early 1990 s, and has rapidly developed. There have been improvements in resolution, sensitivity and processing speed. There have also been developments in functional processing. OCT angiography is the first application in routine clinical work.

[Ocular perfusion pressure and its relevance for glaucoma]. / Der okuläre Perfusionsdruck und seine Bedeutung für das Glaukom.

Ocular perfusion pressure is defined as the difference between arterial and venous pressure in ocular vessels. In practice, mean arterial pressure is used to substitute for arterial pressure in ocular vessels while intraocular pressure gives an estimate for ocular venous pressure. This results in a value that is easy to calculate and which is of importance since several studies have shown that it is correlated to the prevalence, incidence and progression of primary open angle glaucoma. Today, ocular perfusion pressure is used to estimate individual risks. Since no target value for ocular perfusion pressure can be defined, direct therapeutic intervention is difficult. Still, it has to be kept in mind that lowering intraocular pressure automatically leads to an increase in ocular perfusion pressure. The present article also points out problems and limitations in the concept of ocular perfusion pressure and suggests possible solutions for these problems in the future.

Imaging of retinal ganglion cells in glaucoma: pitfalls and challenges.

Imaging has gained a key role in modern glaucoma management. Traditionally, interest was directed toward the appearance of the optic nerve head and the retinal nerve fiber layer. With the improvement of the resolution of optical coherence tomography, the ganglion cell complex has also become routinely accessible in the clinic. Further advances have been made in understanding the structure-function relationship in glaucoma. Nevertheless, direct imaging of the retinal ganglion cells in glaucoma would be advantageous. With the currently used techniques, this goal cannot be achieved, because the transversal resolution is limited by aberrations of the eye. The use of adaptive optics has significantly improved transversal resolution, and the imaging of several cell types including cones and astrocytes has become possible. Imaging of retinal ganglion cells, however, still remains a problem, because of the transparency of these cells. However, the visualization of retinal ganglion cells and their dendrites has been achieved in animal models. Furthermore, attempts have been made to visualize the apoptosis of retinal ganglion cells in vivo. Implementation of these techniques in clinical practice will probably improve glaucoma care and facilitate the development of neuroprotective strategies.

Ocular perfusion pressure and ocular blood flow in glaucoma.

Glaucoma is a progressive optic neuropathy of unknown origin. It has been hypothesized that a vascular component is involved in glaucoma pathophysiology. This hypothesis has gained support from studies showing that reduced ocular perfusion pressure is a risk factor for the disease. The exact nature of the involvement is, however, still a matter of debate. Based on recent evidence we propose a model including primary and secondary insults in glaucoma. The primary insult appears to happen at the optic nerve head. Increased intraocular pressure and ischemia at the post-laminar optic nerve head affects retinal ganglion cell axons. Modulating factors are the biomechanical properties of the tissues and cerebrospinal fluid pressure. After this primary insult retinal ganglion cells function at a reduced energy level and are sensitive to secondary insults. These secondary insults may happen if ocular perfusion pressure falls below the lower limit of autoregulation or if neurovascular coupling fails. Evidence for both faulty autoregulation and reduced hyperemic response to neuronal stimulation has been provided in glaucoma patients. The mechanisms appear to involve vascular endothelial dysfunction and impaired astrocyte-vessel signaling. A more detailed understanding of these pathways is required to direct neuroprotective strategies via the neurovascular pathway.

Ocular hemodynamic effects of nitrovasodilators in healthy subjects.

Nitric oxide (NO) plays a key role in the regulation of ocular blood flow and may be an interesting therapeutic target in ocular ischemic disease. In the present study, we hypothesized that NO-releasing drugs may increase blood flow to the head of the optic nerve and also in the choroid. The study employed a randomized, placebo-controlled, double blind, four-way crossover design. On separate study days, 12 healthy subjects received infusions of nitroglycerin, isosorbide dinitrate, sodium nitroprusside, or placebo. All three study drugs reduced the mean arterial pressure (MAP) and ocular perfusion pressure (OPP) (P < 0.001). None of the administered drugs increased the ocular hemodynamic variables. By contrast, vascular resistance decreased dose dependently during administration of the study drugs (P < 0.001). These results indicate that systemic administration of NO-donor drugs is associated with a decrease in vascular resistance in the ocular vasculature. However, because these drugs also reduce blood pressure, they do not improve perfusion to the posterior eye pole.