Reproducibility of a Long-Range Swept-Source Optical Coherence Tomography Ocular Biometry System and Comparison with Clinical Biometers

Objective To demonstrate a novel swept source optical coherence tomography (SS-OCT) imaging device using a vertical cavity surface-emitting laser (VCSEL) capable of imaging the full eye length and to introduce a method using this device for noncontact ocular biometry. To compare the measurements of intraocular distances using this SS-OCT instrument with commercially available optical and ultrasound biometers. To evaluate the intersession reproducibility of measurements of intraocular distances using SS-OCT. Design Evaluation of technology. Participants Twenty eyes of 10 healthy subjects imaged at the New England Eye Center at Tufts Medical Center and Massachusetts Institute of Technology between May and September 2012. Methods Averaged central depth profiles were extracted from volumetric SS-OCT datasets. The intraocular distances, such as central corneal thickness (CCT), aqueous depth (AD), anterior chamber depth (ACD), crystalline lens thickness (LT), vitreous depth (VD), and axial length (AL), were measured and compared with a partial coherence interferometry device (IOLMaster; Carl Zeiss Meditec, Inc., Dublin, CA) and an immersion ultrasound (IUS) A-scan biometer (Axis-II PR; Quantel Medical, Inc., Cournon d'Auvergne Cedex, France). Main Outcome Measures Reproducibility of the measurements of intraocular distances, correlation coefficients, and intraclass correlation coefficients. Results The standard deviations of the repeated measurements of intraocular distances using SS-OCT were 6 μm (CCT), 16 μm (ACD), 14 μm (AD), 13 μm (LT), 14 μm (VD), and 16 μm (AL). Strong correlations among all 3 biometric instruments were found for AL (r > 0.98). The AL measurement using SS-OCT correlates better with the IOLMaster (r=0.998) than with IUS (r=0.984). The SS-OCT and IOLMaster measured higher AL values than ultrasound (175 and 139 μm, respectively). No statistically significant difference in ACD between the optical (SS-OCT or IOLMaster) and ultrasound methods was detected. High intersession reproducibility of SS-OCT measurements of all intraocular distances was observed with intraclass correlation coefficients >0.99. Conclusions The SS-OCT using VCSEL technology enables full eye length imaging and high-precision, noncontact ocular biometry. The measurements with the prototype SS-OCT instrument correlate well with commercial biometers. The SS-OCT biometry has the potential to provide clinically useful comprehensive biometric parameters for pre- and postoperative eye evaluation.National Institutes of Health (U.S.) (Grant R01-EY011289-27)National Institutes of Health (U.S.) (Grant R01-EY013178-12)National Institutes of Health (U.S.) (Grant R01-EY013516-09)National Institutes of Health (U.S.) (Grant R01-EY019029-04)National Institutes of Health (U.S.) (Grant R44EY022864-01)National Institutes of Health (U.S.) (Grant R01-CA075289-16)National Institutes of Health (U.S.) (Grant R01-NS057476-05)National Institutes of Health (U.S.) (Grant R44CA101067-05)United States. Air Force Office of Scientific Research (Grant FA9550-10-1-0551)United States. Air Force Office of Scientific Research (Grant FA9550-10-1-0063)Thorlabs, Inc

White paper on ophthalmic imaging for choroidal nevus identification and transformation into Melanoma

