Interplay between intraocular and intracranial pressure effects on the optic nerve head in vivo.

Intracranial pressure (ICP) has been proposed to play an important role in the sensitivity to intraocular pressure (IOP) and susceptibility to glaucoma. However, the in vivo effects of simultaneous, controlled, acute variations in ICP and IOP have not been directly measured. We quantified the deformations of the anterior lamina cribrosa (ALC) and scleral canal at Bruch's membrane opening (BMO) under acute elevation of IOP and/or ICP. Four eyes of three adult monkeys were imaged in vivo with OCT under four pressure conditions: IOP and ICP either at baseline or elevated. The BMO and ALC were reconstructed from manual delineations. From these, we determined canal area at the BMO (BMO area), BMO aspect ratio and planarity, and ALC median depth relative to the BMO plane. To better account for the pressure effects on the imaging, we also measured ALC visibility as a percent of the BMO area. Further, ALC depths were analyzed only in regions where the ALC was visible in all pressure conditions. Bootstrap sampling was used to obtain mean estimates and confidence intervals, which were then used to test for significant effects of IOP and ICP, independently and in interaction. Response to pressure manipulation was highly individualized between eyes, with significant changes detected in a majority of the parameters. Significant interactions between ICP and IOP occurred in all measures, except ALC visibility. On average, ICP elevation expanded BMO area by 0.17 mm2 at baseline IOP, and contracted BMO area by 0.02 mm2 at high IOP. ICP elevation decreased ALC depth by 10 µm at baseline IOP, but increased depth by 7 µm at high IOP. ALC visibility decreased as ICP increased, both at baseline (-10%) and high IOP (-17%). IOP elevation expanded BMO area by 0.04 mm2 at baseline ICP, and contracted BMO area by 0.09 mm2 at high ICP. On average, IOP elevation caused the ALC to displace 3.3 µm anteriorly at baseline ICP, and 22 µm posteriorly at high ICP. ALC visibility improved as IOP increased, both at baseline (5%) and high ICP (8%). In summary, changing IOP or ICP significantly deformed both the scleral canal and the lamina of the monkey ONH, regardless of the other pressure level. There were significant interactions between the effects of IOP and those of ICP on LC depth, BMO area, aspect ratio and planarity. On most eyes, elevating both pressures by the same amount did not cancel out the effects. Altogether our results show that ICP affects sensitivity to IOP, and thus that it can potentially also affect susceptibility to glaucoma.

Molecular Mechanisms of Retinal Pigment Epithelium Dysfunction in Age-Related Macular Degeneration.

The retinal pigment epithelium (RPE), situated upon Bruch's membrane, plays multiple roles in the ocular system by interacting with photoreceptors and. Therefore, dysfunction of the RPE causes diseases related to vision loss, such as age-related macular degeneration (AMD). Despite AMD being a global cause of blindness, the pathogenesis remains unclear. Understanding the pathogenesis of AMD is the first step for its prevention and treatment. This review summarizes the common pathways of RPE dysfunction and their effect in AMD. Potential treatment strategies for AMD based on targeting the RPE have also been discussed.

LONG-TERM COURSE AND VISUAL OUTCOMES OF PRECHOROIDAL CLEFT IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION AND POLYPOIDAL CHOROIDAL VASCULOPATHY.

PURPOSE: To evaluate the regression of prechoroidal cleft, its influence on visual outcomes, and differences in visual outcomes between neovascular age-related macular degeneration and polypoidal choroidal vasculopathy. METHODS: This retrospective study included 61 patients exhibiting prechoroidal cleft who were treated with antivascular endothelial growth factors. The patients were divided into two groups according to the following categories: 1) regression of prechoroidal cleft: regression group versus nonregression group and 2) type of neovascularization: neovascular age-related macular degeneration group versus polypoidal choroidal vasculopathy group. Changes in the visual acuity during the follow-up period were also compared between the two groups. RESULTS: During the 52.4 ± 17.4-month follow-up period, regression of prechoroidal cleft was noted in 17 patients (27.9%) at a mean of 25.7 ± 18.3 months after the first identification. The degree of the logarithm of the minimum angle of resolution of visual deterioration was greater in the nonregression group (0.59 ± 0.56, n = 17) than that in the regression group (0.25 ± 0.61, n = 44) (P = 0.007) and in the neovascular age-related macular degeneration group (0.56 ± 0.61, n = 51) than that in the polypoidal choroidal vasculopathy group (0.18 ± 0.33, n = 10) (P = 0.034). CONCLUSION: Approximately 27.9% of prechoroidal cleft cases eventually regressed, in conjunction with relatively favorable visual outcomes. Considering the poor visual prognosis in neovascular age-related macular degeneration accompanied by prechoroidal cleft, more caution is required for this condition.

