Principles of ophthalmoscopy.

Includes bibliography.

Development of Swept Source Optical Coherence Tomography and Adaptive Optics Scanning Laser Ophthalmoscopy: Improved Imaging Speed and Handheld Applications

Optical coherence tomography (OCT) is a noninvasive three-dimensional interferometric imaging technique capable of achieving micrometer scale resolution. It is now a standard of care in ophthalmology, where it is used to improve the accuracy of early diagnosis, to better understand the source of pathophysiology, and to monitor disease progression and response to therapy. In particular, retinal imaging has been the most prevalent clinical application of OCT, but researchers and companies alike are developing OCT systems for cardiology, dermatology, dentistry, and many other medical and industrial applications.

Adaptive optics (AO) is a technique used to reduce monochromatic aberrations in optical instruments. It is used in astronomical telescopes, laser communications, high-power lasers, retinal imaging, optical fabrication and microscopy to improve system performance. Scanning laser ophthalmoscopy (SLO) is a noninvasive confocal imaging technique that produces high contrast two-dimensional retinal images. AO is combined with SLO (AOSLO) to compensate for the wavefront distortions caused by the optics of the eye, providing the ability to visualize the living retina with cellular resolution. AOSLO has shown great promise to advance the understanding of the etiology of retinal diseases on a cellular level.

Broadly, we endeavor to enhance the vision outcome of ophthalmic patients through improved diagnostics and personalized therapy. Toward this end, the objective of the work presented herein was the development of advanced techniques for increasing the imaging speed, reducing the form factor, and broadening the versatility of OCT and AOSLO. Despite our focus on applications in ophthalmology, the techniques developed could be applied to other medical and industrial applications. In this dissertation, a technique to quadruple the imaging speed of OCT was developed. This technique was demonstrated by imaging the retinas of healthy human subjects. A handheld, dual depth OCT system was developed. This system enabled sequential imaging of the anterior segment and retina of human eyes. Finally, handheld SLO/OCT systems were developed, culminating in the design of a handheld AOSLO system. This system has the potential to provide cellular level imaging of the human retina, resolving even the most densely packed foveal cones.

Prevalence of retinopathy among adults with self-reported diabetes mellitus: the Sri Lanka diabetes and Cardiovascular Study

Background: At present there are no large scale nationally-representative studies from Sri Lanka on the prevalence and associations of Diabetic Retinopathy (DR). The present study aims to evaluate the prevalence and risk factors for DR in a community-based nationally-representative sample of adults with self-reported diabetes mellitus from Sri Lanka. Methods: A cross-sectional community-based national study among 5,000 adults (≥18 years) was conducted in Sri Lanka, using a multi-stage stratified cluster sampling technique. An interviewer-administered questionnaire was used to collect data. Ophthalmological evaluation of patients with ‘known’ diabetes (previously diagnosed at a government hospital or by a registered medical practitioner) was done using indirect ophthalmoscopy. A binary-logistic regression analysis was performed with ‘presence of DR’ as the dichotomous dependent variable and other independent covariates. Results: Crude prevalence of diabetes was 12.0%(n=536),of which 344 were patients with ‘known’ diabetes.Mean age was 56.4 ± 10.9 years and 37.3% were males. Prevalence of any degree of DR was 27.4% (Males-30.5%, Females-25.6%; p = 0.41). In patients with DR, majority had NPDR (93.4%), while 5.3% had maculopathy. Patients with DR had a significantly longer duration of diabetes than those without. In the binary-logistic regression analysis in all adults duration of diabetes (OR:1.07), current smoking (OR:1.67) and peripheral neuropathy (OR:1.72)all were significantly associated with DR. Conclusions: Nearly 1/3rd of Sri Lankan adults with self-reported diabetes are having retinopathy. DR was associated with diabetes duration, cigarette smoking and peripheral neuropathy. However, further prospective follow up studies are required to establish causality for identified risk factors

Age-dependent accumulation of lipofuscin in perivascular and subretinal microglia in experimental mice

