[Artificial iris]. / Künstliche Iris.

The flexible iris prosthesis according to Koch with a customized iris design serves for anterior segment reconstruction in patients with partial or complete aniridia. It is designed for implantation in the ciliary sulcus and is recommended only for pseudophakic or aphakic eyes. The multilayered implant consists of a core of a silicone matrix with incorporated color pigment coated with another layer of medical grade silicone. As a design variant the implant is available with or without an additionally embedded tissue layer. Without tissue the implant is more flexible, can be easily folded and perfectly adapts to the anatomical course of the sulcus. In contrast, implants with tissue show a greater rigidity and provide a better grip for sutures. This article describes various techniques for implantation of partial and full prostheses and gives instructions for calculating the implant size. Full prostheses can be combined with other reconstructive measures, such as sutured intraocular lenses and are particularly helpful in silicone oil surgery by avoiding endothelial contact. With careful consideration of the indications and application the flexible iris prosthesis is a valuable extension of the spectrum of reconstructive anterior segment surgery.

[Intravitreal drug therapy for retinal vein occlusion--pathophysiological mechanisms and routinely used drugs]. / Intravitreale Medikamenteneingabe bei retinalem Venenverschluss--pathophysiologische Mechanismen und angewandte Substanzen.

The novel therapeutic principle of intravitreal drug therapy for retinal vein occlusion has become an integrated constituent of clinical practice over the last years. The two substance classes that have been evaluated in large randomised clinical trials so far are corticosteroids and inhibitors of vascular endothelial growth factor (VEGF). The reported treatment success of these intravitreally administered substances has lead not only to a paradigm shift in clinical care but has also advanced our understanding of the underlying pathophysiological principles of retinal vein occlusions. In this review the different substances are discussed, their mechanisms of action are analysed and the results of the large clinical trials available to date are critically evaluated. Furthermore, an approach to integrate these novel treatment options into the existing treatment regimes for retinal vein occlusions is suggested.

[Bilateral tumors of the eyebrows]. / Bilaterale Augenbrauentumoren.

We report about a 5-year-old boy who presented in our clinic with bilateral, slowly progressive solid tumors of the eyebrows. Histological examination of the excised tumors revealed the typical diversified picture of pilomatrixoma with basophilic and shadow cells. The bilateral or multiple manifestation of pilomatrixoma is uncommon and can be associated with myotonic dystrophy, sarcoidosis or Gardner's syndrome.

Z-suture: a new knotless technique for transscleral suture fixation of intraocular implants.

The presented Z-suture is a simple, rapid and safe knotless technique that facilitates transscleral suture fixation of various intraocular implants in the ciliary sulcus, such as sutured intraocular lenses, artificial iris prostheses and iris diaphragms. As the knotless approach reliably avoids suture erosion, external fixation can be performed without any protecting scleral flaps or lamellar grooves. The needle is simply passed through the sulcus and the emerging polypropylene suture is secured in the sclera using a zigzag-shaped intrascleral suture (Z-suture). Each pass starts directly adjacent to the exiting site. Five passes are sufficient to reliably fix the suture so that it resists even maximum tractive forces. Once this procedure is done, the suture can be cut without any knot. By avoiding suture knots, and hence the need for intrascleral flaps, this knotless approach may help to reduce suture-related complications such as scleral atrophy, suture erosion and infections.

[Optic atrophy subsequent to epiretinal triamcinolone deposits in an eye following inner limiting membrane peeling]. / Optikusatrophie nach epiretinalen Triamcinolon-Ablagerungen in einem Auge mit entfernter Membrana limitans interna.

BACKGROUND: Although current in vitro studies show local cytotoxicity of triamcinolone (TA) crystals if they are in direct contact with cells, a toxic effect of epiretinal TA deposits has not been reported yet clinically. For the first time, we present a case of potential cytotoxicity of epiretinal TA deposits in vivo. CASE REPORT: A 68-year old patient underwent a re-vitrectomy with peeling of a macular pucker and the internal limiting membrane (ILM) combined with an intravitreal injection of 25 mg TA due to a secondary macular pucker with cystoid macular edema. Postoperatively, pronounced epiretinal deposits of TA crystals were identified in the area of the posterior pole. Two months after the injection a consecutive optic atrophy with central visual field defect and severe reduction of the visual acuity to hand movements was apparent. CONCLUSION: Our case report indicates possible in-vivo toxicity of TA deposits in eyes subsequent to vitrectomy and peeling of the ILM. This is in accordance with previous in-vitro studies showing ILM and vitreous to be protective biological factors, but demonstrate pronounced cytotoxicity if TA crystals are allowed to directly adhering to denuded ganglion cells. Hence, we consider that TA injection should be carefully weighed in those patients with prior ILM removal.

