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1.  Optical Coherence Tomography for Age-Related Macular Degeneration and Diabetic Macular Edema 
Executive Summary
The purpose of this evidence-based review was to examine the effectiveness and cost-effectiveness of spectral-domain (SD) optical coherence tomography (OCT) in the diagnosis and monitoring of patients with retinal disease, specifically age-related macular degeneration (AMD) and diabetic macular edema (DME). Specifically, the research question addressed was:
What is the sensitivity and specificity of spectral domain OCT relative to the gold standard?
Clinical Need: Target Population and Condition
The incidence of blindness has been increasing worldwide. In Canada, vision loss in those 65 years of age and older is primarily due to AMD, while loss of vision in those 18 years of age and older is mainly due to DME. Both of these conditions are diseases of the retina, which is located at the back of the eye. At the center of the retina is the macula, a 5 mm region that is responsible for what we see in front of us, our ability to detect colour, and fine detail. Damage to the macula gives rise to vision loss, but early detection of asymptomatic disease may lead to the prevention or slowing of the vision loss process.
There are two main types of AMD, ‘dry’ and ‘wet’. Dry AMD is the more prevalent of the two, accounting for approximately 85% of cases and characterized by small deposits of extracellular material called “drusen” that build up in Bruch’s membrane of the eye. Central vision loss is gradual with blurring and eventual colour fading. Wet AMD is a less prevalent condition (15% of all AMD cases) but it accounts for 90% of severe cases. It’s characterized by the appearance of retinal fluid with vision loss due to abnormal blood vessels/leakage within weeks to months of diagnosis. In 2003, the Canadian National Institute for the Blind (CNIB) prevalence estimate for AMD was 1 million Canadians, including approximately 400,000 affected Ontarians. The incidence in 2003 was estimated to be 78,000 new cases in Canada, with approximately one-third of these cases arising in Ontario (n=26,000). Over the next 25 years, the number of new cases is expected to triple.
DME is caused by complications of diabetes mellitus, both Type 1 and Type 2. It is estimated that 1-in-4 persons with diabetes has this condition, though it occurs more frequently among those with type 2 diabetes. The condition is characterized by a swelling of the retina caused by leakage of blood vessels at the back of the eye. In early stages of the disease, vision may still be normal but it can degrade rapidly in later stages. In 2003, the CNIB prevalence estimate for DME was 0.5 million Canadians, with approximately 200,000 Ontarians affected. The incidence of DME is more difficult to ascertain; however, based on an annual incidence rate of 0.8% (for those 20 years of age or older) and the assumption that 1-in-4 persons with diabetes is affected, the incidence of DME in Ontario is estimated to be 21,000 new cases per year.
Optical Coherence Tomography
Prior to the availability of OCT, the standard of care in the diagnosis and/or monitoring of retinal disease was serial testing with fluorescein angiography (FA), biomicroscopy (BM), and stereo-fundus photography (SFP). Each of these is a qualitative measure of disease based on subjective evaluations that are largely dependent on physician expertise. OCT is the first quantitative visual test available for the diagnosis of eye disease. As such, it is allows for a more objective evaluation of the presence/absence of retinal disease and it is the only test that provides a measure of retinal thickness. The technology was developed at the Michigan Institute of Technology (MIT) in 1991 as a real-time imaging modality and is considered comparable to histology. It’s a light-wave based technology producing cross-sectional images with scan rates and resolution parameters that have greatly improved over the last 10 years. It’s also a non-invasive, non-contact visual test that requires just 3 to 5 minutes to assess both eyes.
There are two main types of OCT system, both licensed by Health Canada as class II devices. The original patent was based on a time domain (TD) system (available from 1995) that had an image rate of 100 to 400 scans per second and provided information for a limited view of the retina with a resolution in the range of 10 to 20 μm. The newer system, spectral domain (SD) OCT, has been available since 2006. Improvements with this system include (i) a faster scan speed of approximately 27,000 scans per second; (ii) the ability to scan larger areas of the retina by taking six scans radially-oriented 30 degrees from each other; (iii) increased resolution at 5μm; and (iv) ‘real-time registration,’ which was not previously available with TD.
The increased scan speed of SD systems enables the collection of additional real-time information on larger regions of the retina, thus, reducing the reliance on assumptions required for retinal thickness and volume estimates based on software algorithms. The faster scan speed also eliminates image distortion arising from patient movement (not previously possible with TD), while the improvement in resolution allows for clearer and more distinguishable retinal layers with the possibility of detecting earlier signs of disease. Real-time registration is a new feature of SD that enables the identification of specific anatomical locations on the retina, against which subsequent tests can be evaluated. This is of particular importance in the monitoring of patients. In the evaluation of treatment effects, for example, this enables the same anatomic retinal location to be identified at each visit.
Literature Search
A literature search was performed on February 13, 2009 using Ovid MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 2003 to February 2009. The subject headings and keywords searched included AMD, DME, and OCT (the detailed search strategy can be viewed in Appendix 1). Excluded were case reports, comments, editorials, non-systematic reviews, and letters. Abstacts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. In total, 542 articles were included for review.
English-language articles and health technology assessments.
RCTs and observational studies of OCT and AMD or DME.
Studies focusing on either diagnosis or monitoring of disease.
Studies in which outcomes were not specific to those of interest in this report.
Studies of pediatric populations.
Studies on OCT as a screening tool.
Studies that did not assess comparative effectiveness of OCT with a referent, as specified below in “Comparisons of Interest”.
Outcomes of Interest
Studies of sensitivity, specificity.
Comparisons of Interest
Evidence exists for the following comparisons of interest:
OCT compared with the reference “fluorescein angiography” for AMD.
OCT compared with the reference “biomicroscopy” or “stereo or fundus photography” for DME.
Summary of Existing Evidence
No evidence for the accuracy of SD OCT compared to either FA, BM or SFP was published between January 2006 to February 2009; however, two technology assessments were found, one from Alberta and the other from Germany, both of which contain evidence for TD OCT. Although these HTAs included eight studies each, only one study from each report was specific to this review. Additionally, one systematic review was identified for OCT and DME. It is these three articles, all pertaining to time and not spectral domain OCT, as well as comments from experts in the field of OCT and retinal disease, that comprise the evidence contained in this review.
Upon further assessment and consultations with experts in the methodology of clinical test evaluation, it was concluded that these comparators could not be used as references in the evaluation of OCT. The main conclusion was that, without a third test as an arbiter, it is not possible to directly compare the sensitivity and specificity of OCT relative to either FA for AMD and stereo- or fundus – photography for DME. Therefore, in the absence of published evidence, it was deemed appropriate to consult a panel of experts for their views and opinions on the validity of OCT and its utility in clinical settings. This panel consisted of four clinicians with expertise in AMD and/or DME and OCT, as well as a medical biophysicist with scientific expertise in ocular technologies. This is considered level 5 evidence, but in the absence of an appropriate comparator for further evaluation of OCT, this may be the highest level of evidence possible.
Summary of Findings
The conclusions for SD OCT based on Level 5 evidence, or expert consultation, are as follows:
OCT is considered an essential part of the diagnosis and follow-up of patients with DME and AMD.
OCT is adjunctive to FA for both AMD and DME but should decrease utilization of FA as a monitoring modality.
