Retinal function in Bothnia dystrophy. An electrophysiological study

Using prolonged dark adaptometry, standard dark adaptation (DA) and prolonged DA full-field electroretinograms (ERGs), we analysed the retinal function in patients with Bothnia dystrophy (BD), a variant of recessive retinitis punctata albescens (RPA). A compromised rod and cone function, a likely dysfunction of the Müller cells, and indications of disturbed neuronal function of the inner retina, were found. With prolonged DA, a gradual increase in retinal sensitivity to light and an improvement of the ERG components occurred. The findings indicate a prolonged synthesis of photopigments, retardation of the visual process in the retinal pigment epithelium (RPE), and a loss of retinal cells, probably starting at a relatively early age in BD.     

Usher's syndrome

Summary Three families with Usher's syndrome were fully investigated. Special attention was paid to heterozygous manifestations of the disease.The affected members of one of these families combined complete deafness with total loss of the vestibular function. In the two others, the audiograms showed the type of partial deafness that is characteristic for Usher's syndrome. Four audiograms had undergone no appreciable alteration after a 10-year interval.Vestibular function was on the whole well preserved in one family, while notable variations in the degree of vestibular involvement were present in another.Stress is laid on the intrafamilial constancy of the ocular disease pattern, and on the discrepancy between the severity of the ocular symptoms, on the one hand, and the degree of auditory and vestibular involvement, on the other.The results of adaptometric, electroretinographic and electro-oculographic examination of the heterozygotes warrant the conclusion that impairment of dark adaptation as well as lowering of the EOG values can be considered as heterozygous manifestations of Usher's syndrome. Changes in the ERG failed to occur. Audiometric examination of the heterozygotes revealed, apart from presbyacusis, normal hearing.Two of the pedigrees include a union between a woman with Usher's syndrome and a man with recessive congenital deafness, which had both yielded normal offspring.This investigation was supported by a grant from the Organisation for Health Research (TNO).     

視網膜色素變性(RP)患者的F-ERG特徵分析

目的對RP患者F-ERG進行檢查,以分析病程和作爲眼肌深層鞏膜移植術術後療效跟踪的客觀對照指標.方法采用常規無創傷視覺電生理描記術,測定暗視F-ERG.結果受檢的210名RP患者的420祗眼中,F-ERG爲"熄滅型"的爲67.9%,能記録到ERP的占19.8%,a-波爲28.3%,c-波僅爲4.0%,能記錄到b-波舆負後電位的分别爲10.7%和7.4%.說明RP患者視網膜對閃光刺激反應的機能已經顯著受損.結論 RP患者的F-ERG有不同程度的特有改變,在眼肌深層鞏膜移植術進行治療後,再復查F-ERG時,則觀察到某些波重現,或原有波的波幅增加和峰潜伏期縮短.     

Bilateral spontaneous anterior lens dislocation in a retinitis pigmentosa patient

PURPOSE: To report a case of bilateral spontaneous anterior lens dislocation associated with retinitis pigmentosa (RP). METHODS: A 45-year-old male with RP presented with elevated intraocular pressure (IOP) in the right eye and was treated with laser iridotomy (LI). After LI, complete crystalline lens dislocation into the anterior chamber occurred. Surgical intervention, including anterior vitrectomy, intracapsular cataract extraction (ICCE), and IOL scleral fixation was performed. Two years later, the same episode occurred in his left eye and a similar treatment was done. RESULTS: Surgery was successful in both eyes. CONCLUSIONS: This is the first report of bilateral spontaneous anterior lens dislocation in a RP patient.     