The influence of different intraocular pressure on lamina cribrosa parameters in glaucoma and the relation clinical implication.

Elevated intraocular pressure (IOP) is one of the main risk factors for glaucoma, and pathological changes in the lamina cribrosa (LC) may play a leading role. This study aimed to explore the influence of different IOP on LC parameters and the correlation between parameters and glaucoma severity. A total of 91 eyes were examined by swept-source OCT and divided into IOP ≥ 30 mmHg (group A), 21 mmHg ≤ IOP < 30 mmHg (group B), and normal IOP (control, group C). Clinical parameters and all LC parameters such as cup depth (CD), lamina cribrosa depth (LCD), prelaminar tissue thickness (PTT) and LC curvature index (LCCI) were used for statistical analysis. The bulk of parameters were greater in group A than in the other groups (group B, P < 0.05; group C, P < 0.001). PTT and Bruch's membrane opening minimum rim width (BMO-MRW) were thinner in group A than in group C (P < 0.01). In univariate and multivariable linear regression analysis, visual field (VF), mean retinal nerve fiber layer (RNFL) thickness, CD, LCD, PLCSD, PTT, LCCI, aLCCI, and BMO-MRW were significantly correlated with IOP changes (P < 0.05). Pearson test showed that LCD and LCCI were correlated with mean retinal nerve fiber layer (RNFL) thickness (LCD, r = - 0.420, P = 0.002; LCCI, r = - 0.449, P < 0.001) and BMO-MRW (LCD, r = - 0.245, P = 0.019; LCCI, r = - 0.345, P < 0.001). Therefore, different levels of IOP have a remarkable effect on clinical symptoms (VF, BCVA) and LC parameters, between which there may be a linear relationship. LCCI may exhibit a more significant correlation with RNFL thickness and BMO-MRW, which may further suggest that LCCI shows a better correlation with clinical symptoms under the influence of long-term high IOP.

Visual Field Cluster Map Corresponding to Bruch Membrane Opening-minimum Rim Area Sectors in Open-angle Glaucoma.

PRéCIS:: We generated a new visual field (VF) cluster map corresponding to Bruch membrane opening-minimum rim area (BMO-MRA) sectors, which described in detail the structure-function relationships between the optic nerve head and VF in patients with open-angle glaucoma. PURPOSE: The purpose of this study was to investigate the structure-function relationship between BMO-MRA and VF in patients with open-angle glaucoma. MATERIALS AND METHODS: We retrospectively reviewed 67 eyes of 50 patients with open-angle glaucoma who underwent spectral-domain optical coherence tomography for BMO-MRA and the Humphrey VF test. BMO-MRA of the glaucomatous optic nerve head was divided into 12 sectors. The correlation between BMO-MRA sectors and the VF points was analyzed to generate a new VF cluster map. RESULTS: Forty-three of the 52 VF points showed a significant correlation with at least 1 BMO-MRA sector. The VF cluster map was generated using the BMO-MRA sectors and each VF point that showed the most correlation. The superior hemifield correlated with 5, 6, 7, and 8 o'clock positions (ρ=0.312 to 0.710), whereas the inferior hemifield correlated with 10, 11, 12, and 2 o'clock positions (ρ=0.241 to 0.483). The VF cluster maps of superior and inferior hemifields showed different configurations of VF clusters and topographical relationships with the glaucomatous optic nerve head. CONCLUSION: The newly generated VF cluster map corresponding to BMO-MRA sectors showed a significant structure-function relationship and could be useful in the diagnosis and evaluation of glaucoma.

Retinal pigment epithelium polarity in health and blinding diseases.

The polarized phenotype of the retinal pigment epithelium is crucial for the outer retina-blood barrier and support of photoreceptors and underlying choroid, and its disruption plays a central role in degenerative retinopathies. Although the mechanisms of polarization remain mostly unknown, they are fundamental for homeostasis of the outer retina. Recent research is revealing a growing picture of interconnected tissues in the outer retina, with the retinal pigment epithelium at the center. This review discusses how elements of epithelial polarity relate to emerging apical interactions with the neural retina, basolateral cross-talk with the underlying Bruch's membrane and choriocapillaris, and tight junction biology. An integrated view of outer retina physiology is likely to provide insights into the pathogenesis of blinding diseases.

