[Analysis of the importance of e-learning in ophthalmology and evaluation of an e-learning app]. / Analyse des Stellenwertes von "eLearning" in der Augenheilkunde und Evaluierung einer "eLearning-App".

BACKGROUND: The aim of the study was to analyze the importance of e­learning in the learning and training behavior of ophthalmologists in Germany and to evaluate the acceptance of a new e­learning user software (app). MATERIAL AND METHODS: Ophthalmological residents and specialists were asked about continuing education activities by means of a questionnaire during continuing education events. Furthermore, a structured evaluation was carried out after the presentation and application of an e­learning app. RESULTS: A total of 149 ophthalmologists took part in the survey. While the majority of colleagues (74.3%) used specialist journals weekly or monthly for further education, 45.9% of ophthalmologists used digital print media (books, journals, articles) and 46.5% used specialist books in printed form. Only 35% of the interviewees used online training platforms, e.g. digital courses (CME courses) or portals for retrieving recorded lectures. The use of the offered e­learning app was generally accompanied by a positive acceptance. Of the interviewed colleagues 91.7% would recommend this form of interactive learning. DISCUSSION: Despite a progressive digitalization in all areas of life, e­learning continues to play a minor role as a learning medium in ophthalmological advanced training. Interestingly, the evaluation of app users showed a high level of acceptance, regardless of age or field of work.

Prospective PED-study of intravitreal aflibercept for refractory vascularized pigment epithelium detachment due to age-related macular degeneration: morphologic characteristics of non-responders in optical coherence tomography.

PURPOSE: The aim of this study was to investigate the outcomes of a fixed intravitreal aflibercept regimen in patients with vascular pigment epithelium detachment (vPED) secondary to age-related macular degeneration with refractory subretinal fluid. METHODS: A prospective, interventional case series involved 20 eyes of 20 patients with refractory subretinal fluid and vPED treated with at least three injections of intravitreal anti-VEGF prior to study inclusion. After study inclusion, patients were treated with three injections of intravitreal aflibercept 2 mg/0.05 mL monthly followed by injections every 8 weeks. Best-corrected visual acuity (BCVA) and spectral-domain optical coherence tomography (SD-OCT) were evaluated at all visits. Fluorescein angiography and indocyanine green angiography were performed at baseline and quarterly. Primary outcomes were effectivity of a fixed treatment as measured in change in BCVA, PED greatest linear diameter (GLD), and PED height from baseline to month 12. In an additional post hoc analysis, vPED patients were differentiated into two groups: (1) vPED lesions that showed persistence of subretinal fluid throughout 1 year of treatment and (2) vPED lesions that showed complete resolution of subretinal fluid at least at one of the monthly performed OCT volume scans. Reflectivity values were determined in the subretinal pigment epithelium (RPE) compartment in OCT scans at baseline, month 6 and 12. RESULTS: A total of 18 patients completed the study protocol. The mean age was 74.8 ± 10.6 years, and six patients were female. The median BCVA of all patients was 72.0 ± 8.0 EDTRS letters at baseline and 72.5 ± 9.5 EDTRS letters at 12-month follow-up (p = 0.7420). The median PED height in all patients as measured in the OCT images significantly decreased from 372.0 ± 140.0 µm to 149.0 ± 142.0 µm after 12 months of treatment (p = 0.0020). Persistent subretinal fluid was present at every OCT control in six patients (group 1). Twelve patients showed resolution of subretinal fluid at least at one OCT control (group 2). Reflectivity values in the sub-RPE compartment in OCT scans were 41.48 ± 4.48 (group 1) and 42.62 ± 12.34 (group 2) at baseline (p = 0.854) and 65.88 ± 6.74 and 50.87 ± 14.11 at month 12 (p = 0.038). CONCLUSIONS: Intravitreal aflibercept in refractory vPED leads to a significant reduction in PED height and disease activity as well as preservation of BCVA over 1 year. Persistent subretinal fluid was present in PED lesions with high values of reflectivity under the RPE, suggesting both a diffusion barrier and an increasing fibrovascular maturization of the choroidal neovascularization. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03370380.