Fundus autofluorescence (AF) imaging by confocal scanning laser ophthalmoscopy has been widely used by ophthalmologists in the diagnosis/monitoring of various retinal disorders. It is believed that fundus AF is derived from lipofuscin in retinal pigment epithelial (RPE) cells; however, direct clinicopathological correlation has not been possible in humans. We examined fundus AF by confocal scanning laser ophthalmoscopy and confocal microscopy in normal C57BL/6 mice of different ages. Increasingly strong AF signals were observed with age in the neuroretina and subretinal/RPE layer by confocal scanning laser ophthalmoscopy. Unlike fundus AF detected in normal human subjects, mouse fundus AF appeared as discrete foci distributed throughout the retina. Most of the AF signals in the neuroretina were distributed around retinal vessels. Confocal microscopy of retinal and choroid/RPE flat mounts demonstrated that most of the AF signals were derived from Iba-1+ perivascular and subretinal microglia. An age-dependent accumulation of Iba-1+ microglia at the subretinal space was observed. Lipofuscin granules were detected in large numbers in subretinal microglia by electron microscopy. The number of AF+ microglia and the amount of AF granules/cell increased with age. AF granules/lipofuscin were also observed in RPE cells in mice older than 12 months, but the number of AF+ RPE cells was very low (1.48 mm-2 and 5.02 mm-2 for 12 and 24 months, respectively) compared to the number of AF+ microglial cells (20.63 mm-2 and 76.36 mm-2 for 6 and 24 months, respectively). The fluorescence emission fingerprints of AF granules in subretinal microglia were the same as those in RPE cells. Our observation suggests that perivascular and subretinal microglia are the main cells producing lipofuscin in normal aged mouse retina and are responsible for in vivo fundus AF. Microglia may play an important role in retinal aging and age-related retinal diseases.

CD11b+ bone marrow-derived monocytes are the major leukocyte subset responsible for retinal capillary leukostasis in experimental diabetes in mouse and express high levels of CCR5 in the circulation

We investigated the phenotype of cells involved in leukostasis in the early stages of streptozotocin-induced diabetes in mice by direct observation and by adoptive transfer of calcein-AM-labeled bone marrow-derived leukocytes from syngeneic mice. Retinal whole mounts, confocal microscopy, and flow cytometry ex vivo and scanning laser ophthalmoscopy in vivo were used. Leukostasis in vivo and ex vivo in retinal capillaries was increased after 2 weeks of diabetes (Hb A(1c), 14.2 ± 1.2) when either donor or recipient mice were diabetic. Maximum leukostasis occurred when both donor and recipient were diabetic. CD11b(+), but not Gr1(+), cells were preferentially entrapped in retinal vessels (fivefold increase compared with nondiabetic mice). In diabetic mice, circulating CD11b(+) cells expressed high levels of CCR5 (P = 0.04), whereas spleen (P = 0.0001) and retinal (P = 0.05) cells expressed increased levels of the fractalkine chemokine receptor. Rosuvastatin treatment prevented leukostasis when both recipient and donor were treated but not when donor mice only were treated. This effect was blocked by treatment with mevalonate. We conclude that leukostasis in early diabetic retinopathy involves activated CCR5(+)CD11b(+) myeloid cells (presumed monocytes). However, leukostasis also requires diabetes-induced changes in the endothelium, because statin therapy prevented leukostasis only when recipient mice were treated. The up-regulation of the HMG-CoA reductase pathway in the endothelium is the major metabolic dysregulation promoting leukostasis.