Genetic testing for retinal dystrophies and dysfunctions: benefits, dilemmas and solutions

Human retinal dystrophies have unparalleled genetic and clinical diversity and are currently linked to more than 185 genetic loci. Genotyping is a crucial exercise, as human gene-specific clinical trials to study photoreceptor rescue are on their way. Testing confirms the diagnosis at the molecular level and allows for a more precise prognosis of the possible future clinical evolution. As treatments are gene-specific and the 'window of opportunity' is time-sensitive; accurate, rapid and cost-effective genetic testing will play an ever-increasing crucial role. The gold standard is sequencing but is fraught with excessive costs, time, manpower issues and finding non-pathogenic variants. Therefore, no centre offers testing of all currently 132 known genes. Several new micro-array technologies have emerged recently, that offer rapid, cost-effective and accurate genotyping. The new disease chips from Asper Ophthalmics (for Stargardt dystrophy, Leber congenital amaurosis [LCA], Usher syndromes and retinitis pigmentosa) offer an excellent first pass opportunity. All known mutations are placed on the chip and in 4 h a patient's DNA is screened. Identification rates (identifying at least one disease-associated mutation) are currently approximately 70% (Stargardt), approximately 60-70% (LCA) and approximately 45% (Usher syndrome subtype 1). This may be combined with genotype-phenotype correlations that suggest the causal gene from the clinical appearance (e.g. preserved para-arteriolar retinal pigment epithelium suggests the involvement of the CRB1 gene in LCA). As approximately 50% of the retinal dystrophy genes still await discovery, these technologies will improve dramatically as additional novel mutations are added. Genetic testing will then become standard practice to complement the ophthalmic evaluation.     

Altered expression and interaction of adherens junction proteins in the developing OLM of the Rho(-/-) mouse

Retinitis Pigmentosa (RP) represents a major cause of progressive retinal disease worldwide and comprises a heterogeneous group of inherited diseases that are characterised by primary degeneration of rod photoreceptors and secondary degeneration of cone photoreceptors in the retina. The outer limiting membrane (OLM) which allows for the interaction of photoreceptors with surrounding photoreceptors and Müller cells is compromised in many degenerative retinal diseases. Using indirect immunostaining of retinal cryosections from C-129 Wild Type (WT) and C-129 Rho(-/-) mice, we have determined levels of expression of the adherens junction associated proteins ZO-1, beta-catenin and p120-catenin at the OLM from newborn and 1, 2, 3, 4 and 5-week old animals. We have also used immunoprecipitation analysis to determine changes in the association of E-cadherin with ZO-1, beta-catenin and p120-catenin and the association of alpha-catenin with ZO-1 and beta-catenin at these time points in WT and Rho(-/-) mice. We have found that ZO-1 expression at the OLM is present in WT and Rho(-/-) mice after 2weeks, but that levels of expression at the OLM decrease after this time point in the Rho(-/-) mice. beta-catenin expression in the Rho(-/-) mice became compromised at the OLM after 3 weeks, showing a distinct change in staining pattern after 4 weeks and no staining at the OLM after 5 weeks. Moreover, we have shown that p120-catenin expression is not evident at the OLM of the Rho(-/-) mice at the 4 or 5 week time point. To complement this data, we have performed immunoprecipitation analysis on neural retinal lysates from WT and Rho(-/-) mice and herein report fluctuations in the association of E-cadherin with ZO-1, and beta-catenin, while showing that the interaction of E-cadherin with p120-catenin is not established in the retina of C-129 WT and Rho(-/-) mice until 4 weeks after birth and remains un-changed up to and including 5 weeks after birth. Meanwhile, we report that the association of alpha-catenin with ZO-1 is decreased in retinas of the Rho(-/-) from newborn animals up to and including 5 weeks after birth. We have also shown that the association of alpha-catenin and beta-catenin is not well established in WT and Rho(-/-) mice until at least 5 weeks after birth. We hypothesize that these retinal changes at the OLM may contribute significantly to the pathogenesis of retinal degenerations and may represent a unique therapeutic target for intervention in conditions involving rapid photoreceptor cell death.     

Do we need separate screening strategies for cytomegalovirus retinitis in different underlying immunosuppressed states? A retrospective study from Western India

