Atypical retinopathy in ataxia with vitamin E deficiency: report of a sibship.

Typical retinitis pigmentosa (RP) may not be the only retinal phenotype encountered in ataxia with vitamin E deficiency (AVED). The following short case series describes a novel form of retinopathy in AVED. We describe two patients with AVED belonging to the same consanguineous sibship. Both presented an unusual retinopathy consisting of scattered, multifocal, nummular, hyperautofluorescent atrophic retinal patches. The retinopathy remained stable under vitamin E supplementation. We hypothesize these changes to be the result of arrested AVED-related RP following early supplementation with α-tocopherol acetate.

A unique case of bilateral nanophthalmos and pigmentary retinal abnormality with unilateral angle closure glaucoma and optic disc pit.

BACKGROUND: Microophthalmos or 'dwarf eye' is characterized by an axial length 2 standard deviation less than age-matched controls. It is classified into nanophthalmos, relative anterior microphthalmos, and posterior microphthalmos based on the anterior segment: posterior segment ratio. Nanophthalmos can occur in association with optic disc drusen, foveoschisis, and retinitis pigmentosa, as an autosomal recessive syndrome linked to mutations in the MFRP gene. We report a case of bilateral nanophthalmos and pigmentary retinopathy with angle closure glaucoma and optic disc pit in one eye. We believe this to be the first case presenting with optic disc pit in association with nanophthalmos. CASE PRESENTATION: A 56-year-old female presented with bilateral small eyes, high hypermetropia, shallow anterior chamber depth, increased lens thickness, mid-peripheral retinal flecks, and macular edema. She also had high intraocular pressure in the right eye, with a disc cupping of 0.9 with an Optic disc pit. The macular edema in the right eye was found to occur in association with the Optic disc pit, whereas, in the left eye, it was associated with intra-retinal hemorrhages and diagnosed as macular branch retinal vein occlusion secondary to hypertension. She was started on anti-glaucoma medications in both eyes and planned for Anti-VEGF injection in the left eye. CONCLUSION: This case report is unique as it reports an association of Nanophthalmos with Optic Disc pit, with an associated angle closure glaucoma in the same eye, an association which has never been previously reported in the literature.

Association of retinitis pigmentosa and advanced keratoconus in siblings.

Objective. The aim of the article was to present the rare association of retinitis pigmentosa and bilateral keratoconus in two brothers, one of whom developed corneal hydrops bilaterally, within a short period of time. Methods. A 29-year-old man presented to our service with corneal hydrops in the right eye, complaining of ocular pain and photophobia. He had a history of retinitis pigmentosa, having been diagnosed as an infant. He also had a younger brother carrying the same diagnosis. Slit lamp examination revealed bilateral keratoconus with corneal hydrops in the right eye, posterior subcapsular cataract, macular atrophy and the characteristic retinal signs of retinitis pigmentosa. The patient's brother was also examined, with the same findings being noted, apart from the corneal hydrops. We documented the changes using a slit lamp biomicroscope, a fundus camera, a corneal topography, Anterior Segment Optical Coherence Tomography and visual field testing. Right hydrops regressed in one month after hyperosmolar 5% sodium chloride treatment. However, 4 weeks later, the patient presented with the same corneal findings in the left eye. The same treatment was prescribed for the left eye. Results. Corneal hydrops regressed in both eyes with remaining paracentral corneal scars. However, no other treatment for keratoconus was suitable in the case of this patient. Discussion: Retinitis pigmentosa is currently not amenable to any form of treatment, from vitamin supplementation, medical therapy, gene transfer-based therapy, stem cell-based therapy to retinal implantation. However, molecular genetics may someday provide new therapeutic prospects, that could modify the course of RP. Conclusions. The association of retinitis pigmentosa with keratoconus is a fairly rare finding, worth taking into consideration. Also, presentation with keratoconus in such an advanced state is uncommon and, in our case, it was presumably due to the patient's reduced visual function since childhood, secondary to retinitis pigmentosa, that has prevented him from perceiving any visual modifications caused by keratoconus.

Retinitis pigmentosa-associated cystoid macular oedema: pathogenesis and avenues of intervention.

