Documentation of Intraretinal Retinal Pigment Epithelium Migration via High-Speed Ultrahigh-Resolution Optical Coherence Tomography

Purpose To describe the features of intraretinal retinal pigment epithelium (RPE) migration documented on a prototype spectral-domain, high-speed, ultrahigh-resolution optical coherence tomography (OCT) device in a group of patients with early to intermediate dry age-related macular degeneration (AMD) and to correlate intraretinal RPE migration on OCT to RPE pigment clumping on fundus photographs. Design Retrospective, noncomparative, noninterventional case series. Participants Fifty-five eyes of 44 patients seen at the New England Eye Center between December 2007 and June 2008 with early to intermediate dry AMD. Methods Three-dimensional OCT scan sets from all patients were analyzed for the presence of intraretinal RPE migration, defined as small discreet hyperreflective and highly backscattering lesions within the neurosensory retina. Fundus photographs also were analyzed to determine the presence of RPE pigment clumping, defined as black, often spiculated, areas of pigment clumping within the macula. The en face OCT images were correlated with fundus photographs to demonstrate correspondence of intraretinal RPE migration on OCT and RPE clumping on fundus photography. Main Outcome Measures Drusen, dry AMD, intraretinal RPE migration, and RPE pigment clumping. Results On OCT scans, 54.5% of eyes (61.4% of patients) demonstrated intraretinal RPE migration. Of the fundus photographs, 56.4% demonstrated RPE pigment clumping. All eyes with intraretinal RPE migration on OCT had corresponding RPE pigment clumping on fundus photographs. The RPE pigment migrated most frequently into the outer nuclear layer (66.7% of eyes) and less frequently into more anterior retinal layers. Intraretinal RPE migration mainly occurred above areas of drusen (73.3% of eyes). Conclusions The appearance of intraretinal RPE migration on OCT is a common occurrence in early to intermediate dry AMD, occurring in 54.5% of eyes, or 61.4% of patients. The area of intraretinal RPE migration on OCT always correlated to areas of pigment clumping on fundus photography. Conversely, all but 1 eye with RPE pigment clumping on fundus photography also had areas of intraretinal RPE migration on OCT. The high incidence of intraretinal RPE migration observed above areas of drusen suggests that drusen may play physical and catalytic roles in facilitating intraretinal RPE migration in dry AMD patients.National Institutes of Health (U.S.) (Contract RO1-EY11289-23)National Institutes of Health (U.S.) (Contract R01-EY13178-07)National Institutes of Health (U.S.) (Contract R01-EY013516-07)United States. Air Force Office of Scientific Research (FA9550-07-1-0101)United States. Air Force Office of Scientific Research (FA9550-07-1-0014

Enhanced Vitreous Imaging in Healthy Eyes Using Swept Source Optical Coherence Tomography

Purpose To describe enhanced vitreous imaging for visualization of anatomic features and microstructures within the posterior vitreous and vitreoretinal interface in healthy eyes using swept-source optical coherence tomography (SS-OCT). The study hypothesis was that long-wavelength, high-speed, volumetric SS-OCT with software registration motion correction and vitreous window display or high-dynamic-range (HDR) display improves detection sensitivity of posterior vitreous and vitreoretinal features compared to standard OCT logarithmic scale display. Design Observational prospective cross-sectional study. Methods Multiple wide-field three-dimensional SS-OCT scans (500×500A-scans over 12×12 mm2) were obtained using a prototype instrument in 22 eyes of 22 healthy volunteers. A registration motion-correction algorithm was applied to compensate motion and generate a single volumetric dataset. Each volumetric dataset was displayed in three forms: (1) standard logarithmic scale display, enhanced vitreous imaging using (2) vitreous window display and (3) HDR display. Each dataset was reviewed independently by three readers to identify features of the posterior vitreous and vitreoretinal interface. Detection sensitivities for these features were measured for each display method. Results Features observed included the bursa premacularis (BPM), area of Martegiani, Cloquet's/BPM septum, Bergmeister papilla, posterior cortical vitreous (hyaloid) detachment, papillomacular hyaloid detachment, hyaloid attachment to retinal vessel(s), and granular opacities within vitreous cortex, Cloquet's canal, and BPM. The detection sensitivity for these features was 75.0% (95%CI: 67.8%–81.1%) using standard logarithmic scale display, 80.6% (95%CI: 73.8%–86.0%) using HDR display, and 91.9% (95%CI: 86.6%–95.2%) using vitreous window display. Conclusions SS-OCT provides non-invasive, volumetric and measurable in vivo visualization of the anatomic microstructural features of the posterior vitreous and vitreoretinal interface. The vitreous window display provides the highest sensitivity for posterior vitreous and vitreoretinal interface analysis when compared to HDR and standard OCT logarithmic scale display. Enhanced vitreous imaging with SS-OCT may help assess the natural history and treatment response in vitreoretinal interface diseases.Massachusetts Lions Eye Research Fund, Inc.Research to Prevent Blindness, Inc. (United States)United States. Air Force Office of Scientific Research (grant FA9550-1010551)United States. Air Force Office of Scientific Research (grant FA9550-12-1-0499)German Research Foundation (DFG-HO-1791/11-1)German Research Foundation (DFGGSC80-SAOT)German Research Foundation (DFG Research Training Group 1773)Champalimaud Foundation (Champalimaud Vision Award Fund)National Institutes of Health (U.S.) (R01- EY11289-28)National Institutes of Health (U.S.) (R01-CA075289-16)National Institutes of Health (U.S.) (R44-EY022864-01