Purpose: To discuss the evolution of noninvasive diagnostic methods in the identification of choroidal nevus and determination of risk factors for malignant transformation as well as introduce the novel role that artificial intelligence (AI) can play in the diagnostic process. Methods: White paper. Results: Longstanding diagnostic methods to stratify benign choroidal nevus from choroidal melanoma and to further determine the risk for nevus transformation into melanoma have been dependent on recognition of key clinical features by ophthalmic examination. These risk factors have been derived from multiple large cohort research studies over the past several decades and have garnered widespread use throughout the world. More recent publications have applied ocular diagnostic testing (fundus photog-raphy, ultrasound examination, autofluorescence, and optical coherence tomography) to identify risk factors for the malignant transformation of choroidal nevus based on multimodal imaging features. The widespread usage of ophthalmic imaging systems to identify and follow choroidal nevus, in conjunction with the characterization of malignant transformation risk factors via diagnostic imaging, presents a novel path to apply AI. Conclusions: AI applied to existing ophthalmic imaging systems could be used for both identification of choroidal nevus and as a tool to aid in earlier detection of transformation to malignant melanoma. Translational Relevance: Advances in AI models applied to ophthalmic imaging systems have the potential to improve patient care, because earlier detection and treatment of melanoma has been proven to improve long-term clinical outcomes

Choriocapillaris and Choroidal Microvasculature Imaging with Ultrahigh Speed OCT Angiography

We demonstrate in vivo choriocapillaris and choroidal microvasculature imaging in normal human subjects using optical coherence tomography (OCT). An ultrahigh speed swept source OCT prototype at 1060 nm wavelengths with a 400 kHz A-scan rate is developed for three-dimensional ultrahigh speed imaging of the posterior eye. OCT angiography is used to image three-dimensional vascular structure without the need for exogenous fluorophores by detecting erythrocyte motion contrast between OCT intensity cross-sectional images acquired rapidly and repeatedly from the same location on the retina. En face OCT angiograms of the choriocapillaris and choroidal vasculature are visualized by acquiring cross-sectional OCT angiograms volumetrically via raster scanning and segmenting the three-dimensional angiographic data at multiple depths below the retinal pigment epithelium (RPE). Fine microvasculature of the choriocapillaris, as well as tightly packed networks of feeding arterioles and draining venules, can be visualized at different en face depths. Panoramic ultra-wide field stitched OCT angiograms of the choriocapillaris spanning ~32 mm on the retina show distinct vascular structures at different fundus locations. Isolated smaller fields at the central fovea and ~6 mm nasal to the fovea at the depths of the choriocapillaris and Sattler's layer show vasculature structures consistent with established architectural morphology from histological and electron micrograph corrosion casting studies. Choriocapillaris imaging was performed in eight healthy volunteers with OCT angiograms successfully acquired from all subjects. These results demonstrate the feasibility of ultrahigh speed OCT for in vivo dye-free choriocapillaris and choroidal vasculature imaging, in addition to conventional structural imaging.National Institutes of Health (U.S.) (NIH R01-EY011289-27)National Institutes of Health (U.S.) (NIH R01-EY013178-12)National Institutes of Health (U.S.) (NIH R44-EY022864-01)National Institutes of Health (U.S.) (NIH R01-CA075289-16)United States. Air Force Office of Scientific Research (AFOSR FA9550-10-1-0551)United States. Air Force Office of Scientific Research (AFOSR FA9550-12-1-0499

An Unexpected Function of the Prader-Willi Syndrome Imprinting Center in Maternal Imprinting in Mice

Genomic imprinting is a phenomenon that some genes are expressed differentially according to the parent of origin. Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurobehavioral disorders caused by deficiency of imprinted gene expression from paternal and maternal chromosome 15q11–q13, respectively. Imprinted genes at the PWS/AS domain are regulated through a bipartite imprinting center, the PWS-IC and AS-IC. The PWS-IC activates paternal-specific gene expression and is responsible for the paternal imprint, whereas the AS-IC functions in the maternal imprint by allele-specific repression of the PWS-IC to prevent the paternal imprinting program. Although mouse chromosome 7C has a conserved PWS/AS imprinted domain, the mouse equivalent of the human AS-IC element has not yet been identified. Here, we suggest another dimension that the PWS-IC also functions in maternal imprinting by negatively regulating the paternally expressed imprinted genes in mice, in contrast to its known function as a positive regulator for paternal-specific gene expression. Using a mouse model carrying a 4.8-kb deletion at the PWS-IC, we demonstrated that maternal transmission of the PWS-IC deletion resulted in a maternal imprinting defect with activation of the paternally expressed imprinted genes and decreased expression of the maternally expressed imprinted gene on the maternal chromosome, accompanied by alteration of the maternal epigenotype toward a paternal state spread over the PWS/AS domain. The functional significance of this acquired paternal pattern of gene expression was demonstrated by the ability to complement PWS phenotypes by maternal inheritance of the PWS-IC deletion, which is in stark contrast to paternal inheritance of the PWS-IC deletion that resulted in the PWS phenotypes. Importantly, low levels of expression of the paternally expressed imprinted genes are sufficient to rescue postnatal lethality and growth retardation in two PWS mouse models. These findings open the opportunity for a novel approach to the treatment of PWS

