Transfer characteristics of subretinal visual implants: corneally recorded implant responses.

PURPOSE: The subretinal Alpha IMS visual implant is a CE-approved medical device for restoration of visual functions in blind patients with end-stage outer retina degeneration. We present a method to test the function of the implant objectively in vivo using standard electroretinographic equipment and to assess the devices' parameter range for an optimal perception. METHODS: Subretinal implant Alpha IMS (Retina Implant AG, Reutlingen, Germany) consists of 1500 photodiode-amplifier-electrode units and is implanted surgically into the subretinal space in blind retinitis pigmentosa patients. The voltages that regulate the amplifiers' sensitivity (V gl) and gain (V bias), related to the perception of contrast and brightness, respectively, are adjusted manually on a handheld power supply device. Corneally recorded implant responses (CRIR) to full-field illumination with long duration flashes in various implant settings for brightness gain (V bias) and amplifiers' sensitivity (V gl) are measured using electroretinographic setup with a Ganzfeld bowl in a protocol of increasing stimulus luminances up to 1000 cd/m2. RESULTS: CRIRs are a meaningful tool for assessing the transfer characteristic curves of the electronic implant in vivo monitoring the implants' voltage output as a function of log luminance in a sigmoidal shape. Changing the amplifiers' sensitivity (V gl) shifts the curve left or right along the log luminance axis. Adjustment of the gain (V bias) changes the maximal output. Contrast perception is only possible within the luminance range of the increasing slope of the function. CONCLUSIONS: The technical function of subretinal visual implants can be measured objectively using a standard electroretinographic setup. CRIRs help the patient to optimise the perception by adjusting the gain and luminance range of the device and are a useful tool for clinicians to objectively assess the function of subretinal visual implants in vivo.

Genome-wide, large-scale production of mutant mice by ENU mutagenesis.

In the post-genome era, the mouse will have a major role as a model system for functional genome analysis. This requires a large number of mutants similar to the collections available from other model organisms such as Drosophila melanogaster and Caenorhabditis elegans. Here we report on a systematic, genome-wide, mutagenesis screen in mice. As part of the German Human Genome Project, we have undertaken a large-scale ENU-mutagenesis screen for dominant mutations and a limited screen for recessive mutations. In screening over 14,000 mice for a large number of clinically relevant parameters, we recovered 182 mouse mutants for a variety of phenotypes. In addition, 247 variant mouse mutants are currently in genetic confirmation testing and will result in additional new mutant lines. This mutagenesis screen, along with the screen described in the accompanying paper, leads to a significant increase in the number of mouse models available to the scientific community. Our mutant lines are freely accessible to non-commercial users (for information, see http://www.gsf.de/ieg/groups/enu-mouse.html).

[Therapeutic approaches for retinitis pigmentosa]. / Therapeutische Ansätze bei Patienten mit Retinitis pigmentosa.

BACKGROUND: Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of hereditary retinal disorders, which lead to progressive loss of vision and finally blindness. Yet there is no approved therapy. Advances in unravelling underlying genetic disorders and pathophysiological mechanisms offer new therapeutic approaches of which some are summarised in this review. METHODS: We performed a systematic literature research for defined key words in PubMed. RESULTS: New approaches to therapy for RP include: gene therapy, pharmacological treatment, neuroprotection, electrical stimulation, retinal prostheses, retinal transplantation and optogenetic therapy. CONCLUSIONS: Recently there have been advances in new approaches for therapy of dystrophic retinal diseases. Advances in the different approaches are being made at different rates. Although there is no approved therapy yet, the future for treating RP at least in some patients looks promising.

[Pathophysiology of cataract formation after vitrectomy]. / Pathophysiologie der Katarakt-Entwicklung nach Vitrektomie.