OCT will result in a decline in the use of BM in the monitoring of patients with DME, given its increased accuracy and consistency.
OCT is diffusing rapidly and the technology is changing. Since FA is still considered pivotal in the diagnosis and treatment of AMD and DME, and there is no common outcome against which to compare these technologies, it is unlikely that RCT evidence of efficacy for OCT will ever be forthcoming.
In addition to the accuracy of OCT in the detection of disease, assessment of the clinical utility of this technology included a rapid review of treatment effects for AMD and DME. The treatment of choice for AMD is Lucentis®, with or without Avastin® and photodynamic therapy. For DME the treatment of choice is laser photocoagulation, which may be replaced with Lucentis® injections (Expert consultation). The evidence, as presented in systematic reviews and other health technology assessments, indicates that there are effective treatments available for both AMD and DME.
Considerations for the Ontario Health System
OCT testing is presently an uninsured service in Ontario with patients paying approximately $150 out-of-pocket per test. Several provinces do provide funding for this procedure, including British Columbia, Alberta, Saskatchewan, Newfoundland, Nova Scotia, Prince Edward Island, and the Yukon Territory. Provinces that do not provide such funding are Quebec, Manitoba and New Brunswick.
The demand for OCT is expected to increase with aging of the population.
PMCID: PMC3377511  PMID: 23074517
2.  Comparison of Ultrahigh- and Standard-Resolution Optical Coherence Tomography for Imaging Macular Pathology 
Ophthalmology  2005;112(11):1922.e1-1922.15.
To compare ultrahigh-resolution optical coherence tomography (UHR OCT) with standard-resolution OCT for imaging macular diseases, develop baselines for interpreting OCT images, and identify situations where UHR OCT can provide additional information on disease morphology.
Cross-sectional study.
One thousand two eyes of 555 patients with different macular diseases including macular hole, macular edema, central serous chorioretinopathy, age-related macular degeneration (AMD), choroidal neovascularization, epiretinal membrane, retinal pigment epithelium (RPE) detachment, and retinitis pigmentosa.
A UHR ophthalmic OCT system that achieves 3-μm axial image resolution was developed for imaging in the ophthalmology clinic. Comparative studies were performed with both UHR OCT and standard 10-μm-resolution OCT. Standard scanning protocols of 6 radial 6-mm scans through the fovea were obtained with both systems. Ultrahigh-resolution OCT and standard-resolution OCT images were correlated with standard ophthalmic examination techniques (dilated ophthalmoscopy, fluorescein angiography, indocyanine green angiograms) to assess morphological information contained in the images.
Main Outcome Measures
Ultrahigh-resolution and standard-resolution OCT images of macular pathologies.
Correlations of UHR OCT images, standard-resolution images, fundus examination, and/or fluorescein angiography were demonstrated in full-thickness macular hole, central serous chorioretinopathy, macular edema, AMD, RPE detachment, epiretinal membrane, vitreal macular traction, and retinitis pigmentosa. Ultrahigh-resolution OCT and standard-resolution OCT exhibited comparable performance in differentiating thicker retinal layers, such as the retinal nerve fiber, inner and outer plexiform, and inner and outer nuclear. Ultrahigh-resolution OCT had improved performance differentiating finer structures or structures with lower contrast, such as the ganglion cell layer and external limiting membrane. Ultrahigh-resolution OCT confirmed the interpretation of features, such as the boundary between the photoreceptor inner and outer segments, which is also visible in standard-resolution OCT. The improved resolution of UHR OCT is especially advantageous in assessing photoreceptor morphology.
Ultrahigh-resolution OCT enhances the visualization of intraretinal architectural morphology relative to standard-resolution OCT. Ultrahigh-resolution OCT images can provide a baseline for defining the interpretation of standard-resolution images, thus enhancing the clinical utility of standard OCT imaging. In addition, UHR OCT can provide additional information on macular disease morphology that promises to improve understanding of disease progression and management.
PMCID: PMC1937402  PMID: 16183127
3.  In vivo imaging of the Mouse Model of X-Linked Juvenile Retinoschisis Using Fourier Domain Optical Coherence Tomography 
The purpose of this study is to investigate Fourier Domain Optical Coherence Tomography (FD OCT) as a non-invasive tool for retinal imaging in the Rs1h knockout mouse (model for X-linked Juvenile Retinoschisis).
A prototype spectrometer based FD OCT system was used in combination with a custom optical beam-scanning platform. Images of the retinas from wild type and Rs1h knockout mice were acquired non-invasively using FD OCT with the specimen anesthetized. At the completion of the non-invasive FD OCT imaging, invasive retinal cross sectional images (histology) were acquired from a nearby region for comparison to the FD OCT images.
The retinal layers could be identified in the FD OCT images, permitting delineation and thickness measurement of the outer nuclear layer (ONL). During FD OCT in vivo imaging of the Rs1h knockout mouse, holes were observed in the inner nuclear layer (INL) and retinal cell disorganization was observed as a change in the backscattering intensity profile. Comparison of the ONL measurements acquired non-invasively using FD OCT to measurements taken using histology at nearby locations showed a degeneration of roughly thirty percent of the ONL by the age of two months in Rs1h knockout mice relative to wild type.
FD OCT has been demonstrated for non-invasive imaging of retinal degeneration and observation of retinal holes in Rs1h knockout mice.
PMCID: PMC2693243  PMID: 19182246
4.  Spectral-Domain Optical Coherence Tomography of the Rodent Eye: Highlighting Layers of the Outer Retina Using Signal Averaging and Comparison with Histology 
PLoS ONE  2014;9(5):e96494.
Spectral-Domain Optical Coherence Tomography (SD-OCT) is a widely used method to observe retinal layers and follow pathological events in human. Recently, this technique has been adapted for animal imaging. This non-invasive technology brings a cross-sectional visualization of the retina, which permits to observe precisely each layer. There is a clear expansion of the use of this imaging modality in rodents, thus, a precise characterization of the different outer retinal layers observed by SD-OCT is now necessary to make the most of this technology. The identification of the inner strata until the outer nuclear layer has already been clearly established, while the attribution of the layers observed by SD-OCT to the structures corresponding to photoreceptors segments and retinal pigment epithelium is much more questionable. To progress in the understanding of experimental SD-OCT imaging, we developed a method for averaging SD-OCT data to generate a mean image allowing to better delineate layers in the retina of pigmented and albino strains of mice and rats. It allowed us to locate precisely the interface between photoreceptors and retinal pigment epithelium and to identify unambiguously four layers corresponding to the inner and outer parts of photoreceptors segments. We show that the thickness of the various layers can be measured as accurately in vivo on SD-OCT images, than post-mortem by a morphometric analysis of histological sections. We applied SD-OCT to different models and demonstrated that it allows analysis of focal or diffuse retinal pathological processes such as mutation-dependant damages or light-driven modification of photoreceptors. Moreover, we report a new method of combined use of SD-OCT and integration to quantify laser-induced choroidal neovascularization. In conclusion, we clearly demonstrated that SD-OCT represents a valuable tool for imaging the rodent retina that is at least as accurate as histology, non-invasive and allows longitudinal follow-up of the same animal.