Intravitreal bevacizumab (Avastin) for occult choroidal neovascularization in age-related macular degeneration.

BACKGROUND: The purpose of the study is to report data on short-term safety of intravitreal bevacizumab treatment and its effect on visual function, central retinal thickness, and angiographical changes of occult choroidal neovascularization due to age-related macular degeneration. METHODS: A consecutive interventional case series of 30 patients with active subfoveal occult choroidal neovascularization secondary to age-related macular degeneration was followed after one intravitreal injection of 1.25 mg bevacizumab at baseline and subsequent injections following standardized criteria. At baseline and follow-up visits patients had visual acuity assessment, intraocular pressure measurement, fluorescein angiography, and optical coherence tomography imaging. RESULTS: No serious ocular or systemic adverse events were identified. A significant increase of intraocular pressure or signs of retinal toxicity or endophthalmitis were not detected in any patient. Optical coherence tomography revealed significant decrease (p < 0.001) in central retinal thickness after 1 week, 4 weeks, and 12 weeks, respectively. Fluorescein leakage decreased within 1 week and improvement was maintained at week 12 in the majority of patients. Visual acuity improved or remained stable in 29 of 30 patients; improvement of 3 or more lines was seen in 14 of 30 patients; one patients showed improvement of 6 lines. No patient had severe vision loss of 6 lines or more; moderate vision loss of 3 lines was seen in one patient. Re-injections of bevacizumab according to standard criteria were performed one to two times during the follow-up period of 12 weeks with a re-injection interval of 4 to 18 weeks (median 8 weeks). CONCLUSIONS: Short-term results suggest that intravitreal injection of bevacizumab is well tolerated and for the majority of patients with occult choroidal neovascularization in AMD results in improvement of visual acuity, decrease in central retina thickness, and reduction of angiographic leakage of the lesion. Bevacizumab as intravitreal treatment may provide a novel therapeutic option for selected patients with exudative AMD. Randomized prospective multicenter trials seem justified to further evaluate long term effects and impact of intravitreal bevacizumab on different subtypes of AMD compared to established therapies.

[Injector implantation of a scleral-fixated intraocular lens]. / Injektorimplantation sklerafixierter Faltlinsen.

BACKGROUND: In this pilot study, a new injector technique for small-incision implantation of scleral-fixated intraocular lenses (IOLs) was evaluated for IOL stability and visual rehabilitation. PATIENTS AND METHODS: Secondary lens implantation was performed in 18 aphakic eyes using a new small incision technique with injector implantation. This allowed for haptic suturing with the lens body inside the cartridge. All patients were followed-up for best-corrected visual acuity, refraction, IOL evaluation and ultrasound biomicroscopy. RESULTS: In all eyes the IOL was stable without tilt or torque. Best-corrected visual acuity improved 2.2 ETDRS lines after 1 week and 3.1 lines after a mean follow-up time of 7.9+/-2.8 months. Two eyes were complicated with small, peripheral transillumination defects (n=2), but no pigmentary glaucoma occurred. CONCLUSION: By using a self-sealing tunnel incision and injector technique, significant fluid egress and consecutive transient hypotony is minimized throughout the whole procedure. The technique shows a high IOL stability without tilt and assures rapid visual rehabilitation.

[Bevacizumab for treatment of macular edema secondary to retinal vein occlusion]. / Bevacizumab zur Therapie des sekundären Makulaödems nach venösen Gefässverschlüssen.

