Comparison of Fasanella-Servat and Small-Incision Techniques for Involutional Ptosis Repair.

PURPOSE: To compare the results of the classic Fasanella-Servat internal approach to the newer, small-incision external approach in the repair of involutional ptosis. METHODS: Retrospective review identified 93 patients (104 surgical procedures) at Northwestern Ophthalmology from June 2005 until October 2011 who underwent either the Fasanella-Servat or the small-incision approaches for involutional ptosis repair. Change in vertical palpebral fissure measurement, change in marginal reflex distance 1 (MRD1) measurement, patient satisfaction, surgical complications, operating time, and postoperative pain were compared between groups. RESULTS: Of the 93 patients, most were female with an average age of 69 years. Of the procedures, 48% were small incision and 52% were Fasanella-Servat approaches. Average postoperative follow up was 34.0 days. Vertical palpebral fissure height increased an average of 3.36 mm (±1.15) in the Fasanella-Servat group and 2.74 mm (±1.18) in the small-incision group (p = 0.003). Preoperative vertical palpebral fissure height was lower in the Fasanella-Servat group, but postoperative vertical palpebral fissure height was similar between the 2 groups (p=0.3). MRD1 increased an average of 3.42 mm (±0.86) in the Fasanella-Servat group and 2.68 mm (±0.93) in the small-incision group (p < 0.01). Preoperative MRD1 was lower in the Fasanella-Servat group, but postoperative MRD1 was similar between the 2 groups (p = 0.15). Average operating time was 53 minutes (±16) in the small-incision group and 27 minutes (±6) in the Fasanella-Servat group (p < 0.01). There were no surgical complications in either group with equivalent patient satisfaction between the 2 groups. More patients reported postoperative pain in the Fasanella-Servat group (p < 0.0001). CONCLUSIONS: Both the Fasanella-Servat and small-incision approaches lead to good surgical outcomes with equivalent patient satisfaction, although the Fasanella-Servat approach provides a shorter average operating time with satisfactory postoperative MRD1.

Reticular macular disease is associated with multilobular geographic atrophy in age-related macular degeneration.

PURPOSE: To investigate the incidence of reticular macular disease (RMD), a subphenotype of age-related macular degeneration, in multilobular geographic atrophy (GA) and its relation to GA progression. METHODS: One hundred and fifty-seven eyes of 99 subjects with age-related macular degeneration, primary GA, and good quality autofluorescence, and/or infrared images were classified into unilobular GA (1 lesion) or multilobular GA (≥ 2 distinct and/or coalescent lesions). Thirty-four subjects (50 eyes) had serial imaging. The authors determined the spatiotemporal relationships of RMD to GA and GA progression rates in five macular fields. RESULTS: 91.7% eyes (144 of 157) had multilobular GA, 95.8% of which exhibited RMD. In subjects with serial imaging, the mean GA growth rate significantly differed between the unilobular and multilobular groups (0.40 vs. 1.30 mm2/year, P < 0.001). Of the macular fields in these eyes, 77.1% of fields with RMD at baseline showed subsequent GA progression, while 53.4% of fields without RMD showed progression (P < 0.001). Percentage of fields with RMD significantly correlated with GA progression rate (P = 0.01). CONCLUSION: Autofluorescence and infrared imaging demonstrates that RMD is nearly always present with multilobular GA in age-related macular degeneration. Furthermore, GA lobules frequently develop in areas of RMD, suggesting progression of a single underlying disease process.

A prospective study of reticular macular disease.

