A Proposal for Classification of Retinal Degeneration in Spinocerebellar Ataxia Type 7.

The aim of this study is to propose a classification system for the spinocerebellar ataxia type 7 retinal degeneration (SCA7-RD). Twenty patients with molecularly confirmed SCA7 underwent slit lamp examination, fundus photography, and optical coherence tomography (Spectralis®). Scale for the Assessment and Rating of Ataxia (SARA) and International Cooperative Ataxia Rating Scale (ICARS) were applied, and age, sex, age at symptom onset, and number of CAG expansions were recorded. After analyzing the ophthalmological findings in each participant, a panel of retinal disease experts created a qualitative classification system for SCA7-RD comprising four stages. We assessed the correlations of retinal degeneration severity with SARA and ICARS scores, number of CAG repeats in ATXN7 allele, and age at symptom onset. We graded retinal degeneration as stage 1 in nine participants, as stage 2 in five, and as stage 3 in six. No differences in age and visual symptoms duration were found between groups. SARA and ICARS scores correlated with the severity of SCA7-RD on the classification system (p = 0.024 and p = 0.014, respectively). After adjusting for disease duration, retinal disease stage association with SARA and ICARS scores remained significant (ANCOVA, p < 0.05). The classification system for SCA7-RD was able to characterize different disease stages representing the landmarks in the cone-rod dystrophy natural history. Neurodegeneration appears to occur in parallel in the cerebellum and in the visual pathway. We conclude that retinal degeneration in SCA7 is a potential biomarker of the neurological phenotype severity.

[Degenerative lesions of the peripheral retina]. / Lésions dégénératives de la périphérie rétinienne.

Degenerative lesions of the peripheral retina are present from teenage years onwards and increase with age. These abnormabilities are frequent, some of them being benign while others predispose to retinal tears and detachment. In the latter case, the lesions are rhegmatogenous and may justify prophylactic treatment by laser photocoagulation. We distinguish congenital lesions of the peripheral retina and intraretinal, chorioretinal and vitreoretinal degenerations. The holes and tears observed in 2% of the population consist of round atrophic holes, "horseshoe" tears, oral dialyses and giant tears.

[Experimental models of human retinal degenerations: genetic models].

Existing approaches in experimental animal modeling of human retinal degenerations, genetic models in particular, that allow to study the pathogenesis are reviewed.

Inner and outer retinal mechanisms engaged by epiretinal stimulation in normal and rd mice.

Retinal prosthetic devices are being developed to bypass degenerated retinal photoreceptors by directly activating retinal neurons with electrical stimulation. However, the retinal circuitry that is activated by epiretinal stimulation is not well characterized. Whole-cell patch clamp recordings were obtained from ganglion cells in normal and rd mice using flat-mount and retinal slice preparations. A stimulating electrode was positioned along the ganglion cell side of the preparation at different distances from the stimulated tissue. Pulses of cathodic current evoked action potentials in ganglion cells and less frequently evoked sustained inward currents that appeared synaptic in origin. Sustained currents reversed around E(Cl) and were inhibited by blockade of α-amino-3-hydroxyl-5-methyl-4-isoxazole-proprionate (AMPA)-type glutamate receptors with 2,3-dihydroxy-6-nitro-sulfamoyl-benzo(f)-quinoxaline-2,3-dione (NBQX), γ aminobutyric acid a/c (GABA(a/c)) receptors with picrotoxinin, or glycine receptors with strychnine. This suggests that epiretinal stimulation activates glutamate release from bipolar cell terminals, which in turn evokes release of GABA and glycine from amacrine cells. Synaptic current thresholds were lower in ON ganglion cells than OFF cells, but the modest difference did not attain statistical significance. Synaptic currents were rarely observed in rd mice lacking photoreceptors compared to normal retina. In addition, confocal calcium imaging experiments in normal mice retina slices revealed that epiretinal stimulation evoked calcium increases in the outer plexiform layer. These results imply a contribution from photoreceptor inputs to the synaptic currents observed in ganglion cells. The paucity of synaptic responses in rd mice retina slices suggests that it is better to target retinal ganglion cells directly rather than to attempt to engage the inner retinal circuitry.