PMCID: PMC4008571  PMID: 24788712
5.  Human CRB1-Associated Retinal Degeneration: Comparison with the rd8 Crb1-Mutant Mouse Model 
The common form of Leber congenital amaurosis (LCA) due to CRB1 mutations needs further characterization of the human disease and a test of relevance of currently available animal models. A cohort of these patients was evaluated, and the disease expression was compared to that of the rd8 mouse model, to seek answers to questions of how to move CRB1-LCA closer to therapy.
To investigate the human disease due to CRB1 mutations and compare results with the Crb1-mutant rd8 mouse.
Twenty-two patients with CRB1 mutations were studied. Function was assessed with perimetry and electroretinography (ERG) and retinal structure with optical coherence tomography (OCT). Cortical structure and function were quantified with magnetic resonance imaging (MRI). Rd8 mice underwent ERG, OCT, and retinal histopathology.
Visual acuities ranged from 20/25 to light perception. Rod ERGs were not detectable; small cone signals were recordable. By perimetry, small central visual islands were separated by midperipheral scotomas from far temporal peripheral islands. The central islands were cone mediated, whereas the peripheral islands retained some rod function. With OCT, there were small foveal islands of thinned outer nuclear layer (ONL) surrounded by thick delaminated retina with intraretinal hyperreflective lesions. MRI showed structurally normal optic nerves and only subtle changes to occipital lobe white and gray matter. Functional MRI indicated that whole-brain responses from patients were of reduced amplitude and spatial extent compared with those of normal controls. Rd8 mice had essentially normal ERGs; OCT and histopathology showed patchy retinal disorganization with pseudorosettes more pronounced in ventral than in dorsal retina. Photoreceptor degeneration was associated with dysplastic regions.
CRB1 mutations lead to early-onset severe loss of vision with thickened, disorganized, nonseeing retina. Impaired peripheral vision can persist in late disease stages. Rd8 mice also have a disorganized retina, but there is sufficient photoreceptor integrity to produce largely normal retinal function. Differences between human and mouse diseases will complicate proof-of-concept studies intended to advance treatment initiatives.
PMCID: PMC3176016  PMID: 21757580
6.  Spectral Domain Optical Coherence Tomography in Mouse Models of Retinal Degeneration 
Spectral domain optical coherence tomography (SD-OCT) allows cross-sectional visualization of retinal structures in vivo. Here, we report the efficacy of a commercially available SD-OCT device to study mouse models of retinal degeneration.
C57BL/6 and BALB/c wild type mice and three different mouse models of hereditary retinal degeneration (Rho-/-, rd1, RPE65-/-) were investigated using confocal scanning laser ophthalmoscopy (cSLO) for en face visualization and SD-OCT for cross-sectional imaging of retinal structures. Histology was performed to correlate structural findings in SD-OCT with light microscopic data.
In C57BL/6 and BALB/c mice, cSLO and SD-OCT imaging provided structural details of frequently used control animals (central retinal thickness, CRTC57BL/6 = 237±2μm and CRTBALB/c = 211±10μm). RPE65-/- mice at 11 months of age showed a significant reduction of retinal thickness (CRTRPE65 = 193±2μm) with thinning of the outer nuclear layer. Rho-/- mice at P28 demonstrated degenerative changes mainly in the outer retinal layers (CRTRho = 193±2μm). Examining rd1 animals before and after the onset of retinal degeneration allowed to monitor disease progression (CRTrd1 P11 = 246±4μm, CRTrd1 P28 = 143±4μm). Correlation of CRT assessed by histology and SD-OCT was high (r2 = 0.897).
We demonstrated cross sectional visualization of retinal structures in wild type mice and mouse models for retinal degeneration in vivo using a commercially available SD-OCT device. This method will help to reduce numbers of animals needed per study by allowing longitudinal study designs and facilitate characterization of disease dynamics and evaluation of putative therapeutic effects following experimental interventions.
PMCID: PMC2800101  PMID: 19661229
optical coherence tomography; retinal degeneration; imaging; mouse models
7.  Analysis of Peripapillary Atrophy using Spectral Domain Optical Coherence Tomography 
Ophthalmology  2011;118(3):531-536.
To study retinal morphological changes around the optic disc in patients with peripapillary atrophy (PPA) with high-resolution spectral domain optical coherence tomography (SD OCT).
Cross-sectional, retrospective analysis
One hundred and three eyes of 73 patients with PPA and 21 eyes of 12 normal patients seen at the New England Eye Center, Tufts Medical Center between January 2007 and August 2009.
SD OCT images taken through the region of PPA were quantitatively and qualitatively analyzed. Inclusion criteria included eyes with at least 300 μm of temporal PPA as detected on color fundus photographs. The study population was divided into subgroups according to the following clinical diagnoses: glaucoma (n=13), age-related macular degeneration (n=11), high myopia (n=11), glaucoma and high myopia (n=3), and optic neuropathy (n=11). Fifty-four patients were classified with other diagnoses. Using OCT software, retinal thickness and retinal nerve fiber layer thickness (RNFL) were both manually measured perpendicular to the internal limiting membrane and retinal pigment epithelium (RPE) 300 μm temporal to the optic disc, within the region of peripapillary atrophy. Qualitative analysis for morphological changes in the atrophic area was also performed.
Main outcome measures
Qualitative assessment and quantitative measures of retinal and retinal nerve fiber layer thickness in PPA.
The study group was categorized by 6 characteristics demonstrated in the area of PPA by SD OCT: RPE loss with accompanying photoreceptor loss, RPE disruption, RNFL thickening with plaque-like formation, intraretinal cystic changes, inner and outer retinal thinning, and abnormal retinal sloping. Statistical analysis of measurements revealed a statistically significant difference in the total retinal thickness between normal eyes and eyes with PPA (p = 0.0005), with normals 15% thicker than the PPA group; however, the RNFL thickness was not significantly different between the normal and PPA group (p = 0.05).
Eyes with peripapillary atrophy manifest characteristic retinal changes that can be described via SD OCT.
PMCID: PMC3017221  PMID: 20920826
8.  Non-invasive assessment of retinal alterations in mouse models of infantile and juvenile neuronal ceroid lipofuscinosis by spectral domain optical coherence tomography 
The neuronal ceroid lipofuscinoses constitute a group of fatal inherited lysosomal storage diseases that manifest in profound neurodegeneration in the CNS. Visual impairment usually is an early symptom and selective degeneration of retinal neurons has been described in patients suffering from distinct disease subtypes. We have previously demonstrated that palmitoyl protein thioesterase 1 deficient (Ppt1-/-) mice, a model of the infantile disease subtype, exhibit progressive axonal degeneration in the optic nerve and loss of retinal ganglion cells, faithfully reflecting disease severity in the CNS. Here we performed spectral domain optical coherence tomography (OCT) in Ppt1-/- and ceroid lipofuscinosis neuronal 3 deficient (Cln3-/-) mice, which are models of infantile and juvenile neuronal ceroid lipofuscinosis, respectively, in order to establish a non-invasive method to assess retinal alterations and monitor disease severity in vivo.