Impact of integrated multiple image averaging on OCT angiography image quality and quantitative parameters.

PURPOSE: Multiple image averaging (MIA) is a new approach to improve OCT angiography (OCTA) imaging. The aim of this work was to analyze the impact of MIA on image quality and quantitative OCTA parameters. METHODS: Twenty eyes from 20 healthy volunteers (55.65 ± 14.8 years) were prospectively enrolled. Imaging was performed using two commercially available OCTA devices (Canon OCT HS-100, Optovue AngioVue) using a uniform imaging protocol. Each participant had two single scans of the macula (3 × 3mm, Canon and Optovue) as well as five continuous single scan imaging procedures (3 × 3mm each) using the Canon device. Three out of five of these images with highest quality were manually chosen and then automatically processed by the Canon device using MIA. The superficial retinal plexus of the single scans and of MIA images was analyzed with regard to the device' own image quality scores (IQS), peak signal-to-noise ratio (PSNR), the size of the foveolar avascular zone (FAZ), and vessel density (VD). Image acquisition times were recorded. Parameters were compared between the devices and the different imaging protocols. RESULTS: Average acquisition time was significantly higher for the MIA compared with the single measurements (29.09 ± 10.19 seconds (s) (MIA) vs. 5.56 ± 2.17 s (Canon single scan) vs. 20.28 ± 6.81 s (Optovue) (p < 0.001)). IQS showed no significant differences between the devices and between the recording protocols. PSNR was 12.38 ± 0.20 (Canon single scan), 13.01 ± 0.36 (Canon MIA), and 14.34 ± 0.60 (Optovue) (p < 0.001 between the groups). Mean FAZ area in Canon single scans was 0.29 ± 0.06 mm2, 0.27 ± 0.07 mm2 using MIA, and 0.27 ± 0.08 mm2 using the Optovue device. There was no significant difference between mean FAZ measurements before and after averaging (Canon single scan vs. MIA, p = 0.168). VD of the parafoveal area using MIA was significantly lower compared with both single scans (p < 0.001). CONCLUSIONS: MIA can improve PSNR, but it also reduces imaging speed and significantly affects VD measurements. Therefore, when comparing OCTA data, the use of uniform imaging protocols is required.

[Volumetric analysis of vascularized pigment epithelium detachment in AMD: post hoc analysis of the RECOVER study]. / Volumetrische Analyse der vaskularisierten Pigmentepithelabhebung bei AMD: Post-hoc-Analyse der RECOVER-Studie.

BACKGROUND: The ratio of choroidal neovascularization (CNV) and pigment epithelium detachment (PED) represents an important parameter regarding the risk of developing a tear of the retinal pigment epithelium (RPE) in patients with vascularized PED due to age-related macular degeneration (AMD). METHODS: Within the framework of the RECOVER study a total of 29 treatment-naive patients with vascularized PED underwent fluorescein angiography (FA), indocyanine green angiography (ICGA) and optical coherence tomography (OCT) volume scans. The CNV-PED ratio was evaluated retrospectively by two independent graders in three ways: 1) manually based on the en face image of the FA late phase and 2) manually based on the en face image of the ICGA late phase. 3) In every OCT scan encompassing the PED, the area between the RPE and Bruch's membrane and the CNV area was measured and multiplied by the distance between OCT scans in order to determine volumetric data of CNV, PED and the serous cavity. RESULTS: The FA and ICGA showed a mean serous area of 6.14 ± 4.21 mm2 (ICGA 5.94 ± 4.13 mm2), a mean CNV area of 3.25 ± 1.79 mm2 (ICGA 2.84 ± 1.68 mm2) and a mean PED area of 9.39 ± 4.27 mm2 (ICGA 8.79 ± 4.23 mm2) resulting in a mean two-dimensional morphological ratio of 0.35 ± 0.21 (ICGA 0.32 ± 0.22). The volumetric measurement revealed a mean CNV volume of 0.63 ± 0.67 mm3, a mean serous volume of 3.61 ± 3.83 mm3 and a mean total PED volume of 4.25 ± 3.68 mm3. The mean three-dimensional morphological ratio was 0.15 ± 0.29. The difference between the two-dimensional ratios of FA (p < 0.0001) and ICGA (p = 0.0004) was significant compared to the three-dimensional OCT ratio. CONCLUSION: Assessment of the CNV-PED ratio using volumetric OCT measurements is an additional tool to the en face modalities FA and ICGA. This seems to be clinically relevant regarding the risk stratification of RPE tear development in PED patients and for the planning of the treatment regimen.

