Macular telangiectasia Type 2 is a bilateral, progressive, potentially blinding retinal disease characterized by both vascular and neurodegenerative signs. Both the area of the break in the ellipsoid ...zone seen in "en face" optical coherence tomographic (OCT) images and microperimetric focal retinal sensitivity loss have been proposed as potential measures of progression in macular telangiectasia. The authors aimed to assess the characteristics and interrelationship of these structural and functional disease markers from the data collected in a phase one clinical trial of ciliary neurotrophic factor in macular telangiectasia.
Orthogonal topographic (en face) maps of the ellipsoid zone were generated from Heidelberg Spectralis OCT volume scans (15 × 10° area, 30-μm B-scan intervals) or Zeiss Cirrus HD-OCT 4000 512 × 128 cube scans. Mesopic microperimetry was performed on CenterVue MAIA perimeters, using a Goldmann III stimulus in a custom test grid. Structural and functional data were analyzed by two methods: by calculating aggregate loss and by simple thresholding. The alignment quality of structural and functional data was also evaluated.
Overall, the break area showed a good correlation with aggregate sensitivity loss (ρ = 0.834, P < 0.0001, 95% confidence interval 0.716-0.906) but also with the number of test points below a threshold value (e.g., <20 dB: ρ = 0.843, P < 0.0001, 95% confidence interval 0.755-0.902). Significant misalignment of the MAIA test grid was apparent in 13/48 visits of 7/14 eyes.
The authors found a good correlation between ellipsoid zone break area and function loss. En face OCT mapping of the ellipsoid zone appears to demonstrate structural change before mesopic microperimetry can detect a focal loss of retinal sensitivity. Thresholding offers a quick alternative to calculating aggregate sensitivity loss.
To document the evolution and functional and structural significance of parafoveal rings of high-density fundus autofluorescence (AF) in patients with retinitis pigmentosa and preserved visual ...acuity.
Fifty-two patients with nonsyndromic retinitis pigmentosa or Usher syndrome, who had a parafoveal ring of high-density AF and a visual acuity of 20/30 or better, were ascertained. All had international standard full-field electroretinography and pattern electroretinography. Autofluorescence imaging was repeated in 30 patients after periods of up to 9.3 years. Of the 52 patients, 35 underwent optical coherence tomography.
Progressive constriction of the ring was detected in 17 patients. Ring radius reduced by up to 40% at a mean rate of between 0.8% and 15.8% per year. In 1 patient, a small ring was replaced by irregular AF; visual acuity deteriorated over the same period. There was a high correspondence between the lateral extent of the preserved optical coherence tomography inner segment/outer segment band and the diameter of the ring along the same optical coherence tomographic scan plane (slope, 0.9; r = 0.97; P < 0.005; n = 35) and between preserved inner segment/outer segment lamina and the pattern electroretinography P50 measure of macular function (R = 0.72; P < 0.005; n = 34).
Rings of increased AF surround areas of preserved outer retina and preserved photopic function. Serial fundus AF may provide prognostic indicators for preservation of central acuity and potentially assist in the identification and evaluation of patients suitable for treatment aimed at preservation of remaining function.
To review the evidence that exists concerning the pathogenesis of lesions in late age-related macular disease (AMD).
Review of the literature.
A review of both experimental evidence and clinical ...observations that address these problems.
There is good evidence that choroidal neovascularization (CNV) is due to a change in the balance of growth factors derived from the retinal pigment epithelial basolateral plasma membrane domain (retinal pigment epithelium). Retinal angiomatous proliferation may also have a similar pathogenesis involving the apical domain. Detachment of the retinal pigment epithelium is likely to be a consequence of increased resistance of the Bruch membrane to water flow due to deposition of lipids. Geographic atrophy is preceded by accumulation of autofluorescent material in the retinal pigment epithelium and possible causal relationships between the two have been demonstrated.
There is increasing understanding concerning the sequence of events that lead to those lesions causing loss of central vision in AMD. Therapeutic approaches that address the underlying mechanisms are more likely to succeed than current treatment options. Such an approach has already been initiated in the management of choroidal neovascularization.