Blue laser autofluorescence imaging revealed increased accumulation of autofluorescent storage material in the inner retinae of 7-month-old Ppt1-/- and of 16-month-old Cln3-/- mice in comparison with age-matched control littermates. Additionally, optical coherence tomography demonstrated reduced thickness of retinae in knockout mice in comparison with age-matched control littermates. High resolution scans and manual measurements allowed for separation of different retinal composite layers and revealed a thinning of layers in the inner retinae of both mouse models at distinct ages. OCT measurements correlated well with subsequent histological analysis of the same retinae.
These results demonstrate the feasibility of OCT to assess neurodegenerative disease severity in mouse models of neuronal ceroid lipofuscinosis and might have important implications for diagnostic evaluation of disease progression and therapeutic efficacy in patients. Moreover, the non-invasive method allows for longitudinal studies in experimental models, reducing the number of animals used for research.
PMCID: PMC4035096  PMID: 24887158
Optical coherence tomography; Neuronal ceroid lipofuscinosis; Neurodegeneration; Retinal degeneration; Lysosomal storage disease
9.  Long-Term Characterization of Retinal Degeneration in rd1 and rd10 Mice Using Spectral Domain Optical Coherence Tomography 
We characterize the in vivo changes over time in the retinal structure of wild-type mice alongside two lines of mice deficient in the β-subunit of phosphodiesterase (rd1 and rd10 mice) using spectral domain optical coherence tomography (SD-OCT).
SD-OCT images were obtained using the Bioptigen spectral domain ophthalmic imaging system (SDOIS). Wild-type C57BL/6J, rd1 and rd10 mice ranging in age from P14 to P206 were sedated with 1% isoflurane. Horizontal and vertical linear scans through the optic nerve, and annular scans around the optic nerve were obtained.
SD-OCT imaging of wild-type mice demonstrated visibility of the inner segment/outer segment (IS/OS) junction, external limiting membrane (ELM), outer nuclear layer (ONL), and outer plexiform layer (OPL). At P14, most rd10 mice exhibited normal SD-OCT profiles, but some displayed changes in the IS/OS junction. At the same time point, rd1 mice had severe outer retinal degeneration. In rd10 mice, imaging revealed loss of the IS/OS junction by P18, hyperreflective changes in the ONL at P20, hyperreflective vitreous opacities, and shallow separation of the neural retina from the RPE. Retinal separations were not observed in rd1 mice. Segmentation analysis in wild-type mice demonstrated relatively little variability between animals, while in rd10 and rd1 mice there was a steady decline in outer retinal thickness. Histologic studies demonstrated correlation of retinal features with those seen on SD-OCT scans. Segmentation analysis provides a quantitative and reproducible method for measuring in vivo retinal changes in mice.
SD-OCT provides a non-invasive method of following long-term retinal changes in mice in vivo. Although rd10 and rd1 mice have mutations in the same gene, they demonstrate significantly different features on SD-OCT.
SD-OCT imaging in rd1 and rd10 mice provided quantitative measurements of inner and outer retinal thickness and revealed several previously unreported results including frequent in vivo separation of the retina from the retinal pigment epithelium in the rd10 mouse, but not in the rd1 mouse.
PMCID: PMC3394742  PMID: 22562504
10.  Three-dimensional Retinal Imaging with High-Speed Ultrahigh-Resolution Optical Coherence Tomography 
Ophthalmology  2005;112(10):1734-1746.
To demonstrate high-speed, ultrahigh-resolution, 3-dimensional optical coherence tomography (3D OCT) and new protocols for retinal imaging.
Ultrahigh-resolution OCT using broadband light sources achieves axial image resolutions of ~2 μm compared with standard 10-μm-resolution OCT current commercial instruments. High-speed OCT using spectral/Fourier domain detection enables dramatic increases in imaging speeds. Three-dimensional OCT retinal imaging is performed in normal human subjects using high-speed ultrahigh-resolution OCT. Three-dimensional OCT data of the macula and optic disc are acquired using a dense raster scan pattern. New processing and display methods for generating virtual OCT fundus images; cross-sectional OCT images with arbitrary orientations; quantitative maps of retinal, nerve fiber layer, and other intraretinal layer thicknesses; and optic nerve head topographic parameters are demonstrated.
Three-dimensional OCT imaging enables new imaging protocols that improve visualization and mapping of retinal microstructure. An OCT fundus image can be generated directly from the 3D OCT data, which enables precise and repeatable registration of cross-sectional OCT images and thickness maps with fundus features. Optical coherence tomography images with arbitrary orientations, such as circumpapillary scans, can be generated from 3D OCT data. Mapping of total retinal thickness and thicknesses of the nerve fiber layer, photoreceptor layer, and other intraretinal layers is demonstrated. Measurement of optic nerve head topography and disc parameters is also possible. Three-dimensional OCT enables measurements that are similar to those of standard instruments, including the StratusOCT, GDx, HRT, and RTA.
Three-dimensional OCT imaging can be performed using high-speed ultrahigh-resolution OCT. Three-dimensional OCT provides comprehensive visualization and mapping of retinal microstructures. The high data acquisition speeds enable high-density data sets with large numbers of transverse positions on the retina, which reduces the possibility of missing focal pathologies. In addition to providing image information such as OCT cross-sectional images, OCT fundus images, and 3D rendering, quantitative measurement and mapping of intraretinal layer thickness and topographic features of the optic disc are possible. We hope that 3D OCT imaging may help to elucidate the structural changes associated with retinal disease as well as improve early diagnosis and monitoring of disease progression and response to treatment.
PMCID: PMC1939719  PMID: 16140383
11.  High-Definition and 3-dimensional Imaging of Macular Pathologies with High-speed Ultrahigh-Resolution Optical Coherence Tomography 
Ophthalmology  2006;113(11):2054.e1-2054.14.
To assess high-speed ultrahigh-resolution optical coherence tomography (OCT) image resolution, acquisition speed, image quality, and retinal coverage for the visualization of macular pathologies.
Retrospective cross-sectional study.
Five hundred eighty-eight eyes of 327 patients with various macular pathologies.
High-speed ultrahigh-resolution OCT images were obtained in 588 eyes of 327 patients with selected macular diseases. Ultrahigh-resolution OCT using Fourier/spectral domain detection achieves ~3-μm axial image resolutions, acquisition speeds of ~25 000 axial scans per second, and >3 times finer resolution and >50 times higher speed than standard OCT. Three scan protocols were investigated. The first acquires a small number of high-definition images through the fovea. The second acquires a raster series of high-transverse pixel density images. The third acquires 3-dimensional OCT data using a dense raster pattern. Three-dimensional OCT can generate OCT fundus images that enable precise registration of OCT images with the fundus. Using the OCT fundus images, OCT results were correlated with standard ophthalmoscopic examination techniques.
Main Outcome Measures
High-definition macular pathologies.
Macular holes, age-related macular degeneration, epiretinal membranes, diabetic retinopathy, retinal dystrophies, central serous chorioretinopathy, and other pathologies were imaged and correlated with ophthalmic examination, standard OCT, fundus photography, and fluorescein angiography, where applicable. High-speed ultrahigh-resolution OCT generates images of retinal pathologies with improved quality, more comprehensive retinal coverage, and more precise registration than standard OCT. The speed preserves retinal topography, thus enabling the visualization of subtle changes associated with disease. High-definition high-transverse pixel density OCT images improve visualization of photoreceptor and pigment epithelial morphology, as well as thin intraretinal and epiretinal structures. Three-dimensional OCT enables comprehensive retinal coverage, reduces sampling errors, and enables assessment of 3-dimensional pathology.