Cataract formation is one of the most common complications after vitrectomy and cataract extraction in such cases will have to be performed under more difficult conditions. A knowledge of the different types of cataract, their frequency and causes may help to develop strategies to prevent this complication. In addition to a progressive nuclear opacification, which may occur after any type of vitrectomy, transient feathering of the lens often occurs after intraocular gas tamponade, while permanent subcapsular opacification may occur in silicone oil-filled eyes. Nuclear opacification after vitrectomy morphologically and histologically resembles age-related cataracts, but shows a faster progression: two years after vitrectomy half of the eyes require cataract extraction and there seems to be an age limit: the opacification progresses faster in patients over 50 years old. The main cause for nuclear cataracts most probably is oxidative stress. Oxygen in the avascular lens is provided by diffusion, meaning that the surrounding oxygen content is crucial for the oxygen content within the lens and thus for the formation of reactive oxygen species. In rabbits and also in humans the partial oxygen pressure is highly elevated in the vitreous cavity after vitrectomy and posterior to the lens since the vitreous is lacking as a diffusion barrier for the oxygen. The partial oxygen pressure might be additionally elevated by ventilation with oxygen and a high oxygen pressure in the infusion fluid during surgery. This elevated partial oxygen pressure may lead to increased oxygen stress and thus to lens opacification by oxidation of structural proteins. The key for the prevention of cataract formation therefore seems to be avoidance of oxidative stress, factors that might increase the protective or repair systems are so far not available. Ventilation with oxygen should be minimised as should be the partial oxygen tension in the infusion fluid. New hydrogels as vitreous substitutes might have a beneficial influence on intraocular partial oxygen tension.

[Transcorneal electrical stimulation in primary open angle glaucoma]. / Transkorneale Elektrostimulation bei primärem Offenwinkelglaukom.

Recently, reports have been published on the effectiveness of electrical stimulation in patients and experimental animal models with neurodegenerative ocular diseases. Our study included 14 patients with primary open angle glaucoma (POAG), who were randomized into one of three groups with 0% (sham, n = 5), 66% (n = 5) or 150% (n = 4) of their individual electrical phosphene thresholds. Patients were treated with transcorneal electrical stimulation (TES) for 30 min once a week for 6 consecutive weeks. Outcome measures of our study were the detection of possible adverse events and efficacy of TES using DTL electrodes in subjective and objective parameters of visual function under treatment. TES was tolerated well and no serious adverse events were registered relating to the treatment. One single adverse event was registered as appearance of an optic disc hemorrhage of a sham-stimulated eye. In summary, one significant increase of intra-ocular pressure in the 66% group was observed in comparison to the sham group (p = 0.04), without significant differences compared to the 150% group (both sham vs. 150% group and 66% vs. 150% group). This difference (mean difference compared to baseline of -2.33 mm Hg for the sham group and +0.97 mm Hg for the 66% group; REML) was not clinical meaningful. All other findings, including results of the visual field, were not statistically significant different between groups. It was shown that TES using DTL electrodes did not trigger adverse or serious adverse events in the stimulated groups in patients with POAG. Patients with POAG should currently receive TES only under study conditions.

Implantation of stimulation electrodes in the subretinal space to demonstrate cortical responses in Yucatan minipig in the course of visual prosthesis development.

PURPOSE: During the course of the development of visual prostheses, subretinal stimulation films were implanted in micropigs in order to prove the feasibility of subretinal electrical stimulation with subsequent cortical response. One aim was to demonstrate that epidural recording of visual evoked potentials is possible in the micropig. METHODS: Film-bound stimulation electrode arrays were placed in the subretinal space of micropigs. This enabled the retina to be stimulated subretinally. Since conventional visual evoked potential (VEP) measuring is virtually impossible in the pig from the neurosurgical point of view, epidural recording electrode arrays were positioned over the visual cortex as permanent electrodes. RESULTS: The feasibility of temporary implantation of film-bound stimulation electrode arrays was successfully demonstrated in the micropig model. On stimulation with monopolar voltage pulses (1000 to 3000 mV), reproducible epidural VEP measurements (5 to 10 micronV) were detected. CONCLUSIONS: The feasibility of subretinal stimulation of the retina was demonstrated in a retinal model that is similar to the human retina. This animal model therefore offers a suitable means of studying the tolerability of stimulation situations in the course of visual prosthesis development.

[Status of the subretinal implant project. An overview]. / Stand des subretinalen Implantatprojekts. Eine Ubersicht.