PURPOSE: To determine the risk of progression to advanced age-related macular degeneration (AMD) conferred by reticular pseudodrusen (RPD), an imaging presentation of reticular macular disease (RMD), in high-risk fellow eyes of subjects with AMD and unilateral choroidal neovascularization (CNV) in a large, prospective study. DESIGN: Cohort study. PARTICIPANTS: Two hundred seventy-one subjects with AMD; 94 with RPD and 177 without RPD. METHODS: Images from a cohort of 271 subjects with AMD in the Nutritional AMD treatment phase II (NAT 2) Study, a 3-year prospective study of subjects with unilateral CNV and large soft drusen in the fellow eye, were studied. The fellow eye, at high risk for advanced AMD developing, was the study eye. There were 5 visits per subject. Imaging at each visit consisted of color, red-free, and blue-light photography and fluorescein angiography. The images were analyzed for the presence of RPD, following disease progression throughout the 3-year study. MAIN OUTCOME MEASURES: The development of advanced AMD (CNV or geographic atrophy). RESULTS: For the 271 subjects who completed the full 3-year study, there was a significantly higher rate of advanced AMD (56% or 53/94) in fellow eyes with RPD at any visit compared with eyes without RPD (32% or 56/177; P < 0.0001, chi-square test; relative risk [RR], 1.8; 95% confidence interval [CI], 1.4-2.4). The chance of developing advanced AMD in the fellow eye in women with RPD (66%) was more than double that of women without RPD (30%; P < 0.00001; RR, 2.2; 95% CI, 1.6-3.1). CONCLUSIONS: To the authors' knowledge, this is the first comprehensive prospective study of RMD, a distinct clinical phenotype of AMD that includes RPD. It provides strong confirmation that RMD, a disease entity with stereotypical presentations across imaging methods, is associated with a high risk of progression to advanced AMD, perhaps on an inflammatory or vascular basis. Reticular macular disease deserves wider recognition and consideration by clinicians caring for patients with AMD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

A Validated Phenotyping Algorithm for Genetic Association Studies in Age-related Macular Degeneration.

Age-related macular degeneration (AMD), a multifactorial, neurodegenerative disease, is a leading cause of vision loss. With the rapid advancement of DNA sequencing technologies, many AMD-associated genetic polymorphisms have been identified. Currently, the most time consuming steps of these studies are patient recruitment and phenotyping. In this study, we describe the development of an automated algorithm to identify neovascular (wet) AMD, non-neovascular (dry) AMD and control subjects using electronic medical record (EMR)-based criteria. Positive predictive value (91.7%) and negative predictive value (97.5%) were calculated using expert chart review as the gold standard to assess algorithm performance. We applied the algorithm to an EMR-linked DNA bio-repository to study previously identified AMD-associated single nucleotide polymorphisms (SNPs), using case/control status determined by the algorithm. Risk alleles of three SNPs, rs1061170 (CFH), rs1410996 (CFH), and rs10490924 (ARMS2) were found to be significantly associated with the AMD case/control status as defined by the algorithm. With the rapid growth of EMR-linked DNA biorepositories, patient selection algorithms can greatly increase the efficiency of genetic association study. We have found that stepwise validation of such an algorithm can result in reliable cohort selection and, when coupled within an EMR-linked DNA biorepository, replicates previously published AMD-associated SNPs.

Imaging characteristics of dry age-related macular degeneration.

PURPOSE: To review the current literature regarding the imaging characteristics of dry age-related macular degeneration (AMD) lesions, with a special focus on drusen and geographic atrophy imaging. We also explore the role of novel approach of hyperspectral imaging in AMD. METHODS: Review of current literature as well as findings in a small group of patients imaged with hyperspectral imaging. RESULTS: The use of optical coherence tomography, and especially fourier-domain devices, has enhanced our ability to classify various lesions of dry AMD. The increasing role of autofluorescence in characterization and prognostication in geographic atrophy is reviewed. The advances made in automated detection and multimodal imaging are highlighted, with their potential to revolutionize this area of research. CONCLUSIONS: Recent advances in retinal imaging have improved our understanding of the characteristics and prognostication of dry AMD, with an increasing role for multimodal imaging and image correlations. The potential future role of hyperspectral imaging in dry AMD is also presented herein.

Drusen analysis in a human-machine synergistic framework.

