Paradigm Shifts in Ophthalmic Diagnostics

Abstract

Purpose: Future advances in ophthalmology will see a paradigm shift in diagnostics from a focus on dysfunction and disease to better measures of psychophysical function and health. Practical methods to define genotypes will be increasingly important and non-invasive nanotechnologies are needed to detect molecular changes that predate histopathology.

Methods: This is not a review nor meant to be comprehensive. Specific topics have been selected to illustrate the principles of important paradigm shifts that will influence the future of ophthalmic diagnostics. It is our impression that future evaluation of vision will go beyond visual acuity to assess ocular health in terms of psychophysical function. The definition of disease will incorporate genotype into what has historically been a phenotype-centric discipline. Non-invasive nanotechnologies will enable a paradigm shift from disease detection on a cellular level to a sub-cellular molecular level.

Results: Vision can be evaluated beyond visual acuity by measuring contrast sensitivity, color vision, and macular function, as these provide better insights into the impact of aging and disease. Distortions can be quantified and the psychophysical basis of vision can be better evaluated than in the past by designing tests that assess particular macular cell function(s). Advances in our understanding of the genetic basis of eye diseases will enable better characterization of ocular health and disease. Non-invasive nanotechnologies can assess molecular changes in the lens, vitreous, and macula that predate visible pathology. Oxygen metabolism and circulatory physiology are measurable indices of ocular health that can detect variations of physiology and early disease.

Conclusions: This overview of paradigm shifts in ophthalmology suggests that the future will see significant improvements in ophthalmic diagnostics. The selected topics illustrate the principles of these paradigm shifts and should serve as a guide to further research and development. Indeed, successful implementation of these paradigm shifts in ophthalmology may provide useful guidance for similar developments in all of healthcare.

FIGURE 1

3-DIMENSIONAL THRESHOLD AMSLER GRID (3D-TAG) Left: 3-dimensional Threshold Amsler Grid testing is found superior and inferior nasal steps in the right eye of glaucoma-suspect patient with normal (B) Humphrey visual field. The 3D-TAG is much more sensitive. Grayscale figure on right is a second patient tested by 3-D TAG on two subsequent days that shows identical stair-case pattern of inferior nasal steps in the right eye only seen at lower contrast levels (the lower the contrast, the larger the field defect). Again this was in a patient with normal Humphrey visual field. The similarity between these two tests on subsequent days confirms the test/retest reproducibility. [Adapted from Nazemi et al. Early detection of glaucoma by means of a novel 3D computer-automated visual field test. Br J Ophthalmol. 2007;91(10):1331–36.] Right: Volumetric 3-dimensional plots demonstrate the location and extent of visual distortions before and after surgery for macular pucker. The volume inside the 3-dimensional tracing is calculated and expressed as the percent of the hill-of-vision afflicted with metamorphopsia. Displayed are the plots of the patient’s metamorphopsia before surgery (pre-op) and at 1, 3, 6, and 12 months after surgery (post-op). The distortions index (percent volume loss relative to the entire hill of vision) reduced from 15.80% before surgery to 4.74% at 1 month, 1.33% at 3 months, and 0.34% 12 months after surgery. [Reprinted from Nguyen J, Yee KMP, Sadun AA, Sebag J: Quantifying visual dysfunction and the response to surgery in macular pucker. Ophthalmology 2016; 123:1500–10.]

FIGURE 2

MELANOPSIN RETINAL GANGLION CELL A melanopsin retinal ganglion cell (brown) positioned along a line of normal retinal ganglion cells (blue) in a normal human retina. Note the extensions (dendrites) that are knobby, beaded and full of melanopsin which course down towards the inner nuclear layer.

FIGURE 3

CEP290-ASSOCIATED RETINAL DEGENERATION Wide field fundus (top, left) and autofluorescence images (top, right), and optical coherence tomography image (bottom) from the right eye of a 15 year old with retinal degeneration due to two null mutations in the CEP290 gene. Note the mid-peripheral bone spicule pigmentation (Top, left and right) and relative preservation of the photoreceptor layer centrally (bottom), consistent with a clinical diagnosis of RP. At the time these images were taken, the patient had visual acuity of 20/20 and 20/25, but mid-peripheral visual field loss. Full field ERG testing showed reduced but relatively well preserved scoptopic and photopic responses.

