Ferenc B. Sallo

The IS/OS Junction Layer in the Natural History of Type 2 Idiopathic Macular Telangiectasia

PURPOSE To document the progression of a break in the photoreceptor inner segment/outer segment (IS/OS) junction layer and its functional correlates over time in the natural history of type 2 idiopathic macular telangiectasia (type 2 MacTel). METHODS Patients with at least 1 year of follow-up were selected from the MacTel Study. En face images were created by manual segmentation of the IS/OS junctional line in volume scans acquired using a spatial-domain optical coherence tomography retinal imaging unit. Retinal sensitivity thresholds were determined using a retinal microperimeter unit. Aggregate retinal sensitivity loss within IS/OS lesions was calculated. Changes over time in an area of IS/OS defects and retinal sensitivity were analyzed. RESULTS thirty-nine eyes of 23 patients (mean age: 62.3 ± 9.2 years) were analyzed. Mean follow-up time was 1.9 years (range: 1-3 years). Mean IS/OS break area at baseline was 0.575 mm(2) (SE = 0.092, 95% confidence interval [CI]: 0.394-0.756 mm(2)). The cluster-adjusted mean annual progression rate in IS/OS break area was 0.140 mm(2) (SE = 0.040, 95% CI: 0.062-0.218 mm(2), P < 0.001). Mean aggregate retinal sensitivity loss was at baseline 28.56 dB (SE = 5.43, 95% CI: 17.32-39.80 dB, n = 28), a positive correlation with IS/OS lesion area was present (P < 0.001). The mean annual rate of change in aggregate sensitivity loss was 5.14 dB (SE = 1.51, 95% CI: 2.19-8.10 dB, P < 0.001, n = 37), a significant correlation with lesion area increase was found (P = 0.006). CONCLUSIONS Both IS/OS break area and rate of enlargement correlate with aggregate retinal sensitivity loss in type 2 MacTel. En face OCT imaging of the IS/OS layer provides a functionally relevant method for documenting disease progression in type 2 MacTel.

Cone photoreceptor definition on adaptive optics retinal imaging

Aims To quantitatively analyse cone photoreceptor matrices on images captured on an adaptive optics (AO) camera and assess their correlation to well-established parameters in the retinal histology literature. Methods High resolution retinal images were acquired from 10 healthy subjects, aged 20–35 years old, using an AO camera (rtx1, Imagine Eyes, France). Left eye images were captured at 5° of retinal eccentricity, temporal to the fovea for consistency. In three subjects, images were also acquired at 0, 2, 3, 5 and 7° retinal eccentricities. Cone photoreceptor density was calculated following manual and automated counting. Inter-photoreceptor distance was also calculated. Voronoi domain and power spectrum analyses were performed for all images. Results At 5° eccentricity, the cone density (cones/mm2 mean±SD) was 15.3±1.4×103 (automated) and 13.9±1.0×103 (manual) and the mean inter-photoreceptor distance was 8.6±0.4 μm. Cone density decreased and inter-photoreceptor distance increased with increasing retinal eccentricity from 2 to 7°. A regular hexagonal cone photoreceptor mosaic pattern was seen at 2, 3 and 5° of retinal eccentricity. Conclusions Imaging data acquired from the AO camera match cone density, intercone distance and show the known features of cone photoreceptor distribution in the pericentral retina as reported by histology, namely, decreasing density values from 2 to 7° of eccentricity and the hexagonal packing arrangement. This confirms that AO flood imaging provides reliable estimates of pericentral cone photoreceptor distribution in normal subjects.