Signal reduction in choriocapillaris and segmentation errors in spectral domain OCT angiography caused by soft drusen.

PURPOSE: To analyze signal reduction in choriocapillaris (CC) and segmentation errors in spectral domain optical coherence tomography angiography (OCT-A) caused by soft drusen due to age-related macular degeneration (AMD). METHODS: Twenty-four eyes of 24 patients underwent multimodal retinal imaging including central 3 × 3mm2 OCT-A (AngioVue, Optovue). Three drusen per study eye were randomly chosen and evaluated regarding drusen height, diameter, and accuracy of OCT-A layer segmentation in lesion proximity. Structural en-face OCT CC images were graded qualitatively and quantitatively regarding signal loss underneath the individual drusen area. Those drusen that showed no distinct signal loss in structural en-face OCT CC images were further evaluated in OCT-A. CC decorrelation signal index was measured within a 30-µm OCT-A CC slab in the exact area of drusen affection. Data were compared to healthy age-matched control subjects. Accuracy of layer segmentation, OCT CC data, and OCT-A CC data were correlated to morphological drusen parameters. RESULTS: Mean drusen height and diameter were 91.57 ± 19.5µm and 315.17 ± 116.7µm. OCT-A layer segmentation of the inner plexiform layer (IPL) was disturbed by more than 50 µm in proximity to 26 drusen (36.1%). In these patients, drusen height was significantly higher compared to those with accurate IPL segmentation (p = 0.0126). Sixty-six out of 72 drusen (91.7%) caused a distinct signal loss in the structural en-face OCT CC image. Drusen height and drusen diameter were significantly higher in this group compared to the six drusen with a sufficient signal (p = 0.0276, p = 0.0025). CC decorrelation signal index measured in the area of these six drusen without OCT signal loss (8.3%) was reduced compared to age-matched healthy controls (73.6 vs. 100.1; p = 0.001). CONCLUSIONS: Signal attenuation in CC slabs and segmentation errors of the IPL depend on drusen morphology. Both are frequent artifacts in OCT-A imaging in patients with soft drusen and must be considered during image analysis.

Impact of eye-tracking technology on OCT-angiography imaging quality in age-related macular degeneration.

OBJECTIVE: To evaluate the impact of eye-tracking (ET) technology on optical coherence tomography angiography (OCT-A) image quality and manifestation of motion artifacts in patients with age-related macular degeneration (AMD). METHODS: In a prospective trial, multimodal retinal imaging including OCT-A was performed in 30 patients (78.97 ± 9.7 years) affected by different stages of AMD. Central 3 × 3 mm2 OCT-A imaging was performed four times consecutively in each patient, twice with active, and twice with inactive ET. Parameters for image evaluation were signal strength index (SSI), variability of foveal vessel density (VD), acquisition time, presence of motion artifacts caused by eye movement (blink lines, displacement) and by software correction of eye movement (quilting, stretch artifacts, vessel doubling). Images were evaluated by two independent readers with subsequent senior reader arbitration for presence of artifacts, and an OCT-A motion artifact score (MAS) was calculated. RESULTS: Eight patients had early and eight patients had intermediate stages of AMD. Four patients had an atrophic late stage and ten patients an exudative stage of the disease. SSI was 53.55 with inactive and 57.18 with active ET (p = 0.0005). Coefficients of variability of VD between the first and second measurement were 8.9% with inactive and 5.7% with active ET. Mean image acquisition time was 15.97 s (active ET: 22.88 s, p < 0.001). Presence of motion artifacts was significantly higher with inactive ET (mean MAS 3.27 vs. 1.93; p < 0.0001). MAS correlated with AMD disease stage [p = 0.0031 (inactive ET) and p < 0.0001 (active ET)] and with SSI (p = 0.0072 and p = 0.0006). CONCLUSIONS: In patients with AMD, active ET technology offers an improved image quality in OCT-A imaging regarding presence of motion artifacts at the expense of higher acquisition time.