FIGURE 4

CACNA1F-ASSOCIATED RETINAL DEGENERATION Top: Fundus images from a 4 year old with CACNA1F-associated retinal degeneration Bottom: Full-field flash electroretinography according to ISCEV standards at age 3.5 months. ERG responses were recording in response to single flashes of 0.01 cd.s/m² (rod response), 3.0 cd.s/m² (rod-cone responses), or repeated flashes of 3.0 cd.s/m² (30Hz cone responses). All responses were severely attenuated, consistent with the clinical diagnosis of LCA. [adapted from Brennan ML, Schrijver I. Cystic Fibrosis: A review of associated phenotypes, use of molecular diagnostic approaches, genetic characteristics, progress, and Dilemmas. J Mol Diag 2016;18:3–14]

FIGURE 5

DYNAMIC LIGHT SCATTERING OF THE HUMAN LENS IN VIVO Left: Particle size distribution of the human lens at different ages The histograms display the particle size distribution obtained with non-invasive dynamic light scattering in 3 individuals of different ages. There is a shift to the right denoting larger particle sizes with advancing age. [courtesy of Dr. Rafat Ansari and Dr. Manuel Datiles] Right: Progression of Nuclear Sclerosis in a 43 year-old patient over 20 months. There is a decrease in the a-crystallin index (ACI) corresponding to an increase in lens opacification (NO=nuclear opacification) as assessed by AREDS nuclear opacification grading. [AREDS: Age-Related Eye Disease Study; OD=right eye; OS=left eye] [Reprinted with permission from: Datiles MB 3rd, Ansari RR, Yoshida J, et al: Longitudinal study of age-related cataract using dynamic light scattering: loss of α-crystallin leads to nuclear cataract development. Ophthalmology. 2016;123(2):248–54.]

FIGURE 6

OCT ANGIOGRAPHY (OCTA) IN GLAUCOMA Disc photographs (A1, A2), optical coherence tomography (OCT) reflectance (B1, B2), whole-depth OCT angiograms (C1, C2, en face maximum projection), and cross-sectional angiograms (D1, D2, overlaying on OCT reflectance in gray scale) in the right eye of a normal subject (A1) and the left eye of a perimetric glaucoma (PG) subject (A2). Disc margins are marked by the black elliptical outlines (B1, B2, C1, C2). The position of the cross-section is shown by dotted blue lines (C1, C2). A dense microvascular network is visible on the OCTA of the normal disc (C1). This network was greatly attenuated in the glaucomatous disc (C2). [courtesy of Dr. Liang Liu, Dr. Yali Jia, and Dr. David Huang; reprinted from: Jia Y, Wei E, Wang X, Zhang X, Morrison JC, Parikh M, Lombardi LH: Optical coherence tomography angiography of optic disc perfusion in glaucoma. Ophthalmology 2014;121(7):1322–32.]

FIGURE 7

OCT ANGIOGRAPHY (OCTA) IN AGE-RELATED MACULAR DEGENERATION (Top, left) En face OCTA of the inner retina. (Top, center) En face OCTA of the outer retina showing the CNV. (Top, right) Early-phase fluorescein angiography (FA). (Bottom, left) Composite en face OCTA showing intraretinal fluid (light blue) over the CNV (yellow). (Bottom, center) Retinal thickness deviation map showing thickening over the CNV. [courtesy of Dr. Liang Liu, Dr. Yali Jia, and Dr. David Huang; Reprinted with permission from Jia Y, Bailey ST, Wilson DJ, Tan O, Klein ML, Flaxel CJ, Potsaid B: Quantitative optical coherence tomography angiography of choroidal neovascularization in age-related macular degeneration. Ophthalmology 2014;121(7):1435–44]