Necdin Protects Embryonic Motoneurons from Programmed Cell Death

NECDIN belongs to the type II Melanoma Associated Antigen Gene Expression gene family and is located in the Prader-Willi Syndrome (PWS) critical region. Necdin-deficient mice develop symptoms of PWS, including a sensory and motor deficit. However, the mechanisms underlying the motor deficit remain elusive. Here, we show that the genetic ablation of Necdin, whose expression is restricted to post-mitotic neurons in the spinal cord during development, leads to a loss of 31% of specified motoneurons. The increased neuronal loss occurs during the period of naturally-occurring cell death and is not confined to specific pools of motoneurons. To better understand the role of Necdin during the period of programmed cell death of motoneurons we used embryonic spinal cord explants and primary motoneuron cultures from Necdin-deficient mice. Interestingly, while Necdin-deficient motoneurons present the same survival response to neurotrophic factors, we demonstrate that deletion of Necdin leads to an increased susceptibility of motoneurons to neurotrophic factor deprivation. We show that by neutralizing TNFα this increased susceptibility of Necdin-deficient motoneurons to trophic factor deprivation can be reduced to the normal level. We propose that Necdin is implicated through the TNF-receptor 1 pathway in the developmental death of motoneurons

Primary Vitreoretinal Lymphoma Presenting as a Posterior Capsule Plaque

Primary vitreoretinal lymphoma (PVRL) can be a diagnostic challenge and commonly presents as a partially steroid-responsive vitritis or as subretinal cream-colored infiltrates. The authors present a patient with PVRL who initially presented with bilateral vitritis; however, after two non-diagnostic vitrectomy specimens and two unremarkable brain MRIs, she was lost to follow-up. She presented 2.5 years later with a white plaque on the posterior capsule of her left intraocular lens, though the vitreous cavity was free of infiltrate. Repeat biopsy revealed diffuse large B-cell lymphoma, and brain MRI demonstrated an enhancing lesion of the cerebellum, consistent with primary central nervous system lymphoma

Transpupillary thermotherapy of occult subfoveal choroidal neovascularization in patients with age-related macular degeneration

To evaluate the efficacy of transpupillary thermotherapy for the treatment of occult subfoveal choroidal neovascularization (CNV) in patients with age-related macular degeneration. A retrospective, noncomparative case series. Sixteen eyes of 15 consecutive patients who presented with occult subfoveal choroidal neovascularization secondary to age-related macular degeneration. After informed consent was obtained, 16 eyes of 15 patients were treated with transpupillary thermotherapy. All patients underwent pretreatment fluorescein angiography and were deemed untreatable by the Macular Photocoagulation Study standard. Transpupillary thermotherapy was delivered using a diode laser at 810 nm. A variable spot size of 1.2 mm, 2.0 mm, or 3.0 mm was used depending on the size of CNV. The diode laser was delivered through a contact lens, and treatment was initiated in one spot for 60 seconds’ duration at a power range between 360 and 1000 mW. The end point was an area of no visible color change to a light-gray appearance. In all eyes, outcome was assessed by Snellen chart visual acuity and clinical examination. In 10 of 16 eyes, preoperative and postoperative fluorescein angiography and optical coherence tomography were available. In the remaining 6 of 16 eyes, exudation was measured by postoperative clinical examination alone. Three eyes (19%) showed a two-or-more-line improvement in visual acuity over a period of 6 to 25 months. Mean follow-up was 13 months. Visual acuity remained stable (no change or one-line improvement) in nine treated eyes (56%). The remaining four eyes (25%) showed a decline (equal to one-line worsening or greater) in visual acuity. Fifteen eyes (94%) demonstrated decreased exudation on fluorescein angiography, optical coherence tomography, and/or clinical examination. Transpupillary thermotherapy shows no deleterious side effects in treating occult subfoveal choroidal neovascularization. A randomized, prospective study is necessary to evaluate treatment efficacy

