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1.  Analysis of macular OCT images using deformable registration 
Biomedical Optics Express  2014;5(7):2196-2214.
Optical coherence tomography (OCT) of the macula has become increasingly important in the investigation of retinal pathology. However, deformable image registration, which is used for aligning subjects for pairwise comparisons, population averaging, and atlas label transfer, has not been well–developed and demonstrated on OCT images. In this paper, we present a deformable image registration approach designed specifically for macular OCT images. The approach begins with an initial translation to align the fovea of each subject, followed by a linear rescaling to align the top and bottom retinal boundaries. Finally, the layers within the retina are aligned by a deformable registration using one-dimensional radial basis functions. The algorithm was validated using manual delineations of retinal layers in OCT images from a cohort consisting of healthy controls and patients diagnosed with multiple sclerosis (MS). We show that the algorithm overcomes the shortcomings of existing generic registration methods, which cannot be readily applied to OCT images. A successful deformable image registration algorithm for macular OCT opens up a variety of population based analysis techniques that are regularly used in other imaging modalities, such as spatial normalization, statistical atlas creation, and voxel based morphometry. Examples of these applications are provided to demonstrate the potential benefits such techniques can have on our understanding of retinal disease. In particular, included is a pilot study of localized volumetric changes between healthy controls and MS patients using the proposed registration algorithm.
PMCID: PMC4102359  PMID: 25071959
(100.0100) Image processing; (170.4470) Ophthalmology; (170.4500) Optical coherence tomography
2.  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
3.  Validation of Retinal Image Registration Algorithms by a Projective Imaging Distortion Model 
Fundus camera imaging of the retina is widely used to document ophthalmologic disorders including diabetic retinopathy, glaucoma, and age-related macular degeneration. The retinal images typically have a limited field of view due mainly to the curvedness of human retina, so multiple images are to be joined together using image registration technique to form a montage with a larger field of view. A variety of methods for retinal image registration have been proposed, but evaluating such methods objectively is difficult due to the lack of a reference standard for the true alignment of the individual images that make up the montage. A method of generating simulated retinal image set by modeling geometric distortions due to the eye geometry and the image acquisition process is described in this paper. We also present the validation tool for any retinal image registration method by tracing back the distortion path and accessing the geometric misalignment from the coordinate system of reference standard. The quantitative comparison for different registration methods is given in the experiment, so the registration performance is evaluated in an objective manner.
PMCID: PMC2739576  PMID: 18003507
4.  Trends in blind registration in the adult population of the Republic of Ireland 1996–2003 
The Republic of Ireland has a centralised database of all registered, blind people in the country. The last study of the national blind register was undertaken in 1996. The current study sought, firstly, to investigate and identify any recent changes in the register composition. Secondly, there is concern that many eligible people are not appropriately registered. To examine this further, registration levels among patients attending an Irish outpatient ophthalmology clinic were determined.
Criteria for blind registration in Ireland are (1) a best corrected visual acuity of 6/60 or less in the better eye, or (2) a visual field subtending an angle of 20 degrees or less. The National Council for the Blind in Ireland (NCBI) is the sole custodian of a national registration database recording all eligible, registered people. This computerised database was analysed to provide information on the demographics and blind registration condition of those on the register in 2003. This information was compared with the results of the 1996 study. To assess the accuracy of the current register, the registration status of eligible patients attending the outpatient clinic of a busy, tertiary referral ophthalmology department, over a 9 week period, was studied.
6862 adults were registered as blind on the NCBI register in Ireland in 2003, representing an increase of 37% since 1996. The leading causes of registration were age related macular degeneration (ARMD) (25%), glaucoma (12%), and retinitis pigmentosa (7%). Comparing the 1996 and 2003 data, dramatic increases in the numbers registered caused by ARMD (from 812 to 1729 people, a 113% increase) and diabetic retinopathy (DR) (from 147 people to 323 people, a 120% increase) were found. The numbers registered as a result of glaucoma were relatively stable (795 in 1996 and 811 in 2003). A substantial drop, of 53%, was noted in the number of people registered as a result of cataracts, from 561 people to 261. Of the 672 new cases registered in 2003, ARMD accounted for 44%, glaucoma 13%, and DR 7%. Over the 9 week study period 75 patients, out of a total 2320 patients who attended the outpatient department, fulfilled the blind registration criteria. It was found that 21% (16 of 75) of the eligible clinic outpatients had not been appropriately registered.
An overall increase in adult blind registration of 37% in the Republic of Ireland was found between 1996 and 2003. There were large increases in registered blindness as a result of ARMD (113%) and DR (120%). A notable decrease in registration as a result of cataracts was discovered. Vigilance by clinicians is necessary to ensure that eligible patients are registered.
PMCID: PMC1856962  PMID: 16488964
blind registration; Ireland
5.  A computational pipeline for quantification of pulmonary infections in small animal models using serial PET-CT imaging 
EJNMMI Research  2013;3:55.
Infectious diseases are the second leading cause of death worldwide. In order to better understand and treat them, an accurate evaluation using multi-modal imaging techniques for anatomical and functional characterizations is needed. For non-invasive imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), there have been many engineering improvements that have significantly enhanced the resolution and contrast of the images, but there are still insufficient computational algorithms available for researchers to use when accurately quantifying imaging data from anatomical structures and functional biological processes. Since the development of such tools may potentially translate basic research into the clinic, this study focuses on the development of a quantitative and qualitative image analysis platform that provides a computational radiology perspective for pulmonary infections in small animal models. Specifically, we designed (a) a fast and robust automated and semi-automated image analysis platform and a quantification tool that can facilitate accurate diagnostic measurements of pulmonary lesions as well as volumetric measurements of anatomical structures, and incorporated (b) an image registration pipeline to our proposed framework for volumetric comparison of serial scans. This is an important investigational tool for small animal infectious disease models that can help advance researchers’ understanding of infectious diseases.