The development of a subretinal prosthesis has come to a stage where human trials are forthcoming. Subretinal prostheses are designed to replace degenerated photoreceptors in diseases such as retinitis pigmentosa or age-related macular degeneration. Microphotodiode arrays are implanted between retinal pigment epithelium and retina. Our group has collected convincing evidence for the principle feasibility of a subretinal prosthesis. Animal experiments have shown that subretinal electrical stimulation can successfully elicit spatially ordered responses in the visual cortex; visual acuity is estimated to reach 0.25 degrees of visual angle. Histological long-term examinations have demonstrated that the retina tolerates a subretinal implant well and also that the implant itself sustains the ocular environments. Surgical procedures have been successfully developed to implant complex subretinal devices.

[Ocular electrical stimulation: Therapeutic application and active retinal implants for hereditary retinal degenerations]. / Okuläre elektrische Stimulation : Therapeutische Anwendung und aktive retinale Implantate bei hereditären Netzhautdegenerationen.

BACKGROUND: Electrical stimulation has a long history in ophthalmology. Subthreshold electrical stimulation can have beneficial therapeutic effects on hereditary degenerative retinal diseases. Suprathreshold stimulation is able to elicit visual perceptions and, if multielectrode fields are arranged as an array, usable pictures can be perceived by blind patients. OBJECTIVES: This is a review article on the current situation and studies on therapeutic transcorneal electrical stimulation. Moreover, the challenges, surgical concepts and visual results of active retinal implants are discussed. MATERIAL AND METHODS: This article gives an overview on transcorneal electrical stimulation and active retinal implants based on published results, with special emphasis on the clinical application. RESULTS: The results of initial controlled studies on therapeutic transcorneal electrical stimulation in hereditary retinal diseases were very promising. The largest controlled study so far in patients with retinitis pigmentosa (RP) has yielded many positive trends and some significant improvements in electrophysiological data. Currently, two retinal implants have regulatory approval, the Argus II retinal prosthesis system® (SecondSight®) and the Alpha-IMS© (Retina Implant AG). Both systems can be used to improve visual perception and under test conditions can achieve visual acuities of 0.02 and 0.04, respectively. CONCLUSION: In-depth analyses and follow-up studies in larger patient groups are currently planned to definitively clarify the potential of therapeutic transcorneal electrical stimulation in RP patients. The challenges of currently available active retinal implants are the technical biostability and the limited spatial resolution.

[The role of the vitreous body in diseases of neighboring structures]. / Rolle des Glaskörpers für Erkrankungen benachbarter Strukturen.

BACKGROUND: The vitreoretinal interface is not merely the space between the vitreous body and the retina but it is also a site for highly complex pathologies with the vitreous body exerting an influence on all the neighbouring structures. METHODS: A literature search was performed in Pubmed and current book articles RESULTS: This review article highlights the role of the vitreous body in vitreomacular adhesion and traction, in the development of macular holes and epiretinal membranes as well as its role in age-related macular degeneration. In the retinal periphery the vitreous structures play a pivotal role in retinal tears and detachment as well as in diabetic and other proliferative vitreoretinopathies. The role of the vitreous bodyin the emergence of various forms of cataract is often underestimated. DISCUSSION: Vitreo-etinal surgeons should thoroughly understand the pathophysiological relationship between the vitreous body and the neighboring structures, especially in the era of medical vitreolysis.

In vivo biocompatibility of a new cyanine dye for ILM peeling.

PURPOSE: To investigate the biocompatibility of the new cyanine dye: 3,3'-Di-(4-sulfobutyl)-1,1,1',1'-tetramethyl-di-1H-benz[e]indocarbocyanine (DSS) as a vital dye for intraocular application in an in vivo rat model and to evaluate the effects of this dye on retinal structure and function. METHODS: DSS at a concentration of 0.5% was applied via intravitreal injections to adult Brown Norway rats with BSS serving as a control. Retinal toxicity was assessed 7 days later by means of retinal ganglion cell (RGC) counts, light microscopy, optical coherence tomography (OCT), and electroretinography (ERG). RESULTS: No significant decrease in RGC numbers was observed. No structural changes of the central retina were observed either in vivo (OCT) or under light microscopy. ERGs detected a temporary reduction of retinal function 7 days after injection; this was no longer evident 14 days after injection. CONCLUSIONS: DSS showed good biocompatibility in a well-established experimental in vivo setting and may be usable for intraocular surgery as an alternative to other cyanine dyes. In contrast to indocyanine green, it additionally offers fluorescence in the visual spectrum. Further studies with other animal models are needed before translation into clinical application.