Functional aspects of drusen regression in Age-Related Macular Degeneration

Aims: To investigate the functional implications of macular soft drusen regression in AMD eyes. Methods: Patients were selected from a large ongoing collection of clinical data at Moorfields Eye Hospital. Phenotyping based on standard colour fundus images was performed according to the system defined by the International Classification for ARM, by certified graders masked to the main aim of the study. Fundus autofluorescence (FA) was recorded using a Heidelberg Retina Angiograph 2. Where drusen regression was confirmed by independent grading, the patient was invited for photopic and scotopic fine matrix mapping (FMM). Phenotype and functional data were analysed for correlations between fundus appearance, autofluorescence and retinal sensitivity. Results: Fundus and FA images of 960 patients were screened, soft drusen regression was detected in 34 cases, and 14 patients agreed to participate in the study, ranging in age from 52 to 84 years (median 72). The mean follow-up period was 5.9 years (range 2.8–14.4 years). FMM showed generalised threshold elevation relative to normal controls both under photopic and scotopic conditions. Scotopic sensitivity loss exceeded photopic loss in all cases. Sensitivity loss over areas with drusen or regressed drusen did not differ significantly from that over non-drusen areas. Conclusion: Macular soft drusen may fade or disappear without detectable ophthalmoscopic, FA or psychophysical signs of local dysfunction. This phenomenon is a potential source of misclassification. The prognosis for cases with true regression of drusen compared with those without needs to be considered in future studies on AMD.

Bruch's membrane changes in transgenic mice overexpressing the human biglycan and apolipoprotein b-100 genes

Age-Related Macular Degeneration (AMD) is characterized by the accumulation of lipid- and protein-rich deposits in Bruchs Membrane (BrM). A consequent decrease in hydraulic conductivity and impairment of transport through BrM may play a central role in the pathogenesis of AMD. The mechanism of deposit formation in AMD had been suggested to show similarities to the formation of atherosclerotic plaques in which the interactions of extracellular matrix proteoglycans with apolipoprotein-B 100 (apoB-100) play an important role. A prime candidate for this interaction is the small leucin-rich proteoglycan biglycan. The aim of our study was to test the effect of the simultaneous overexpression of human apoB-100 and biglycan genes in combination with a high-cholesterol diet on BrM morphology in transgenic mice. Six-weeks-old homozygous apoB-100 or biglycan, hemizygous apoB-100/biglycan transgenic and wild-type C57Bl/6 mice were fed either a standard chow or a diet supplemented with 2% cholesterol for 17 weeks. Animals were sacrificed, serum lipid levels were measured and eyes were processed for transmission electron microscopy (TEM) according to standard protocol. Morphometric analysis of digitally acquired TEM images of BrM showed that in apoB-100 and double transgenic animals fed a high-cholesterol diet, the BrM thickness was significantly increased compared to wild-type animals. Both groups had electron-lucent profiles in clusters, scattered throughout the collagenous layers of BrM, and focal nodules of an amorphous material of intermediate electron-density between the plasma and basement membranes of the retinal pigment epithelium (RPE). BrM thickness in these two groups correlated well with elevated cholesterol levels. Unexpectedly, animals overexpressing biglycan alone showed a marked, diet-independent increase in BrM thickness associated with a layer of a basement membrane-like material in outer BrM. The effects of biglycan overexpression are intriguing and further investigations are needed to elucidate the underlying mechanisms.

The International Classification system and the progression of age-related macular degeneration.

Purpose: To determine whether grading based on the International Classification (IC) for age-related macular degeneration (AMD) allows recognition of change during the progression of the disease. Methods: Stereoscopic color fundus photographs of 50 eyes of 25 patients with AMD and at least 5 years of review were graded in a random and masked fashion for changes over time in the characteristics of drusen, pigmentary changes, and end-stage disease, according to the system defined by the IC for AMD, by two independent graders (F.B.S., I.L.). Fundus images were also analyzed in time sequence for clinical changes by a senior grader (I.L.) and two ophthalmologists (A.C.B., T.P.) without access to the grading forms of the IC grading. Clinical change, as recorded by the IC grading and the individual analysis, were compared. Results: There was 97.8% (κ = 0.70) concordance in identification of change. In four cases, the clinical classification differed from the IC grading: Two cases of drusen and two of end-stage disease grading. Inter-observer agreement for the IC grading was 89.4% for predominant phenotype (κ = 0.84), 89.36–91.49% for presence of choroidal neovascularization (CNV) (κ = 0.79–0.83), 87.23–89.36% for geographic atrophy (GA) (κ = 0.62–0.74) and 55.32% for area covered by drusen (κ = 0.31). Conclusions: Overall, progression from earlier stages of AMD to either of the two forms of advanced AMD were reflected accurately by the IC grading in the vast majority of cases.