Quantification of changes in foveal capillary architecture caused by idiopathic epiretinal membrane using OCT angiography.

PURPOSE: To quantify the extent and depth of distortion of the foveal capillary architecture due to traction of an idiopathic epiretinal membrane (ERM) using optical coherence tomography angiography (OCT-A). METHODS: Multimodal imaging including OCT-A (Angiovue, Optovue) was performed in 42 eyes with idiopathic ERM (72.4 years ±6.8). Best corrected visual acuity (BCVA), OCT-A vessel density of the foveal (VDfo) and parafoveal (VDp) region were assessed. Based on 6 × 6-mm2 OCT-A images, a macular vessel density ratio (MVR = VDfo/VDp) was calculated for the superficial (s), deep (d) and full-thickness (f) slabs to assess a depth-resolved, non-invasive evaluation of foveal distortion. The acquired data were subdivided in a patient group with mild and significant BCVA reduction due to ERM. Data was compared to age-matched healthy controls. RESULTS: In all three slabs, MVR was significantly smaller in the control group in comparison with the ERM group: MVRs: 0.63 ± 0.1 vs 0.83 ± 0.1 (p > 0.001); MVRd: 0.60 ± 0.1 vs 0.73 ± 0.1 (p < 0.001); MVRf: 0.68 ± 0.1 vs 0.82 ± 0.1 (p < 0.001). Group 1 (BCVA <0.4 LogMar) showed a significantly higher MVR in comparison with the control group in the superficial plexus only: MVRs: 0.64 ± 0.1 vs 0.78 ± 0.1 (p < 0.001); MVRd: 0.60 ± 0.1 vs 0.65 ± 0.2 (p = 0.3); MVRf: 0.68 ± 0.1 vs 0.77 ± 0.1 (p = 0.01). However, group 2 (BCVA > = 0.4 LogMar) showed a significantly higher MVR in all three slabs: MVRs: 0.64 ± 0.1 vs 0.86 ± 0.1 (p < 0.001); MVRd: 0.60 ± 0.1 vs 0.77 ± 0.2 (p < 0.001); MVRf: 0.68 ± 0.1 vs 0.85 ± 0.1 (p < 0.001). CONCLUSION: Assessing MVR using OCT-A may serve as a tool to quantify the extent and depth of distortion of the foveal capillary architecture due to traction of ERM. BCVA reduction appears to be associated with extent and depth of distortion.

Characterisation of reticular pseudodrusen and their central target aspect in multi-spectral, confocal scanning laser ophthalmoscopy.