Hereditary retinal diseases are now the leading cause of blindness certification in the working age population (age 16-64 years) in England and Wales, of which retinitis pigmentosa (RP) is the most common disorder. RP may be complicated by cystoid macular oedema (CMO), causing a reduction of central vision. The underlying pathogenesis of RP-associated CMO (RP-CMO) remains uncertain, however, several mechanisms have been proposed, including: (1) breakdown of the blood-retinal barrier, (2) failure (or dysfunction) of the pumping mechanism in the retinal pigment epithelial, (3) Müller cell oedema and dysfunction, (4) antiretinal antibodies and (5) vitreous traction. There are limited data on efficacy of treatments for RP-CMO. Treatments attempted to date include oral and topical carbonic anhydrase inhibitors, oral, topical, intravitreal and periocular steroids, topical non-steroidal anti-inflammatory medications, photocoagulation, vitrectomy with internal limiting membrane peel, oral lutein and intravitreal antivascular endothelial growth factor injections. This review summarises the evidence supporting these treatment modalities. Successful management of RP-CMO should aim to improve both quality and quantity of vision in the short term and may also slow central vision loss over time.

[Retinal and Cortical Activation by Electrical Stimulation with Retina Implants]. / Retinale und kortikale Aktivierung durch elektrische Stimulation mit Netzhautimplantaten.

In Germany, about 30,000 to 40,000 people suffer from retinitis pigmentosa (RP), which ultimately results in blindness. The only aid to blind RP patients are retinal implants: These have been under development for several years and have now been approved as a medical product. Retinal implants produce visual perceptions in response to electrical stimulation of the degenerated retina and are useful in the everyday life of blind people. However, the currently achievable quality of vision is such that people with a retinal implant are still legally blind. The visual quality that can be achieved with epi- and subretinal implants depends not only on patient-specific factors such as individual history and status of retinal degeneration, but especially on the interface between implant and retina and the quality of the achievable neuronal activation. Biophysical approaches to functional improvements of the implants are founded on the physiology of the retina (cell density, intraretinal interconnections), are based on technical optimisation of the interface (electrode materials, size and density), and exploit the stimulation protocols with which visual information is fed into the degenerated retina (time courses of electrical stimuli, spatiotemporal stimulation pattern). Optimisation of stimulation parameters can be supported by a detailed analysis of cortical responses, with appropriate electrophysiological and optical methods. This article looks at both the physiological and biophysical fundamentals of electrical retinal stimulation, as well as the resulting retinal and cortical activation.

[Clinical Results after Implantation of Epiretinal Visual Prostheses]. / Klinische Ergebnisse epiretinaler Sehprothesen.

Epiretinal visual prostheses have already been implanted in blind retinitis pigmentosa (RP) patients. Here we report on clinical experience with the Argus® II device and the EPIRET 3 device, on the basis of data from patients operated in Germany. Twenty-eight patients were implanted with the Argus II device and followed for up to three years. EPIRET 3 was implanted in six patients for a period of four weeks. With Argus II, an improvement in visual performance was achieved in the majority of cases, as demonstrated by improved localisation of a light spot and a better perception of moving targets. Mobility and self-confidence improved. The main complications were conjunctival erosion due to the combined extra- and intraocular concept of the device. Among the 28 implanted systems, two needed to be removed because complications refractive to treatment. In contrast, EPIRET 3 is a fully intraocular epiretinal system. During a four week implantation, period thresholds were recorded and exhibited high variability between subjects. However, patients were able to recognise simple patterns. Epiretinal implants for electrical stimulation of the retina should be considered to treat advanced photoreceptor degeneration, and thus to restore basic visual functions at an acceptable rate of complications.

Towards an assistive peripheral visual prosthesis for long-term treatment of retinitis pigmentosa: evaluating mobility performance in immersive simulations.

