Chai Lin Chou

Progressive Constriction of the Hyperautofluorescent Ring in Retinitis Pigmentosa

PURPOSE To evaluate the constriction of the hyperautofluorescent ring over time in patients with retinitis pigmentosa (RP). DESIGN Prospective study. METHODS Fourteen eyes of 14 RP patients with a hyperautofluorescent ring were studied. Ring constriction was evaluated by measurements of its external and internal boundaries along the vertical and horizontal axes at baseline and at 12-, 24-, 36-, and 48-month follow-ups. Repeat fundus autofluorescence was obtained at 12, 24, 36, and 48 months in 13, 7, 5, and 1 eyes respectively. Spectral-domain optical coherence tomography (SD-OCT) images were obtained on 8 eyes and the horizontal extent of the inner segment/outer segment (IS/OS) junction was measured. SD-OCT was repeated at 12 and 24 months in 6 and 4 eyes respectively. RESULTS The external boundaries of the ring were identified along the horizontal axis in 12 eyes and along the vertical axis in 13. Internal boundaries were identified in 7 eyes. Constriction was demonstrated in all patients except 1 who demonstrated minimal expansion of the internal boundary along the horizontal axis. SD-OCT measurements showed a decrease in the IS/OS junction length. CONCLUSION Progressive constriction of the hyperautofluorescent ring and a concordant decrease in IS/OS junction length were observed over time.

Cellular Origin of Fundus Autofluorescence in Patients and Mice with Defective NR2E3 Gene

Aim: To characterise new clinical features in a family with enhanced S-cone syndrome (ESCS) and investigate the pathogenesis of these clinical features in the homozygous Nr2e3rd7 (rd7) mutant mice. Methods: Four patients from an affected family were included for genotypic and phenotypic study. Eye tissues from rd7 mice were used to detect a possible relationship between macrophages and autofluorescent material by immunohistochemistry (IHC) staining. Results: Homozygous mutation in R311Q in NR2E3 was detected in this family. Colour photographs revealed that white dots do not correlate to hyperautofluorescent spots seen in autofluorescence imaging of the macula. OCT showed rosette-like lesions similar to those found in rd7 mice histology sections. From IHC analysis, we observed that F4/80 (a pan macrophage marker) and autofluorescence were colocalised to the same cells within the retina rosettes. Conclusions: The retinal structure of a young ESCS patient with homozygous R311Q mutation in the NR2E3 gene is similar to that seen in the rd7 mice. The macrophages were found to contain autofluorescent materials in the retinal rosettes of rd7 mice. These data are consistent with macrophage infiltration contributing to the hyperautofluorescent spots found in our patients.

A Novel Mutation and Phenotypes in Phosphodiesterase 6 Deficiency

PURPOSE To develop a systematic approach for the molecular diagnosis of retinitis pigmentosa (RP) and to report new genotype-phenotype correlations for phosphodiesterase 6 (PDE6)-based RP mutations. DESIGN Clinical and molecular studies on a retrospective case series. METHODS We screened 40 unrelated RP patients with an autosomal recessive RP microarray. Individuals with RP caused by PDE6 deficiency underwent genetic segregation and phenotype analysis. RESULTS A disease-associated allele was identified in 32% of patients. Two probands (5%) had PDE6 mutations. The first proband was a compound heterozygote for known R102C and N216S alleles in PDE6A (MIM#180071). Pedigree analysis determined that the N216S variant was benign and direct sequencing discovered a novel, S303C allele. The second proband had a homozygous D600N mutation in the PDE6B gene (MIM#180072). Visual acuities of PDE6-deficient patients ranged from 20/40 to 20/200. Clinical studies showed unusual vitreomacular traction, cystoid macular edema, macular atrophy, and ring hyperfluorescence in PDE6-deficient patients. Such extensive vitreoretinal degeneration is not characteristic of photoreceptor-specific enzyme deficiencies. CONCLUSION High-throughput deoxyribonucleic acid microarray chips can be used in combination with clinical imaging to precisely characterize patients with RP. Identifying the precise mutation in RP may become the standard of care as gene therapy emerges.

Phenotype-genotype correlations in autosomal dominant retinitis pigmentosa caused by RHO, D190N

Purpose: To phenotype a family with RHO (Asp190Asn or D190N) dominantly inherited retinitis pigmentosa (RP) and to describe an approach to surveying affected families. Methods: Four patients from a family with a history of autosomal dominant RP had complete clinical examinations and underwent full-field electroretinography (ERG), fundus autofluorescence (AF) imaging, and genetic testing. One patient had microperimetry (MP) mapping. Results: The patients’ ages ranged from 6 years to 47 years. The proband, the father, had fundoscopic findings typical of RP. A small hyperfluorescent ring centered at the fovea was apparent on AF. MP showed preservation of central 7 degrees of visual field within this ring. The three children were all asymptomatic with visual acuity of 20/15 in each eye. One child had mild retinal pigment epithelium migration on fundoscopy; the other two children had normal fundoscopic examinations. Two children showed increased parafoveal AF. In the two affected children, average ERG b-wave implicit times were delayed in scotopic conditions, and maximal ERG tracings had abnormal waveforms. Genetic analysis confirmed that two of three asymptomatic children carried the D190N allele. Conclusions: Patients with RHO (D190N) autosomal dominant retinitis pigmentosa (adRP) can show classic signs of RP on fundus examination and may be able to maintain good central visual acuity into adulthood. By combining clinical examination with AF imaging and electrophysiology, it is possible to offer presymptomatic clinical evaluation to families with this RP.