Analysis of retinal flecks in fundus flavimaculatus using high-definition spectral-domain optical coherence tomography.

PURPOSE: To assess morphologic changes associated with retinal flecks in fundus flavimaculatus using spectral-domain optical coherence tomography (SD-OCT). DESIGN: Observational case series. METHODS: Simultaneous recordings of SD-OCT and confocal scanning laser ophthalmoscope (cSLO) fundus autofluorescence images were obtained in fundus flavimaculatus patients. Morphologic aspects of the retinal flecks were analyzed and classified. RESULTS: Thirty-one eyes of 17 consecutive patients (8 male, 9 female; mean age 47.9 +/- 17.1 years) were included for analysis. SD-OCT revealed 5 distinct types of lesions. Group A lesions were limited to the outer segment (OS) of the photoreceptors, the retinal pigment epithelium (RPE) interdigitations, and the RPE/Bruch membrane complex. Group B showed a protrusion of the hyper-reflective material through the interface of inner segment (IS)/OS of the photoreceptors up to the external limiting membrane. A further protrusion of the hyper-reflective material into the outer nuclear layer was seen in group C lesions. Group D lesions were characterized by an accumulation of the hyper-reflective material limited to the outer nuclear layer. Type E lesions can be described as drusen-like retinal pigment detachments. No significant correlation between the different types of flecks and visual acuity was observed (P > .05). CONCLUSIONS: SD-OCT allows one to distinguish at least 5 different types of lesions associated with retinal flecks in fundus flavimaculatus. The ability to characterize the different types of flecks and to analyze the photoreceptor layers surrounding these lesions suggests that SD-OCT might have a potential clinical role in the evaluation and follow-up of the structural changes in fundus flavimaculatus.

[Development of disease-specific patient groups within Pro Retina]. / Entwicklung diagnosespezifischer Gruppen in der Pro Retina.

The formation, development and external impact of the following eight disease-specific patient groups with rare forms of retinal degeneration (RRD) within the patient organization Pro Retina are described: Gyrate Atrophy, Bardet-Biedl Syndrome (BBS), Adult Refsum's Disease, Usher Syndrome, Rod-Cone Dystrophy, Leber's Congenital Amaurosis, Choroideremia and Stargardt Disease/juvenile macular degeneration. Within the project sponsored by the German Ministry of Health (BMG) approaches of patient self-help for an adequate organization and interaction with the professional medical care system were supported, analyzed and documented. In syndromic RRD a relatively high proportion of patients are organized in patient groups (Refsum's disease 25%, BBS 14%, Usher Syndrome 8%). Patients with syndromic RRD are more highly motivated to contribute to self-help work than patients with non-syndromic RRD. At the same time, these patients are more dependent on the support from their relatives and on technical aids. The following tendencies in the development of RRD groups were observed: increasing focus on one patient organization (PRO RETINA Deutschland, Self-Help Organisation of People with Retinal Degenerations) all RRD groups in Pro Retina grew; RRD groups became increasingly independent within Pro Retina; external activities of the groups showed considerable increase. Stable work relationships with scientific and medical care institutions have been established. The example of RRD demonstrates how rare and isolated patients receive basic coping support by self-help groups, how they deal with resources in a collective way and how they can interact with the medical care system.

Neural regeneration and cell replacement: a view from the eye.

Neuronal degenerations in the retina are leading causes of blindness. Like most other areas of the CNS, the neurons of the mammalian retina are not replaced following degeneration. However, in nonmammalian vertebrates, endogenous repair processes restore neurons very efficiently, even after complete loss of the retina. We describe the phenomenon of retinal regeneration in nonmammalian vertebrates and attempts made in recent years to stimulate similar regenerative processes in the mammalian retina. In addition, we review the various strategies employed to replace lost neurons in the retina and the recent use of stem cell technologies to address problems of retinal repair.

[Patient participation in medical care, taking rare retinal degenerations as examples]. / Patientenselbsthilfe und seltene Erkrankungen. Mitgestaltung der Versorgungsrealität am Beispiel seltener Netzhautdegenerationen.