INTACT RETINAL TISSUE AND RETINAL PIGMENT EPITHELIUM IDENTIFIED WITHIN A COLOBOMA BY HIGH-SPEED, ULTRAHIGH-RESOLUTION OPTICAL COHERENCE TOMOGRAPHY

Purpose—To report on a posterior segment coloboma manifesting unusual morphology as determined by high-speed, ultrahigh resolution optical coherence tomography imaging (hsUHROCT). Methods—A 47-year-old patient with bilateral colobomas was evaluated via fundus examination and hsUHR-OCT. Results—Imaging with hsUHR-OCT showed intact retinal pigment epithelium (RPE) within the posterior segment coloboma. Most of the retinal layers appeared to continue into the coloboma, although they exhibited slight attenuation. The external limiting membrane (ELM) was clearly visible continuing within the coloboma, suggesting that Muller cells and the inner segments of the photoreceptors were still present in this area. The junction between the inner and outer segments of the photoreceptors ended at the margin of the coloboma, which may be due to either photoreceptor disruption or a change in the orientation of the outer segments. Conclusion—hsUHR-OCT demonstrated the presence of Muller cells and photoreceptor inner segments within a posterior segment coloboma. The retinal pigment epithelium (RPE) was intact within the coloboma, representing an unusual morphology.National Institutes of Health (U.S.) (Grant R01-EY11289-21)United States. Air Force Office of Scientific Research (Contract FA9550-07-1-0101

Ultrahigh Speed Imaging of the Rat Retina Using Ultrahigh Resolution Spectral/Fourier Domain OCT

We performed OCT imaging of the rat retina at 70,000 axial scans per second with ~3 μm axial resolution. Three-dimensional OCT (3D-OCT) data sets of the rat retina were acquired. The high speed and high density data sets enable improved en face visualization by reducing eye motion artifacts and improve Doppler OCT measurements. Minimal motion artifacts were visible and the OCT fundus images offer more precise registration of individual OCT images to retinal fundus features. Projection OCT fundus images show features such as the nerve fiber layer, retinal capillary networks and choroidal vasculature. Doppler OCT images and quantitative measurements show pulsatility in retinal blood vessels. Doppler OCT provides noninvasive in vivo quantitative measurements of retinal blood flow properties and may benefit studies of diseases such as glaucoma and diabetic retinopathy. Ultrahigh speed imaging using ultrahigh resolution spectral / Fourier domain OCT promises to enable novel protocols for measuring small animal retinal structure and retinal blood flow. This non-invasive imaging technology is a promising tool for monitoring disease progression in rat and mouse models to assess ocular disease pathogenesis and response to treatment.National Institutes of Health (U.S.) (Contract 5R01-EY011289-23)National Institutes of Health (U.S.) (Contract 5R01-EY013178-09)National Institutes of Health (U.S.) (Contract 2R01-EY013516-16)National Institutes of Health (U.S.) (Contract 1R01-EY019029-01)United States. Air Force Office of Scientific Research (FA9550-07-1-0101)United States. Air Force Office of Scientific Research (FA9550-07-1-0014