Classification of fundus autofluorescence patterns in early age-related macular disease

PURPOSE. To describe and classify patterns of abnormal fundus autofluorescence (FAF) in eyes with early nonexudative age-related macular disease (AMD). METHODS. FAF images were recorded in eyes with early AMD by confocal scanning laser ophthalmoscopy (cSLO) with excitation at 488 nm (argon or OPSL laser) and emission above 500 or 521 nm (barrier filter). A standardized protocol for image acquisition and generation of mean images after automated alignment was applied, and routine fundus photographs were obtained. FAF images were classified by two independent observers. The ? statistic was applied to assess intra- and interobserver variability. RESULTS. Alterations in FAF were classified into eight phenotypic patterns including normal, minimal change, focal increased, patchy, linear, lacelike, reticular, and speckled. Areas with abnormal increased or decreased FAF signals may or may not have corresponded to funduscopically visible alterations. For intraobserver variability, ? of observer I was 0.80 (95% confidence interval [CI]0.71-0.89) and of observer II, 0.74. (95% CI, 0.64-0.84). For interobserver variability, ? was 0.77 (95% CI, 0.67-0.87). CONCLUSIONS. Various phenotypic patterns of abnormal FAF can be identified with cSLO imaging. Distinct patterns may reflect heterogeneity at a cellular and molecular level in contrast to a nonspecific aging process. The results indicate that the classification system yields a relatively high degree of intra- and interobserver agreement. It may be applicable for determination of novel prognostic determinants in longitudinal natural history studies, for identification of genetic risk factors, and for monitoring of future therapeutic interventions to slow the progression of early AMD. Copyright © Association for Research in Vision and Ophthalmology.

Screening tests for detecting open-angle glaucoma: systematic review and meta-analysis

PURPOSE: To assess the comparative accuracy of potential screening tests for open angle glaucoma (OAG).

METHODS: Medline, Embase, Biosis (to November 2005), Science Citation Index (to December 2005), and The Cochrane Library (Issue 4, 2005) were searched. Studies assessing candidate screening tests for detecting OAG in persons older than 40 years that reported true and false positives and negatives were included. Meta-analysis was undertaken using the hierarchical summary receiver operating characteristic model.

RESULTS: Forty studies enrolling over 48,000 people reported nine tests. Most tests were reported by only a few studies. Frequency-doubling technology (FDT; C-20-1) was significantly more sensitive than ophthalmoscopy (30, 95% credible interval [CrI] 0-62) and Goldmann applanation tonometry (GAT; 45, 95% CrI 17-68), whereas threshold standard automated perimetry (SAP) and Heidelberg Retinal Tomograph (HRT II) were both more sensitive than GAT (41, 95% CrI 14-64 and 39, 95% CrI 3-64, respectively). GAT was more specific than both FDT C-20-5 (19, 95% CrI 0-53) and threshold SAP (14, 95% CrI 1-37). Judging performance by diagnostic odds ratio, FDT, oculokinetic perimetry, and HRT II are promising tests. Ophthalmoscopy, SAP, retinal photography, and GAT had relatively poor performance as single tests. These findings are based on heterogeneous data of limited quality and as such are associated with considerable uncertainty.

CONCLUSIONS: No test or group of tests was clearly superior for glaucoma screening. Further research is needed to evaluate the comparative accuracy of the most promising tests.

What is the best method for diagnosing glaucoma?

Glaucoma is characterized by a typical appearance of the optic disc and peripheral visual field loss. However, diagnosis may be challenging even for an experienced clinician due to wide variability among normal and glaucomatous eyes. Standard automated perimetry is routinely used to establish the diagnosis of glaucoma. However, there is evidence that substantial retinal ganglion cell damage may occur in glaucoma before visual field defects are seen. The introduction of newer imaging devices such as confocal scanning laser ophthalmoscopy, scanning laser polarimetry and optical coherence tomography for measuring structural changes in the optic nerve head and retinal nerve fiber layer seems promising for early detection of glaucoma. New functional tests may also help in the diagnosis. However, there is no evidence that a single measurement is superior to the others and a combination of tests may be needed for detecting early damage in glaucoma. © 2010 Expert Reviews Ltd.

The United Kingdom Glaucoma Treatment Study:a multicenter, randomized, placebo-controlled clinical trial: design and methodology

Elevated intraocular pressure (IOP) is a major risk factor for the deterioration of open-angle glaucoma (OAG); medical IOP reduction is the standard treatment, yet no randomized placebo-controlled study of medical IOP reduction has been undertaken previously. The United Kingdom Glaucoma Treatment Study (UKGTS) tests the hypothesis that treatment with a topical prostaglandin analog, compared with placebo, reduces the frequency of visual field (VF) deterioration events in OAG patients by 50% over a 2-year period.