High-definition 3-dimensional imaging using high-speed ultrahigh-resolution OCT improves image quality, retinal coverage, and registration. This new technology has the potential to become a useful tool for elucidating disease pathogenesis and improving disease diagnosis and management.
PMCID: PMC1939823  PMID: 17074565
12.  Projection OCT fundus imaging for visualising outer retinal pathology in non-exudative age-related macular degeneration 
To demonstrate ultrahigh-resolution, three-dimensional optical coherence tomography (3D-OCT) and projection OCT fundus imaging for enhanced visualisation of outer retinal pathology in non-exudative age-related macular degeneration (AMD).
A high-speed, 3.5 μm resolution OCT prototype instrument was developed for the ophthalmic clinic. Eighty-three patients with non-exudative AMD were imaged. Projection OCT fundus images were generated from 3D-OCT data by selectively summing different retinal depth levels. Results were compared with standard ophthalmic examination, including fundus photography and fluorescein angiography, when indicated.
Projection OCT fundus imaging enhanced the visualisation of outer retinal pathology in non-exudative AMD. Different types of drusen exhibited distinct features in projection OCT images. Photoreceptor disruption was indicated by loss of the photoreceptor inner/outer segment (IS/OS) boundary and external limiting membrane (ELM). RPE atrophy can be assessed using choroid-level projection OCT images.
Projection OCT fundus imaging facilities rapid interpretation of large 3D-OCT data sets. Projection OCT enhances contrast and visualises outer retinal pathology not visible with standard fundus imaging or OCT fundus imaging. Projection OCT fundus images enable registration with standard ophthalmic diagnostics and cross-sectional OCT images. Outer retinal alterations can be assessed and drusen morphology, photoreceptor impairment and pigmentary abnormalities identified.
PMCID: PMC2743133  PMID: 18662918
13.  Retinal Structure and Function in Achromatopsia: Implications for Gene Therapy 
Ophthalmology  2013;121(1):234-245.
To characterize retinal structure and function in achromatopsia (ACHM) in preparation for clinical trials of gene therapy.
Cross-sectional study.
Forty subjects with ACHM.
All subjects underwent spectral domain optical coherence tomography (SD-OCT), microperimetry, and molecular genetic testing. Foveal structure on SD-OCT was graded into 5 distinct categories: (i) continuous inner segment ellipsoid (ISe), (ii) ISe disruption, (iii) ISe absence, (iv) presence of a hyporeflective zone (HRZ), and (v) outer retinal atrophy including retinal pigment epithelial (RPE) loss. Foveal and outer nuclear layer (ONL) thickness was measured, and presence of hypoplasia determined.
Main Outcome Measures
Photoreceptor appearance on SD-OCT imaging; foveal and ONL thickness; presence of foveal hypoplasia; retinal sensitivity and fixation stability; and association of these parameters with age and genotype.
Forty subjects with mean age of 24.9 years (range 6 to 52) were included. Disease-causing variants were found in CNGA3 (n=18), CNGB3 (n=15), GNAT2 (n=4), and PDE6C (n=1). No variants were found in 2 individuals. 22.5% of subjects had a continuous ISe layer at the fovea; 27.5% had ISe disruption; 20% had an absent ISe layer; 22.5% had a HRZ; and 7.5% had outer retinal atrophy. No significant differences in age (p=0.77), mean retinal sensitivity (p=0.21) or fixation stability (p=0.34) across the 5 SD-OCT categories were evident. No significant correlation was found between age and foveal thickness (p=0.84), or between age and foveal ONL thickness (p=0.12).
The lack of clear association of disruption of retinal structure or function in ACHM with age suggests that the window of opportunity for intervention by gene therapy is wider in some individuals than previously indicated. Therefore the potential benefit for a given subject is likely to be better predicted by specific measurement of photoreceptor structure rather than simply by age. The ability to directly assess cone photoreceptor preservation with SD-OCT and/or adaptive optics imaging is likely to prove invaluable in selecting subjects for future trials and measuring their impact.
PMCID: PMC3895408  PMID: 24148654
14.  Inner and Outer Retinal Changes in Retinal Degenerations Associated With ABCA4 Mutations 
To investigate in vivo inner and outer retinal microstructure and effects of structural abnormalities on visual function in patients with retinal degeneration caused by ABCA4 mutations (ABCA4-RD).
Patients with ABCA4-RD (n = 45; age range, 9–71 years) were studied by spectral-domain optical coherence tomography (OCT) scans extending from the fovea to 30° eccentricity along horizontal and vertical meridians. Thicknesses of outer and inner retinal laminae were analyzed. Serial OCT measurements available over a mean period of 4 years (range, 2–8 years) allowed examination of the progression of outer and inner retinal changes. A subset of patients had dark-adapted chromatic static threshold perimetry.
There was a spectrum of photoreceptor layer thickness changes from localized central retinal abnormalities to extensive thinning across central and near midperipheral retina. The inner retina also showed changes. There was thickening of the inner nuclear layer (INL) that was mainly associated with regions of photoreceptor loss. Serial data documented only limited change in some patients while others showed an increase in outer nuclear layer (ONL) thinning accompanied by increased INL thickening in some regions imaged. Visual function in regions both with and without INL thickening was describable with a previously defined model based on photoreceptor quantum catch.
Inner retinal laminar abnormalities, as in other human photoreceptor diseases, can be a feature of ABCA4-RD. These changes are likely due to the retinal remodeling that accompanies photoreceptor loss. Rod photoreceptor-mediated visual loss in retinal regionswith inner laminopathy at the stages studied did not exceed the prediction from photoreceptor loss alone.
ABCA4-retinal degenerations were studied for inner retinal microstructural changes in patients representing a wide spectrum of outer retinopathy. Inner retinal laminar defects were associated with outer retinal abnormality. Visual dysfunction in retina with inner laminopathy was not more than expected from photoreceptor loss alone.
PMCID: PMC3968929  PMID: 24550365
retinal remodeling; optical coherence tomography; Stargardt disease
15.  Different effects of valproic acid on photoreceptor loss in Rd1 and Rd10 retinal degeneration mice 
Molecular Vision  2014;20:1527-1544.
The histone-deacetylase inhibitor activity of valproic acid (VPA) was discovered after VPA’s adoption as an anticonvulsant. This generated speculation for VPA’s potential to increase the expression of neuroprotective genes. Clinical trials for retinitis pigmentosa (RP) are currently active, testing VPA’s potential to reduce photoreceptor loss; however, we lack information regarding the effects of VPA on available mammalian models of retinal degeneration, nor do we know if retinal gene expression is perturbed by VPA in a predictable way. Thus, we examined the effects of systemic VPA on neurotrophic factor and Nrl-related gene expression in the mouse retina and compared VPA’s effects on the rate of photoreceptor loss in two strains of mice, Pde6brd1/rd1 and Pde6brd10/rd10.