We tested the utility of our proposed methodology by using sequentially acquired CT and PET images of rabbit, ferret, and mouse models with respiratory infections of Mycobacterium tuberculosis (TB), H1N1 flu virus, and an aerosolized respiratory pathogen (necrotic TB) for a total of 92, 44, and 24 scans for the respective studies with half of the scans from CT and the other half from PET. Institutional Administrative Panel on Laboratory Animal Care approvals were obtained prior to conducting this research. First, the proposed computational framework registered PET and CT images to provide spatial correspondences between images. Second, the lungs from the CT scans were segmented using an interactive region growing (IRG) segmentation algorithm with mathematical morphology operations to avoid false positive (FP) uptake in PET images. Finally, we segmented significant radiotracer uptake from the PET images in lung regions determined from CT and computed metabolic volumes of the significant uptake. All segmentation processes were compared with expert radiologists’ delineations (ground truths). Metabolic and gross volume of lesions were automatically computed with the segmentation processes using PET and CT images, and percentage changes in those volumes over time were calculated. (Continued on next page)(Continued from previous page) Standardized uptake value (SUV) analysis from PET images was conducted as a complementary quantitative metric for disease severity assessment. Thus, severity and extent of pulmonary lesions were examined through both PET and CT images using the aforementioned quantification metrics outputted from the proposed framework.
Each animal study was evaluated within the same subject class, and all steps of the proposed methodology were evaluated separately. We quantified the accuracy of the proposed algorithm with respect to the state-of-the-art segmentation algorithms. For evaluation of the segmentation results, dice similarity coefficient (DSC) as an overlap measure and Haussdorf distance as a shape dissimilarity measure were used. Significant correlations regarding the estimated lesion volumes were obtained both in CT and PET images with respect to the ground truths (R2=0.8922,p<0.01 and R2=0.8664,p<0.01, respectively). The segmentation accuracy (DSC (%)) was 93.4±4.5% for normal lung CT scans and 86.0±7.1% for pathological lung CT scans. Experiments showed excellent agreements (all above 85%) with expert evaluations for both structural and functional imaging modalities. Apart from quantitative analysis of each animal, we also qualitatively showed how metabolic volumes were changing over time by examining serial PET/CT scans. Evaluation of the registration processes was based on precisely defined anatomical landmark points by expert clinicians. An average of 2.66, 3.93, and 2.52 mm errors was found in rabbit, ferret, and mouse data (all within the resolution limits), respectively. Quantitative results obtained from the proposed methodology were visually related to the progress and severity of the pulmonary infections as verified by the participating radiologists. Moreover, we demonstrated that lesions due to the infections were metabolically active and appeared multi-focal in nature, and we observed similar patterns in the CT images as well. Consolidation and ground glass opacity were the main abnormal imaging patterns and consistently appeared in all CT images. We also found that the gross and metabolic lesion volume percentage follow the same trend as the SUV-based evaluation in the longitudinal analysis.
We explored the feasibility of using PET and CT imaging modalities in three distinct small animal models for two diverse pulmonary infections. We concluded from the clinical findings, derived from the proposed computational pipeline, that PET-CT imaging is an invaluable hybrid modality for tracking pulmonary infections longitudinally in small animals and has great potential to become routinely used in clinics. Our proposed methodology showed that automated computed-aided lesion detection and quantification of pulmonary infections in small animal models are efficient and accurate as compared to the clinical standard of manual and semi-automated approaches. Automated analysis of images in pre-clinical applications can increase the efficiency and quality of pre-clinical findings that ultimately inform downstream experimental design in human clinical studies; this innovation will allow researchers and clinicians to more effectively allocate study resources with respect to research demands without compromising accuracy.
PMCID: PMC3734217  PMID: 23879987
Quantitative analysis; Pulmonary infections; Small animal models; PET-CT; Image segmentation; H1N1; Tuberculosis
6.  2-D Registration and 3-D Shape Inference of the Retinal Fundus from Fluorescein Images 
Medical image analysis  2007;12(2):174-190.
This study presents methods to 2-D registration of retinal image sequences and 3-D shape inference from fluorescein images. The Y-feature is a robust geometric entity that is largely invariant across modalities as well as across the temporal grey level variations induced by the propagation of the dye in the vessels. We first present a Y-feature extraction method that finds a set of Y-feature candidates using local image gradient information. A gradient-based approach is then used to align an articulated model of the Y-feature to the candidates more accurately while optimizing a cost function. Using mutual information, fitted Y-features are subsequently matched across images, including colors and fluorescein angiographic frames, for registration. To reconstruct the retinal fundus in 3-D, the extracted Y-features are used to estimate the epipolar geometry with a plane-and-parallax approach. The proposed solution provides a robust estimation of the fundamental matrix suitable for plane-like surfaces, such as the retinal fundus. The mutual information criterion is used to accurately estimate the dense disparity map, while the Y-features are used to estimate the bounds of the range space. Our experimental results validate the proposed method on a set of difficult fluorescein image pairs.