Structure versus function: correlation between outer retinal and choroidal thicknesses measured by swept-source OCT with multifocal electroretinography and visual acuity

Background: To correlate retina-choroidal anatomy as assessed via swept-source OCT (SS-OCT) with retinal function as determined by best-corrected visual acuity (BCVA) and multifocal electroretinogram (mfERG). Methods: Thirty-three eyes from 33 patients including 16 with neovascular AMD (nvAMD) and 17 controls were included. Patients were included in the present study after a complete ophthalmologic examination, including BCVA, slit-lamp study, intraocular pressure measurement, dilated fundus examination after tropicamide instillation, SD-OCT, SS-OCT, fundus photographs and mfERG. Age, sex, BCVA, number of anti-VEGF intravitreal injections in the nvAMD group, were recollected. Outer retinal and choroidal thickness were determined at the fovea and 500 μm temporal, superior, nasal and inferior. First-order response from mfERG was collected. P1 amplitude was recorded in R1, R2 and the average of R1 + R2. The measurements recollected from the SS-OCT, mfERG and BCVA were compared. Results: Better BCVA was found with thicker outer retina foveal thickness (r = 0.349; P = 0.047), with thicker subfoveal choroidal thickness (r = 0.443; P = 0.010), and with higher amplitude in P1 at R1 (r = 0.346; P = 0.037). Outer retina foveal thickness did not correlate with P1 amplitude at R1 (r = 0.072; P = 0.692), R2 (r = 0.265; P = 0.137) either with the average P1 amplitude at R1 + R2 (r = 0.253; P = 0.156). A thicker subfoveal choroidal thickness was related with higher amplitude in P1 at R1 (r = 0.383; P = 0.028), R2 (r = 0.409; P = 0.018) and the average of R1 + R2 (r = 0.419; P = 0.015). Conclusions: Choroidal thickness demonstrated a positive correlation with retinal function in the sample studied, so a thicker choroid is related to a better retinal function measured with mfERG and BCVA

Characterization of Choroidal Layers in Normal Aging Eyes Using Enface Swept-Source Optical Coherence Tomography

Purpose To characterize qualitative and quantitative features of the choroid in normal eyes using enface swept-source optical coherence tomography (SS-OCT). Methods Fifty-two eyes of 26 consecutive normal subjects were prospectively recruited to obtain multiple three-dimensional 12x12mm volumetric scans using a long-wavelength high-speed SS-OCT prototype. A motion-correction algorithm merged multiple SS-OCT volumes to improve signal. Retinal pigment epithelium (RPE) was segmented as the reference and enface images were extracted at varying depths every 4.13 mu m intervals. Systematic analysis of the choroid at different depths was performed to qualitatively assess the morphology of the choroid and quantify the absolute thicknesses as well as the relative thicknesses of the choroidal vascular layers including the choroidal microvasculature (choriocapillaris, terminal arterioles and venules;CC) and choroidal vessels (CV) with respect to the subfoveal total choroidal thickness (TC). Subjects were divided into two age groups: younger (= 40 years). Results Mean age of subjects was 41.92 (24-66) years. Enface images at the level of the RPE, CC, CV, and choroidal-scleral interface were used to assess specific qualitative features. In the younger age group, the mean absolute thicknesses were: TC 379.4 mu m (SD +/- 75.7 mu m),CC 81.3 mu m (SD +/- 21.2 mu m) and CV 298.1 mu m (SD +/- 63.7 mu m). In the older group, the mean absolute thicknesses were: TC 305.0 mu m (SD +/- 50.9 mu m),CC 56.4 mu m (SD +/- 12.1 mu m) and CV 248.6 mu m (SD +/- 49.7 mu m). In the younger group, the relative thicknesses of the individual choroidal layers were: CC 21.5% (SD +/- 4.0%) and CV 78.4% (SD +/- 4.0%). In the older group, the relative thicknesses were: CC 18.9% (SD +/- 4.5%) and CV 81.1% (SD +/- 4.5%). The absolute thicknesses were smaller in the older age group for all choroidal layers (TC p=0.006, CC p=0.0003, CV p=0.03) while the relative thickness was smaller only for the CC (p=0.04). Conclusions Enface SS-OCT at 1050nm enables a precise qualitative and quantitative characterization of the individual choroidal layers in normal eyes. Only the CC is relatively thinner in the older eyes. In-vivo evaluation of the choroid at variable depths may be potentially valuable in understanding the natural history of age-related posterior segment disease