To assess the relationships of drusen, pigment, and focally increased autofluorescence (FIAF) and the reticular pattern of hypoautofluorescence, to distinguish the combined photographic and AF ...characteristics of early, atrophic, and high-risk fellow eyes in AMD.
In a retrospective interinstitutional clinical study, AF and color photograph pairs of 221 eyes were examined: 166 eyes of 83 patients with bilateral large, soft drusen, with and without geographic atrophy (GA), and 55 fellow eyes of 55 patients with unilateral choroidal neovascularization (CNV). Forty-two eyes (one eye from each of 42 patients with early or atrophic AMD) were divided into four groups: 14 with drusen only, 9 with drusen and pigment abnormalities, 11 fellow eyes of patients with unilateral GA, and 8 eyes of patients with bilateral GA (acronyms for the groups: D-D, D-Pig, D-GA and GA-GA, respectively). The 55 fellow eyes of patients with CNV were divided into three groups: 19 eyes with no FIAF (CNV-0), 16 with FIAF without reticular AF (CNV-1), and 20 eyes with reticular AF and/or pseudodrusen (CNV-R). Image pairs of eyes with FIAF were registered, and drusen, pigment, and FIAF were segmented using automated background leveling and thresholding. All 221 eyes were surveyed for reticular AF and reticular pseudodrusen. The main outcome measures were (1) the fraction and relative probability of FIAF colocalizing with drusen and pigment and (2) the presence or absence of reticular AF and reticular pseudodrusen.
The mean fractions of FIAF that colocalized with large drusen were: D-D group, 0.46 +/- 0.21; D-Pig group, 0.42 +/- 0.29; D-GA group, 0.13 +/- 0.09; and GA-GA group, 0.11 +/- 0.12. Comparisons between groups showed significant differences when comparing either the D-D group or the D-Pig group with either the D-GA group or the GA-GA group (P between 0.0001 and 0.015), whereas other comparisons were nonsignificant (Mann-Whitney rank sum test). The mean probabilities of FIAF colocalizing with large drusen relative to chance (1.0) were: D-D group, 4.7 +/- 2.5; D-Pig group, 4.3 +/- 2.3; D-GA group, 1.4 +/- 0.8; and GA-GA group, 1.8 +/- 1.3, with similar significant differences as for the colocalization fractions. The mean probability of FIAF colocalizing with small to intermediate drusen in the D-D group was 1.5 +/- 1.3, which was not significantly different from chance. In the D-Pig group, the median probability of FIAF colocalizing with pigment abnormalities was 10.0 (range, 1.1-51.0). The AF patterns in 15 of 19 eyes in the CNV-0 group were normal; the remainder had nonreticular hypoautofluorescence only. In the CNV-1 group, the relations of FIAF with drusen and pigment were similar to those in the early AMD groups. CNV-R comprised 20 of 55 eyes in the CNV group, but reticular autofluorescence and/or pseudodrusen were found in only 14 of 166 eyes of the early and atrophic groups. Of the 34 total eyes with reticular AF or pseudodrusen, 28 had both, 4 had reticular AF only, and 2 had reticular pseudodrusen only.
There are clear relationships between AF patterns and clinical AMD status. In early AMD, FIAF's colocalization with large, soft drusen and hyperpigmentation is several times greater than chance, suggesting linked disease processes. In advanced atrophic AMD, FIAF is found mostly adjacent to drusen and GA, suggesting that dispersal of drusen-associated lipofuscin is a marker of atrophic disease progression. In the neovascular case, a large group of fellow eyes have no FIAF abnormalities, suggesting that lipofuscin is not a major determinant of CNV. However, reticular hypoautofluorescence, consistent with widespread inflammatory damage to the RPE, appears to be a highly sensitive imaging marker for the disease that determines reticular pseudodrusen and is strongly associated with CNV.
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.
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.