Application of VEGF inhibitors represents a treatment option for macular edema secondary to retinal vein occlusion that targets the disease at the causal molecular level. First reports on intravitreal injections of bevacizumab show promising morphological and functional effects and demonstrate that bevacizumab is a potent antiedematous agent in this context. A significant reduction of the central retinal thickness followed by a rapid improvement of visual acuity may be achieved within days. In a pilot study with a review period of 3 months, we found a significant improvement of one or more lines in 93% and four or more lines in 27% of eyes. This was associated with a concomitant significant reduction in central retinal thickness, which, however, was not sustained by a single injection (64% reduction after 1 month and 28% after 3 months). No relevant adverse events were noted. The duration of action after intravitreal bevacizumab administration is currently unknown. Reinjections will be necessary to maintain a lasting beneficial effect. Prospective, controlled long-term studies are mandatory to develop standardized treatment protocols that allow a safe and effective application of this off-label therapy.

[Intravitreal bevacizumab for neovascular age-related macular degeneration]. / Intravitreales Bevacizumab bei der neovaskulären altersabhängigen Makuladegeneration.

The efficacy and safety of the therapeutic anti-VEGF concept has already been demonstrated for pegaptanib and ranibizumab. Bevacizumab acts as an antibody against all VEGF-A isoforms and has been developed for oncological indications with intravenous application. Initial reports on intravitreal administration in patients with neovascular age-related macular disease (AMD) have shown beneficial morphological and functional effects. In the meantime, bevacizumab has been used off-label in thousands of patients with AMD. However, data from prospective, controlled, randomized trials on both safety and efficacy are lacking. Herein recent experiences with bevacizumab are summarized and discussed. Furthermore, a web-based platform for online data registration and pooled analyses is presented.

[Recommendation for the implementation of intravitreal injections--statement of the German Retina Society, the German Society of Ophthalmology (DOG) and the German Professional Association of Ophthalmologists (BVA)]. / Empfehlung für die Durchführung von intravitrealen Injektionen -- Stellungnahme der Retinologischen Gesellschaft, der Deutschen Ophthalmologischen Gesellschaft (DOG) und des Berufsverbands der Augenärzte Deutschland (BVA).

The intravitreal injection as a minimally invasive intervention has proved to be an effective therapy in the management of numerous vitreoretinal diseases. However, non-standardized performance of the procedure might cause severe complications. The recommendations for intravitreal injections discussed here are intended to contribute to a minimization of the risk for complications. Of particular importance are a meticulous preoperative antisepsis with povidone iodine, a sterile environment using a sterile lid speculum, drape and gloves, the use of an adequate injection technique and the exclusion of postoperative retinal non-perfusion.

[Ocular side effects and complications of intravitreal triamcinolone acetonide injection]. / Nebenwirkungen und Komplikationen der intravitrealen Triamcinolonacetonid-Therapie.

With the advent of intravitreal triamcinolone acetonid injections major focus was assigned to potential ocular side effects. The current discussion is dominated by the potential cytotoxicity of particular biologically incompatible components. Those are regarded as substantial pathogenetic factor of the sterile pseudoendophthalmitis that seems to be avoidable by meticulous purification of the commercially available preparations. Even sustained subretinal or epiretinal deposits disclosed no signs of retinal toxicity. Major ocular side effects comprise temporary corticosteroid glaucoma and progressive cataract formation. Infectious endophthalmitis represents a rare but serious complication that might be set into critical context with hygienic surgical standards applied. Due to steroid-induced immune suppression clinical signs of inflammation might be masked and a proper diagnosis delayed. Other rare complications reported include a transient central retinal artery occlusion, conjunctival ulcerations, retinal detachment and potential reactivation of a cytomegalovirus retinitis. In conclusion, ocular side effects and complications show a wide variety of clinical signs and underlying causal mechanisms. However, the consequences are mostly temporary and show a good response to therapeutic intervention.

Synaptic vesicle alterations in rod photoreceptors of synaptophysin-deficient mice.

