Diagnostic Technologies in Ophthalmology

Clinicians routinely face the challenge of diagnosing a medical condition, or assessing the severity and prognosis of disease based upon the diagnostic information at their disposal. Using such information to determine a diagnosis (e.g. imagining technology to diagnose glaucoma), is called a diagnostic test. Most diagnostic tests fall comfortably short of perfection in their diagnosis. When assessing a diagnostic test there are two related aspects to be concerned about – how well the test deals with diseased and non-diseased cases. Research is needed to assess the diagnostic performance and more generally the role a diagnostic test should play in clinical care: if, when and how it should be used. In this chapter, measures of diagnostic performance will be described using an example study. The challenges in conducting a robust and clinically relevant diagnostic study will be considered.

Anterior segment imaging is a rapidly advancing field of ophthalmology. New imaging modalities, such as rotating Scheimpflug imaging (Pentacam-Scheimpflug) and anterior segment optical coherence tomography (Visante OCT and Slit-Lamp OCT), have become commercially available. These new modalities supplement the more established imaging devices of Orbscan scanning slit topography and ultrasound biomicroscopy (UBM). All devices provide software that allows quantitative information, as well as, qualitative imaging of the cornea and anterior chamber. They provide quantitative angle estimation by calculating the angle between the iris surface and the posterior corneal surface. Direct angle visualization is also possible with the OCT devices and UBM; they provide images of the scleral spur, ciliary body, ciliary sulcus and even canal of Schlemm in some eyes. Pentacam- Scheimpflug can measure net corneal power, a feature particularly useful for cataract patients having undergone previous corneal surgery. Anterior segment OCT can also measure corneal dimensions and anterior chamber width prior to phakic intraocular lens implantation. Latest findings show it to be useful in the presence of corneal opacities. The arrival of the new imaging devices may herald the dawn of a new era for ophthalmic diagnosis, particularly in view of the ease and non-contact nature of many of the examination modalities.

Traditional ophthalmic instruments such as the slit-lamp are limited in their ability to permit high resolution evaluation of ocular structures. In contrast, in vivo corneal confocal microscopy (IVCCM) utilizes the principle of confocal optics where the observation and illumination system of the optical device meet at a single point. Light reflected by structures from outside the focal point is thus excluded, increasing the image resolution and contrast compared to conventional light biomicroscopy. The technology of IVCCM has been applied in Ophthalmology and commercially available devices provide non-invasive high-resolution images of the cornea, limbus and conjunctiva, providing images with magnification of up to 400 times. IVCCM allows early detection and diagnosis of infectious keratitis, showing features of bacterial, viral, fungal or protozoal infection. In Acanthamoeba keratitis, IVCCM is particularly helpful in disease management compared to other methods. In corneal dystrophies, IVVCM can be used to characterize dystrophies, as well as, assess disease progression. Although a range of interesting applications has been found, there are still limitations of IVCCM due to the narrow field of view and dependence on skilled operators and interpretators. Despite these constraints, the usefulness of IVCM to analyze ocular surface structures at a cellular level in normal and pathologic conditions is proving to be helpful in disease management.

Ocular samples include: ocular cells or tissue (conjunctiva, cornea, retina, or orbital tissue), bio-fluids such as tears, aqueous or vitreous, therapeutic or cosmetic contact lenses, implanted devices (intraocular lenses, corneal rings), or transplanted tissue (e.g. Infected corneal graft tissue). Sampling extends beyond the careful collection of ocular material to involve sample storage and transfer. Reliable results require avoiding sample contamination at any stage of sampling, storage, and processing. In order to aid the laboratory scientist to provide an accurate interpretation of the investigations, it is extremely important to give details of all relevant clinical history, other related medical conditions, clinical differential diagnosis, and in some cases demographical details such as race, birth place and current postcode. This chapter will provide a précis of common sample collection in ophthalmology and an overview of culture-dependent and independent techniques including immunohistochemistry and molecular biological techniques used for ophthalmological diagnosis.

Anterior segment optical coherence tomography (AS-OCT) is a non-contact imaging modality, which was developed to obtain cross-sectional images of anterior segment structures including the angle.The advantages of AS-OCT over more traditional methods of examining the angle such as gonioscopy and ultrasound biomicroscopy (UBM) are that it is quick, non-invasive and requires less skill to acquire and interpret images. The current roles of AS-OCT imaging include confirmation of the diagnosis of angle closure and measurement of change in angle width following laser or surgical interventions for angle closure.In regions of the world where angle closure glaucoma is prevalent, AS-OCT has potential as a future screening method for the disease.Currently this technology is limited by having difficulty in identifying important landmarks in the angle due to suboptimal image quality in many cases. This results in apparent over detection of angle closure when compared with gonioscopy and difficulty in applying quantitative measurement parameters in image analysis. Rapid developments in imaging technology including fourier domain OCT and 3-dimensional OCT may help overcome some of these limitations.