OBJECTIVE: The prospective efficacy of a future peripheral retinal prosthesis complementing residual vision to raise mobility performance in non-end stage retinitis pigmentosa (RP) was evaluated using simulated prosthetic vision (SPV). APPROACH: Normally sighted volunteers were fitted with a wide-angle head-mounted display and carried out mobility tasks in photorealistic virtual pedestrian scenarios. Circumvention of low-lying obstacles, path following, and navigating around static and moving pedestrians were performed either with central simulated residual vision of 10° alone or enhanced by assistive SPV in the lower and lateral peripheral visual field (VF). Three layouts of assistive vision corresponding to hypothetical electrode array layouts were compared, emphasizing higher visual acuity, a wider visual angle, or eccentricity-dependent acuity across an intermediate angle. Movement speed, task time, distance walked and collisions with the environment were analysed as performance measures. MAIN RESULTS: Circumvention of low-lying obstacles was improved with all tested configurations of assistive SPV. Higher-acuity assistive vision allowed for greatest improvement in walking speeds-14% above that of plain residual vision, while only wide-angle and eccentricity-dependent vision significantly reduced the number of collisions-both by 21%. Navigating around pedestrians, there were significant reductions in collisions with static pedestrians by 33% and task time by 7.7% with the higher-acuity layout. Following a path, higher-acuity assistive vision increased walking speed by 9%, and decreased collisions with stationary cars by 18%. SIGNIFICANCE: The ability of assistive peripheral prosthetic vision to improve mobility performance in persons with constricted VFs has been demonstrated. In a prospective peripheral visual prosthesis, electrode array designs need to be carefully tailored to the scope of tasks in which a device aims to assist. We posit that maximum benefit might come from application alongside existing visual aids, to further raise life quality of persons living through the prolonged early stages of RP.

Photoactivation-induced instability of rhodopsin mutants T4K and T17M in rod outer segments underlies retinal degeneration in X. laevis transgenic models of retinitis pigmentosa.

Retinitis pigmentosa (RP) is an inherited neurodegenerative disease involving progressive vision loss, and is often linked to mutations in the rhodopsin gene. Mutations that abolish N-terminal glycosylation of rhodopsin (T4K and T17M) cause sector RP in which the inferior retina preferentially degenerates, possibly due to greater light exposure of this region. Transgenic animal models expressing rhodopsin glycosylation mutants also exhibit light exacerbated retinal degeneration (RD). In this study, we used transgenic Xenopus laevis to investigate the pathogenic mechanism connecting light exposure and RD in photoreceptors expressing T4K or T17M rhodopsin. We demonstrate that increasing the thermal stability of these rhodopsins via a novel disulfide bond resulted in significantly less RD. Furthermore, T4K or T17M rhodopsins that were constitutively inactive (due to lack of the chromophore-binding site or dietary deprivation of the chromophore precursor vitamin A) induced less toxicity. In contrast, variants in the active conformation accumulated in the ER and caused RD even in the absence of light. In vitro, T4K and T17M rhodopsins showed reduced ability to regenerate pigment after light exposure. Finally, although multiple amino acid substitutions of T4 abolished glycosylation at N2 but were not toxic, similar substitutions of T17 were not tolerated, suggesting that the carbohydrate moiety at N15 is critical for cell viability. Our results identify a novel pathogenic mechanism in which the glycosylation-deficient rhodopsins are destabilized by light activation. These results have important implications for proposed RP therapies, such as vitamin A supplementation, which may be ineffective or even detrimental for certain RP genotypes.

Frequency and amplitude modulation have different effects on the percepts elicited by retinal stimulation.

PURPOSE: In an effort to restore functional form vision, epiretinal prostheses that elicit percepts by directly stimulating remaining retinal circuitry were implanted in human subjects with advanced retinitis pigmentosa RP). In this study, manipulating pulse train frequency and amplitude had different effects on the size and brightness of phosphene appearance. METHODS: Experiments were performed on a single subject with severe RP (implanted with a 16-channel epiretinal prosthesis in 2004) on nine individual electrodes. Psychophysical techniques were used to measure both the brightness and size of phosphenes when the biphasic pulse train was varied by either modulating the current amplitude (with constant frequency) or the stimulating frequency (with constant current amplitude). RESULTS: Increasing stimulation frequency always increased brightness, while having a smaller effect on the size of elicited phosphenes. In contrast, increasing stimulation amplitude generally increased both the size and brightness of phosphenes. These experimental findings can be explained by using a simple computational model based on previous psychophysical work and the expected spatial spread of current from a disc electrode. CONCLUSIONS: Given that amplitude and frequency have separable effects on percept size, these findings suggest that frequency modulation improves the encoding of a wide range of brightness levels without a loss of spatial resolution. Future retinal prosthesis designs could benefit from having the flexibility to manipulate pulse train amplitude and frequency independently (clinicaltrials.gov number, NCT00279500).

A neuroprosthesis for restoring sight.