The expression of Bdnf, Gdnf, Cntf, and Fgf2 was measured by quantitative PCR after single and multiple doses of VPA (intraperitoneal) in wild-type and Pde6brd1/rd1 mice. Pde6brd1/rd1 mice were treated with daily doses of VPA during the period of rapid photoreceptor loss. Pde6brd10/rd10 mice were also treated with systemic VPA to compare in a partial loss-of-function model. Retinal morphology was assessed by virtual microscopy or spectral-domain optical coherence tomography (SD-OCT). Full-field and focal electroretinography (ERG) analysis were employed with Pde6brd10/rd10 mice to measure retinal function.
In wild-type postnatal mice, a single VPA dose increased the expression of Bdnf and Gdnf in the neural retina after 18 h, while the expression of Cntf was reduced by 70%. Daily dosing of wild-type mice from postnatal day P17 to P28 resulted in smaller increases in Bdnf and Gdnf expression, normal Cntf expression, and reduced Fgf2 expression (25%). Nrl gene expression was decreased by 50%, while Crx gene expression was not affected. Rod-specific expression of Mef2c and Nr2e3 was decreased substantially by VPA treatment, while Rhodopsin and Pde6b gene expression was normal at P28. Daily injections with VPA (P9–P21) dramatically slowed the loss of rod photoreceptors in Pde6brd1/rd1 mice. At age P21, VPA-treated mice had several extra rows of rod photoreceptor nuclei compared to PBS-injected littermates. Dosing started later (P14) or dosing every second day also rescued photoreceptors. In contrast, systemic VPA treatment of Pde6brd10/rd10 mice (P17–P28) reduced visual function that correlated with a slight increase in photoreceptor loss. Treating Pde6brd10/rd10 mice earlier (P9–P21) also failed to rescue photoreceptors. Treating wild-type mice earlier (P9–P21) reduced the number of photoreceptors in VPA-treated mice by 20% compared to PBS-treated animals.
A single systemic dose of VPA can change retinal neurotrophic factor and rod-specific gene expression in the immature retina. Daily VPA treatment from P17 to P28 can also alter gene expression in the mature neural retina. While daily treatment with VPA could significantly reduce photoreceptor loss in the rd1 model, VPA treatment slightly accelerated photoreceptor loss in the rd10 model. The apparent rescue of photoreceptors in the rd1 model was not the result of producing more photoreceptors before degeneration. In fact, daily systemic VPA was toxic to wild-type photoreceptors when started at P9. However, the effective treatment period for Pde6brd1/rd1 mice (P9–P21) has significant overlap with the photoreceptor maturation period, which complicates the use of the rd1 model for testing of VPA’s efficacy. In contrast, VPA treatment started after P17 did not cause photoreceptor loss in wild-type mice. Thus, the acceleration of photoreceptor loss in the rd10 model may be more relevant where both photoreceptor loss and VPA treatment (P17–P28) started when the central retina was mature.
PMCID: PMC4225157  PMID: 25489226
16.  Optical Coherence Tomography Study of Experimental Anterior Ischemic Optic Neuropathy and Histologic Confirmation 
The optic nerve is part of the central nervous system, and interruption of this pathway due to ischemia typically results in optic atrophy and loss of retinal ganglion cells. In this study, we assessed in vivo retinal changes following murine anterior ischemic optic neuropathy (AION) by using spectral-domain optical coherence tomography (SD-OCT) and compared these anatomic measurements to that of histology.
We induced ischemia at the optic disc via laser-activated photochemical thrombosis, performed serial SD-OCT and manual segmentation of the retinal layers to measure the ganglion cell complex (GCC) and total retinal thickness, and correlated these measurements with that of histology.
There was impaired perfusion and leakage at the optic disc on fluorescein angiography immediately after AION and severe swelling and distortion of the peripapillary retina on day-1. We used SD-OCT to quantify the changes in retinal thickness following experimental AION, which revealed significant thickening of the GCC on day-1 after ischemia followed by gradual thinning that plateaued by week-3. Thickness of the peripapillary sensory retina was also increased on day-1 and thinned chronically. This pattern of acute retinal swelling and chronic thinning on SD-OCT correlated well with changes seen in histology and corresponded to loss of retinal ganglion layer cells after ischemia.
This was a serial SD-OCT quantification of acute and chronic changes following experimental AION, which revealed changes in the GCC similar to that of human AION, but over a time frame of weeks rather than months.
SD-OCT imaging in experimental murine AION revealed the spectrum of anatomic changes following ischemia with initial swelling and gradual thinning out to 3-4 weeks. SD-OCT findings were corroborated by histologic analysis and correlated with gradual loss of retinal ganglion cells over several weeks.
PMCID: PMC3771554  PMID: 23887804
AION; animal model; SD-OCT; retinal ganglion cell; optic neuropathy
17.  Structural Correlation Between the Nerve Fiber Layer and Retinal Ganglion Cell Loss in Mice with Targeted Disruption of the Brn3b Gene 
Manual segmentation of SD-OCT images allows for the noninvasive characterization of retinal layers in Brn3b knockout mice. Brn3b knockouts have generalized loss of retinal ganglion cells; segmentation results were correlated with histologic cell counts.
Mice with a targeted disruption of Brn3b (knockout Brn3b-/-) undergo the loss of a majority of retinal ganglion cells (RGCs) before birth. Spectral domain optical coherence tomography (SD-OCT) allows for the noninvasive examination of Brn3b-/- cellular loss in vivo.
The central retinas of Brn3b-/- and phenotypically wild-type (Brn3b+/+ and Brn3b±) mice were imaged by SD-OCT. The combined nerve fiber layer (NFL) and inner plexiform layer (IPL) were manually segmented and thickness maps were generated. The results were confirmed by histologic and immunofluorescence cell counts of the RGC layer (RGCL) of the same retinas.
The combined NFL and IPL of the Brn3b-/- retinas were significantly thinner, and the histologic cell counts significantly lower, than those of the phenotypically wild-type retinas (paired t-test; P < 0.01 and P < 0.01, respectively). The combined NFL and IPL thickness and the histologic cell count correlated highly (R2 = 0.9612). Immunofluorescence staining revealed significant RGC-specific loss in Brn3b-/- retinas (paired t-test; P < 0.01). The distribution of combined central NFL and IPL loss was not localized or sectorial.
The strong correlation between the combined layer thickness and histologic cell counts validates manual OCT segmentation as a method of monitoring cell loss in the RGCL. A retinal thickness map assessed if combined NFL and IPL thickness loss in Brn3b-/- eyes was topographically specific. Generalized RGC and combined NFL and IPL loss was observed in the Brn3b-/- retinas, in contrast to topographically specific RGC loss observed in glaucomatous DBA2/J eyes.
PMCID: PMC3176044  PMID: 21622702
18.  TUDCA Slows Retinal Degeneration in Two Different Mouse Models of Retinitis Pigmentosa and Prevents Obesity in Bardet-Biedl Syndrome Type 1 Mice 
TUDCA treatment preserved ERG b-waves and the outer nuclear layer in Bardet-Biedl syndrome mice and prevented obesity assessed at P120. TUDCA treatment preserved ERG b-waves and the outer nuclear layer in rd10 mice to P30.
To evaluate and compare the protective effect of tauroursodeoxycholic acid (TUDCA) on photoreceptor degeneration in different models of retinal degeneration (RD) in mice.