The Heidelberg Retina Tomograph (HRT) has been available in the clinical practice for over a decade. The device utilizes the principle of confocal scanning laser ophthalmoscopy to acquire three-dimensional topographical images of the optic nerve head. The basic principles of image acquisition are discussed, along with the use of the HRT in assisting clinicians to discriminate between normal and glaucomatous optic discs and to detect glaucomatous progression. The native software incorporates a number of easily interpreted classification algorithms such as the ‘Moorfields Regression Analysis’ and the ‘Glaucoma Probability Score’. When using the HRT to aid diagnosis, clinicians should use clinical information to judge the ‘pre-test probability’ that glaucoma is present together with the information supplied by the HRT to derive the ‘post-test probability’ of a patient having a diagnosis of glaucoma. Methods to improve the signal to noise ratio are central in improving the detection of progression using longitudinal HRT imaging.

Glaucoma is the second leading cause of blindness worldwide. It is characterized by the accelerated death of retinal ganglion cells and is presented as progressive functional damage in the visual field. Disease detection is dependent on the clinical capabilities of the eye care provider identifying structural changes in the retina and optic nerve head region compatible with glaucoma. The first-line diagnostic tools for identifying glaucoma are clinical examination with direct or indirect ophthalmoscopy and/or stereoscopic optic nerve head photographs. Unfortunately, these tools are prone to high intra- and inter-observer variability. A number of imaging devices have been incorporated into clinical practice with the goal of early detection and quantification of structural glaucomatous changes in the retinal nerve fiber layer and optic nerve head. One of the commercially available glaucoma imaging devices is optical coherence tomography (OCT).OCT generates cross-sectional and three-dimensional images of retinal structures.Its application in glaucoma diagnostics and monitoring will be discussed in this chapter.

Scanning laser polarimetry is one of the widely used imaging technologies developed to detect glaucoma. The method is based on the non-invasive measurement of retardation of the illuminating polarized laser light by the peripapillary retinal nerve fibre layer. Since the measurement principle is tissue specific, no time-consuming delineation of the optic nerve head is necessary. The recent software versions (GDx-VCC and GDx-ECC) show favorable diagnostic accuracy and have been completed with an advanced program for the detection of glaucoma progression during long-term follow-up.

Here we analyze the evolution of perimetric strategies, from the time that it became known that prolonged examination decreases their accuracy. The new strategies do not seek great accuracy in measuring threshold, which is assumed to be impossible to achieve, but rather estimate it with an acceptable level of error, adapted by the clinical usefulness of examinations. This approach exploits the redundancy inherent to the glaucomatous visual field. Thresholds are not independent of each other, and the results obtained in some areas are applicable to the measurement of thresholds and defects in other areas. The estimation of threshold values has to be addressed from a probabilistic point of view. These new strategies are accepted as being superior in many ways to traditional strategies, and even facilitate interpretation of the degree of reliability of perimetric studies. The first examinations of the patient can be repeated without too much loss of time to ensure sufficient training.

Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world. With the advent of anti-VEGF therapy only a small proportion of patients with neovascular AMD will develop severe visual impairment. Although, monthly injections of anti-VEGF treatment may have the potential to achieve excellent visual outcomes, this regime is costly and not without risk. Hence, most retinal specialists opt to use optical coherent topography (OCT) to guide patient’s re-treatment. OCT is also being used as a screening tool to detect early signs of neovascular AMD in patients with age-related maculopathy as well as to help in characterizing AMD phenotypes. Thus, OCT can be used to help in the differentiation between pure serous retinal pigment epithelial detachment (PED) and vascularized PED. In the latter, subretinal fluid (SRF) is present and can be identified by OCT; vascularized PED is amenable to anti-VEGF treatment. OCT may also be helpful in the identification of retinal angiomatous proliferation (RAP) and polypoidal choriovasculopathy (PCV), two forms of neovascular AMD which often require more intensive treatment.