Origin of fundus hyperautofluorescent spots and their role in retinal degeneration in a mouse model of Goldmann-Favre syndrome.

SUMMARY Goldmann-Favre syndrome, also known as enhanced S-cone syndrome, is an inherited retinal degeneration disease in which a gain of photoreceptor cell types results in retinal dysplasia and degeneration. Although microglia have been implicated in the pathogenesis of many neurodegenerative diseases, the fundamental role of these cells in this disease is unknown. In the current study, sequential analyses suggest that microglia are recruited and appear after outer nuclear layer folding. By crossing rd7 mice (a model for hereditary retinal degeneration owing to Nr2e3 mutation) with mice carrying the macrophage Fas-induced apoptosis (Mafia) transgene, we generated double-mutant mice and studied the role of the resident retinal microglia. Microglial cells in these double-mutant mice express enhanced green fluorescent protein (EGFP) and a suicide gene that can trigger Fas-mediated apoptosis via systemic treatment with AP20187 (FK506 dimerizer). We demonstrated that more than 80% of the EGFP+ cells in retinas from rd7/rd7;Tg/Tg mice express Iba-1 (a microglial marker), and resident microglia are still present in the retina because AP20187 does not cross the blood-brain barrier. Hence, only circulating bone marrow (BM)-derived microglia are depleted. Depletion of circulating BM-derived microglia accelerates retinal degeneration in rd7 mice. An increased number of autofluorescent (AF) spots is a consequence of resident microglia proliferation, which in turn establishes an inflammatory cytokine milieu via the upregulation of IL-1β, IL-6 and TNFα expression. This inflammation is likely to accelerate retinal degeneration. This study not only identifies inflammation as a crucial step in the pathogenesis of retinal degeneration, but also highlights the involvement of specific cytokine genes that could serve as future treatment targets in retinal degenerations.

Electronegative electroretinogram associated with topiramate toxicity and vitelliform maculopathy

Topiramate is known to cause ocular side effects such as refractive changes and angle closure. We describe a patient with an electronegative electroretinogram (ERG) which may have been related to topiramate use. Electronegative ERG’s have been associated with other drugs in humans as well as topiramate use in rabbits. However, this would be the first suggestion of causality in humans.

Non-vascular vision loss in pseudoxanthoma elasticum.

Pseudoxanthoma elasticum patients with angioid streaks are well-known to have acute vision loss due to choroidal bleeding. However, chronic vision loss due to macular atrophy is less well characterized. We describe a patient with sub-acute vision loss in one eye due to loss of macular retinal pigment epithelium function. Autofluorescence and pattern electroretinogram were useful adjuncts to help diagnose the source of her vision loss.

Fundus autofluorescence, optical coherence tomography, and electroretinogram findings in choroidal sclerosis.

Purpose: The purpose of this study was to describe fundus autofluorescence (FAF), optical coherence tomography, and electroretinogram findings in choroidal sclerosis. Methods: This is a retrospective case series. Eight eyes of four patients with choroidal sclerosis were evaluated with FAF, optical coherence tomography, and electroretinogram testing. Results: In all eight eyes, FAF imaging showed hypofluorescent placoid lesions corresponding to areas of chorioretinal atrophy seen on stereo biomicroscopy. Prominent hyperfluorescent linear markings underlying regions of atrophic disease were observed in all eyes, likely representative of normal choroidal vessel autofluorescence. In two eyes, FAF showed punctate hypofluorescent lesions in the fovea that were not visualized on biomicroscopy. In one eye, FAF identified a central island of preserved retinal pigment epithelium that was not realized on ophthalmoscopic examination. Optical coherence imaging was significant for loss of choroidal fine tubular structures, retinal pigment epithelium, and outer nuclear layer in regions of chorioretinal atrophy. Full-field electroretinogram testing showed generalized rod-cone dysfunction in all patients with a lower B- to A-wave ratio in two patients. Conclusion: Fundus autofluorescence and optical coherence tomography are nonin-vasive diagnostic adjuncts that can aid in the diagnosis of choroidal sclerosis. Fundus autofluorescence may be a more sensitive marker of disease extent and progression than clinical examination alone. Electroretinogram testing can result in an electronegative maximal response.

Rapid and Noninvasive Imaging of Retinal Ganglion Cells in Live Mouse Models of Glaucoma

PurposeWe report a noninvasive method for the monitoring of retinal ganglion cell (RGC) survival in live mice utilizing standard fluorescence microscopy.ProceduresTransgenic mice expressing cyan fluorescent protein (CFP) under the regulation of an RGC-specific promoter Thy1 were used in this study.ResultsWe established that Thy1-CFP expression is a quantitative reflection of the number of surviving RGCs, the fluorescence emission is stable for at least a year and that the loss of fluorescence correlates directly to glaucomatous damage. In high pressure glaucoma model, the peripheral retina is preferentially affected.ConclusionsOur live-imaging technique allows for the longitudinal assessment of RGC survival from the same animal. Noninvasive monitoring of neuronal cell death and survival is a powerful technique that would allow investigators to validate new potential glaucoma therapy based on neuroprotection.