Subretinal surgery: functional and histological consequences of entry into the subretinal space.

BACKGROUND AND OBJECTIVES: Gene-therapy, stem-cell transplantation and surgical robots hold the potential for treatment of currently untreatable retinal degenerative diseases. All of the techniques require entry into the subretinal space, which is a potential space located between the retina and the retinal pigment epithelium (RPE). Knowledge about obstacles and critical steps in relation to subretinal procedures is therefore needed. This thesis explores the functional and histological consequences of separation of the retina from the RPE, extensive RPE damage, a large cut in the retina (retinotomy) and RPE phagocytosis in a porcine model. METHODS: Experiments were performed in 106 female domestic pigs of Danish landrace distributed over five studies. Under general anesthesia, different procedures for expansion of the subretinal space were conducted. Outcomes were visual function measured electrophysiologically with multifocal electroretinogram (mfERG) and retinal morphology examined histologically. Study I: The effect of anesthesia on mfERG was examined by repeated recordings for 3 hr in isoflurane or propofol anesthesia. Outcome was mfERG amplitude. Study II: Consequences of a large separation of the photoreceptors from the RPE were examined by injecting a perfluorocarbon-liquid (decalin) into the subretinal space. Two weeks after, in a second surgery, decalin was withdrawn. Outcomes were mfERG and histology 4 weeks after decalin injection. Study III: Extensive RPE damage was examined by expanding the subretinal space with saline and removing large sheets of RPE-cells through a retinotomy. Outcomes were mfERG and histology 2, 4 and 6 weeks after the procedure. Study IV: Consequences of a large retinotomy were examined by similar procedures as in Study III, but in study IV only a few RPE cells were removed. Outcomes were mfERG and histology 2 and 6 weeks after surgery. Study V: Clearance of the subretinal space was examined by injecting fluorescent latex beads of various sizes into the subretinal space. Outcome was histologic location of the beads at different time intervals after the procedure. RESULTS: Study I: MfERG amplitudes decreased linearly as a function of time in propofol or isoflurane anesthesia. Duration of mfERG recording could be decreased without compromising quality, and thereby could time in anesthesia be reduced. Study II: MfERG and histology remained normal after reattachment of a large and 2-week long separation of the photoreceptors and RPE. Repeated entry into the subretinal space was well tolerated. Fluid injection into the subretinal space constitutes a risk of RPE-damage. Study III: Removal of large sheets of retinal pigment epithelial cells triggered a widespread rhegmatogenous-like retinal detachment resulting in visual loss. Study IV: A large retinotomy with limited damage of the RPE was well tolerated, and visual function was preserved. Study V: Subretinal latex beads up to 4 µm were phagocytosed by the RPE and passed into the sub-RPE space. Beads up to 2 µm travelled further through the Bruch's membrane and were found in the choroid, sclera and inside blood vessels. CONCLUSION: A large expansion of the subretinal space, repeated entry, a large retinotomy and limited RPE damage is well tolerated and retinal function is preserved. Subretinal injection of fluid can damage the RPE and extensive RPE damage can induce a rhegmatogenous-like retinal detachment with loss of visual function. Foreign substances exit the subretinal space and can reach the systemic circulation.

In vivo characterization of the deformation of the human optic nerve head using optical coherence tomography and digital volume correlation.