BACKGROUND: To analyse reticular pseudodrusen (RPD) in patients with age-related macular degeneration (AMD) using multi-spectral (MS), confocal scanning laser ophthalmoscopy (cSLO). METHODS: cSLO images (blue fundus autofluorescence [FAF; exc., λ = 488; em., λ = 500-700 nm], near-infrared reflectance [IR; λ = 820 nm], MS [blue reflectance (BR) λ = 488 nm, green reflectance (GR) λ = 515 nm, IR λ = 820 nm], as well as colour fundus photographs (CFP) were taken of 200 eyes from 100 AMD patients suspected to show RPD on the basis of funduscopy or previous fundus imaging. FAF and IR images were graded by two independent readers. If both readers concordantly confirmed the presence of RPD in both modalities, eyes were subsequently also graded for RPD in MS, BR, GR, green-blue enhanced mode (GBE), and CFP. Besides, FAF, IR, and MS images were evaluated for the presence of a target aspect, which represents a common feature of RPD lesions. RESULTS: The presence of RPD was confirmed using FAF and IR images by both readers in 130 eyes of 76 patients. In those eyes, both readers concordantly diagnosed RPD in MS images in 124 (95.4%) eyes (BR: 52 [40.0%], GR: 63 [48.5%], GBE: 101 [77.7%], CF: 27 [20.8%]). Cohen kappa statistics revealed excellent inter-observer agreement for MS (0.95) and GBE (0.85), substantial agreement for BR (0.75), GR (0.78), and moderate agreement for CFP (0.59). A target aspect within RPD lesions was detected in 45 of 130 (35.0%) included eyes using FAF and IR. The presence of a target aspect improved the recognition of RPD lesions in all modalities. If a target aspect was present, RPD were diagnosed in 45 eyes (100%) using MS (GBE: 42 eyes [93.3%], BR: 30 eyes [66.7%], GR: 37 eyes [82.2%], CFP: 17 eyes [37.8%]). Using MS cSLO, a target aspect could be identified in 75 of 130 (57.7%) included eyes. CONCLUSIONS: MS cSLO imaging is equivalent to FAF and IR in identifying RPD in AMD patients. Higher identification rates in BR and GR of those RPD lesions featuring a target aspect confirm the current hypothesis of RPD localisation and its progression further into the photoreceptor layers. MS seems to be more sensitive in identifying a central target aspect in RPD lesions compared to blue FAF and IR.

Non-viral gene therapy for GDNF production in RCS rat: the crucial role of the plasmid dose.

Glial cell line-derived neurotrophic factor (GDNF) is one of the candidate molecules among neurotrophic factors proposed for a potential treatment of retinitis pigmentosa (RP). It must be administered repeatedly or through sustained releasing systems to exert prolonged neuroprotective effects. In the dystrophic Royal College of Surgeon's (RCS) rat model of RP, we found that endogenous GDNF levels dropped during retinal degeneration time course, opening a therapeutic window for GDNF supplementation. We showed that after a single electrotransfer of 30 µg of GDNF-encoding plasmid in the rat ciliary muscle, GDNF was produced for at least 7 months. Morphometric, electroretinographic and optokinetic analyses highlighted that this continuous release of GDNF delayed photoreceptors (PRs) as well as retinal functions loss until at least 70 days of age in RCS rats. Unexpectedly, increasing the GDNF secretion level accelerated PR degeneration and the loss of electrophysiological responses. This is the first report: (i) demonstrating the efficacy of GDNF delivery through non-viral gene therapy in RP; (ii) establishing the efficacy of intravitreal administration of GDNF in RP associated with a mutation in the retinal pigment epithelium; and (iii) warning against potential toxic effects of GDNF within the eye/retina.

[Use of nanoparticles in ophthalomology]. / Einsatz von Nanopartikeln in der Augenheilkunde.

Nanotechnology, the manufacture and use of structures and implements of around a few 100 nm in size, is becoming a key technology of the twenty-first century. An important element for the manufacture of nanoparticles is gold. Gold nanoparticles can be custom made and chemically modified in their size and form. Initial investigations have shown that they are physiologically non-hazardous. A potential application is in neovascular age-related macular degeneration. Gold nanoparticles of suitable dimensions introduced into newly forming blood vessels can be targeted and heated which selectively destroys these blood vessels. This principle has already been demonstrated in cultivated endothelial cells.

[Localisation of bevacizumab in the monkey retina after an intravitreal injection of Avastin]. / Lokalisation von Bevacizumab in der Netzhaut von Affen nach einer intravitrealen Bevacizumab-Injektion.

BACKGROUND: The aim was to investigate to what extent the vascular endothelial growth factor (VEGF) antibody bevacizumab is able to penetrate the retina in primates after an intravitreal injection of Avastin. MATERIAL AND METHODS: Monkeys (Macaca fascicularis) were injected intravitreally with radioactively labelled and free Avastin. The animals were sacrificed 1, 4, 7, or 14 days after the injection, and the eyes were examined histologically and immunohistochemically. Blood samples were also taken on several days. RESULTS: In the fundoscopic images, no pathologic changes could be found during the experiment. Using immunohistochemistry, bevacizumab was found in the choroid and the inner layers of the retina 1 day after the injection. Bevacizumab penetrated more quickly in the fovea than in the rest of the retina. It was also encountered in the photoreceptors and blood vessels. When (125)I-labelled Avastin was used, radioactivity could be determined in the blood serum 1 day after the injection. CONCLUSION: The results show that the bevacizumab molecule can penetrate the retina after intravitreal injection of Avastin. However, there is an active uptake in the retinal cells.