PMCID: PMC2556232  PMID: 18060827
3-D reconstruction; Mutual information; Global registration; Retinal fundus image
Optical coherence tomography (OCT) of the macular cube has become an increasingly important tool for investigating and managing retinal pathology. One important new area of investigation is the analysis of anatomic variably across a population. Such an analysis on the retina requires the construction of a normalized space, which is generally created through deformable registration of each subject into a common template. Unfortunately, state-of-the-art 3D registration tools fail to adequately spatially normalize retinal OCT images. This work proposes a new deformable registration algorithm for OCT images using the similarity between pairs of A-mode scans. First, a retinal OCT specific affine step is presented, which uses automated landmarks to perform global translations and individual rescaling of all the subject’s A-mode scans. Then, a deformable registration using regularized one-dimensional radial basis functions is applied to further align the retinal layers. Results on 15 subjects show the improved accuracy of this approach in comparison to state of the art methods with respect to registration for labeling. Additional results show the ability to generate stereotaxic spaces for retinal OCT.
PMCID: PMC3892764  PMID: 24443687
Optical coherence tomography; registration
8.  Prevalence of Age-Related Macular Degeneration in Nakuru, Kenya: A Cross-Sectional Population-Based Study 
PLoS Medicine  2013;10(2):e1001393.
Using digital retinal photography and slit lamp examination in a population-based sample in the Nakuru District of Kenya, Andrew Bastawrous and colleagues determined the prevalence of age-related macular degeneration in adults 50 years and older.
Diseases of the posterior segment of the eye, including age-related macular degeneration (AMD), have recently been recognised as the leading or second leading cause of blindness in several African countries. However, prevalence of AMD alone has not been assessed. We hypothesized that AMD is an important cause of visual impairment among elderly people in Nakuru, Kenya, and therefore sought to assess the prevalence and predictors of AMD in a diverse adult Kenyan population.
Methods and Findings
In a population-based cross-sectional survey in the Nakuru District of Kenya, 100 clusters of 50 people 50 y of age or older were selected by probability-proportional-to-size sampling between 26 January 2007 and 11 November 2008. Households within clusters were selected through compact segment sampling.
All participants underwent a standardised interview and comprehensive eye examination, including dilated slit lamp examination by an ophthalmologist and digital retinal photography. Images were graded for the presence and severity of AMD lesions following a modified version of the International Classification and Grading System for Age-Related Maculopathy. Comparison was made between slit lamp biomicroscopy (SLB) and photographic grading.
Of 4,381 participants, fundus photographs were gradable for 3,304 persons (75.4%), and SLB was completed for 4,312 (98%). Early and late AMD prevalence were 11.2% and 1.2%, respectively, among participants graded on images. Prevalence of AMD by SLB was 6.7% and 0.7% for early and late AMD, respectively. SLB underdiagnosed AMD relative to photographic grading by a factor of 1.7.
After controlling for age, women had a higher prevalence of early AMD than men (odds ratio 1.5; 95% CI, 1.2–1.9). Overall prevalence rose significantly with each decade of age. We estimate that, in Kenya, 283,900 to 362,800 people 50 y and older have early AMD and 25,200 to 50,500 have late AMD, based on population estimates in 2007.
AMD is an important cause of visual impairment and blindness in Kenya. Greater availability of low vision services and ophthalmologist training in diagnosis and treatment of AMD would be appropriate next steps.
Please see later in the article for the Editors' Summary
Editors' Summary
Worldwide, 39 million people are blind, and 246 million people (mainly living in developing countries) have moderate or severe visual impairment. The third leading global cause of blindness (after cataracts and glaucoma) is age-related macular degeneration (AMD). This group of conditions is characterized by lesions in the macular (central) region of the retina, the tissue at the back of the eye that converts light into electrical messages and sends them to the brain. AMD, which affects older people, destroys the sharp central vision that is needed for reading or driving, leaving only dim, blurred images or a black hole at the center of vision. AMD can be diagnosed by examining digital photographs of the retina or by examining the retina directly using a special magnifying lens (slit lamp biomicroscopy). There is no cure for AMD, although injections into the eye of certain drugs, such as bevacizumab, that block the activity of vascular endothelial growth factor can slow the rate of vision loss caused by some forms of AMD.
Why Was This Study Done?
Most investigations of the prevalence (the proportion of a population with a disease) of AMD and of risk factors for AMD have studied people with European or Asian ancestry. Very little is known about AMD in African populations, and the data that are available mainly come from African populations living outside Africa. It is important to know whether AMD is an important cause of visual impairment and blindness in Africa, so that informed decisions can be made about the need for AMD programs in African countries. In this cross-sectional population-based study, the researchers investigate the prevalence of AMD among people aged 50 years or older living in Nakuru District (an ethnically diverse region of Kenya) and look for predictors of AMD in this population. In a cross-sectional population-based study, researchers observe a representative subset of a population at a single time point.
What Did the Researchers Do and Find?
The researchers randomly selected 100 clusters of 50 people aged 50 years or older for their study. Between January 2007 and November 2008, study participants had a comprehensive eye examination and completed a standardized interview that included questions about their age, gender, other demographic details, medical history, and exposure to possible risk factors for AMD. Based on digital retinal images, the prevalences of early and late AMD among the study population were 11.2% and 1.2%, respectively. The prevalences of early and late AMD judged by slit lamp biomicroscopy were 6.7% and 0.7%, respectively. After controlling for age, women had a higher prevalence of both early and late AMD than men. The overall prevalence of AMD rose with age: compared to the youngest age group, the oldest age group had a three-fold higher risk of developing late AMD. Of the people with any grade of AMD, 25.6% had some visual impairment and 2.5% were blind. Overall, 9.9% of the blindness seen in the study was attributable to AMD.
What Do These Findings Mean?