We developed a method to measure the 3-dimensional (3D) strain field in the optic nerve head (ONH) in vivo between two intraocular pressures (IOP). Radial optical coherence tomography (OCT) scans were taken of the ONH of 5 eyes from 5 glaucoma patients before and after IOP-lowering surgery and from 5 eyes from 3 glaucoma suspect patients before and after raising IOP by wearing tight-fitting swimming goggles. Scans taken at higher and lower IOP were compared using a custom digital volume correlation (DVC) algorithm to calculate strains in the anterior lamina cribrosa (ALC), retina, and choroid. Changes in anterior lamina depth (ALD) relative to Bruch's membrane were also analyzed. Average displacement error was estimated to be subpixel and strain errors were smaller than 0.37%. Suturelysis decreased IOP by 9-20 mmHg and decreased compressive anterior-posterior strain Ezz in the ALC by 0.76% (p=0.002,n=5). Goggle-wearing increased IOP by 3-4 mmHg and produced compressive Ezz in the ALC (-0.32%,p=0.001,n=5). Greater IOP decrease was associated with greater ALD change (p=0.047,n=10) and greater strains in the ALC (Ezz:p=0.002,n=10). A deepening of ALD was associated with lower IOP and greater ALC strains (p⩽0.045,n=10). A DVC-based method to measure strains from OCT images caused by IOP changes as small as 2.3 mmHg provides preliminary evidence that ALD is shallower and ALC strains are less compressive at higher IOP and that ALD change is associated with ALC strains. STATEMENT OF SIGNIFICANCE: Glaucoma causes vision loss through progressive damage of the retinal ganglion axons at the lamina cribrosa, a connective tissue structure in the optic nerve head that supports the axons as they pass through the eye wall. It is hypothesized that strains caused by intraocular pressure (IOP) may initiate this damage, but few studies have measured the strain response to pressure of the optic nerve head in patients. We present a method to measure the 3D displacement and strain field in the optic nerve head caused by IOP alteration in glaucoma patients using clinically available images. We used this method to measure strain within the optic nerve head from IOP changes caused by glaucoma surgery and wearing tight-fitting swimming goggles.

Structure-Function Relationship Between the Bruch Membrane Opening-based Minimum Rim Width and Visual Field Defects in Advanced Glaucoma.

PURPOSE: To investigate the relationship between the Bruch membrane opening-minimum rim width (BMO-MRW) (global and temporal) parameters with spectral-domain optical coherence tomography (SD-OCT) and visual field (VF) sensitivity on the 10-2 test in patients with advanced glaucoma. MATERIALS AND METHODS: This cross-sectional, observational study included a total of 33 eyes of 29 patients. To evaluate VF sensitivity, automated white-on-white perimetry was performed using a Humphrey field analyzer. The mean deviation (MD) and pattern SD values were used to characterize the degree of functional damage. BMO-MRW and peripapillary retinal nerve fiber layer thickness were obtained with SD-OCT. According to the Garway-Heath map and fovea and BMO axis, the 90 degrees temporal sector of the optic disc corresponding to the central VF was divided into upper and lower parts. RESULTS: The upper and lower temporal BMO-MRW parameters showed stronger correlations with the MD parameters of their corresponding VFs when compared with both global and temporal MRW parameters. Global and temporal retinal nerve fiber layer thickness parameters were also correlated with global MD parameters. CONCLUSIONS: BMO-MRW measurements in the upper and lower parts of the 90 degrees temporal sector of the optic nerve head by SD-OCT and their corresponding VF sensitivity on the 10-2 test were found highly correlated. These BMO-MRW measurements could offer a means of predicting the status of visual hemifields in patients who are unable to undergo VF testing. Further longitudinal studies with larger series evaluating BMO-MRW parameters with SD-OCT are also needed to monitor progression in advanced glaucoma.

In Vivo Detection of Laminar and Peripapillary Scleral Hypercompliance in Early Monkey Experimental Glaucoma.

PURPOSE: To compare optical coherence tomography (OCT) detected, optic nerve head (ONH) compliance within control and experimental glaucoma (EG) eyes of 15 monkeys at EG onset. METHODS: Intraocular pressure (IOP) was chronically elevated in one eye of each animal using a laser. Experimental glaucoma onset was identified using confocal scanning laser tomography (CSLT). Optical coherence tomography ONH imaging (40 radial B-scans) was performed at 10 mm Hg before and after laser. At EG onset, OCT scans were obtained at IOP 10 and 30 mm Hg. Optical coherence tomography landmarks within the IOP 10/30 images were delineated to quantify IOP 10/30 differences (compliance) for anterior lamina cribrosa surface depth (ALCSD) relative to Bruch's membrane opening (BMO) (ALCSD-BMO), ALCSD relative to peripheral BM (ALCSD-BM), and BMO depth relative to peripheral BM (BMOD-BM). A linear mixed effects model assessed for acute IOP elevation effects, control versus EG eye effects, and their interaction. RESULTS: Effects of IOP elevation were greater in EG versus control eyes for ALCSD-BMO (-46 ± 45 vs. -8 ± 13 µm, P = 0.0042) and ALCSD-BM (-92 ± 64 vs. -42 ± 22 µm, P = 0.0075). Experimental glaucoma eye-specific ALCSD-BMO and ALCSD-BM compliance exceeded the range of control eye compliance in 9 and 8 of the 15 EG eyes, respectively. Post-laser peak IOP (R2 = 0.798, P < 0.0001) and post-laser mean IOP (R2 = 0.634, P < 0.0004) most strongly correlated to EG versus control eye differences in ALCSD-BMO compliance. CONCLUSIONS: Laminar (ALCSD-BMO) and peripapillary scleral (ALCSD-BM) hypercompliance are present in most monkey eyes at the onset of EG.