[Chances and risks of anti-VEGF therapy]. / Chancen und Risiken der Anti-VEGF-Therapie.

Vascular endothelial growth factor (VEGF) plays a pivotal role in angiogenesis. Through regulation of haemodynamics, haematopoesis and the immune system, endocrinology and reparative processes, inhibition of VEGF can cause multiple adverse events. Previous data suggest that--even after intravitreal injection--systemic exposure might occur, thus bearing the risk of manifestation of side effects. Experience with intravenous administration of the antibody bevacizumab (Avastin) pointed to the potential consequences of a pan-VEGF blockade. The change of haemodynamic parameters implies a potential influence on the patient's morbidity. Studies already conducted during the approval process do not provide sufficient statistical power when evaluating whether systemic events significantly differ between the treatment and control groups. Retinal perfusion showed an altered vascular tone (change in vessel diameter) following anti-VEGF treatment. Physiological fenestration of the choroicapillaris is significantly reduced. Possible effects on the local oxygen supply in ischaemic tissue have to be considered. In contrast to destructive treatment modalities (laser, cryo), VEGF inhibitors promise the prompt and efficient response of retinal neovascularisation and the preservation of a better function (visual fields). The maturation of growing vessels (pericytes) and the secondary formation of membranes are limiting factors with regard to the time-point at which anti-VEGF therapy is most effective. A diligent use of the available drugs has to take into account which types of exudative retinopathy are showing no or only very limited response to the treatment.

Immunohistochemical localisation of intravitreally injected bevacizumab at the posterior pole of the primate eye: implication for the treatment of retinal vein occlusion.

AIM: To locate bevacizumab in the posterior pole within 1-14 days after intravitreal injection in the primate eye. METHODS: Four Cynomolgus monkeys received an intravitreal injection of 1.25 mg of bevacizumab. The eyes were enucleated on days 1, 4, 7 and 14 for immunohistochemistry using donkey anti-human Cy3-IgG. Control eyes remained untreated. RESULTS: In the optic nerve, immunoreactivity for bevacizumab was most prominent on day 1 after injection and diminished rapidly. In the blood vessels of the nerve fibre layer, the staining was intense in the walls and weak in the lumen from day 1 to 4, and was only localised in the lumen thereafter. In the macula, an accumulation of bevacizumab was observed 1 day after injection in the nerve fibre layer, the ganglion cell layer and in the photoreceptors at the level of the outer nuclear layer in the fovea centralis. CONCLUSION: Bevacizumab penetrates quickly into the macula, the retinal veins and the optic nerve after intravitreal injection in the primate eye, and accumulates preferentially and specifically on the vessel walls and inside the photoreceptors localised in the fovea centralis 1 day after injection. Our finding supports the clinically observed rapid effect in the treatment of retinal vein occlusion and macular oedema.

Immunohistochemical localisation of intravitreally injected bevacizumab in the anterior chamber angle, iris and ciliary body of the primate eye.

AIMS: To locate bevacizumab in the tissues related to neovascularisation in the anterior segment within 1-14 days after intravitreal injection in the primate eye. METHODS: Four cynomolgus monkeys received an intravitreal injection of 1.25 mg bevacizumab. Control eyes remained untreated. The eyes were enucleated on day 1, 4 and 14 for immunohistochemistry, using donkey anti-human Cy3-IgG. RESULTS: Immunoreactivity for bevacizumab was found in the blood vessels walls of the iris, anterior chamber angle and ciliary body. In the iris and chamber angle, immunoreactivity was most prominent on day 1 after injection and diminished until day 14. In the ciliary body, staining was most intense on day 4 and remained prominent until day 14. Immunoreactivity was also present in certain vessel lumens, especially in the ciliary body and the iris on day 4 and 14. CONCLUSION: Bevacizumab penetrates quickly into the iris, anterior chamber angle and ciliary body after intravitreal injection in the primate eye and accumulates particularly in blood-vessel walls. The highest concentration of bevacizumab in these tissues is present on day 1-4, the iris and anterior chamber angle being penetrated slightly earlier than the ciliary body. Our findings support the clinically observed rapid effect in the treatment of iris neovascularisation.