The abundance of the integral membrane protein synaptophysin in synaptic vesicles and its multiple possible functional contributions to transmitter exocytosis and synaptic vesicle formation stand in sharp contrast to the observed lack of defects in synaptophysin knockout mice. Assuming that deficiencies are compensated by the often coexpressed synaptophysin isoform synaptoporin, we now show that retinal rod photoreceptors, which do not synthesize synaptoporin either in wild-type or in knockout mice, are affected by the loss of synaptophysin. Multiple pale-appearing photoreceptors, as seen by electron microscopy, possess reduced cytoplasmic electron density, swollen mitochondria, an enlarged cell surface area, and, most importantly, a significantly reduced number of synaptic vesicles with an unusually bright interior. Quantification of the number of synaptic vesicles per unit area, not only in these, but also in all other rod terminals of knockout animals, reveals a considerable reduction in vesicles that is even more pronounced during the dark period, i.e., at times of highest synaptic activity. Moreover, activity-dependent reduction in synaptic vesicle diameter, typically occurring in wild-type mice, is not detected in knockout animals. The large number of clathrin-coated pits and vesicles in dark-adapted synaptophysin knockout mice is taken as an indication of compensatory usage of synaptophysin-independent pathway(s), and, conversely, in view of the overall reduction in the number of synaptic vesicles, as an indication for the presence of another synaptophysin-dependent synaptic vesicle recycling pathway. Our results provide in vivo evidence for the importance of the integral membrane protein synaptophysin for synaptic vesicle recycling and formation.

Identification of Usher syndrome subtypes by ERG implicit time.

PURPOSE: Usher syndrome (US) is a recessively inherited disorder combining retinitis pigmentosa (RP) and a sensorineural hearing loss. The classification in subtypes is based mainly on auditory tests. The purpose of this study was to analyze implicit time (IT) differences in the electroretinogram (ERG) between RP alone, US I, and US II. METHODS: The data of 15 control subjects and of 15 patients with US I, 15 with US II, and 15 with RP with nonzero 33-Hz flicker ERG responses were analyzed. The ITs of three signal peaks (P1-P3) were evaluated. Sensitivity and specificity of a test to distinguish between US I and II based on timing differences were determined. Multifocal (mf)ERGs were used to assess differences in disease topography. RESULTS: Despite the similar amplitude loss with retinal eccentricity in the mfERG in all three groups, the peak delay in US I was negligible compared with that in US II and RP. In the flicker ERG data, US I and control subjects had almost identical peak times, and the same was true for subjects with US II and RP. Because of the slight overlap between US I and II, the diagnostic test achieved a sensitivity of 100% and a specificity of 93.3%. CONCLUSIONS: Substantial timing differences between US I and II and their usefulness for a diagnostic test were demonstrated. This finding may also be the basis for further investigations regarding the structural differences of retinal impairment between US I and II on a cellular level.

New views on RPE65 deficiency: the rod system is the source of vision in a mouse model of Leber congenital amaurosis.

Leber congenital amaurosis (LCA) is the most serious form of the autosomal recessive childhood-onset retinal dystrophies. Mutations in the gene encoding RPE65, a protein vital for regeneration of the visual pigment rhodopsin in the retinal pigment epithelium, account for 10-15% of LCA cases. Whereas previous studies of RPE65 deficiency in both animal models and patients attributed remaining visual function to cones, we show here that light-evoked retinal responses in fact originate from rods. For this purpose, we selectively impaired either rod or cone function in Rpe65-/- mice by generating double- mutant mice with models of pure cone function (rhodopsin-deficient mice; Rho-/-) and pure rod function (cyclic nucleotide-gated channel alpha3-deficient mice; Cnga3-/-). The electroretinograms (ERGs) of Rpe65-/- and Rpe65-/-Cnga3-/- mice were almost identical, whereas there was no assessable response in Rpe65-/-Rho-/- mice. Thus, we conclude that the rod system is the source of vision in RPE65 deficiency. Furthermore, we found that lack of RPE65 enables rods to mimic cone function by responding under normally cone-isolating lighting conditions. We propose as a mechanism decreased rod sensitivity due to a reduction in rhodopsin content to less than 1%. In general, the dissection of pathophysiological processes in animal models through the introduction of additional, selective mutations is a promising concept in functional genetics.

Prevention of photoreceptor apoptosis by activation of the glucocorticoid receptor.