These findings identify AMD as an important cause of visual impairment and blindness in Nakuru District, Kenya. Extrapolation of these findings to the whole of Kenya suggests that 283,900 to 362,800 Kenyans had early AMD and 25,200 to 50,500 had late AMD in 2007. The accuracy of these findings is limited by the inability to obtain digital retinal images from all the participants (often because of electricity failures) and by other aspects of the study design. Moreover, because the methodology used in this study differed from some other studies of AMD, the prevalence of AMD reported here cannot be compared directly to those found in other studies. Nevertheless, these findings have several important implications. In particular, although recent evidence suggests that bevacizumab is likely to be both effective and affordable in Africa, the infrastructure required to deliver an adequate AMD service is currently prohibitively expensive in most African countries. Thus, these findings suggest that it is essential that research is undertaken to support the development of AMD treatment programs that are affordable and deliverable in Africa, and that low vision resources are provided for individuals with vision impairment.
Additional Information
Please access these websites via the online version of this summary at
The US National Eye Institute provides detailed information about age-related macular degeneration
The UK National Health Service Choices website also provides information about age-related macular degeneration, including personal stories about the condition
The UK Royal National Institute of Blind People has information on age-related macular degeneration, including a video of a person describing their experiences of the condition
AMD Alliance International provides written and audio information in several languages about age-related macular degeneration, including a large selection of personal stories; the Macular Degeneration Partnership also provides information about age-related macular degeneration, including a simulation of the condition
MedlinePlus has links to additional resources about age-related macular degeneration (in English and Spanish)
PMCID: PMC3576379  PMID: 23431274
9.  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
10.  Retinal Flavoprotein Autofluorescence as a Measure of Retinal Health 
To establish that increased autofluorescence of mitochondrial flavoproteins, an indicator of mitochondrial oxidative stress, correlates with retinal cell dysfunction.
Retinal flavoprotein autofluorescence (FA) was imaged in humans with a fundus camera modified with 467DF8-nm excitation and 535-nm emission filters and a back-illuminated, electron-multiplying, charge-coupled device camera interfaced with a computer equipped with customized image capture software. Multiple digital images, centered on the fovea, were obtained from each eye. Histograms of pixel intensities in grayscale units were analyzed for average intensity and average curve width. Adults with diabetes mellitus, age-related macular degeneration (ARMD), central serous retinopathy, and retinal dystrophies, as well as healthy control volunteers, were imaged. Monolayers of cultured human retinal pigment epithelial (HRPE) cells, HRPE cells exposed to sublethal doses of H2O2, and HRPE cells exposed to H2O2 in the presence of antioxidants were imaged for FA using fluorescent photomicroscopy.
Control patients demonstrated low levels of retinal FA, which increased progressively with age. Diabetics without visible retinopathy demonstrated increased FA levels compared to control volunteers (P < .001). Diabetics with retinopathy demonstrated significantly higher FA values than those without retinopathy (P < .04). Patients with ARMD, central serous retinopathy, or retinal dystrophies also demonstrated significantly increased FA. Compared to control RPE cells, cells oxidatively stressed with H2O2 had significantly elevated FA (P < .05), which was prevented by antioxidants (P < .05).
Retinal FA is significantly increased with age and diseases known to be mediated by oxidative stress. Retinal FA imaging may provide a novel, noninvasive method of assessing retinal health and retinal dysfunction prior to retinal cell death.
PMCID: PMC2646450  PMID: 19277237
11.  Automated drusen detection in retinal images using analytical modelling algorithms 
Drusen are common features in the ageing macula associated with exudative Age-Related Macular Degeneration (ARMD). They are visible in retinal images and their quantitative analysis is important in the follow up of the ARMD. However, their evaluation is fastidious and difficult to reproduce when performed manually.
This article proposes a methodology for Automatic Drusen Deposits Detection and quantification in Retinal Images (AD3RI) by using digital image processing techniques. It includes an image pre-processing method to correct the uneven illumination and to normalize the intensity contrast with smoothing splines. The drusen detection uses a gradient based segmentation algorithm that isolates drusen and provides basic drusen characterization to the modelling stage. The detected drusen are then fitted by Modified Gaussian functions, producing a model of the image that is used to evaluate the affected area.
Twenty two images were graded by eight experts, with the aid of a custom made software and compared with AD3RI. This comparison was based both on the total area and on the pixel-to-pixel analysis. The coefficient of variation, the intraclass correlation coefficient, the sensitivity, the specificity and the kappa coefficient were calculated.
The ground truth used in this study was the experts' average grading. In order to evaluate the proposed methodology three indicators were defined: AD3RI compared to the ground truth (A2G); each expert compared to the other experts (E2E) and a standard Global Threshold method compared to the ground truth (T2G).
The results obtained for the three indicators, A2G, E2E and T2G, were: coefficient of variation 28.8 %, 22.5 % and 41.1 %, intraclass correlation coefficient 0.92, 0.88 and 0.67, sensitivity 0.68, 0.67 and 0.74, specificity 0.96, 0.97 and 0.94, and kappa coefficient 0.58, 0.60 and 0.49, respectively.
The gradings produced by AD3RI obtained an agreement with the ground truth similar to the experts (with a higher reproducibility) and significantly better than the Threshold Method. Despite the higher sensitivity of the Threshold method, explained by its over segmentation bias, it has lower specificity and lower kappa coefficient. Therefore, it can be concluded that AD3RI accurately quantifies drusen, using a reproducible method with benefits for ARMD evaluation and follow-up.
PMCID: PMC3148202  PMID: 21749717
12.  MRI Reveals Differential Regulation of Retinal and Choroidal Blood Volume in Rat Retina 
NeuroImage  2010;54(2):1063-1069.