Eight rare retinal degenerations were chosen to exemplify self-organisation and involvement of patient self-help groups in medical care. They were studied and supported in their development on the following levels: disease-specific groups (level 1), patient organisations (level 2), umbrella organisation (level 3). Databases of defined needs and concerns ("Themenspeicher") of disease-specific patient groups and of patient organisations with respect to care, research and patient networking were established. Priority concerns were implemented in the following areas: specialised medical care; quality assurance; quality management; expert panel with international dialogue of patients and physicians (including consensus statement on treatment recommendations); glossary internet portal; criteria for patient-oriented disease descriptions; structured documentation of patient experiences; patient management of health care records (paper bound and electronic health records). Apart from disease- specific approaches, interdisciplinary disease approaches were also applied, e.g. by contributing to the establishment of the German Alliance for Rare Diseases (ACHSE). This umbrella organisation has substantially improved chances for cooperation and patient advocacy. Patient participation was promoted by a federal regulation in 2004 ("Patientenbeteiligungsverordnung"). The example of rare retinal degenerations demonstrates the advantage of strong patient and umbrella organisations. Further development of qualified self-help resources is required for patient participation in rare diseases.

Calpain activity in retinal degeneration.

Retinal degenerations such as retinitis pigmentosa (RP) or glaucoma are a major cause of blindness in humans. Understanding the mechanisms underlying the various types of retinal degeneration is a pre-requisite for the development of rational therapies for these diseases. Activation of the calcium dependent protease, calpain, has been suggested to play an important role in cell death in various neuronal tissues including the retina. Improved detection and analysis of calpain activity during degenerative processes is likely to expand the list of pathological conditions with calpain involvement. We give a short overview of the methods available for the detection of calpain activity, and briefly discuss properties of calpain inhibitors. We then discuss the role of calpains in different cell death mechanisms and review existing work on retinal degeneration and the possible involvement of calpains therein. The implication of calpains in retinal cell death raises the possibility to use calpain inhibitors to prevent or delay retinal degeneration.

The spectrum of retinal phenotypes caused by mutations in the ABCA4 gene.

BACKGROUND: The majority of studies on the retina-specific ATP-binding cassette transporter (ABCA4) gene have focussed on molecular genetic analysis; comparatively few studies have described the clinical aspects of ABCA4-associated retinal disorders. In this study, we demonstrate the spectrum of retinal dystrophies associated with ABCA4 gene mutations. METHODS: Nine well-documented patients representing distinct phenotypes in the continuum of ABCA4-related disorders were selected. All patients received an extensive ophthalmologic evaluation, including kinetic perimetry, fluorescein angiography, and electroretinography (ERG). Mutation analysis had been performed previously with the genotyping microarray (ABCR400 chip) and/or single-strand conformation polymorphism analysis in combination with direct DNA sequencing. RESULTS: In all patients, at least one pathologic ABCA4 mutation was identified. Patient 10034 represented the mild end of the phenotypic spectrum, demonstrating exudative age-related macular degeneration (AMD). Patient 24481 received the diagnosis of late-onset fundus flavimaculatus (FFM), patient 15168 demonstrated the typical FFM phenotype, and patient 19504 had autosomal recessive Stargardt disease (STGD1). Patients 11302 and 7608 exhibited progression from FFM/STGD1 to cone-rod dystrophy (CRD). A more typical CRD phenotype was found in patients 15680 and 12608. Finally, the most severe ABCA4-associated phenotype was retinitis pigmentosa (RP) in patient 11366. This phenotype was characterised by extensive atrophy with almost complete loss of peripheral and central retinal functions. CONCLUSION: We describe nine patients during different stages of disease progression; together, these patients form a continuum of ABCA4-associated phenotypes. Besides characteristic disorders such as FFM/STGD1, CRD and RP, intermediate phenotypes may be encountered. Moreover, as the disease progresses, marked differences may be observed between initially comparable phenotypes. In contrast, distinctly different phenotypes may converge to a similar final stage, characterised by extensive chorioretinal atrophy and very low visual functions. The identified ABCA4 mutations in most, but not all, patients were compatible with the resulting phenotypes, as predicted by the genotype-phenotype model for ABCA4-associated disorders. With the advent of therapeutic options, recognition by the general ophthalmologist of the various retinal phenotypes associated with ABCA4 mutations is becoming increasingly important.

Best's vitelliform macular dystrophy with pseudohypopyon: an optical coherence tomography study.