Communication in Individuals with Rett Syndrome: an Assessment of Forms and Functions

In the present study we assessed the forms and functions of prelinguistic communicative behaviors for 120 children and adults with Rett syndrome using the Inventory of Potential Communicative Acts (IPCA) (Sigafoos et al. Communication Disorders Quarterly 21:77–86, 2000a). Informants completed the IPCA and the results were analysed to provide a systematic inventory and objective description of the communicative forms and functions present in each individual’s repertoire. Results show that respondents reported a wide variety of communicative forms and functions. By far most girls used prelinguistic communicative behaviors of which eye contact/gazing was the most common form. The most often endorsed communicative functions were social convention, commenting, answering, requesting and choice-making. Problematic topographies (e.g., self-injury, screaming, non-compliance) were being used for communicative purposes in 10 to 41% of the sample. Exploratory analyses revealed that several communicative forms and functions were related to living environment, presence/absence of epilepsy, and age. That is, higher percentages of girls who showed some forms/functions were found in those who lived at home, who had no epilepsy and who were relatively young

Chronic recurrent Gorham-Stout syndrome with cutaneous involvement

Type IV osteolysis or Gorham-Stout syndrome is a rare condition characterized by recurrent vascular tumors that disrupt normal anatomical architecture. Gorham-Stout syndrome is most commonly associated with the skeletal system with resulting replacement of bone with scar tissue following tumor regression. The loss of entire bones has given Gorham-Stout syndrome the moniker vanishing bone disease. Natural progression of Gorham-Stout syndrome is characterized by spontaneous disease resolution. However, rare variants of recurrent, progressive, and/or systemic disease have been reported. We present a patient with a history of recurrent Gorham- Stout disease refractory to all treatment options considered. In addition to skeletal disease, our patient had soft tissue and cutaneous involvement, thus reflecting the more aggressive disease variant. Previous surgical attempts to control disease had been ineffective and the patient was referred to us for radiation therapy. Treatment with external beam radiation therapy resulted in good local control and symptom palliation, but full disease resolution was never accomplished. In addition to presentation of this patient, a review of the literature on etiological hypotheses and past/future treatment options was conducted and is included

Birdshot chorioretinopathy: current knowledge and new concepts in pathophysiology, diagnosis, monitoring and treatment

Birdshot chorioretinopathy (BCR) is a rare form of chronic, bilateral, posterior uveitis with a distinctive clinical phenotype, and a strong association with HLA-A29. It predominantly affects people in middle age. Given its rarity, patients often encounter delays in diagnosis leading to delays in adequate treatment, and thus risking significant visual loss. Recent advances have helped increase our understanding of the underlying autoimmune mechanisms involved in disease pathogenesis, and new diagnostic approaches such as multimodality imaging have improved our ability to both diagnose and monitor disease activity. Whilst traditional immunosuppressants may be effective in BCR, increased understanding of immune pathways is enabling development of newer treatment modalities, offering the potential for targeted modulation of immune mediators. In this review, we will discuss current understanding of BCR and explore recent developments in diagnosis, monitoring and treatment of this disease. Synonyms for BCR: Birdshot chorioretinopathy, Birdshot retinochoroiditis, Birdshot retino-choroidopathy, Vitiliginous choroiditis. Orphanet number: ORPHA179 OMIM: 605808

Characterization of Outer Retinal Morphology with HighSpeed, Ultrahigh-Resolution Optical Coherence Tomography