Reticular Pseudodrusen in Age-Related Macular Degeneration

Historically, drusen, which are recognized as the hallmark of age-related macular degeneration (AMD), have been described in terms of size, margins, and texture, and several studies have emphasized the importance of large soft drusen particularly when combined with focal pigmentary irregularities in determining the risk of progression to neovascular AMD. However, recent developments in imaging over the past decade have revealed a further distinct phenotype strongly associated with the development of late AMD, namely, reticular pseudodrusen (RPD) or reticular drusen. Reticular pseudodrusen appear as yellowish interlacing networks in the fundus and, although visible on color photography, are better visualized using infrared imaging or spectral domain optical coherence tomography. Studies correlating spectral domain optical coherence tomography and confocal scanning laser ophthalmoscopy have shown that RPD are subretinal deposits located internal to the retinal pigment epithelium in contrast to traditional drusen, which are located external to the retinal pigment epithelium. As multiple longitudinal studies have revealed RPD are strong predictors for progression to both neovascular AMD and geographic atrophy, the interest in understanding the role that RPD play in the pathogenesis of AMD has grown. This review focuses on the current literature concerning RPD and considers what is currently known regarding their epidemiology, risk factors, appearance in both retinal imaging and histology, impact on visual function, relationship to other AMD lesions, and association with the development of late AMD.

Impact of age, various forms of cataract, and visual acuity on whole-field scotopic sensitivity screening for glaucoma in rural Taiwan.

OBJECTIVE: To evaluate the impact of age, various forms of cataract, and visual acuity on whole-field scotopic sensitivity screening for glaucoma in a rural population. DESIGN: Clinic-based study with population-based recruitment. SETTING: Jin Shan Township near Taipei, Taiwan. SUBJECTS: Three hundred forty-six residents (ages, > or = 40 years) of Jin Shan Township. INTERVENTIONS: Whole-field scotopic testing, ophthalmoscopy with dilation of the pupils, cataract grading against photographic standards, and screening visual field testing in a random one-third subsample. MAIN OUTCOME MEASURES: Whole-field scotopic sensitivity (in decibels) and diagnostic status as a case of glaucoma, glaucoma suspect, or normal. RESULTS: Participants in Jin Shan Township did not differ significantly in the rate of blindness, low visual acuity, or family history of glaucoma from a random sample of nonrespondents. Scotopic sensitivity testing detected 100% (6/6) of subjects with open-angle glaucoma at a specificity of 80.2%. The mean +/- SE scotopic sensitivity for six subjects with open-angle glaucoma (32.78 +/- 1.51 dB) differed significantly from that of 315 normal individuals (38.51 +/- 0.22 dB), when adjusted for age and visual acuity (P = .05, t test). With linear regression modeling, factors that correlated significantly with scotopic sensitivity were intraocular pressure, screening visual field, best corrected visual acuity, presence of cortical cataract, and increasing age. CONCLUSIONS: Although cataract affects the whole-field scotopic threshold, it appears that scotopic testing may be of value in field-based screening for glaucoma.

Une nouvelle méthode de détection du glaucome par la mesure de l'asymétrie interoculaire : l’asymétrie du rapport de la surface neurorétinienne sur la surface du disque optique ou rim area to disc area asymmetry ratio (RADAAR)