PURPOSE: To report optical coherence tomography (OCT) changes in Best's vitelliform macular dystrophy (BVMD) with pseudohypopyon. DESIGN: Observational case report. METHODS: Both eyes of a patient with BVMD showing pseudohypopyon were examined with OCT. RESULTS: OCT demonstrated the presence of serous retinal elevation with normal appearing retinal pigment epithelium (RPE) superiorly, and broadening of the outer-retina-choroid-complex signal under retinal elevation, inferiorly. CONCLUSIONS: OCT findings in our study suggest the accumulation of material under neurosensory retina in BVMD with pseudohypopyon.

[Hereditary retinochoroidal dystrophies. Part 2: differential diagnosis]. / Hereditäre Netzhaut-Aderhaut-DystrophienTeil 2: Differenzialdiagnose.

A generally accepted classification for inherited retinochoroidal dystrophies does not exist. The names given to certain disorders are either based on ophthalmoscopic findings, or on histologic, electrophysiologic and genetic findings. Future research on the molecular genetic background will result in better definition of clinical entities. The purpose of this project is to outline a practical approach to inherited retinochoroidal dystrophies. For this reason, disorders with similar clinical symptoms are grouped together. Generalized retinochoroidal dystrophies affecting all retinal areas can be distinguished from regional dystrophies. Generalized dystrophies can be subdivided into those with peripheral onset, usually associated with initial rod function loss (night blindness, peripheral field loss: e.g. retinitis pigmentosa, choroideremia) and those with central onset associated with cone function loss (visual acuity loss, central scotoma, color vision deficits: e.g. cone or cone-rod dystrophies). Regionally limited dystrophies include the multitude of macular dystrophies and the autosomal dominant vitreoretinochoroidopathy, which remains limited to the periphery. It is important for a differential diagnosis to exclude involvement of other organ systems in syndromic disorders. Stationary inherited retinal dysfunction (e.g. monochromatism, congenital stationary night blindness) and other inherited or acquired diseases have to be excluded as well. Guidelines for differential diagnosis are presented.

Full-field ERG responses recorded with skin electrodes in paediatric patients with retinal dystrophy.

PURPOSE: Assess ERG responses recorded with skin electrodes in children with retinal dystrophies. METHOD: ERG responses were recorded using skin electrodes in 17 healthy children and 43 paediatric patients with retinal dystrophy. Subjects were aged 4-14 years. ERG responses were recorded to full-field stimuli similar to those recommended in the ISCEV standard. The type of retinal dystrophy was classified on the basis of standard clinical criteria and the ERG responses were compared with those of the age-matched controls. RESULTS: ERG responses were abnormal in every patient. The specific type of ERG abnormality was also consistent with the clinical findings in the majority of patients. Rod responses were abnormal in every patient with a rod-cone dystrophy and cone responses were also abnormal in the majority of patients. Those patients with cone dystrophy or rod monochromatism had normal or near normal rod responses but sub-normal or absent cone responses. Patients with CSNB or XLRS had a sub-normal b-wave but normal amplitude a-wave. CONCLUSION: ERGs can be recorded successfully with skin electrodes in paediatric patientsand responses can aid the diagnosis of the type of retinal dystrophy.

Progress toward understanding the genetic and biochemical mechanisms of inherited photoreceptor degenerations.

More than 80 genes associated with human photoreceptor degenerations have been identified. Attention must now turn toward defining the mechanisms that lead to photoreceptor death, which occurs years to decades after the birth of the cells. Consequently, this review focuses on topics that offer insights into such mechanisms, including the one-hit or constant risk model of photoreceptor death; topological patterns of photoreceptor degeneration; mutations in ubiquitously expressed splicing factor genes associated only with photoreceptor degeneration; disorders of the retinal pigment epithelium; modifier genes; and global gene expression analysis of the retina, which will greatly increase our understanding of the downstream events that occur in response to a mutation.

[Macular dystrophies]. / Les dystrophies maculaires.