Multimodal imaging in type 2 idiopathic macular telangiectasia

Background: Macular telangiectasia Type 2 is a bilateral, progressive potentially blinding retinal disease characterized by both vascular and neurodegenerative signs that have been documented using different imaging techniques. The correlation between macular telangiectasia Type 2 signs from various imaging modalities is unknown. Our aim was to investigate the relationship of various macular telangiectasia Type 2 signs using fundus fluorescein angiography, optical coherence tomography and dual-wavelength autofluorescence images. Methods: Participants were selected from the macular telangiectasia Type 2 Natural History Observation Study, based on a confirmed diagnosis and the availability of images. Signs in fundus fluorescein angiography, dual-wavelength autofluorescence, and optical coherence tomography images were graded according to standardized categories, and agreement among the multimodel imaging was assessed statistically. Results: One hundred and ninety-one eyes of 96 patients were examined. Significant correlations were found between early and late fundus fluorescein angiography (&rgr; = 0.82, P < 0.0001), luteal pigment loss and early/late fundus fluorescein angiography signs (&rgr; = 0.52, P < 0.0001 and &rgr; = 0.62, P < 0.0001, respectively), inner and outer segment break length and pigment loss (Class 1 vs. 2/3, P < 0.0001; Class 2 vs. 3, P = 0.04). Correlation between pigment loss and retinal spaces/atrophic retinal restructuring was fair (&kgr; = 0.25–0.33). Bilateral symmetry was slight to substantial (&kgr; = 0.18–0.62). Conclusion: Our data demonstrate the relative extent of neurodegenerative and vascular signs; it may be useful for designing systems for staging disease severity using multimodal imaging and may also provide clues to the pathogenesis of the disease.

Nigeria Normative Data for Defining Glaucoma in Prevalence Surveys

ABSTRACT Purpose: To determine normative values for defining glaucoma in cross-sectional surveys in Nigerian adults. Methods: Multistage stratified cluster random sampling with probability-proportional-to-size procedures to select a nationally representative sample of 15,027 persons aged ≥40 years in 305 clusters across Nigeria. Systematic sampling of 1 in 7 participants gave 1759 who were examined in detail to construct a normative database. The normative subset was used to determine values for vertical cup/disc ratio (VCDR) and intraocular pressure (IOP) for glaucoma diagnosis according to the International Society of Geographical and Epidemiological Ophthalmology (ISGEO) criteria. Examinations included visual field testing by frequency doubling technology (FDT), Goldmann applanation tonometry, and optic disc image grading by Moorfields Eye Hospital Reading Centre. Results: In the normative dataset, 1057/1759 persons (60.1%) had normal FDTs, and constituted the hypernormal. Of these, 851 had VCDR and 973 had IOP measurements taken in both eyes. For category 1 (structural and functional evidence of glaucoma), the 97.5th percentile VCDR was 0.7. For category 2 (advanced structural damage with unproven visual field loss), the 99.5th percentile VCDR was 0.75. In addition, asymmetry in VCDR was 0.1 difference at the 97.5th percentile and 0.2 difference at the 99.5th percentile. Category 3 criteria were used when the optic disc was not visible and field testing not possible; 99.5th percentile IOP is one criterion (28 mmHg). Conclusion: While these results do not differentiate between open-angle and angle-closure mechanisms, they can be applied to determine the prevalence of glaucoma in Nigeria and sub-Saharan African countries with similar sociodemographic characteristics.

The prevalence of type 2 idiopathic macular telangiectasia in two African populations.