The retina is nourished by two unique (retinal and choroidal) circulations. The lack of depth-resolved blood-volume (BV) imaging techniques hampers investigation of vascular-specific regulation of the retina in vivo. This study presents a high-resolution, laminar-specific magnetic resonance imaging (MRI) study to image retinal and choroidal BV, their responses to physiologic challenges in normal and Royal-College-of-Surgeons (RCS) rats (a model of retinal degeneration). Retinal and choroidal BV's were imaged by MRI (3×3×800μm) with intravascular administration of monocrystalline iron oxide nanocolloid (MION) contrast agent. Relative baseline BV and BV changes due to physiologic challenges were calculated in normal and RCS rat retinas. BV-MRI revealed two well-resolved retinal and choroidal vascular layers located on either side of the retina and an intervening avascular layer. The ratio of choroidal:retinal BV in normal rats at baseline was 9.8±3.2 in control rat retinas (N=7). Hyperoxia decreased retinal BV (-51±17%, p<0.05) more than choroidal BV (-28±14%), and hypercapnia increased retinal BV (52±11%, p<0.01) more than choroidal BV (12±11%). BV-MRI in degenerated retinas of RCS rats (N=7) revealed thinning of the avascular layer and an increase in relative baseline retinal and choroidal BV. Only hypercapnia-induced BV changes in the retinal vasculature of RCS rats were significantly different (smaller) from controls (p<0.05). These findings suggest that BV in both retinal vasculatures is regulated. The relative baseline BV in both vasculatures increased in retinal degeneration. BV-MRI provides clinically relevant data that may prove useful for early detection and longitudinal probing of retinal diseases, and could complement optical imaging techniques.
PMCID: PMC3190232  PMID: 20850550
13.  In vivo sectional imaging of the retinal periphery using conventional optical coherence tomography systems 
Indian Journal of Ophthalmology  2012;60(3):235-239.
Optical coherence tomography (OCT) has transformed macular disease practices. This report describes the use of conventional OCT systems for peripheral retinal imaging. Thirty-six eyes with peripheral retinal pathology underwent imaging with conventional OCT systems. In vivo sectional imaging of lattice degeneration, snail-track degeneration, and paving-stone degeneration was performed. Differences were noted between phenotypes of lattice degeneration. Several findings previously unreported in histopathology studies were encountered. Certain anatomic features were seen that could conceivably explain clinical and intraoperative behavior of peripheral lesions. Peripheral OCT imaging helped elucidate clinically ambiguous situations such as retinal breaks, subclinical retinal detachment, retinoschisis, choroidal nevus, and metastasis. Limitations of such scanning included end-gaze nystagmus and far peripheral lesions. This first of its kind study demonstrates the feasibility of peripheral retinal OCT imaging and expands the spectrum of indications for which OCT scanning may be clinically useful.
PMCID: PMC3361828  PMID: 22569394
Choroidal nevus; in vivo; lattice degeneration; optical coherence tomography; peripheral retinal lesions; retinoschisis
14.  Linking Structure and Function in Glaucoma 
The glaucomas are a group of relatively common optic neuropathies, in which the pathological loss of retinal ganglion cells causes a progressive loss of sight and associated alterations in the retinal nerve fiber layer and optic nerve head. The diagnosis and management of glaucoma are often dependent on methods of clinical testing that either, 1) identify and quantify patterns of functional visual abnormality, or 2) quantify structural abnormality in the retinal nerve fiber layer, both of which are caused by loss of retinal ganglion cells. Although it is evident that the abnormalities in structure and function should be correlated, propositions to link losses in structure and function in glaucoma have been formulated only recently. The present report describes an attempt to build a model of these linking propositions using data from investigations of the relationships between losses of visual sensitivity and thinning of retinal nerve fiber layer over progressive stages of glaucoma severity. A foundation for the model was laid through the pointwise relationships between visual sensitivities (behavioral perimetry in monkeys with experimental glaucoma) and histological analyses of retinal ganglion cell densities in corresponding retinal locations. The subsequent blocks of the model were constructed from clinical studies of aging in normal human subjects and of clinical glaucoma in patients to provide a direct comparison of the results from standard clinical perimetry and optical coherence tomography. The final formulation is a nonlinear structure-function model that was evaluated by the accuracy and precision of translating visual sensitivities in a region of the visual field to produce a predicted thickness of the retinal nerve fiber layer in the peripapillary sector that corresponded to the region of reduced visual sensitivity. The model was tested on two independent patient populations, with results that confirmed the predictive relationship between the retinal nerve fiber layer thickness and visual sensitivities from clinical perimetry. Thus, the proposed model for linking structure and function in glaucoma has provided information that is important in understanding the results of standard clinical testing and the neuronal losses caused by glaucoma, which may have clinical application for inter-test comparisons of the stage of disease.
PMCID: PMC2878911  PMID: 20226873
glaucoma; optical coherence tomography; perimetry; retinal ganglion cells; retinal nerve fiber layer; structure-function
15.  Registering Histological and MR Images of Prostate for Image-based Cancer Detection 
Academic radiology  2007;14(11):1367-1381.
Rationale and Objectives
Needle biopsy is currently the only way to confirm prostate cancer. To increase prostate cancer diagnostic rate, needles are expected to be deployed at suspicious cancer locations. High contrast MR imaging provides a powerful tool for detecting suspicious cancerous tissues. To do this, MR appearances of cancerous tissue should be characterized and learned from a sufficient number of prostate MR images with known cancer information. However, ground-truth cancer information is only available in histological images. Therefore, it is necessary to warp ground-truth cancerous regions in histological images to MR images by a registration procedure. The objective of this paper is to develop a registration technique for aligning histological and MR images of the same prostate.
Material and Methods
Five pairs of histological and T2-weighted MR images of radical prostatectomy specimens are collected. For each pair, registration is guided by two sets of correspondences that can be reliably established on prostate boundaries and internal salient blob-like structures of histological and MR images.