Macular dystrophies are a group of hereditary disorders of the macula occurring in children or young adults. The most frequent in France will be presented in detail: Best disease, Stargardt macular dystrophy, cone dystrophy, X-linked retinoschisis, pattern dystrophy, and malattia leventinese. Molecular biology studies have now mapped and identified the genes involved in these macular dystrophies. Analysis of the features of fundus examination will lead to further examinations such as fluorescein angiography, indocyanine green angiography, optical coherent tomography, electroretinography, or electrooculography, in order to confirm the diagnosis. We will also present the differential diagnosis of each of these macular dystrophies.

[Simplified electroretinography protocol and diagnosis of retinal dystrophies in children]. / Protocole simplifié d'électrorétinographie et diagnostic des dystrophies rétiniennes de l'enfant.

PURPOSE: To report results of a simplified electroretinogram in children. PATIENTS: 124 children under 6 years of age with nystagmus, blindness, neurological disease, cone rod dystrophy in the family, or abnormal fundus appearance were examined. METHOD: The electroretinogram was recorded by corneal electrodes in an awake state without sedation. A light-emitting orange diode stimulator was used. Stimulation was performed subsequently after 3 minutes of light adaptation and after 8 minutes of darkness. If the electroretinogram was abnormal, a second recording was done a few weeks later using the same method. In some cases, the children were re-examined, and a ganzfeld stimulation ERG was recorded. RESULTS AND DISCUSSION: This method allowed a reliable diagnosis of photoreceptor dystrophy: Leber's congenital amaurosis with or without rare metabolic diseases, X link pigmentary retinopathy or retinal dystrophy with general disease in children. It helped to differentiate isolated retinal pigment changes with normal electroretinogram from functional retinal impairment and rod-cone dystrophy from other retinal dystrophies.

Rhodopsin mutations as the cause of retinal degeneration. Classification of degeneration phenotypes in the model system Drosophila melanogaster.

Insight into the molecular basis of inherited photoreceptor cell degeneration has been rapidly evolving during the last decade. The Drosophila Rh1 rhodopsin gene was the first gene shown to cause retinal degeneration when mutated. Many more degeneration-causing mutations in genes encoding rhodopsin and other photoreceptor proteins have been isolated since then in both, Drosophila and humans. To date some 70 mutations of the Drosophila Rh1 gene have been isolated, most of them have been characterized at the molecular level, and more than 60% of them cause retinal degeneration. This review lists the known Rh1 mutations that cause retinal degeneration up to April 1998, gives an overview on the ultrastructural and biochemical correlates of photoreceptor cell degeneration, and suggests a system for the classification of degeneration-causing Rh1 mutations.

[Pattern dystrophies and intrafamilial phenotypic variation]. / Pattern dystrophies et variation phenotypique intrafamiliale.

BACKGROUND: Transmitted in an autosomal dominant fashion, the pattern dystrophies involve the retinal pigment epithelium and the external macular retina and are usually divided into four different entities. However, a progression from one form to another is possible, various forms may coexist in the same patient and a combination of different entities may be present in the same family. CASE REPORTS: Two families (4 cases) are described, in which a butterfly dystrophy coexist with a vitelliform dystrophy or with a central atrophy. Whereas the vitelliform dystrophy is usually characterised by a unique centromacular lesion, a case of multiple lesions is described. The possible association with a neovascular membrane is also presented. CONCLUSION: The coexistence of various forms of pattern dystrophies in a same family suggests a variable expression of a same genetic disorder. The presence of a centromacular atrophy in one patient demonstrates also that the spectrum of the disease is not limited to the four classic entities.

A new classification of the retinoschises.

BACKGROUND: Two classifications of retinoschisis were published in the 1960s. A marked expansion of our knowledge of the diseases that give rise to retinoschisis indicates the need for an updated classification. METHODS: The new classification is based on the authors' clinical experience, an extensive review of the literature, and a survey of 20 vitreoretinal specialists. RESULTS: There are three types of retinoschisis: degenerative, hereditary, and secondary. Degenerative retinoschisis is very common and has been published extensively. In addition to the well known X-linked hereditary retinoschisis, there are less common pedigrees with autosomal recessive or autosomal dominant patterns. There are at least 18 ocular diseases that may show varying degrees of secondary retinoschisis. CONCLUSION: The many types of retinoschisis are divided into these major categories. The multiplicity of types is emphasized by the plural form of the term: "the retinoschises."