Purpose: Type 2 idiopathic macular telangiectasia (MacTel) is a progressive retinal disease associated with a slow deterioration of visual acuity, starting in the fifth to seventh decades of life. The etiology and pathogenesis of the disease are little known, and no effective therapy is available. We aimed to estimate the prevalence and describe the phenotype of type 2 MacTel in two African populations. Methods: From two population-based cross-sectional surveys conducted nationally in Nigeria and in the Nakuru district of Kenya, patients with fundus features of type 2 MacTel were selected. Diagnosis was based on color fundus images, grading performed according to the MacTel Study protocol and staged using the Gass and Blodi system. Disease phenotype and clinical characteristics of affected participants were assessed. Results: Of 8599 total participants, five showed a phenotype compatible with type 2 MacTel. Prevalence was estimated as 0.06% (95% confidence interval [CI] 0.02–0.21%) in Kenya, 0.06% (95% CI 0.01–0.17%) in Nigeria, and overall at 0.06% (95% CI 0.02–0.14%). Mean age was 62 years (SD 5 years), four of five affected participants were female, and none had a history of diabetes. Median corrected visual acuity was 6/12 in the better eye and 6/69 in the worse eye. Conclusions: The estimated prevalence and phenotype of type 2 MacTel in the African populations examined were similar to those in predominantly white populations. All data published so far are based on the analysis of color fundus images only and are thus likely to underestimate the true prevalence of this disease.

Agreement between Time-Domain and Spectral-Domain Optical Coherence Tomography in the Assessment of Macular Thickness in Patients with Idiopathic Macular Telangiectasia Type 2

Purpose: To estimate the conversion factors to transpose macular thickness measurements on time-domain (TD) to various spectral-domain (SD) optical coherence tomography (OCT) machines in patients with macular telangiectasia type 2a (MacTel). Procedures: Macular scans on TD- and SD-OCT were performed on patients at the same visit. The retinal thickness values in various ETDRS subfields and macular volume were compared between different OCT machines. Results: The macular thickness and volume were significantly greater (p < 0.0001, r = 0.678-0.822) on SD-OCT. The mean differences in macular thickness between TD Stratus and SD-OCT by Spectralis, Cirrus and Topcon were 62, 41 and 20 μm, respectively. The conversion factor of macular thickness from TD-OCT to Spectralis, Cirrus and Topcon were +65, +39 and +25 μm, respectively. Conclusion and Message: The estimates of conversion of macular thickness from TD- to SD-OCT using simple mean differences between machines and those by linear regression were similar suggesting that the former may be used for the longitudinal follow-up of MacTel patients.

Is indocyanine green angiography useful for the diagnosis of macular telangiectasia type 2

Macular telangiectasia (MacTel) type 2 is a bilateral disease of unknown origin exhibiting characteristic changes of the macular deep capillary network and neurosensory retina.1–3 Originally considered a predominantly vascular disorder, the introduction of novel imaging techniques has altered prevailing impressions of its underlying pathophysiology, suggesting a significant role of structural changes to the neurosensory retina. The MacTel study, a major multicenter observational study, attempts to shed light on the natural history of the disease and to identify optimal surrogates of disease progression that could be used as end points in interventional clinical trials. In view of the exploratory nature of the study, various imaging modalities were used at baseline and on annual follow-up visits to investigate their contribution to disease diagnosis and their role in offering clues on disease progression. These modalities included colour fundus imaging (CFI), fundus fluorescein angiography (FFA), autofluorescence imaging (AF), optical coherence tomography (OCT) and indocyanine green angiography (ICGA). All obtained images were sent to the Reading Centre at Moorfields Eye Hospital, UK, where the diagnosis was confirmed. During the MacTel study, it has been established that there are characteristic changes on CFI, AF, FFA and OCT that uniquely identify the disease.4 ,5 The primary aim of this project is to determine whether ICGA is helpful in establishing the diagnosis of MacTel and, therefore, whether its inclusion in the MacTel imaging protocol was justified. The secondary aim was to identify any changes specific to MacTel on ICGA over the course of …