Macular degeneration (MD) and retinitis pigmentosa (RP), two diseases that cause degeneration of retinal photoreceptor cells, are the leading causes of blindness in the United States. Anatomical studies have shown that other retinal neuronal cells (bipolar cells, ganglion cells) are preserved in these diseases and they are capable of eliciting visual percepts when electrically stimulated. We describe the design of a prototype 16-electrode retinal prosthesis, and the physiological and clinical results on six blind patients with RP who had the device implanted. The US Department of Energy artificial retina program is described. The goal of the program is construction of a 1000-electrode retinal neuroprosthesis with the potential of enabling blind patients to read large print and ambulate with ease.

Retinal prostheses for the blind.

INTRODUCTION: Using artificial means to treat extreme vision impairment has come closer to reality during the past few decades. The goal of this research has been to create an implantable medical device that provides useful vision for those patients who are left with no alternatives. Analogous to the cochlear implants for some forms of hearing loss, these devices could restore useful vision by converting visual information into patterns of electrical stimulation that excite the remaining viable inner retinal neurons in patients with retinitis pigmentosa or age-related macular degeneration. METHODS: Data for this review were selected through a comprehensive literature search. RESULTS: Advances in microtechnology have facilitated the development of a variety of prostheses that can be implanted in the visual cortex, around the optic nerve, or in the eye. Some of these approaches have shown the promise of providing useful visual input to patients with visual impairments. CONCLUSION: While the development of various retinal prostheses have shown promise in limited clinical trials, there are distinct advantages and disadvantages for each type of prosthesis. This review will focus primarily on the Epiretinal Intraocular Retinal Prosthesis, studied by our group, but will also briefly review other modalities: the subretinal prosthesis, cortical prosthesis, and optic nerve prosthesis.

Perceptual thresholds and electrode impedance in three retinal prosthesis subjects.

Three test subjects blind from retinitis pigmentosa were implanted with retinal prostheses as part of a FDA-approved clinical trial. The implant consisted of an extraocular unit that contained electronics for wireless data, power, and generation of stimulus current, and an intraocular unit that consisted of 16 platinum stimulating electrodes arranged in a 4 x 4 pattern within a silicone rubber substrate. The array was held to the retina by a small tack. The stimulator was connected to the array by a multiwire cable and was controlled by a computer based external system that allowed precise control over each electrode. Perception thresholds and electrode impedance were obtained on each electrode from the subjects over several months of testing. The electrode distance from the retina was determined from optical coherence tomography imaging of the array and retina. Across all subjects, average thresholds ranged from 24-702 microA (1-ms pulse). The data show that proximity to the retina played a role in determining the threshold and impedance, but only for electrodes that were greater than 0.5 mm from the retina.

Creating a meaningful visual perception in blind volunteers by optic nerve stimulation.

A blind volunteer, suffering from retinitis pigmentosa, has been chronically implanted with an optic nerve visual prosthesis. Vision rehabilitation with this volunteer has concentrated on the development of a stimulation strategy according to which video camera images are converted into stimulation pulses. The aim is to convey as much information as possible about the visual scene within the limits of the device's capabilities. Pattern recognition tasks were used to assess the effectiveness of the stimulation strategy. The results demonstrate how even a relatively basic algorithm can efficiently convey useful information regarding the visual scene. By increasing the number of phosphenes used in the algorithm, better performance is observed but a longer training period is required. After a learning period, the volunteer achieved a pattern recognition score of 85% at 54 s on average per pattern. After nine evaluation sessions, when using a stimulation strategy exploiting all available phosphenes, no saturation effect has yet been observed.

Treatable forms of retinitis pigmentosa associated with systemic neurological disorders.

In this chapter; we have described the role of nutritional supplements or selective dietary restriction (or both) on the maintenance and function of the retina and nervous system in some diseases. Oral vitamin A therapy has proven to be effective in the treatment of the common forms of retinitis pigmentosa. Bassen-Kornzweig disease can be treated with vitamin A and vitamin E and, in some cases, with vitamin K. Vitamin E therapy for Friedreich-like ataxia associated with retinitis pigmentosa has been shown to be effective in the short term. Classic Refsum's disease responds to a low phytol-low phytanic acid diet. Undoubtedly, future research will bring more insight into the biochemical pathways responsible for other diseases and, it is hoped, aid in developing treatments for additional retinal degenerations associated with systemic neurological disease.

Artificial vision.