THE ASSOCIATION BETWEEN CUTICULAR DRUSEN AND KIDNEY FUNCTION: A Population-Based Case-Control Study.

PURPOSE: To determine the association between cuticular drusen (CD) and kidney function. DESIGN: observational case-control study. SETTING: Population-based. Patients or Study Population: 53 participants with (CD) and 53 age- and sex-matched controls, selected from the Danish Rural Eye Study. Cuticular drusen participants were diagnosed using fluorescein angiography and controls were excluded if the patients were suspected of having CD on fundus photography or did not have an available estimated glomerular filtration rate. MAIN OUTCOME MEASURES: creatinine and estimated glomerular filtration rate. RESULTS: The mean estimated glomerular filtration rate of those with CD was 73.3 mL·min·1.73 m (95% confidence interval [CI]: 70.0-76.6) and 73.4 mL·minute·1.73 m (95% CI: 69.5-77.3) in controls. The difference was not significant (P: 0.970). The mean creatinine among those with CD was 72.8 µmol/L (69.3-76.4) and 73.5 µmol/L (95% CI: 69.3-77.6) among controls. The difference was not significant (P = 0.820). CONCLUSION: The authors did not find an association between a (CD) diagnosis and decreased kidney function at a population level.

Corneal Viscoelastic Properties in Patients with Angioid Streaks.

PURPOSE: The aim of this study is to investigate the possible corneal biomechanical changes in patients with angioid streaks and to understand if the calcified and thickened Bruch's membrane associated with angioid streaks influences elasticity of the eye and intraocular pressure. MATERIALS AND METHODS: Twelve eyes of 12 patients with angioid streaks (six males and six females) and 12 eyes of 12 age- and sex-matched healthy volunteers were enrolled in the study. Corneal hysteresis (CH), corneal resistance factor (CRF), corneal compensated intraocular pressure (IOPcc) and Goldmann-correlated intraocular pressure (IOPg) were measured with an Ocular Response Analyzer (ORA). Central corneal thickness (CCT) was measured with an ultrasound pachymeter. RESULTS: Mean CRF and IOPg values in eyes with angioid streaks (12.10 ± 1.27 and 17.76 ± 2.73, respectively) were significantly higher than those in matched control eyes (10.70 ± 1.28 and 14.67 ± 2.72, respectively; p = 0.01 for CRF, p = 0.007 for IOPg). There was no statistically significant difference between eyes with angioid streaks and matched control eyes in measured CH, IOPcc and CCT values (p = 0.29, p = 0.09 and p = 0.86, respectively). CONCLUSIONS: This study revealed that angioid streaks can affect corneal biomechanical properties by increasing CRF, as compared to the healthy eyes. Increased CRF means increased resistance for effect of IOP on eye so it can be speculated that these patients tend to be more protected for glaucoma.

A comparison of some organizational characteristics of the mouse central retina and the human macula.

Mouse models have greatly assisted our understanding of retinal degenerations. However, the mouse retina does not have a macula, leading to the question of whether the mouse is a relevant model for macular degeneration. In the present study, a quantitative comparison between the organization of the central mouse retina and the human macula was made, focusing on some structural characteristics that have been suggested to be important in predisposing the macula to stresses leading to degeneration: photoreceptor density, phagocytic load on the RPE, and the relative thinness of Bruch's membrane. Light and electron microscopy measurements from retinas of two strains of mice, together with published data on human retinas, were used for calculations and subsequent comparisons. As in the human retina, the central region of the mouse retina possesses a higher photoreceptor cell density and a thinner Bruch's membrane than in the periphery; however, the magnitudes of these periphery to center gradients are larger in the human. Of potentially greater relevance is the actual photoreceptor cell density, which is much greater in the mouse central retina than in the human macula, underlying a higher phagocytic load for the mouse RPE. Moreover, at eccentricities that correspond to the peripheral half of the human macula, the rod to cone ratio is similar between mouse and human. Hence, with respect to photoreceptor density and phagocytic load of the RPE, the central mouse retina models at least the more peripheral part of the macula, where macular degeneration is often first evident.