OBJECTIVES: To demonstrate how human-machine intelligence can be integrated for efficient image analysis of drusen in age-related macular degeneration and to validate the method in 2 large, independently graded, population-based data sets. METHODS: We studied 358 manually graded color slides from the Netherlands Genetic Isolate Study. All slides were digitized and analyzed with a user-interactive drusen detection algorithm for the presence and quantity of small, intermediate, and large drusen. A graphic user interface was used to preprocess the images, choose a region of interest, select appropriate corrective filters for images with photographic artifacts or prominent choroidal pattern, and perform drusen segmentation. Weighted κ statistics were used to analyze the initial concordance between human graders and the drusen detection algorithm; discordant grades from 177 left-eye slides were subjected to exhaustive analysis of causes of disagreement and adjudication. To validate our method further, we analyzed a second data set from our Columbia Macular Genetics Study. RESULTS: The graphical user interface decreased the time required to process images in commercial software by 60.0%. After eliminating borderline size disagreements and applying corrective filters for photographic artifacts and choroidal pattern, the weighted κ values were 0.61, 0.62, and 0.76 for small, intermediate, and large drusen, respectively. Our second data set demonstrated a similarly high concordance. CONCLUSIONS: Drusen identification performed by our user-interactive method presented fair to good agreement with human graders after filters for common sources of error were applied. This approach exploits a synergistic relationship between the intelligent user and machine computational power, enabling fast and accurate quantitative retinal image analysis.

Image registration and multimodal imaging of reticular pseudodrusen.

PURPOSE: To characterize reticular pseudodrusen (RPD) by using a point-to-point comparison of the reticular pattern on infrared reflectance (IR), autofluorescence (AF), and red-free (RF) images registered with en face sections of the choroid from spectral domain optical coherence tomography (SD-OCT) scans. METHODS: A cross-sectional, retrospective study of all patients with the diagnosis of AMD who presented to the Doheny Retina Institute between December 2007 and November 2009 was conducted to identify patients with RPD. IR, AF, and RF images were obtained using confocal scanning laser ophthalmoscopy and were manually registered to OCT choroidal sections to study the location of RPD. The main outcome measured was point-to-point localization of RPD across multiple imaging modalities. RESULTS: Of the 153 patients with AMD, 51 had RPD. In all 51 patients (97 eyes), RPD appeared as areas of hypoautofluorescence and hyporeflectance on AF and IR imaging, respectively, and as hyporeflective interlacing networks on RF. Reticular lesions on AF, IR, and RF images consistently colocalized with stromal regions between large choroidal vessels on registered en face choroidal sections. In contrast, outer retinal changes and subretinal deposits tended to localize immediately adjacent to the RPD. CONCLUSIONS: Point-to-point correlation of registered IR, AF, and RF images consistently localizes the reticular pattern to the intervascular choroidal stroma on en face OCT sections. In contrast, subretinal deposits and disturbances of the inner outer segment on OCT did not colocalize with the RPD, and may represent secondary mechanical or biologic disturbances in the overlying RPE and outer retina.

Complement factor H 402H variant and reticular macular disease.

OBJECTIVE: To determine the association of high-risk alleles in the complement factor H (CFH; Y402H, rs1061170) and age-related maculopathy susceptibility (ARMS2; A69S, rs10490924) genes with reticular macular disease (RMD), a major clinical subphenotype of age-related macular degeneration (AMD). METHODS: Using retinal images from the Columbia Macular Genetics Study, we identified 67 subject individuals with RMD. A comparison group of 64 subjects with AMD without RMD was matched by ethnicity, age, sex, and AMD clinical stage. RESULTS: In the RMD group, 53 of 67 subjects (79.1%) were female, the mean age was 83 years, and 47 of 67 (70.1%) had late AMD, with closely matched values in the non-RMD group. The frequencies of the CFH 402H allele were 39.6% in the RMD group (53 of 134 individuals) and 58.6% in the non-RMD group (75 of 128 individuals) (χ(2) = 8.8; P = .003; odds ratio, 0.46 [95% confidence interval, 0.28-0.76]). The corresponding frequencies of the risk allele for ARMS2 were 44.0% (40 of 128 individuals) and 31.3% (40 of 128 individuals), respectively (χ(2) = 4.0; P = .045; odds ratio, 1.73 [95% confidence interval, 1.04-2.90]). Homozygosity for 402H was particularly associated with the absence of RMD, occurring in 8 of 67 subjects (11.9%) with RMD vs 24 of 64 subjects (37.5%) without RMD (P < .001). Retinal macular disease also was associated with hypertension among male patients. CONCLUSIONS: The AMD-associated CFH 402H risk variant is significantly associated with the absence of RMD but enhanced risk for RMD is conferred by the ARMS2 69S AMD risk allele. These results are consistent with the hypothesis that 402H may confer a survival benefit against certain infections, some of which may cause RMD. CLINICAL RELEVANCE: Reticular macular disease may be genetically distinct from the rest of AMD.