Purpose:The aim of this study was to describe the clinical features, course, and clinical outcomes of eyes with cytomegalovirus (CMV) retinitis in immunosuppressed patients of different etiologies.Methods:This was a retrospective observational study from a single ophthalmic tertiary care center. The patients included referrals from the nodal cancer center and the local human immunodeficiency virus (HIV) treatment clinic. Demographics, history, visual acuity, ocular features, treatment protocol, and final visual outcome of patients who were diagnosed with CMV retinitis in the period of five years from 2014 to 2019 were studied.Results:CMV retinitis was diagnosed in 25 eyes of 14 patients. Age of the patients ranged from 11–54 years. Ten (71.43%) patients were male and four (29.57%) were female. Eight of them had acute lymphoblastic leukemia (ALL), four were suffering from HIV infection and one patient each had lymphoma and history of a kidney transplant. The treatment for CMV retinitis ranged from two to sixty weeks depending on disease activity and systemic condition. Three of the patients were on maintenance therapy for ALL at the time of reactivation.Conclusion:Duration of treatment for CMV retinitis in patients of ALL was longer as compared to the other etiologies, and in recurrences, it needed to be continued till the completion of maintenance therapy for ALL. It is prudent to advise regular ophthalmic screening of all immunocompromised patients, as they are at a high risk of developing CMV retinitis. Patients of ALL, especially while on maintenance therapy, should be monitored for possible development or reactivation of CMV retinitis.     

Mathematical and computational models of the retina in health,development and disease

The retina confers upon us the gift of vision, enabling us to perceive the world in a manner unparalleled by any other tissue. Experimental and clinical studies have provided great insight into the physiology and biochemistry of the retina; however, there are questions which cannot be answered using these methods alone. Mathematical and computational techniques can provide complementary insight into this inherently complex and nonlinear system. They allow us to characterise and predict the behaviour of the retina, as well as to test hypotheses which are experimentally intractable. In this review, we survey some of the key theoretical models of the retina in the healthy, developmental and diseased states. The main insights derived from each of these modelling studies are highlighted, as are model predictions which have yet to be tested, and data which need to be gathered to inform future modelling work. Possible directions for future research are also discussed.Whilst the present modelling studies have achieved great success in unravelling the workings of the retina, they have yet to achieve their full potential. For this to happen, greater involvement with the modelling community is required, and stronger collaborations forged between experimentalists, clinicians and theoreticians. It is hoped that, in addition to bringing the fruits of current modelling studies to the attention of the ophthalmological community, this review will encourage many such future collaborations.     

Compound subretinal prostheses with extra-ocular parts designed for human trials: successful long-term implantation in pigs

Background Subretinal implants aim to replace photoreceptor function in patients suffering from degenerative retinal disease like retinitis pigmentosa by topically applying electrical stimuli in the subretinal space. This study—as a last step before upcoming human trials—explored a newly developed surgical technique for permanent implantation of complex subretinal implants with extra-ocular parts. Methods The implant consisted of a microphotodiode array (MPDA) with 1,550 electrodes and a 4×4 array of gold electrodes for direct electrical stimulation; both were mounted onto a polyimide foil for transscleral placement into the subretinal space. The foil carried connection lanes to a silicone cable that was implanted under the skin and led to a stimulator box in the animal’s neck. Surgery was performed in 11 domestic pigs. Improved vitreo-retinal surgical technique consisted of a 180° peripheral retinotomy and use of diathermy to penetrate the choroid in order to avoid choroidal haemorrhage. Subretinal forceps were used to place the implant safely onto the retinal pigment epithelium before the retina was flattened, peripheral laser photocoagulation was applied and the eye was filled with silicon oil. The implant was stabilized by a scleral fixation patch, use of a metal clamp with bone screws on the animal’s skull and a tissue ring under the animal’s skin in the neck. Behaviour was observed in the freely moving animals after direct subretinal electrical stimulation and funduscopy, optical coherence tomography, fluorescein angiography and histology were performed. Results All implants were successfully placed subretinally. In three animals a proliferative vitreo-retinopathy was observed after approximately 2 weeks. Otherwise, funduscopy and OCT demonstrated complete retinal attachment and FA showed no retinal vascular abnormalities over and around the implant. The animals showed clear behavioural reactions to electrical stimulation over the whole examination period. Histological examination failed to show any voltage-induced alteration in the cellular architecture of the retina overlying the stimulation electrodes. Conclusions This study demonstrates the feasibility of a new surgical procedure for highly safe and controlled implantation of complex subretinal devices with extra-ocular parts. The new implant design proved to be safely implantable in free-moving pigs for an observation period of 4 weeks.