Bruch's membrane diffusivity for vascular endothelial growth factors may explain variable response to wet age-related macular degeneration treatment: clinical implications.

The hypothesis presented is that diffusivity of vascular endothelial growth factors (VEGF) across Bruch's membrane is an important parameter that distinguishes prompt and slow responders to anti-VEGF treatment in wet age-related macular degeneration (AMD). Accordingly, slow-responders have a high diffusivity and will attain peak VEGF levels on the choroidal side of Bruch's membrane rapidly, probably before or around the time of the next monthly anti-VEGF injection. If a fixed dose of anti-VEGF is used at each monthly treatment (as is the current practice), depending on the initial level of VEGF at that time of injection, VEGF with each treatment will vary. Therefore, diffusion will occur at a different concentration gradient in each treatment cycle subsequent to the injection. Hence, by Fick's Second Law of Diffusion, the slope of the concentration versus time curve for each treatment cycle will be different from the preceding cycle. This leads to a different peak concentration just prior to the next monthly injection. So, when a fixed dose of the anti-VEGF is used at each monthly treatment peak VEGF level fluctuates instead of going down continuously which prolongs the treatment. Thus, doses of anti-VEGF may have to be tapered to decrease the concentration gradient and to slow down the rate of diffusion of VEGF. Diffusivity of Bruch's membrane with regards to VEGF is a simple concept that can explain the variable response to anti-VEGF treatment in wet AMD. If validated through clinical trial the treatment protocol for wet AMD can be more precise and tailored to individual patients.

[Pigment epithelial detachment in exudative macular degeneration: clinical characteristics and therapeutic options]. / Pigmentepithelabhebung bei exsudativer Makuladegeneration: Klinische Charakteristika und therapeutische Optionen.

Vascularized pigment epithelial detachment (PE detachment) can be viewed as a special form of occult choroidal neovascularization (CNV) owing to the natural course of the disease, its specific pathogenesis and its response to various forms of treatment. This applies to serous PE detachment associated with both occult CNV and also with retinal angiomatous proliferation (RAP). A tear in the retinal pigment epithelium (RIP) represents a serious complication of vascularized PE detachment and is often associated with acute vision deterioration that not uncommonly also involves massive subretinal hemorrhaging. The pathomechanism underlying the development of RIP has not yet been completely elucidated. The notion that the PED bursts as a result of the increased pressure stands in contrast to the theory that the CNV contracts and causes scarring which in turn causing secondary RIP. Anti-VEGF therapy is currently the preferred treatment. However, the initial stabilization of visual acuity after treatment could not be confirmed in long-term studies and after 2 years visual acuity deteriorated significantly. Furthermore, optimal VEGF treatment regimens have also not been defined and the criteria for repeated treatment have not been established as yet. Presently, visual deterioration and the presence of subretinal and intraretinal exudates seem to indicate that treatment will be effective. Here, high resolution OCT imaging should help to provide further insight into the matter.

[Pathogenetic concepts for pigment epithelial detachment in exudative AMD]. / Pathogenetische Konzepte zur Pigmentepithelabhebung bei exsudativer AMD.

Retinal pigment epithelial detachment (PED) as a specific manifestation in exudative age-related macular degeneration (AMD) may lead to a substantial decrease of central vision. An understanding of important events during the development of PED is necessary for a successful therapeutic intervention. At present the leading pathogenetic theory is that of reduced hydraulic conductivity of Bruch's membrane. The mechanisms underlying this process are caused by increased deposition of lipids, enhanced collagen cross-linking and alteration in the ratio of tissue-dissolving enzymes and their inhibitors. The association of newly formed vessels and an unaltered RPE pump activity can lead to the clinical picture of serous PED during exudative AMD.

An experimental study of the elastic properties of the human Bruch's membrane-choroid complex: relevance to ageing.