Cette thèse constitue à la fois un apport de nature clinique et technologique dans l’approche diagnostique du glaucome. Plus précisément, nous nous proposons d’étudier une nouvelle façon de détecter le glaucome par la mesure de l’asymétrie du rapport de la surface de l’anneau neurorétinien et de la surface de la papille ou du disque optique ou rim to disc area asymmetry ratio (RADAAR). Pour atteindre cet objectif, nous avons recours à une base de données composée d’une population subdivisée en 4 différents groupes de diagnostic (normal, glaucome possible, glaucome probable et glaucome définitif). Les mesures du RADAAR sont calculées de différentes façons à partir des paramètres stéréométriques de la tête du nerf optique des sujets, produits par la microscopie confocale à balayage laser (Heidelberg Retina Tomograph (HRT) (Heidelberg Engineering, Germany)). Nous procédons à une analyse de données grâce au logiciel SPSS où nous mettons en exergue la distribution du RADAAR dans les différentes populations, sa validité et son utilité dans le dépistage du glaucome. Nous enrôlons donc 523 sujets dans cette étude avec 82 sujets atteints de glaucome définitif. La moyenne d’âge est de 62 ans. Il y a plus de femmes que d’hommes et plus de Caucasiens que d’Africains Caribéens. Nous trouvons que la distribution de la mesure du RADAAR est différente des sujets d’un groupe de diagnostic à l’autre. En termes de performance, la sensibilité de la mesure du RADAAR est très basse c'est-à-dire que sa capacité de détecter la maladie est basse. En revanche la mesure du RADAAR est plus spécifique c'est-à-dire que sa capacité d’identifier les sujets exempts de la maladie est plus grande. Elle tendrait à être aussi plus performante chez les Africains Caribéens que chez les Caucasiens. De même, elle serait plus sensible chez les hommes que chez les femmes. La mesure du RADAAR est utile si on l’associe à une autre méthode de diagnostic comme l’analyse de Régression de Moorfields (MRA) incluse dans le logiciel du HRT3 spécialement lors de la détection du glaucome dans la population à haut risque. En définitive, nous déterminons que la mesure du RADAAR se veut un outil d’aide au diagnostic. Elle est particulièrement intéressante dans le contexte de dépistage de glaucome.

Macrodisco y glaucoma en individuos estudiados con tomografía óptica coherente

Introducción: El glaucoma representa la tercera causa de ceguera a nivel mundial y un diagnóstico oportuno requiere evaluar la excavación del nervio óptico que está relacionada con el área del mismo. Existen reportes de áreas grandes (macrodiscos) que pueden ser protectoras, mientras otros las asocian a susceptibilidad para glaucoma. Objetivo: Establecer si existe asociación entre macrodisco y glaucoma en individuos estudiados con Tomografía Optica Coherente (OCT ) en la Fundación Oftalmológica Nacional. Métodos: Estudio transversal de asociación que incluyó 25 ojos con glaucoma primario de ángulo abierto y 74 ojos sanos. A cada individuo se realizó examen oftalmológico, campo visual computarizado y OCT de nervio óptico. Se compararon por grupos áreas de disco óptico y número de macrodiscos, definidos según Jonas como un área de la media más dos desviaciones estándar y según Adabache como área ≥3.03 mm2 quien evaluó población Mexicana. Resultados: El área promedio de disco óptico fue 2,78 y 2,80 mm2 glaucoma Vs. sanos. De acuerdo al criterio de Jonas, se observó un macrodisco en el grupo sanos y según criterio de Adabache se encontraron ocho y veinticinco macrodiscos glaucoma Vs. sanos. (OR=0,92 IC95%=0.35 – 2.43). Discusión: No hubo diferencia significativa (P=0.870) en el área de disco entre los dos grupos y el porcentaje de macrodiscos para los dos grupos fue similar, aunque el bajo número de éstos no permitió concluir en términos estadísticos sobre la presencia de macrodisco y glaucoma.

Screening for diabetic retinopathy using a non-mydriatic retinal camera in rural Victoria