Our developed registration method can accurately register histological and MR images. It yields results comparable to manual registration, in terms of landmark distance and volume overlap. It also outperforms both affine registration and boundary-guided registration methods.
We have developed a novel method for deformable registration of histological and MR images of the same prostate. Besides the collection of ground-truth cancer information in MR images, the method has other potential applications. An automatic, accurate registration of histological and MR images actually builds a bridge between in vivo anatomical information and ex vivo pathological information, which is valuable for various clinical studies.
PMCID: PMC2483248  PMID: 17964460
Prostate cancer; Histological image; MR image; Biopsy; Deformable registration
16.  Adaptive Optics Technology for High-Resolution Retinal Imaging 
Sensors (Basel, Switzerland)  2012;13(1):334-366.
Adaptive optics (AO) is a technology used to improve the performance of optical systems by reducing the effects of optical aberrations. The direct visualization of the photoreceptor cells, capillaries and nerve fiber bundles represents the major benefit of adding AO to retinal imaging. Adaptive optics is opening a new frontier for clinical research in ophthalmology, providing new information on the early pathological changes of the retinal microstructures in various retinal diseases. We have reviewed AO technology for retinal imaging, providing information on the core components of an AO retinal camera. The most commonly used wavefront sensing and correcting elements are discussed. Furthermore, we discuss current applications of AO imaging to a population of healthy adults and to the most frequent causes of blindness, including diabetic retinopathy, age-related macular degeneration and glaucoma. We conclude our work with a discussion on future clinical prospects for AO retinal imaging.
PMCID: PMC3574679  PMID: 23271600
adaptive optical systems; optical sensors; biomedical imaging techniques; eye
17.  High-Resolution Optical Coherence Tomography Retinal Imaging: A Case Series Illustrating Potential and Limitations 
Journal of Ophthalmology  2011;2011:764183.
Purpose. To present a series of retinal disease cases that were imaged by spectral domain optical coherence tomography (SD-OCT) in order to illustrate the potential and limitations of this new imaging modality. Methods. The series comprised four selected cases (one case each) of age-related macular degeneration (ARMD), diabetic retinopathy (DR), central retinal artery occlusion (CRAO), and branch retinal vein occlusion (BRVO). Patients were imaged using the Heidelberg Spectralis (Heidelberg Engineering, Germany) in SD-OCT mode. Patients also underwent digital fundus photography and clinical assessment. Results. SD-OCT imaging of a case of age-related macular degeneration revealed a subfoveal choroidal neovascular membrane with detachment of the retinal pigment epithelium (RPE) and neurosensory retina. Using SD-OCT, the cases of DR and BRVO both exhibited macular edema with cystoid spaces visible in the outer retina. Conclusions. The ability of SD-OCT to clearly and objectively elucidate subtle morphological changes within the retinal layers provides information that can be used to formulate diagnoses with greater confidence.
PMCID: PMC3182576  PMID: 21969910
18.  Prospective Image Registration for Automated Scan Prescription of Follow-up Knee Images in Quantitative Studies 
Magnetic resonance imaging  2011;29(5):693-700.
Consistent scan prescription for MRI of the knee is very important for accurate comparison of images in a longitudinal study. However, consistent scan region selection is difficult due the complexity of the knee joint. We propose a novel method for registering knee images using a mutual information registration algorithm to align images in a baseline and follow-up exam. The output of the registration algorithm, three translations and three Euler angles, is then used to redefine the region to be imaged and acquire an identical oblique imaging volume in the follow-up exam as in the baseline. This algorithm is robust to articulation of the knee and anatomical abnormalities due to disease (e.g. osteophytes). The registration method is performed only on the distal femur and is not affected by the proximal tibia or soft tissues. We have incorporated this approach in a clinical MR system and have demonstrated its utility in automatically obtaining consistent scan regions between baseline and follow-up examinations, thus improving the precision of quantitative evaluation of cartilage. Results show an improvement with prospective registration in the coefficient of variation for cartilage thickness, cartilage volume, and T2 relaxation measurements.
PMCID: PMC3100398  PMID: 21546186
19.  Changes in cortical grey matter density associated with long-standing retinal visual field defects 
Brain  2009;132(7):1898-1906.
Retinal lesions caused by eye diseases such as glaucoma and age-related macular degeneration can, over time, eliminate stimulation of parts of the visual cortex. This could lead to degeneration of inactive cortical neuronal tissue, but this has not been established in humans. Here, we used magnetic resonance imaging to assess the effects of prolonged sensory deprivation in human visual cortex. High-resolution anatomical magnetic resonance images were obtained in subjects with foveal (age-related macular degeneration) and peripheral (glaucoma) retinal lesions as well as age-matched controls. Comparison of grey matter between patient and control groups revealed density reductions in the approximate retinal lesion projection zones in visual cortex. This indicates that long-term cortical deprivation, due to retinal lesions acquired later in life, is associated with retinotopic-specific neuronal degeneration of visual cortex. Such degeneration could interfere with therapeutic strategies such as the future application of artificial retinal implants to overcome lesion-induced visual impairment.
PMCID: PMC2702836  PMID: 19467992
macular degeneration; glaucoma; visual field; visual cortex; voxel-based morphometry; grey matter density
20.  Automated Drusen Segmentation and Quantification in SD-OCT Images 
Medical image analysis  2013;17(8):1058-1072.