Optical Coherence Tomography (OCT) is part of the routine examination of all vitreomacular disorders. Spectral domain technology has provided images with better resolution, which are also easier to interpret reliably. In most of these pathologic cases, it is now possible to visualize the status of the posterior hyaloid, its connection to the retinal surface, and its thickness and reflectivity. OCT plays an essential role in the diagnosis and preoperative assessment of macular holes. In impending macular holes, it shows minute irregularities of the foveal curvature, and/or tiny intrafoveal tractional retinal cysts. In full thickness macular holes, OCT clearly shows defects in the retinal tissue and allows full thickness macular holes to be distinguished from macular lamellar holes or pseudoholes. The quality of the OCT scan profiles also allows accurate measurement of macular hole diameter, which is a major indicator of the chances of successful surgery and may affect the choice of surgical technique. Furthermore, OCT allows assessment of the quality of macular hole closure. Although the presence of epiretinal membranes may also be diagnosed on red-free and blue reflectance photographs, OCT has the advantage of showing the degree of retinal thickening in the fovea, as well as the presence of any intrafoveal cysts or vitreomacular traction. Diagnosis of the vitreomacular traction syndrome has also been greatly facilitated by the use of OCT, which shows, more clearly than ultra sound or biomicroscopy, the elevation of the foveal surface due to the focal traction of a thick and hyper-reflective posterior hyaloid. Finally, OCT has allowed the identification of myopic foveoschisis, a hitherto unknown but relatively common complication related to myopic staphyloma. This vision - threatening complication may benefit from surgery, depending on its OCT characteristics. In conclusion, although OCT is still a technique in evolution, but it already provides invaluable information on vitreomacular disorders and plays an essential part in their diagnosis and management.

Ocular imaging plays a vital role in the diagnosis and management of diabetic eye disease. Stereoretinal photographs are used to grade diabetic retinopathy for research and, in the UK, digital retinal photography is the standard mode of screening for sight threatening diabetic retinopathy. Fundus fluorescein angiography (FFA) provides additional information on the retinal vasculature and is used to plan retinal laser therapy. Optical coherence tomography (OCT) produces detailed cross sectional images of the retina and is increasingly being used in the detection and follow-up of diabetic maculopathy. Ultrasonography (US) is essential for examining eyes where there is an inadequate view of the fundus and is able to identify features of advanced diabetic retinopathy including vitreous hemorrhage and tractional retinal detachment. Ultrasound biomicroscopy only penetrates the anterior part of the eye but it can detect fibrovascular ingrowths at sclerotomy sites following vitrectomy.

Conventional fundus autofluorescence (AF) and near-infrared autofluorescence (NIA) are imaging techniques now used routinely in clinical practice by most retinal specialists. Detecting different fluorophores [predominantly lipofuscin in the retinal pigment epithelium (RPE) by the former and melanin in the RPE and choroid by the latter] AF and NIA provide different information to the clinician with regards to the status of the retina. Wider experience exists, to date, with the use of AF as the technique of NIA has been described only recently. Accordingly, several studies have demonstrated the value of AF imaging in the management of patients with posterior segment disorders, not only as a diagnostic tool but also providing prognostic information. Agerelated macular degeneration, inherited retinal diseases, posterior uveitis, intraocular tumors, central serous chorioretinopathy and vitreo-retinal disorders are some of the conditions in which fundus AF has been shown to be helpful to the clinician. As more knowledge on conventional fundus AF is emerging, and the use of NIA is becoming more widespread, it is likely that the scope for these imaging techniques will expand.

Electrophysiological testing allows objective assessment of retinal function. By changing the nature of the stimulus presented to the patient and the adaptive state of the eye (light or dark adapted) responses from different retinal cell types and layers can be obtained. The primary tests used in the evaluation of inherited retinal disease are the full-field electroretinogram (ERG), the pattern electroretinogram (PERG) and the electrooculogram (EOG), obtained following the International Standards for Clinical Electrophysiology in Vision (ISCEV) as well as the more recent techniques multi-focal electroretinogram (mfERG), ON/OFF ERG and s-cone ERG. Electrophysiological testing is useful for both the diagnosis and follow-up of patients with inherited retinal disease and is indicated when (1) the retina is morphologically “normal” but the patient is symptomatic, (2) the fundal appearance may not reflect the severity or nature of the disorder; (3) an accurate diagnosis is required or (4) prognostic information is required for the management of the patient. This chapter provides the basics of the electrophysiological techniques that can be used, suggests the pertinent tests to make the diagnosis and reviews the typical electrophysiological findings in a range of the more commonly encountered inherited retinal diseases.