AIM: To investigate the mechanical properties (stress-strain relation, elasticity, hysteresis, response to stress spikes and drops) of isolated human Bruch's membrane-choroid, as well as the effect of ageing and aged related macular degeneration (AMD). METHODS: 13 Bruch's membrane-choroid complexes were obtained from human donors (21-97 years). Two samples (aged 85 and 95) showed signs of AMD including large, soft drusen, choroidal neovascularisation, and/or disciform scars. Various hydrostatic pressures (stress) were applied to the choroidal surface of mid-peripheral samples mounted in a modified open Ussing chamber. Linear scans of the tissue were recorded by optical coherence tomography (OCT) and the pressure induced deformation (strain), elasticity, hysteresis, and response to pressure spikes and drops measured. RESULTS: The elasticity of human Bruch's membrane-choroid complex decreased linearly with ageing (p<0.001) after the age of 21 with an approximate reduction of 1% per year. The decrease was not exaggerated in AMD. The recoil capacity of Bruch's membrane-choroid was not affected by ageing. The response to pressure spikes/drops was similar in age matched normal and AMD eyes. The results suggest that although the aged induced decrease in Bruch's membrane elasticity may contribute to breaks in this membrane in AMD leading to neovascularisation this is not sufficient. The presence of other factors is required for its development. CONCLUSION: The elasticity of Bruch's membrane-choroid complex decreases with age while recoil capacity does not. The decrease was not exaggerated in AMD.

Keypathophysiologic pathways in age-related macular disease.

PURPOSE: To review current knowledge of key pathogenetic pathways in age-related macular disease (AMD). METHODS: Experimental evidence and clinical observations are reviewed. RESULTS: A number of common downstream pathophysiologic pathways appear to be relevant in AMD manifestations irrespective of primary heterogeneous etiologies. These include sequelae of oxidative damage, retinal pigment epithelium (RPE) cell dysfunction with accumulation of lipofuscin and impairment of lysosomal functions, deposition of subsequently incompletely degraded material at the basal RPE cell side and alterations in Bruch's membrane extracellular matrix, immunologic responses to extracellular material (drusen) with subsequent growth of drusen, induction of choroidal neovascularization as a result of imbalance between anti-angiogenetic and proangiogenetic factors as well as cell death (geographic atrophy) without prior neovascular events. CONCLUSIONS: Understanding is expanding regarding the sequence of events that lead to early and late lesions in AMD. Therapeutic approaches that focus on the molecular mechanisms are more likely to succeed than currently available treatment options as exemplified by the management of choroidal neovascularisations.

[The molecular mechanisms of neovascular age-related macular degeneration]. / Die molekularen Mechanismender neovaskulären AMD.

Age-related macular degeneration is the leading cause of irreversible vision loss in industrialized countries. While early forms of this disease with drusen and focal pigment alterations generally do not lead to relevant functional limitations, later forms of the disease, either through atrophy or choroidal neovascularization, are associated with significant visual impairment. A significant increase in knowledge about the molecular mechanisms of new vessel formation from the choriocapillaries has occurred over the past few years. This has already allowed for the clinical testing of pharmacological agents which inhibit the formation of new vessels in AMD. This article describes current research in the pathophysiology of choroidal neovascularization secondary to age-related macular degeneration.

Matrix and the retinal pigment epithelium in proliferative retinal disease.

In their normal state, RPE cell are strongly adherent to Bruch's membrane. Certain pathological conditions such as retinal detachment cause an injury-type response (probably augmented or induced by the local accumulation of a variety of substances which modulate cell behaviour) in which RPE begin to dissociate from the membrane. This RPE-Bruch's membrane separation may be mediated by proteins with counter-adhesive properties and proteolytic enzymes, partly derived from the RPE themselves. Concomitant with the RPE disassociation, the cells begin to lose tertiary differentiation characteristics and gain macrophage-like features. When the "free" RPE arrive at the surface of the neuroretina, they may attach to or create a provisional matrix. Some of the cells adopt a fibroblast-like phenotype. This phenotype is similar to that of the dermal fibroblast during cutaneous wound repair and the fibroblastic RPE synthesise the types of matrix components found in healing skin wounds. Many of these molecules in turn further modulate the activities of the cells via several families of cell surface receptors, while the RPE continue to remodel the new matrix with a range of proteolytic enzymes. The resulting tissue (or membrane) has many of the features of a contractile scar and is the hallmark of the condition known as proliferative vitreoretinopathy (PVR). Thus the development of PVR, and the resulting tractional distortion of the neuroretina, appears to be dependent on RPE-matrix interactions. The interactions present a number of potential therapeutic targets for the management of the disorder.