BbsM390R/M390R mice were injected subcutaneously twice a week, from P40 to P120, and rd10 mice were injected every 3 days from P6 to P38 with TUDCA or vehicle (0.15 M NaHCO3). Rd1 and rd16 mice were injected daily from P6 to P30 with TUDCA or vehicle. Retinal structure and function were determined at multiple time points by electroretinography (ERG), optical coherence tomography (OCT), and histology.
The amplitude of ERG b-waves was significantly higher in TUDCA-treated Bbs1 and rd10 animals than in controls. Retinal thickness on OCT was slightly greater in treated Bbs1 animals than in the controls. Histologically, outer segments were preserved, and the outer nuclear layer was significantly thicker in the treated Bbs1 and rd10 mice than in the controls. Bbs1M390R/M390R mice developed less obesity than the control Bbs1M390R/M390R while receiving TUDCA. The Rd1 and rd16 mice showed no improvement with TUDCA treatment, and the rd1 mice did not have normal weight gain during treatment.
TUDCA treatment preserved ERG b-waves and the outer nuclear layer in Bbs1M390R/M390R mice, and prevented obesity assessed at P120. TUDCA treatment preserved ERG b-waves and the outer nuclear layer in the rd10 mice to P30. TUDCA is a prime candidate for treatment of humans with retinal degeneration, especially those with Bardet-Biedl syndrome, whom it may help not only with the vision loss, but with the debilitating obesity as well.
PMCID: PMC3292352  PMID: 22110077
19.  Real-Time Imaging of Rabbit Retina with Retinal Degeneration by Using Spectral-Domain Optical Coherence Tomography 
PLoS ONE  2012;7(4):e36135.
Recently, a transgenic rabbit with rhodopsin Pro 347 Leu mutation was generated as a model of retinitis pigmentosa (RP), which is characterized by a gradual loss of vision due to photoreceptor degeneration. The purpose of the current study is to noninvasively visualize and assess time-dependent changes in the retinal structures of a rabbit model of retinal degeneration by using speckle noise-reduced spectral-domain optical coherence tomography (SD-OCT).
Methodology/Principal Findings
Wild type (WT) and RP rabbits (aged 4–20 weeks) were investigated using SD-OCT. The total retinal thickness in RP rabbits decreased with age. The thickness of the outer nuclear layer (ONL) and between the external limiting membrane and Bruch's membrane (ELM–BM) were reduced in RP rabbits around the visual streak, compared to WT rabbits even at 4 weeks of age, and the differences increased with age. However, inner nuclear layer (INL) thickness in RP rabbits did not differ from that of WT during the observation period. The ganglion cell complex (GCC) thickness in RP rabbits increased near the optic nerve head but not around the visual streak in the later stages of the observation period. Hyper-reflective change was widely observed in the inner segments (IS) and outer segments (OS) of the photoreceptors in the OCT images of RP rabbits. Ultrastructural findings in RP retinas included the appearance of small rhodopsin-containing vesicles scattered in the extracellular space around the photoreceptors.
In the current study, SD-OCT provided the pattern of photoreceptor degeneration in RP rabbits and the longitudinal changes in each retinal layer through the evaluation of identical areas over time. The time-dependent changes in the retinal structure of RP rabbits showed regional and time-stage variations. In vivo imaging of RP rabbit retinas by using SD-OCT is a powerful method for characterizing disease dynamics and for assessing the therapeutic effects of experimental interventions.
PMCID: PMC3338600  PMID: 22558356
20.  Spectral-Domain Optical Coherence Tomography as a Noninvasive Method to Assess Damaged and Regenerating Adult Zebrafish Retinas 
These experiments assessed the ability of spectral-domain optical coherence tomography (SD-OCT) to accurately represent the structural organization of the adult zebrafish retina and reveal the dynamic morphologic changes during either light-induced damage and regeneration of photoreceptors or ouabain-induced inner retinal damage.
Retinas of control dark-adapted adult albino zebrafish were compared with retinas subjected to 24 hours of constant intense light and recovered for up to 8 weeks or ouabain-damaged retinas that recovered for up to 3 weeks. Images were captured and the measurements of retinal morphology were made by SD-OCT, and then compared with those obtained by histology of the same eyes.
Measurements between SD-OCT and histology were very similar for the undamaged, damaged, and regenerating retinas. Axial measurements of SD-OCT also revealed vitreal morphology that was not readily visualized by histology.
SD-OCT accurately represented retinal lamination and photoreceptor loss and recovery during light-induced damage and subsequent regeneration. SD-OCT was less accurate at detecting the inner nuclear layer in ouabain-damaged retinas, but accurately detected the undamaged outer nuclear layer. Thus, SD-OCT provides a noninvasive and quantitative method to assess the morphology and the extent of damage and repair in the zebrafish retina.
SD-OCT imaging accurately reveals the laminar organization in the intact adult zebrafish retina and can also assess the extent of either light-induced or ouabain-induced damage. Additionally, SD-OCT imaging can be used to monitor regeneration of the damaged adult zebrafish retina.
PMCID: PMC3383185  PMID: 22499984
21.  Multimodal Assessment of Microscopic Morphology and Retinal Function in Patients With Geographic Atrophy 
To correlate retinal function and visual sensitivity with retinal morphology revealed by ultrahigh-resolution imaging with adaptive optics–optical coherence tomography (AO-OCT), on patients with geographic atrophy.
Five eyes from five subjects were tested (four with geographic atrophy [66.3 ± 6.4 years, mean ± 1 SD] and one normal [61 years]). Photopic and scotopic multifocal electroretinograms (mfERGs) were recorded. Visual fields were assessed with microperimetry (mP) combined with a scanning laser ophthalmoscope for high-resolution confocal retinal fundus imaging. The eye tracker of the microperimeter identified the preferred retinal locus that was then used as a reference for precise targeting of areas for advanced retinal imaging. Images were obtained with purpose-built, in-house, ultrahigh resolution AO-OCT. Fundus autofluorescence (FAF) and color fundus (CF) photographs were also acquired.
The AO-OCT imaging provided detailed cross-sectional structural representation of the retina. Up to 12 retinal layers were identified in the normal subject while many severe retinal abnormalities (i.e., calcified drusen, drusenoid pigment epithelium detachment, outer retinal tubulation) were identified in the retinae of the GA patients. The functional tests showed preservation of sensitivities, although somewhat compromised, at the border of the GA.
The images provided here advance our knowledge of the morphology of retinal layers in GA patients. While there was a strong correlation between altered retinal structure and reduction in visual function, there were a number of examples in which the photoreceptor inner/outer segment (IS/OS) junctions lost reflectivity at the margins of GA, while visual function was still demonstrated. This was shown to be due to changes in photoreceptor orientation near the GA border.
Patients with geographic atrophy were tested with a battery of functional and structural tests including mfERGs and AO-OCT. There were a number of examples in which the photoreceptor IS/OS junction lost reflectivity at the margins of GA, but visual function was still demonstrated.
PMCID: PMC3694790  PMID: 23696601
geographic atrophy; adaptive-optics OCT; multifocal ERG; scotopic mfERG; microperimetry
22.  Non-Invasive Detection of Early Retinal Neuronal Degeneration by Ultrahigh Resolution Optical Coherence Tomography 
PLoS ONE  2014;9(4):e93916.