Benign panretinal uniform radial linear-shaped flecks

Our case illustrates a new presentation of benign retina flecks with line-shaped and panretinal, uniform and radial distribution. Compared with previous reports of fleck retina disorders, our case does not show increased autofluorescence deposits, no delay in dark adaptation, neither significant macular nor nasal disc involvement.1–5 A 51-year-old woman with consanguinous parents was referred for evaluation of bilateral retinal lesions. On examination, best-corrected visual acuity was 6/7.5 with moderate hyperopic correction in both eyes. Visual fields were normal. The anterior segments were unremarkable. Fundus examination revealed multiple yellow-creamy discrete round and mostly linear-shaped flecks scattered throughout the retina in both eyes with relative sparing of the fovea. The flecks distributed in a radial pattern centred around the posterior pole (Fig. 1) and were located well posterior to the retinal vasculature. The discs, maculae and retinal vessels appeared unremarkable. Fundus autofluorescence imaging (cSLO, Heidelberg Retina Angiograph 2; Heidelberg Engineering, Dossenheim, Germany) did not show hyper- or hypofluorescent flecks (Fig. 2a), but multiple discrete round lesions above the retinal pigment epithelium were apparent in the infrared imaging (Fig. 2b). Corresponding spectral optical coherence tomography (Optivue SD-OCT, Fremont, CA, and Cirrus, Carl Zeiss Meditec Inc., Dublin, CA, USA) revealed that these lesions span across the retinal pigment epithelium complex and photoreceptor inner–outer segment junction layers, without involving the choroid (Figs 3,​,4).4). To assess retinal function, ISCEV (International Society for Clinical Electrophysiology of Vision) standardized full-field electroretinography were performed following 20 min and overnight dark adaptation. The electroretinography traces showed that both scotopic and photopic responses were symmetric and within normal limits (Fig. 5). Figure 1 A wide-angle montage of the right (a) and left (b) fundi demonstrates multiple yellow-cream discrete flecks widely distributed in the equator and far periphery of the retina. A few flecks are centred in the posterior pole. Figure 2 (a) Fundus autofluorescence of the right eye showing absence of hyper- or hypofluorescent flecks; (b) infrared imaging of the right eye showing multiple discrete round lesions in the para-foveal area. Figure 3 Spectral-domain OCT of the right eye (Optivue). (a) Multiple flecks in the posterior pole (yellow and green arrows represent OCT scans on (b) and (c), respectively, and white square represents longitudinal SLO scan on (d); (b) normal appearing macula; ... Figure 4 Spectral-domain OCT of the right eye (Cirrus Zeiss). (a) Multiple flecks in the posterior pole (yellow and green arrows represent OCT scans on (b) and (c), respectively, and white square represents longitudinal scan on (d); (b) normal appearing macula; ... Figure 5 Representative photopic and scotopic electroretinogram recordings compared with normal control after 20 min in the right eye and overnight dark adaptation in the left eye. Full-field electroretinographies were performed with Ganzfeld stimulation on this ... In contrast to previous reports,1–3 the retinal lesions in our patient appeared to be significantly smaller, more of a linear shape(s) and uniform in size(s). These lesions were distributed ubiquitously in the equator and mid and far periphery of the fundus. The centrally located flecks in the posterior pole appeared sparse, small, round and dot-like. Unfortunately, the patient’s family members were not available for eye examination. In contrast to the classic findings reported by Audo et al.,4 where the retinal flecks demonstrated increased autofluorescence, the fundus imaging of our patient did not show any specks of abnormal autofluorescence. Infrared imaging (Fig. 2b) and optical coherence tomography (Figs 3,​,4)4) revealed numerous subretinal dot-like lesions, which correspond to those observed in funduscopy. Different types of flecked retinal disorders such as dominant radial drusen, fleck retina of Kandori,1 fundus albipunctatus, retinitis punctata albescens, fundus flavimaculatus and vitamin A deficiency5 may be considered as differential diagnosis. However, the lack of drusen on the nasal side of the optic disc, extension of flecks to peripheral retina, absence of high-density autofluorescent deposits on scanning laser ophthalmoscopy imaging and presence of intact EFEMP1 gene sequence made the diagnosis of dominant radial drusen unlikely. Moreover, normal scotopic electroretinography response excludes fundus albipunctatus. In addition to clinical assessment, electrophysiology testing was essential to exclude fundus albipunctatus and autofluorescent imaging can be a helpful tool to characterize hyper-autofluorescent deposits observed in different variants of benign fleck retina. The normal electrophysiology and visual field testing, in addition to good visual acuity and lack of symptoms justify the condition as benign. Hence, our case represents a different presentation of benign fleck retina,4 with linear-shaped flecks and a panretinal, uniform and radial distribution.