A placebo-controlled crossover trial of creatine in mitochondrial diseases.

To test the efficacy and safety of creatine (Cr) monohydrate in mitochondrial diseases, 16 patients with chronic progressive external ophthalmoplegia or mitochondrial myopathy were randomized in a crossover design to receive double-blind placebo or 20 g Cr/day for 4 weeks. Cr was well tolerated, but there were no significant effects with regard to exercise performance, eye movements, or activities of daily life. The power of this pilot study was limited and future multicenter trials are needed.

Changes in contrast sensitivity induced by defocus and their possible relations to emmetropization in the chicken.

PURPOSE: To test whether the level of contrast adaptation (CA) relates to refractive development in the chicken. (CA refers to a spatial frequency-selective increase of suprathreshold contrast sensitivity after exposure to low-contrast patterns). METHODS: CA was determined in individual chicks by comparing their optomotor gain in response to drifting low-contrast stripe patterns before and after treatment with spectacle lenses. The amount of CA was compared with the loss of contrast predicted from defocus at the tested spatial frequency. The reversion of CA and recovery from deprivation myopia were studied while the retinal image features were controlled by forcing the animals to watch spatially filtered digital video clips. RESULTS: CA was induced by wearing positive and negative lenses for 1.5 hours, both without and with cycloplegia, but was less pronounced in the case of positive lenses when accommodation was intact. The amount of CA at a tested spatial frequency was predicted from the loss of contrast calculated from the modulation transfer function for a defocused optical system. Watching low-pass-filtered video clips induced deprivation myopia and inhibited recovery from it. It also prevented the reversal of CA that was previously induced by deprivation. Both recovery from deprivation myopia and recovery from CA occurred with sharp video clips, although less so than with normal visual exposure. CONCLUSIONS: CA changes with retinal image sharpness and occurs even when accommodation is intact. Because CA correlates with myopia induced by frosted occluders, negative lenses, and low-pass-filtered video clips, and its reversal correlates with recovery from myopia, it is possible that shifts in CA may represent a signal related to refractive error development.

[Physiological functional evaluation of retinal implants in animal models]. / Physiologische Funktionsprüfungen von Retinaimplantaten an Tiermodellen.

Retinal implants can--by electrical stimulation--create visual impressions in people with certain kinds of degenerative retinal diseases (e.g. Retinitis Pigmentosa). Electrically evoked potentials in the retina must be transferred into the visual cortex in an orderly manner, a prerequisite for any kind of form- and movement-perception. In the current developmental stage the difficult investigations are performed in various animal models: isolated retinae of intact chicken and of RCS-rats (a model for Retinitis Pigmentosa), as well as in anesthetised rabbits, pigs and cats with intact retinae. Our investigations show that spatially selective ganglion-cell responses can be recorded following focal electrical stimulation, in healthy and as well in degenerated retinae. Registration of activities in area 17 of the visual cortex demonstrate that electrical retinal stimulation can indeed activate it.

[Subretinal microphotodiode array as replacement for degenerated photoreceptors?]. / Subretinales Mikrophotodioden-Array als Ersatz für degenerierte Photorezeptoren?

A survey is given on the status of developments, concerning a subretinal electronic microphotodiode array that aims at replacing degenerated photoreceptors. Various prototypes have been developed, tested, and implanted in various experimental animals up to 18 months. The fact that electrical responses were recorded from the visual cortex of pigs after electrical stimulation by subretinal electrodes and the fact that responses are also recorded in-vitro in degenerated rat retinae, shows the feasibility of this approach. However, there are a number of open questions concerning the biocompatibility, the long-time stability, and the type of transmitted image to be solved before application in patients can be considered.

[Effects of transcorneal electrical stimulation in patients with Stargardt's disease]. / Transkorneale Elektrostimulation bei Patienten mit Morbus Stargardt.