Preimplantation genetic diagnosis for stargardt disease.

PURPOSE: To report the first use of in vitro fertilization (IVF) and preimplantation genetic diagnosis to achieve an unaffected pregnancy in an autosomal-recessive retinal dystrophy. DESIGN: Case report. METHODS: An affected male with Stargardt disease and his carrier wife underwent IVF. Embryos obtained by intracytoplasmic sperm injection underwent single-cell DNA testing via polymerase chain reaction and restriction enzyme analysis to detect the presence of ABCA4 mutant alleles. Embryos were diagnosed as being either affected by or carriers for Stargardt disease. A single carrier embryo was implanted. RESULTS: Chorionic villus sampling performed during the first trimester verified that the fetus possessed only 1 mutant paternal allele and 1 normal maternal allele, thus making her an unaffected carrier of the disease. A healthy, live-born female was delivered. CONCLUSION: IVF and preimplantation genetic diagnosis can assist couples with an affected spouse and a carrier spouse with recessive retinal dystrophies to have an unaffected child.

Dynamic soft drusen remodelling in age-related macular degeneration.

AIMS: To demonstrate and quantify the dynamic remodelling process of soft drusen resorption and new drusen formation in age-related macular degeneration (AMD) with novel interactive methods. METHODS: Twenty patients with large soft drusen bilaterally and without advanced AMD were imaged at baseline and again at a mean interval of 2 years (40 eyes, 80 images). Each of the 40 serial pairs of images was precisely registered by an automated technique. The drusen were segmented by a user-interactive method based on a background levelling algorithm and classified into three groups: new drusen (only in the final image), resorbed drusen (present initially but not in the final image) and stable drusen (present in both images). We measured each of these classes as well as the absolute change in drusen |D1-D0| and the dynamic drusen activity (creation and resorption) D(new)+D(resorbed). RESULTS: Mean dynamic activity for the right eye (OD) was 7.33±5.50%, significantly greater than mean absolute change (2.71±2.89%, p=0.0002, t test), with similar results for the left eye (OS). However, dynamic activity OD compared with OS (mean 7.33±5.50 vs 7.91±4.16%, NS) and absolute net change OD versus OS (2.71±2.89 vs 3.46±3.97%, NS) tended to be symmetrical between fellow eyes. CONCLUSIONS: Dynamic remodelling processes of drusen resorption and new drusen formation are distinct disease activities that can occur simultaneously and are not captured by change in total drusen load. Dynamic changes occur at rates more than twice that of net changes, and may be a useful marker of disease activity.

Reticular macular disease.

PURPOSE: To present a unified description of reticular macular disease (RMD), a common clinical entity that includes reticular pseudodrusen (RPD) and confers high-risk of progression to advanced age-related macular degeneration. DESIGN: Population-based, retrospective, cross-sectional study. Forty-two patients with reticular findings in at least one imaging method, of whom 21 were followed up. METHODS: RMD was defined as RPD in color or red-free photography, in a reticular pattern on scanning laser ophthalmoscope imaging (autofluorescence scans, infrared photographs, or indocyanine green angiography), or both. Color and red-free images were contrast-enhanced, and color photographs were examined in green and blue channels. Image registration in different methods allowed comparison of areas involved and assessment of lesion colocalization. RESULTS: RMD generally was present in both photography and scanning laser ophthalmoscope imaging. When present in two image methods, areas of RMD either largely overlapped or one fell within the other. Individual lesions had high spatial correspondence. Serial imaging showed faded to absent findings in eyes in which choroidal neovascularization developed. CONCLUSIONS: RMD is a single disease entity with stereotypical presentations in multiple imaging methods, of which RPD is one. Autofluorescence, infrared imaging, and indocyanine green angiography suggest that it involves the retinal pigment epithelium and choriocapillaris, whereas photographic patterns implicate the inner choroid. Infrared imaging, unlike other methods, can demonstrate RMD in the central macula. RMD is associated with progression to advanced age-related macular degeneration, perhaps on an inflammatory basis. RMD deserves wider recognition among clinicians caring for elderly patients.