One hundred and ninety-one eyes of 96 patients were examined. Significant correlations were found between early and late fundus fluorescein angiography (ρ = 0.82, P < 0.0001), luteal pigment loss and early/late fundus fluorescein angiography signs (ρ = 0.52, P < 0.0001 and ρ = 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 (κ = 0.25-0.33). Bilateral symmetry was slight to substantial (κ = 0.18-0.62).
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.
Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case-control studies in populations of European ...ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking.
To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, 'Y402H') with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26,494 individuals, including 14,174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene-smoking interaction; and 16 published studies from non-European ancestry.
In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 95% confidence interval (CI) 2.10-2.45; P = 1.1 x 10(-161). There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies.
The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.
To evaluate the spatial distribution and total amount of macular pigment (MP) in patients with idiopathic macular telangiectasia type 2 (MacTel) compared to healthy subjects.
Totals of 53 MacTel ...patients and 38 normal subjects underwent macular pigment optical density (MPOD) measurement using a 2-wavelength autofluorescence (2-AF) technique. The peak MPOD and total MP (sum of pixel OD values) were measured within the central 21 degrees. Data were correlated with motion photometry in a cohort of normal subjects.
A Bland-Altman analysis revealed minimal differences between psychophysical and 2-AF measurements of MPOD (bias = 0.025, SD = 0.06, N = 156 values). In the normal comparison group, 2-AF MPOD peak had a median value of 0.57 (range 0.21-0.93), and median eccentricity of the peak was 0.19 degrees (range 0.00-0.41). In the MacTel group, MPOD peak had a median value of 0.08 (range 0.01-0.26), and median eccentricity of the peak was 5.04 degrees (range 0.18-7.27). The median total amount of MP within the central 21 degrees was greater for normal subjects (4802, range 2362-9215) than for the patients (2938, range 142-7198), but there was marked overlap between the groups. Comparison of the total amount within the central 8, 12, or 16 degrees to that within the central 21 degrees revealed underestimation of up to 68% (median 53%), 42% (27%), and 24% (8%), respectively.
Most MacTel patients have a normal total complement of MP with an abnormal paracentral distribution. The study highlights the limitations of MP measurement techniques that assume minimal MP at eccentricities less than 10.5 degrees.
To characterize the phenotype and investigate the associations of intraretinal crystalline deposits in a large cohort with type 2 idiopathic macular telangiectasia (MacTel).
Case-control study.
...Patients with and without retinal crystals from the Macular Telangiectasia Project, an international multicenter prospective study of type 2 MacTel.
Grading of stereoscopic 30-degree color fundus (CF), confocal blue light reflectance (CBR), red-free (RF), and infrared (IR) images was performed according to the MacTel Natural History Study protocol and staged using the classification system devised by Gass and Blodi. Spectral domain-optical coherence tomography (SD-OCT) and adaptive optics imaging were used for a finer analysis of the phenotype. Associations between crystals and other characteristics of the disease, as well as potential risk factors, were investigated.
Presence of crystals, fundus signs of MacTel, clinical characteristics, and presence of potential risk factors of MacTel.
Of 443 probands enrolled in the MacTel study, 203 (46%) had crystalline deposits present; 60% of the cases were bilateral at baseline. Eyes with crystals had a mean letter score of 70.7 (standard deviation SD = 15.9), whereas those without crystals had a mean letter score of 66.5 (SD = 15.5, P < 0.001). Crystals were present at all stages of the disease and showed high reflectivity within a wide wavelength range. They were located at the anterior surface of the nerve fiber layer, arranged along the nerve fibers, within an annular area centered on the fovea. Significant associations of crystalline deposits were found with a loss of retinal transparency, macular pigment optical density (MPOD) loss, fluorescein leakage, retinal thickness, and a break in the inner segment/outer segment junction line. Associations with environmental risk factors were not found.
Intraretinal crystals are a frequent phenomenon associated with type 2 MacTel. They may appear at all stages and aid in the early diagnosis of the disease. Their morphology further implicates Müller cells in the pathogenesis of the disease. Insight into their physical and chemical properties may provide clues to the metabolic pathways involved in the pathogenesis of the disease.
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