Outer retinal degenerations such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD) lead to blindness because of photoreceptor degeneration. To test whether controlled electrical stimulation of the remaining retinal neurons could provide form vision, we electrically stimulated the inner retinal surface with micro-electrodes inserted through the sclera/eye wall of 14 of these patients (12 RP and 2 AMD). This procedure was performed in the operating room under local anaesthesia and all responses were recorded via a video camera mounted on the surgical microscope. Electrical stimulation of the inner retinal surface elicited visual perception of a spot of light (phosphene) in all subjects. This perception was retinotopically correct in 13 of 14 patients. In a resolution test in a subject with no light perception, the patient could resolve phosphenes at 1.75 degrees centre-to-centre distance (i.e. visual acuity compatible with mobility; Snellen visual acuity of 4/200).

[Clinical and cellular studies in a patient with Cockayne syndrome]. / Un caso di sindrome di Cockayne: caratteristiche cliniche e cellulari.

Hypersensitivity to the lethal effect of ultraviolet light (UV) and other DNA-damaging agents has been observed in cells from patients affected by Cockayne syndrome, suggesting that this syndrome is deficient in the capability to repair damage in cellular DNA. We report a case showing the main clinical features of Cockayne syndrome in which the clinical and cellular photosensitivity described as typical for Cockayne syndrome is not present. These cytological results suggest that there is considerable clinical and cellular heterogeneity in Cockayne syndrome and that cellular sensitivity to UV might not be as essential for the diagnosis of Cockayne syndrome as previously thought.

Retinitis pigmentosa associated with glaucoma--clinical analysis.

A clinical analysis of Retinitis Pigmentosa (RP) was made in 2,789 eyes of 1,400 patients seen over a 5 year period (1983-1987), 64 eyes of 32 cases (2.3%) of RP associated with glaucoma were investigated. Of these 32 cases, the angle closure glaucoma was much more than the open angle glaucoma (30/2). More than half of the 32 cases were without cupping of disk, 5 cases did not have the glaucomatous damage to disk in spite of persistent elevated intraocular pressure for 0.5-5 yrs under the maximum medical therapy. 31 cases (97%) had subnormal blood pressure compared with the normal blood pressure value in different age groups. Histopathologic changes of the trabecular meshwork (TM) of 14 eyes showed a little bit more pigment cells in the TM than normal subjects, no typical features that would obstruct the outflow channels.

[Maculopathy in typical retinitis pigmentosa apropos of 33 cases]. / La maculopathie dans la rétinopathie pigmentaire typique. A propos de 33 cas.

The authors studied 33 maculopathies in 54 patients affected by typic retinitis pigmentosa: atrophic macular degeneration 31 cases (49%); cystoïd macular oedema: 1 case (3%) and macular retraction syndrome: 1 case (3%). These results are confronted with those of the literature. Two therapeutical trials based on pathogenical hypothesis were conducted. The patient with cystoïd macular oedema was treated by Hyperbar oxygenotherapy, basing one of selves on the theory ischemia. Six other patients with atrophic foveolopathies were treated by the cyclophosphamide, according to the autoimmune theory. In the first trial, the result was positive. In the second one, the results did not permit any available conclusion.

Computed tomography in oculocraniosomatic disease (Kearns-Sayre syndrome).

Computed tomography (CT) in patients with oculocraniosomatic disease (OCSD) or Kearns-Sayre syndrome has not been previously reported to the authors' knowledge. CT scans were performed in 6 children and 3 adults with OCSD. Abnormalities in children included: intracranial calcifications (4 patients); white matter disease (3 patients); cerebellar hypoplasia (1 patient); and scattered areas of decreased density in the cerebellar hemispheres, mesencephalon, and thalamus (1 patient). CT scans were normal in all adults. OCSD should be considered in the differential diagnosis in patients with intracranial calcification and white matter disease.

Gelastic epilepsy.

A case of retinitis pigmentosa with laughing epilepsy is described. Stereotyped repetitive episodes of limb movement, rigidity, and cackling laughter responding to diazepam are recorded. One episode is presented as gelastic status epilepticus and the clinical and EEG features are reported. Features of gelastic epilepsy are discussed and briefly compared with other laughing disorders. A short history of the condition is accompanied by a relevant review of the literature. The possible importance of hypothalamic lesions in laughing epilepsy is discussed and the absence of consistent EEG findings is noted.