Implantable visual prostheses.

Visual impairment and blindness is primarily caused by optic neuropathies like injuries and glaucomas, as well as retinopathies like agerelated macular degeneration (MD), systemic diseases like diabetes, hypertonia and hereditary retinitis pigmentosa (RP). These pathological conditions may affect retinal photoreceptors, or retinal pigment epithelium, or particular subsets of retinal neurons, and in particular retinal ganglion cells (RGCs). The RGCs which connect the retina with the brain are unique cells with extremely long axons bridging the distance from the retina to visual relays within the thalamus and midbrain, being therefore vulnerable to heterogeneous pathological conditions along this pathway. When becoming mature, RGCs loose the ability to divide and to regenerate their accidentally or experimentally injured axons. Consequently, any loss of RGCs is irreversible and results to loss of visual function. The advent of micro- and nanotechnology, and the construction of artificial implants prompted to create visual prostheses which aimed at compensating for the loss of visual function in particular cases. The purpose of the present contribution is to review the considerable engineering expertise that is essential to fabricate current visual prostheses in connection with their functional features and applicability to the animal and human eye. In this chapter, 1) Retinal and cortical implants are introduced, with particular emphasis given to the requirements they have to fulfil in order to replace very complex functions like vision. 2) Advanced work on material research is presented both from the technological and from the biocompatibility aspect as prerequisites of any perspectives for implantation. 3) Ultimately, experimental studies are presented showing the shaping of implants, the procedures of testing their biocompatibility and essential modifications to improve the interfaces between technical devices and the biological environment. The review ends by pointing to future perspectives in the rapidly accelerating process of visual prosthetics and in the increasing hope that restoration of the visual system becomes reality.

[Neuroprotection and regeneration after traumatic lesion of the optic nerve]. / Neuroprotektion und Regeneration nach Durchtrennung des Sehnervs.

BACKGROUND: After a traumatic lesion of the optic nerve, retinal ganglion cells (RGC) undergo massive degeneration by apoptosis, which leads to loss of vision in the affected eye. Like other neurones in the central nervous system, RGC are not able to regenerate their damaged axons spontaneously. We used special surgical methods and pharmacological measures to achieve enhanced survival and regeneration of damaged RGC. MATERIALS AND METHODS: Studies were performed using the model of RGC degeneration induced by severing the optic nerve of adult rats. RGC were loaded with a fluorescent dye, and several drugs were applied intravitreally. The effects were evaluated after two weeks by counting the surviving RGC. For regeneration studies, an autologous peripheral nerve graft was sutured to the stump of the cut optic nerve, or the ends of the cut optic nerve were re-sutured. Recovery of RGC function was assessed by VEP measurements. RESULTS: The number of RGC surviving an axotomy increased significantly after intravitreal injections of aurintricarboxylic acid, cortisol, a caspase inhibitor, brimonidine or microglia-targeted substances. Regeneration of cut axons was enhanced by aurintricarboxylic acid or cortisol. In addition, considerable neuroprotective and regenerative effects including partial restoration of VEP were induced by lens injury, which results in a gradual release of crystallins into the vitreous, or by intravitreal injection of purified crystallins. CONCLUSION: The loss of vision after an optic nerve trauma can be reduced in this animal model by suitable neuroprotective measures, which raises hope for the treatment of patients.

Role of a neuronal small non-messenger RNA: behavioural alterations in BC1 RNA-deleted mice.