Stargardt's disease is an autosomal recessive inherited juvenile macular degeneration and at present no acknowledged science-based therapy is available for these patients. Recently, reports have been published on the effectiveness of electrical stimulation in experimental animal models and in patients with neurodegenerative ocular disease, particularly retinitis pigmentosa. This study included 12 patients with Stargardt's disease who were randomized into one of three groups (n = 4) with 0% (sham), 66% or 150% of the individual electrically stimulated phosphene threshold. Outcome measures of the study were safety and efficacy of transcorneal electrical stimulation (TES) with DTL electrodes in subjective and objective parameters of visual function under therapy. In general TES was well tolerated and no adverse or serious events were noted. Neither Ganzfeld, multifocal ERG, OCT nor visual field testing showed statistically significant changes in any group.

[Transcorneal electrostimulation]. / Transkorneale Elektrostimulation.

Stimulation with weak electrical currents as a potential therapy for ophthalmic diseases has been propagated for a long time and encountered mixed acceptance but has recently regained interest due to observations in retinal implant projects. In these projects involving patients with retinitis pigmentosa a neuroprotective effect of weak, even subthreshold, electrical stimulation was found which led to improvement in visual functions even in areas distant from the implant. Results of several animal studies clearly substantiate a neuroprotective effect in degenerative retinal diseases and traumatic optic neuropathies. Studies in patients have so far been published for nonarteritic anterior ischemic and traumatic optic neuropathy, retinal artery occlusion and Stargardt's disease. These studies were mostly small and of short duration so that effects did not reach statistical significance. A controlled, randomized study in patients with retinitis pigmentosa has recently been published where positive tendencies and several statistically significant improvements in visual function were observed in one subgroup. Electrical stimulation further deserves further attention as several companies currently offer devices which should enable patients to self-administer electrical stimulation. This article gives an overview of the scientific background of electrical stimulation and critically assesses data from animal and human studies with focus on retinitis pigmentosa.

[What can blind patients see in daily life with the subretinal Alpha IMS implant? Current overview from the clinical trial in Tübingen]. / Was können blinde Patienten mit dem subretinalen Alpha-IMS-Implantat im Alltag sehen? Aktuelle Übersicht aus der Tübinger klinischen Studie.

The subretinal visual implant is a scientific research approach to restore partial vision in end-stage hereditary retinal diseases by replacing the function of the degenerated photoreceptors by microelectronic chips. In a clinical trial in Tübingen these implants were tested on voluntary blind patients. By using the implants in daily living the patients reported valuable visual information. The subretinal microchip mediates subjectively useful visual information in near as well as in distant vision.

A new DTL-electrode holder for recording of electroretinograms in animals.

PURPOSE: Contact lens electrodes (CLEs) are frequently used to register electroretinograms (ERGs) in small animals such as mice or rats. CLEs are expensive to buy or difficult to be produced individually. In addition, CLE's have been noticed to elicit inconstant results and they carry potential to injure the cornea. Therefore, a new electrode holder was constructed based on the clinically used DTL-electrode and compared to CLEs. MATERIAL AND METHODS: ERGs were recorded with both electrode types in nine healthy Brown-Norway rats under scotopic conditions. For low intensity responses a Naka-Rushton function was fitted and the parameters V(max), k and n were analyzed. The a-wave, b-wave and oscillatory potentials were analyzed for brighter flash intensities (1-60 scot cds/m²). Repeatability was assessed for both electrode types in consecutive measurements. RESULTS: The new electrode holder was faster in setting up than the CLE and showed lower standard deviations. No corneal alterations were observed. Slightly higher amplitudes were recorded in most of the measurements with the new electrode holder (except amplitudes induced by 60 cds/m²). A Bland-Altman test showed good agreement between the DTL holder and the CLE (mean difference 35.2 µV (Holder-CLE)). Pearson's correlation coefficient for test-retest-reliability was r=0.783. CONCLUSIONS: The DTL holder was superior in handling and caused far less corneal problems than the CLE and produced comparable or better electrophysiological results. The minimal production costs and the possibility of adapting the DTL holder to bigger eyes, such as for dogs or rabbits, offers with broader application prospects.