Spectral domain optical coherence tomography (SD-OCT) is a useful tool for the visualization of drusen, a retinal abnormality seen in patients with age-related macular degeneration (AMD); however, objective assessment of drusen is thwarted by the lack of a method to robustly quantify these lesions on serial OCT images. Here, we describe an automatic drusen segmentation method for SD-OCT retinal images, which leverages a priori knowledge of normal retinal morphology and anatomical features. The highly reflective and locally connected pixels located below the retinal nerve fiber layer (RNFL) are used to generate a segmentation of the retinal pigment epithelium (RPE) layer. The observed and expected contours of the RPE layer are obtained by interpolating and fitting the shape of the segmented RPE layer, respectively. The areas located between the interpolated and fitted RPE shapes (which have nonzero area when drusen occurs) are marked as drusen. To enhance drusen quantification, we also developed a novel method of retinal projection to generate an en face retinal image based on the RPE extraction, which improves the quality of drusen visualization over the current approach to producing retinal projections from SD-OCT images based on a summed-voxel projection (SVP), and it provides a means of obtaining quantitative features of drusen in the en face projection. Visualization of the segmented drusen is refined through several post-processing steps, drusen detection to eliminate false positive detections on consecutive slices, drusen refinement on a projection view of drusen, and drusen smoothing. Experimental evaluation results demonstrate that our method is effective for drusen segmentation. In a preliminary analysis of the potential clinical utility of our methods, quantitative drusen measurements, such as area and volume, can be correlated with the drusen progression in non-exudative AMD, suggesting that our approach may produce useful quantitative imaging biomarkers to follow this disease and predict patient outcome.
PMCID: PMC3795829  PMID: 23880375
Drusen segmentation; SD-OCT; projection image; retinal pigment epithelium; AMD
21.  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
22.  Colour photographs for screening in neovascular age-related macular degeneration: are they necessary? 
Eye  2011;25(7):918-921.
To investigate whether optical coherence tomography (OCT) with associated infra-red images provide enough information to determine treatment decisions in the management of neovascular age-related macular degeneration (nAMD), or whether retinal colour photography is also necessary.
In all, 87 OCT scans of 82 eyes with nAMD undergoing monitoring post ranibizumab treatment were taken using the Zeiss Stratus (Carl Zeiss Meditec, Jena, Germany; n=87) together with their corresponding infra-red images. Fundus colour photographs were also taken. These images were reviewed by an experienced assessor, and a ranibizumab treatment decision was made during a multidisciplinary team retinal image review meeting.
In all, 30 OCT scans (34.5%) showed intraretinal or subretinal oedema. A total of 24 colour photographs (19.5%) demonstrated retinal haemorrhage. Corresponding OCT infra-red images gave poor sensitivity in detecting haemorrhages (0.176). In 16.7% of decisions to treat, haemorrhage alone was the deciding factor. Signs of disease activity seen only on colour photography were the deciding factor in clinical decisions for 8% of scans assessed.
The presence or increase of intra-retinal oedema is an important sign of activity triggering ranibizumab retreatment, but some eyes show signs of retinal haemorrhage without coexisting oedema. These haemorrhages are often only seen on either colour imaging or fundoscopy and are unclear or invisible on OCT scans and infra-red images. Therefore, although retinal colour photography creates additional expense, it is indispensable for making informed retreatment decisions, if patients are monitored using retinal imaging alone.
PMCID: PMC3178153  PMID: 21587273
age-related macular degeneration; AMD; retinal imaging; choroidal neovascularisation; exudative AMD, OCT
23.  Lentiviral Gene Transfer of Rpe65 Rescues Survival and Function of Cones in a Mouse Model of Leber Congenital Amaurosis 
PLoS Medicine  2006;3(10):e347.
RPE65 is specifically expressed in the retinal pigment epithelium and is essential for the recycling of 11-cis-retinal, the chromophore of rod and cone opsins. In humans, mutations in RPE65 lead to Leber congenital amaurosis or early-onset retinal dystrophy, a severe form of retinitis pigmentosa. The proof of feasibility of gene therapy for RPE65 deficiency has already been established in a dog model of Leber congenital amaurosis, but rescue of the cone function, although crucial for human high-acuity vision, has never been strictly proven. In Rpe65 knockout mice, photoreceptors show a drastically reduced light sensitivity and are subject to degeneration, the cone photoreceptors being lost at early stages of the disease. In the present study, we address the question of whether application of a lentiviral vector expressing the Rpe65 mouse cDNA prevents cone degeneration and restores cone function in Rpe65 knockout mice.
Methods and Findings
Subretinal injection of the vector in Rpe65-deficient mice led to sustained expression of Rpe65 in the retinal pigment epithelium. Electroretinogram recordings showed that Rpe65 gene transfer restored retinal function to a near-normal pattern. We performed histological analyses using cone-specific markers and demonstrated that Rpe65 gene transfer completely prevented cone degeneration until at least four months, an age at which almost all cones have degenerated in the untreated Rpe65-deficient mouse. We established an algorithm that allows prediction of the cone-rescue area as a function of transgene expression, which should be a useful tool for future clinical trials. Finally, in mice deficient for both RPE65 and rod transducin, Rpe65 gene transfer restored cone function when applied at an early stage of the disease.
By demonstrating that lentivirus-mediated Rpe65 gene transfer protects and restores the function of cones in the Rpe65−/− mouse, this study reinforces the therapeutic value of gene therapy for RPE65 deficiencies, suggests a cone-preserving treatment for the retina, and evaluates a potentially effective viral vector for this purpose.
In theRpe65-/- mouse model of Leber congenital amaurosis, injection of a lentiviral vector expressing the Rpe65 mouse cDNA was able to prevent cone degeneration and restore cone function.