PURPOSE: To develop a screening programme for the early detection of diabetic retinopathy using non-mydriatic retinal photography. METHODS: A community based screening service was offered to all people with known diabetes mellitus in selected townships in the LaTrobe and Goulburn Valleys in Victoria. At the local examination centre, basic sociodemographic information was collected as well as details of previous use of eye care services for the early detection of diabetic retinopathy. The examination included visual acuity (VA), glycosylated haemoglobin level and Polaroid photographs of each fundus using a Canon CR5-45NM non-mydriatic retinal camera (Canon, Tochigiken, Japan). Dilating drops were not used. Photographs were subsequently reviewed and letters were sent to all participants (with copies to their general practitioners) with recommendations for appropriate follow up. RESULTS: A total of 1177 people with diabetes attended the screening service, which is estimated to be 40% of the total population with known diabetes in the study area. The mean age was 65 years (range 20-94 years); 559 (48%) people reported not having a dilated fundus examination within the past 2 years; 345 (29%) people had never had a dilated fundus examination. Of the 2354 eyes, 2126 (90%) of the photographs were gradable. A total of 704 people (60%) had normal VA and no evidence of diabetic retinopathy, 209 people (18%) had diabetic retinopathy, 101 people (9%) had evidence of other fundus pathology, 42 people (3%) had reduced acuity (< 6/18) in one or both eyes (with no fundus pathology evident) and 121 people (10%) had ungradable photographs in one or both eyes. CONCLUSIONS: The present study demonstrates the usefulness of a screening programme with non-mydriatic retinal photography as an adjunct to current eye care services for the early detection of diabetic retinopathy.

Utilidade do exame fundoscópico realizado por não-oftalmologistas na avaliação de pacientes hipertensos

O objetivo deste estudo foi avaliar a utilidade da oftalmoscopia direta realizada por não-oftalmologistas em 400 pacientes hipertensos não diabéticos. Em um estudo transversal, analisou-se a associação entre exame fundoscópico, categorizado em normal e anormal e de acordo com uma classificação de Keith, Wagener e Barker (KW) modificada, com pressão arterial, duração da hipertensão e anormalidades eletrocardiográficas. Associações entre pressão arterial e anormalidades eletrocardiográficas também foram realizadas. As anormalidades de fundo-de-olho foram mais freqüentes em pacientes com pressão arterial diastólica maior que 105 mmHg (P = 0,001), pressão sistólica maior que 180 mmHg (P < 0,001) e com duração da hipertensão maior que 3 anos (P = 0.003). Também houve maior freqüência de anormalidades à fundoscopia em pacientes com estágios mais graves de hipertensão segundo a classificação do V Joint National Committee (V-JNC). Não houve associação entre gravidade da hipertensão e as classes KW 1 e KW 2: 34,5% dos pacientes classificados como KW 1 tinham pressão diastólica acima de 105 mmHg, contra somente 25,3% daqueles classificados como KW 2. Esta categoria também foi mais freqüente em todos os estágios de hipertensão segundo o V-JNC. As anormalidades da classe 3 de KW foram pouco freqüentes, ocorrendo em somente 2,5% dos pacientes da coorte. Em um modelo de regressão logística, o estreitamento arteriolar difuso foi associado com maior pressão diastólica (P = 0,002) e maior idade (P < 0,001). Anormalidades de cruzamentos arteriovenosos foram associados com maior pressão sangüínea sistólica (P = 0,003) e duração da hipertensão maior do que 3 anos (P = 0,024). O valor preditivo positivo de qualquer anormalidade fundoscópica estimar a gravidade da hipertensão foi de 75,20% e o valor preditivo negativo, 41,75%. Observou-se maior proporção de eletrocardiograma anormal (qualquer anormalidade) e de sobrecarga ventricular esquerda em pacientes com pressão diastólica maior que 105 mmHg (P = 0,039 e P = 0,032 respectivamente) e com sistólica maior que 180 mmHg (P = 0,034 e P = 0,001 respectivamente). Anormalidades entre oftalmoscopia e eletrocardiograma não mostraramse associadas. Os resultados deste estudo demostraram que, apesar das anormalidades fundoscópicas terem sido mais freqüentes em hipertensos mais graves, o exame de fundode- olho não proporcionou uma idéia acurada da gravidade da hipertensão na maioria dos pacientes examinados por internistas e cardiologistas e, que a classificação de Keith, Wagener e Barker teve uma aplicação limitada. A observação de um cruzamento arteriovenoso alterado sugere que a pressão sistólica seja elevada. A presença de estreitamento arteriolar difuso é mais freqüente em pacientes mais velhos e naqueles com pressão diastólica elevada.