BC1 RNA is a small non-messenger RNA common in dendritic microdomains of neurons in rodents. In order to investigate its possible role in learning and behaviour, we compared controls and knockout mice from three independent founder lines established from separate embryonic stem cells. Mutant mice were healthy with normal brain morphology and appeared to have no neurological deficits. A series of tests for exploration and spatial memory was carried out in three different laboratories. The tests were chosen as to ensure that different aspects of spatial memory and exploration could be separated and that possible effects of confounding variables could be minimised. Exploration was studied in a barrier test, in an open-field test, and in an elevated plus-maze test. Spatial memory was investigated in a Barnes maze and in a Morris water maze (memory for a single location), in a multiple T-maze and in a complex alley maze (route learning), and in a radial maze (working memory). In addition to these laboratory tasks, exploratory behaviour and spatial memory were assessed under semi-naturalistic conditions in a large outdoor pen. The combined results indicate that BC1 RNA-deficient animals show behavioural changes best interpreted in terms of reduced exploration and increased anxiety. In contrast, spatial memory was not affected. In the outdoor pen, the survival rates of BC1-depleted mice were lower than in controls. Thus, we conclude that the neuron-specific non-messenger BC1 RNA contributes to the aptive modulation of behaviour.

Lens-injury-stimulated axonal regeneration throughout the optic pathway of adult rats.

Axonal regrowth and restoration of visual function were studied in adult rats. The optic nerve was completely cut behind the eye. The proximal and distal nerve stumps were realigned and the meninges sutured back together. During the same surgical procedure, the lens was lesioned in order to induce secondary cellular cascades, which are known to strongly support the survival of retinal ganglion cells (RGCs) and to promote axonal regeneration. The anatomical and topographic restoration of the visual pathway was assessed neuroanatomically with the aid of anterograde and retrograde tracing using fluorescent dyes. It appeared that the axons formed growth cones at the junction of the suture soon after injury, before glial cells and extracellular matrix proteins were able to cause local scar formation. Growth cones first entered the distal optic nerve stump 3 days after injury, grew through it to reach the optic chiasm approximately 3 weeks after the lesion was made, and terminated within the retinoreceptive layers of the superior colliculus 5 weeks after lesioning. Quantification of the retrogradely labeled cell bodies within the regenerating retina revealed that up to 30% of the RGCs, which includes all major cell types, were capable of regenerating their axons along the entire visual pathway. To assess whether topography was restored, double-labeling experiments were performed, revealing only crude topographic restoration during the initial stages of regeneration. However, visual-evoked potentials could be recorded, indicating that synaptic transmission in higher visual areas was relatively intact. The data show, in principle, that cut axons can regenerate over long distances within the white matter of a central nerve like the adult optic nerve, spanning over 11 mm to the chiasm and between 12 and 15 mm to the thalamus and midbrain. The findings suggest, for the first time, that lentogenic stimulation of RGCs is sufficient to induce the formation of growth cones that can override inhibitors at the site of injury, grow through the white matter of the optic nerve, pass through the optic chiasm, and make synaptic connections within the brain.

Perforated microelectrode arrays implanted in the regenerating adult central nervous system.

Adult mammalian optic nerve axons are able to regenerate, when provided with the permissive environment of an autologous peripheral nerve graft, which is usually the sciatic nerve. This study demonstrates the ability of adult rat optic nerve axons to regenerate through the preformed perforations of a polyimide electrode carrier implanted at the interface between the proximal stump of the cut optic nerve and the stump of the peripheral nerve piece used for grafting. Evidence that retinal ganglion cells regenerated their axons through the perforated electrode carrier was obtained by retrograde labeling with a fluorescent dye deposited into the sciatic nerve graft beyond the nerve-carrier-nerve junction. The number of regenerating cells could be enhanced by injecting neuroprotective drugs like aurintricarboxylic acid and cortisol intravitreally. A second line of evidence was obtained by immunohistochemical staining with antibodies to neurofilament. Third, electrical activity of the regenerating nerves was recorded after stimulating the retina with a flash of light. The results suggest that a regenerating central nerve tract may serve as an experimental model to implant artificial microdevices to monitor the physiological and topographical properties of neurites passing through the device or to stimulate them, thus interfering with their potential to grow. This study reports for the first time that the optic nerve has unique properties, which aids in the realization of these goals.