Optical coherence tomography (OCT) has revolutionises the diagnosis of retinal disease based on the detection of microscopic rather than subcellular changes in retinal anatomy. However, currently the technique is limited to the detection of microscopic rather than subcellular changes in retinal anatomy. However, coherence based imaging is extremely sensitive to both changes in optical contrast and cellular events at the micrometer scale, and can generate subtle changes in the spectral content of the OCT image. Here we test the hypothesis that OCT image speckle (image texture) contains information regarding otherwise unresolvable features such as organelle changes arising in the early stages of neuronal degeneration. Using ultrahigh resolution (UHR) OCT imaging at 800 nm (spectral width 140 nm) we developed a robust method of OCT image analyses, based on spatial wavelet and texture-based parameterisation of the image speckle pattern. For the first time we show that this approach allows the non-invasive detection and quantification of early apoptotic changes in neurons within 30 min of neuronal trauma sufficient to result in apoptosis. We show a positive correlation between immunofluorescent labelling of mitochondria (a potential source of changes in cellular optical contrast) with changes in the texture of the OCT images of cultured neurons. Moreover, similar changes in optical contrast were also seen in the retinal ganglion cell- inner plexiform layer in retinal explants following optic nerve transection. The optical clarity of the explants was maintained throughout in the absence of histologically detectable change. Our data suggest that UHR OCT can be used for the non-invasive quantitative assessment of neuronal health, with a particular application to the assessment of early retinal disease.
PMCID: PMC4002422  PMID: 24776961
23.  Structural Changes in Individual Retinal Layers in Diabetic Macular Edema 
Journal of Diabetes Research  2013;2013:920713.
Optical coherence tomography (OCT) has enabled objective measurement of the total retinal thickness in diabetic macular edema (DME). The central retinal thickness is correlated modestly with visual impairment and changes paradoxically after treatments compared to the visual acuity. This suggests the clinical relevance of the central retinal thickness in DME and the presence of other factors that affect visual disturbance. Recent advances in spectral-domain (SD) OCT have provided better delineation of the structural changes and fine lesions in the individual retinal layers. Cystoid spaces in the inner nuclear layer and outer plexiform layer are related to quantitative and qualitative parameters in fluorescein angiography. OCT often shows vitreoretinal interface abnormalities in eyes with sponge-like retinal swelling. Serous retinal detachment is sometimes accompanied by hyperreflective foci in the subretinal fluid, which exacerbates the pathogenesis at the interface of the photoreceptors and retinal pigment epithelium. Photoreceptor damage at the fovea is thought to be represented by disruption of the external limiting membrane or the junction between the inner and outer segment lines and is correlated with visual impairment. Hyperreflective foci in the outer retinal layers on SD-OCT images, another marker of visual disturbance, are associated with foveal photoreceptor damage.
PMCID: PMC3773460  PMID: 24073417
24.  Fundus Autofluorescence Findings in a Mouse Model of Retinal Detachment 
Fundus autofluorescence (fundus AF) changes were monitored in a mouse model of retinal detachment (RD).
RD was induced by transscleral injection of hyaluronic acid (Healon) or sterile balanced salt solution (BSS) into the subretinal space of 4–5-day-old albino Abca4 null mutant and Abca4 wild-type mice. Images acquired by confocal scanning laser ophthalmoscopy (Spectralis HRA) were correlated with spectral domain optical coherence tomography (SD-OCT), infrared reflectance (IR), fluorescence spectroscopy, and histologic analysis.
In the area of detached retina, multiple hyperreflective spots in IR images corresponded to punctate areas of intense autofluorescence visible in fundus AF mode. The puncta exhibited changes in fluorescence intensity with time. SD-OCT disclosed undulations of the neural retina and hyperreflectivity of the photoreceptor layer that likely corresponded to histologically visible photoreceptor cell rosettes. Fluorescence emission spectra generated using flat-mounted retina, and 488 and 561 nm excitation, were similar to that of RPE lipofuscin. With increased excitation wavelength, the emission maximum shifted towards longer wavelengths, a characteristic typical of fundus autofluorescence.
In detached retinas, hyper-autofluorescent spots appeared to originate from photoreceptor outer segments that were arranged within retinal folds and rosettes. Consistent with this interpretation is the finding that the autofluorescence was spectroscopically similar to the bisretinoids that constitute RPE lipofuscin. Under the conditions of a RD, abnormal autofluorescence may arise from excessive production of bisretinoid by impaired photoreceptor cells.
Autofluorescent puncta that are a feature of retinal degeneration when imaged by fundus autofluorescence, may reflect retinal folds and/or rosettes within which photoreceptor outer segments form hyperfluorescent cores.
PMCID: PMC3416030  PMID: 22786896
25.  Comparison of Ultrahigh- and Standard-Resolution Optical Coherence Tomography for Imaging Macular Hole Pathology and Repair 
Ophthalmology  2004;111(11):2033-2043.
To compare ultrahigh-resolution optical coherence tomography (UHR-OCT) technology to a standard-resolution OCT instrument for the imaging of macular hole pathology and repair; to identify situations where UHR-OCT provides additional information on disease morphology, pathogenesis, and management; and to use UHR-OCT as a baseline for improving the interpretation of the standard-resolution images.
Observational and interventional case series.
Twenty-nine eyes of 24 patients clinically diagnosed with macular hole in at least one eye.
A UHR-OCT system has been developed and employed in a tertiary-care ophthalmology clinic. Using a femtosecond laser as the low-coherence light source, this new UHR-OCT system can achieve an unprecedented 3-μm axial resolution for retinal OCT imaging. Comparative imaging was performed with UHR-OCT and standard 10-μm resolution OCT in 29 eyes of 24 patients with various stages of macular holes. Imaging was also performed on a subset of the population before and after macular hole surgery.
Main Outcome Measures
Ultrahigh- and standard-resolution cross-sectional OCT images of macular hole pathologies.
Both UHR-OCT and standard-resolution OCT exhibited comparable performance in differentiating various stages of macular holes. The UHR-OCT provided improved imaging of finer intraretinal structures, such as the external limiting membrane and photoreceptor inner segment (IS) and outer segment (OS), and identification of the anatomy of successful surgical repair. The improved resolution of UHR-OCT enabled imaging of previously unidentified changes in photoreceptor morphology associated with macular hole pathology and postoperative repair. Visualization of the junction between the photoreceptor IS and OS was found to be an important indicator of photoreceptor integrity for both standard-resolution and UHR-OCT images.
Ultrahigh-resolution optical coherence tomography improves the visualization of the macular hole architectural morphology. The increased resolution of UHR-OCT enables the visualization of photoreceptor morphology associated with macular holes. This promises to lead to a better understanding of the pathogenesis of macular holes, the causes of visual loss secondary to macular holes, the timing of surgical repair, and the evaluation of postsurgical outcome. Ultrahigh-resolution optical coherence tomography imaging of macular holes that correspond to known alterations in retinal morphology can be used to interpret retinal morphology in UHR-OCT images. Comparisons of UHR-OCT images with standard-resolution OCT images can establish a baseline for the better interpretation of clinical standard-resolution OCT images. The ability to visualize photoreceptors and their integrity or impairment is an indicator of macular hole progression and surgical outcome.
PMCID: PMC1937401  PMID: 15522369

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