PURPOSE. To visualize, quantitatively assess, and interpret outer retinal morphology by using high-speed, ultrahigh-resolution (UHR) OCT. METHODS. Retinal imaging was performed in the ophthalmic clinic in a cross-section of 43 normal subjects with a 3.5-m, axial-resolution, high-speed, UHR OCT prototype instrument, using a radial scan pattern (24 images, 1500 axial scans). Outer retinal layers were automatically segmented and measured. High-definition imaging was performed with a 2.8-m axialresolution, high-speed, UHR OCT research prototype instrument, to visualize the finer features in the outer retina. RESULTS. Quantitative maps of outer retinal layers showed clear differences between the cone-dominated fovea and the roddominated parafovea and perifovea, indicating that photoreceptor morphology can explain the appearance of the outer retina in high-speed, UHR OCT images. Finer, scattering bands were visualized in the outer retina using high-definition imaging and were interpreted by comparison to known anatomy. CONCLUSIONS. High-speed UHR OCT enables quantification of scattering layers in the outer retina. An interpretation of these features is presented and supported by quantitative measurements in normal subjects and comparison with known anatomy. The thick scattering region of the outer retina previously attributed to the retinal pigment epithelium (RPE) is shown to consist of distinct scattering bands corresponding to the photoreceptor outer segment tips, RPE, and Bruch's membrane. These results may advance understanding of the outer retinal appearance in OCT images. The normative measurements may also aid in future investigations of outer retinal changes in age-related macular degeneration and other diseases. (Inves

A Comparison Between Optical Coherence Tomography Angiography and Fluorescein Angiography for the Imaging of Type 1 Neovascularization.

Purpose: To determine the sensitivity of the combination of optical coherence tomography angiography (OCTA) and structural optical coherence tomography (OCT) for detecting type 1 neovascularization (NV) and to determine significant factors that preclude visualization of type 1 NV using OCTA. Methods: Multicenter, retrospective cohort study of 115 eyes from 100 patients with type 1 NV. A retrospective review of fluorescein (FA), OCT, and OCTA imaging was performed on a consecutive series of eyes with type 1 NV from five institutions. Unmasked graders utilized FA and structural OCT data to determine the diagnosis of type 1 NV. Masked graders evaluated FA data alone, en face OCTA data alone and combined en face OCTA and structural OCT data to determine the presence of type 1 NV. Sensitivity analyses were performed using combined FA and OCT data as the reference standard. Results: A total of 105 eyes were diagnosed with type 1 NV using the reference. Of these, 90 (85.7%) could be detected using en face OCTA and structural OCT. The sensitivities of FA data alone and en face OCTA data alone for visualizing type 1 NV were the same (66.7%). Significant factors that precluded visualization of NV using en face OCTA included the height of pigment epithelial detachment, low signal strength, and treatment-naïve disease (P \u3c 0.05, respectively). Conclusions: En face OCTA and structural OCT showed better detection of type 1 NV than either FA alone or en face OCTA alone. Combining en face OCTA and structural OCT information may therefore be a useful way to noninvasively diagnose and monitor the treatment of type 1 NV

Mutations in genes encoding condensin complex proteins cause microcephaly through decatenation failure at mitosis

Correction to Martin et al. available at: Genes & Development 30 (19): 2158 (http://genesdev.cshlp.org/content/31/9/953.full.pdf+html).Compaction of chromosomes is essential for accurate segregation of the genome duringmitosis. In vertebrates, two condensin complexes ensure timely chromosome condensation, sister chromatid disentanglement, and maintenance of mitotic chromosome structure. Here,we report that biallelic mutations inNCAPD2,NCAPH, orNCAPD3, encoding subunits of these complexes, cause microcephaly. In addition, hypomorphic Ncaph2 mice have significantly reduced brain size, with frequent anaphase chromatin bridge formation observed in apical neural progenitors during neurogenesis. Such DNA bridges also arise in condensin-deficient patient cells, where they are the consequence of failed sister chromatid disentanglement during chromosome compaction. This results in chromosome segregation errors, leading to micronucleus formation and increased aneuploidy in daughter cells. These findings establish “condensinopathies” as microcephalic disorders, with decatenation failure as an additional disease mechanism for microcephaly, implicating mitotic chromosome condensation as a key process ensuring mammalian cerebral cortex size.This work was supported by funding from the Medical Research Council, the Lister Institute for Preventative Medicine, and the European Research Council (ERC; 281847 to A.P.J.); a Biotechnology and Biological Sciences Research Council grant (BB/ K017632/1 to P.V); a Sir Henry Dale Fellowship (grant 102560/ Z/13/Z to A.J.W.); Medical Research Scotland (to L.S.B.); the Potentials Foundation (to C.A.W.); and the Indian Council of Medical Research (BMS 54/2/2013 to S.R.P). The Deciphering Developmental Disorders Study presents independent research commissioned by the Health Innovation Challenge Fund (grant no. HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant no. WT098051). The views expressed here are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83) granted by the Cambridge South Research Ethics Committee, and GEN/ 284/12 granted by the Republic of Ireland. We acknowledge the support of the National Institute for Health Research through the Comprehensive Clinical Research Network