Editors' Summary
Leber congenital amaurosis (LCA) is the name of a group of hereditary diseases that cause blindness in infants and children. Changes in any one of a number of different genes can cause the blindness, which affects vision starting at birth or soon after. The condition was first described by a German doctor, Theodore Leber, in the 19th century, hence the first part of the name; “amaurosis” is another word for blindness. Mutations in one gene called retinal pigment epithelium-specific protein, 65 kDa (RPE65)—so called because it is expressed in the pigment epithelium, a cell layer adjacent to the light-sensitive cells, and is 65 kilodaltons in size—cause about 10% of cases of LCA. The product of this gene is essential for the recycling of a substance called 11-cis-retinal, which is necessary for the light-sensitive rods and cones of the retina to capture light. If the gene is abnormal, the sensitivity of the retina to light is drastically reduced, but it also leads to damage to the light-sensitive cells themselves.
Why Was This Study Done?
Potentially, eyes diseases such as this one could be treated by gene therapy, which works by replacing a defective gene with a normal functional one, usually by putting a copy of the normal gene into a harmless virus and injecting it into the affected tissue—in this case, the eye. The researchers here wanted to see whether expressing wild-type RPE65 using a particular type of gene vector that can carry large pieces of DNA transcript—a lentiviral vector—could prevent degeneration of cone cells and restore cone function in a mouse model of this type of LCA—mice who had had this Rpe65 gene genetically removed.
What Did the Researchers Do and Find?
Injection of the normal gene into the retina of Rpe65-deficient mice led to sustained expression of the protein RPE65 in the retinal pigment epithelium. Electrical recordings of the activity of the eyes in these mice showed that Rpe65 gene transfer restored retinal function to a near-normal level. In addition, Rpe65 gene transfer completely prevented cone degeneration until at least four months, an age at which almost all cones have degenerated in the untreated Rpe65-deficient mice.
What Do These Findings Mean?
These findings suggest that it is theoretically possible to treat this type of blindness by gene therapy. However, because this study was done in mice, many other steps need to be taken before it will be clear whether the treatment could work in humans. These steps include a demonstration that the virus is safe in humans, and experiments to determine what dose of virus would be needed and how long the effects of the treatment would last. Another question is whether it would be necessary (or even possible) to treat affected children during early childhood or when children start losing vision.
Additional Information.
Please access these Web sites via the online version of this summary at
The Foundation for Retinal Research has detailed information on Leber's congenital amaurosis
Contact a Family is a UK organization that aims to put families of children with illnesses in touch with each other
The Foundation for Fighting Blindness funds research into, and provides information about many types of blindness, including Leber's congenital amaurosis
This Web site provides information on gene therapy clinical trials, including those dedicated to cure eye diseases
This foundation provides information on diseases leading to blindness, including Leber's congenital amaurosis
PMCID: PMC1592340  PMID: 17032058
24.  Is the incidence of registrable age-related macular degeneration increasing? 
AIMS/BACKGROUND: Age-related macular degeneration (ARMD) is a growing public health problem in Britain; currently its aetiology is unclear. The aim of this study was to test the hypothesis that the age specific incidence of blinding ARMD has increased in Britain in the past 50 years, using data on cause of visual loss in people registered as blind, published every 10 years since 1950. METHODS: Data were abstracted from published sources for the years 1950, 1960, 1970, and 1980. Data for the standard year, 1990, were provided in a database from the Office of Population Censuses and Surveys. The numbers of new registrations attributed to ARMD per head of population were compared with registrations for cataract, glaucoma, and optic atrophy. Indirect standardisation was used to control for changes in the age structure of the population over time. RESULTS: After controlling for changes in the age structure of the population, registration rates for all causes, cataract, glaucoma, and optic atrophy have decreased while registrations attributed to ARMD have increased in the order of 30-40%. CONCLUSIONS: These findings are compatible with the hypothesis that the incidence of ARMD is increasing in Britain. It is difficult to exclude potential sources of bias in these data, however, particularly with respect to classification and coding of cause; more reliable population based data on ARMD in Britain are needed.
PMCID: PMC505375  PMID: 8664242
25.  Automated Detection of Macular Drusen Using Geometric Background Leveling and Threshold Selection 
Archives of ophthalmology  2005;123(2):200-206.
Age-related macular degeneration (ARMD) is the most prevalent cause of visual loss in patients older than 60 years in the United States. Observation of drusen is the hallmark finding in the clinical evaluation of ARMD.
To segment and quantify drusen found in patients with ARMD using image analysis and to compare the efficacy of image analysis segmentation with that of stereoscopic manual grading of drusen.
Retrospective study.
University referral center.
Photographs were randomly selected from an available database of patients with known ARMD in the ongoing Columbia University Macular Genetics Study. All patients were white and older than 60 years.
Twenty images from 17 patients were selected as representative of common manifestations of drusen. Image preprocessing included automated color balancing and, where necessary, manual segmentation of confounding lesions such as geographic atrophy (3 images). The operator then chose among 3 automated processing options suggested by predominant drusen type. Automated processing consisted of elimination of background variability by a mathematical model and subsequent histogram-based threshold selection. A retinal specialist using a graphic tablet while viewing stereo pairs constructed digital drusen drawings for each image.
Main Outcome Measures
The sensitivity and specificity of drusen segmentation using the automated method with respect to manual stereoscopic drusen drawings were calculated on a rigorous pixel-by-pixel basis.
The median sensitivity and specificity of automated segmentation were 70% and 81%, respectively. After preprocessing and option choice, reproducibility of automated drusen segmentation was necessarily 100%.
Automated drusen segmentation can be reliably performed on digital fundus photographs and result in successful quantification of drusen in a more precise manner than is traditionally possible with manual stereoscopic grading of drusen. With only minor preprocessing requirements, this automated detection technique may dramatically improve our ability to monitor drusen in ARMD.
PMCID: PMC2884376  PMID: 15710816

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