PURPOSE: Evidence has accumulated that excessive light exposure may promote age-related and inherited retinal degeneration, in which photoreceptor death by apoptosis leads to loss of vision. In the current study, the effect of elevated corticosteroid levels on light-induced apoptosis of photoreceptors was determined. METHODS: Photoreceptor apoptosis was induced in retinas of BALB/c mice by exposure to diffuse white light. High levels of corticosteroids were induced, either endogenously (fasting-mediated stress) or by a single intraperitoneal injection of dexamethasone (DEX). Photoreceptor damage was assessed morphologically and by electroretinography. Glucocorticoid receptor (GR) and activator protein (AP)-1 activities were shown by Western blot analysis and electrophoretic mobility shift assay (EMSA) of retinal nuclear extracts. RESULTS: Fasting and injection of DEX led to an activation of GR in the retina, as judged by its translocation to the nucleus of retinal cells. On induction of GR activity before light exposure, AP-1 activity, normally induced by damaging doses of light, remained at basal levels. Both treatments completely prevented photoreceptor apoptosis and preserved retinal function. CONCLUSIONS: Activity of the transcription factor AP-1 is associated with light-induced apoptosis. In the current study, pharmacologic suppression of AP-1 activity protected against light damage. Inhibition of AP-1 activity may have occurred by the protein-protein interaction of GR and AP-1.

Evaluation of the rhodopsin knockout mouse as a model of pure cone function.

PURPOSE: To determine a time window in the rhodopsin knockout (Rho(-/-)) mouse during which retinal function is already sufficiently developed but cone degeneration is not yet substantial, thus representing an all-cone retina. METHODS: Electroretinograms (ERGs) were obtained from 14 homozygous Rho(-/-) mice and eight C57Bl/6 control mice. The same individuals were tested every 7 days, beginning as early as postnatal day (P)14. The ERG protocols included flash and flicker stimuli, both under photopic and scotopic conditions. Retinal and choroidal morphology was observed in animals of comparable age. RESULTS: Functionally, the developmental phase lasted until postnatal week (PW)3 in both the Rho(-/-) mice and the control animals. During PW4 to 6, the Rho(-/-) mice showed a plateau in ERG parameters with normal or even supernormal cone responses and complete absence of rod contributions. At PW7, there was a marked onset of degeneration, which progressed so that no ERG signals were left at PW13, when the control eyes still had normal ERG responses. Microscopically, cone degeneration paralleled the functional changes, beginning at approximately PW6 and almost complete at PW13, whereas retinal pigment epithelium (RPE) and choroid did not show any abnormalities. CONCLUSIONS: From PW4 to 6, Rho(-/-) mice appear to have normal cone and no rod function. Despite the missing rod outer segment (OS), the structure of retina, RPE, and choroid remained unchanged. Therefore, the Rho(-/-) mice can serve during this age period as a model for pure cone function. Such a model is particularly useful to evaluate rod-cone interaction and to dissect rod- from cone-mediated signaling pathways in vivo.

Oa1 knock-out: new insights on the pathogenesis of ocular albinism type 1.

Ocular albinism type I (OA1) is an X-linked disorder characterized by severe reduction of visual acuity, strabismus, photophobia and nystagmus. Ophthalmologic examination reveals hypopigmentation of the retina, foveal hypoplasia and iris translucency. Microscopic examination of both retinal pigment epithelium (RPE) and skin melanocytes shows the presence of large pigment granules called giant melanosomes or macromelanosomes. In this study, we have generated and characterized Oa1-deficient mice by gene targeting (KO). The KO males are viable, fertile and phenotypically indistinguishable from the wild-type littermates. Ophthalmologic examination shows hypopigmentation of the ocular fundus in mutant animals compared with wild-type. Analysis of the retinofugal pathway reveals a reduction in the size of the uncrossed pathway, demonstrating a misrouting of the optic fibres at the chiasm, as observed in OA1 patients. Microscopic examination of the RPE shows the presence of giant melanosomes comparable with those described in OA1 patients. Ultrastructural analysis of the RPE cells, suggests that the giant melanosomes may form by abnormal growth of single melanosomes, rather than the fusion of several, shedding light on the pathogenesis of ocular albinism.

Selective loss of cone function in mice lacking the cyclic nucleotide-gated channel CNG3.

Two types of photoreceptors, rods and cones, coexist in the vertebrate retina. An in-depth analysis of the retinal circuitry that transmits rod and cone signals has been hampered by the presence of intimate physical and functional connections between rod and cone pathways. By deleting the cyclic nucleotide-gated channel CNG3 we have generated a mouse lacking any cone-mediated photoresponse. In contrast, the rod pathway is completely intact in CNG3-deficient mice. The functional loss of cone function correlates with a progressive degeneration of cone photoreceptors but not of other retinal cell types. CNG3-deficient mice provide an animal model to dissect unequivocally the contribution of rod and cone pathways for normal retinal function.