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These congenital, non-progressive lesions are benign, and often solitary and unilateral. Patients are usually asymptomatic, although some may experience decreased vision and neurologic symptoms, such as seizures and cranial nerve palsies [15, 87]. Cutaneous or cerebral hemangiomas may also be found, especially in cases of inherited lesions [2, 4, 15, 22, 23, 58]. Pedigree analysis suggests that this neurooculocutaneous syndrome may be inherited in an autosomal dominant pattern, with incomplete penetrance or variable expressivity [23, 58]. [ABSTRACT FROM AUTHOR]

Sickle cell hemoglobinopathies all share the common feature of an abnormal globin chain, which leads to sickling of erythrocytes and obstruction of the microcirculation. Sickle vaso-occlusive events are insidious and affect virtually every vascular bed in the eye, often with visually devastating consequences. Vaso-occlusion most profoundly affects the retina, the light-sensitive tissue that lines the inside wall of the posterior aspect of the eye, because it is exquisitely sensitive to deprivation of oxygen. Even temporary vaso-occlusion, if longer than about 1.5-2 h, can result in permanent infarction of the retina. Most, if not all, of the complications of sickle cell disease in retina originate from the vaso-occlusive processes. The pathological changes can be divided into nonproliferative and proliferative events. [ABSTRACT FROM AUTHOR]

The classification of fundus changes secondary to arterial hypertension has been used for monitoring the severity of vascular alterations. In the past, this was the only possibility to assess the status of the microcirculation. Therefore, very detailed classifications have been developed. These classifications are described below. The detailed classification of hypertensive vascular fundus changes may be still important for scientific reasons. However, for the clinical management of systemic hypertension today these detailed classifications are no longer necessary. Nevertheless, the separation between minor vascular changes in systemic hypertension (stage I and II) and hypertensive retinopathy (stage III and IV) is still very important for the management of arterial hypertension. Patients with hypertensive retinopathy have to be treated and monitored intensively by internal medicine since these patients are at high risk for cardiovascular and cerebrovascular complications. [ABSTRACT FROM AUTHOR]

Henry Eales, a British ophthalmologist, described this condition almost 125 years ago [14, 15]. Eales' original description was of recurring retinal and vitreous hemorrhages along with epistaxis, headaches, variation in peripheral circulation, dyspepsia, and chronic constipation in young men. He felt it was a vasomotor neurosis, wherein constriction of the alimentary vessels resulted in compensatory dilatation of the vessels in the head, leading to bleeding. Though Eales was honored with the eponym for this disease, Wadsworth was the first to describe the presence of retinal inflammation, 5 years later [37]. Duke Elder considered Eales' disease to be a clinical manifestation of many diseases. [ABSTRACT FROM AUTHOR]

Purtscher's retinopathy was first described by Otmar Purtscher in 1910 as a syndrome of multiple, white retinal patches, superficial retinal hemorrhages, and papillitis occurring in five patients with severe head trauma [11]. He originally named this condition angiopathia retinae traumatica and hypothesized that white, superficial retinal patches were lymphatic extravasations caused by a sudden increase in intracranial pressure secondary to massive head trauma. [ABSTRACT FROM AUTHOR]

Uveal melanomas present in adulthood, their incidence peaking at around the age of 60 years [4]. More than 90% of uveal melanomas arise in choroid, about 40% extending close to optic disk or fovea. These tumors tend to cause visual loss from retinal pigment epithelial disease, macular edema, and exudative retinal detachment (Fig. 23.1). In advanced cases, the presence of a large intraocular tumor and extensive retinal detachment can result in rubeosis, neovascular glaucoma, phthisis, and a blind and painful eye. Approximately 50% of patients develop metastatic disease, which usually involves the liver and which is usually fatal within a few months. [ABSTRACT FROM AUTHOR]

A complicated well-regulated balance exists between the thrombosis and fibrinolysis systems. This chapter will cover the two main categories of retinal vascular occlusive disease (RVOD): central (CVO) or branch retinal vein occlusion (BVO) and central (CAO) or branch retinal artery occlusion (BAO). This chapter will not address the overall diagnostic evaluation of patients with retinal vascular disease. Patients with CAO/BAO should be evaluated by their medical doctor for common underlying causes such as ipsilateral carotid disease and heart disease. Patients with bilateral, simultaneous CVO/BVO of course should be evaluated for common causes of hypercoagulable states such as Waldenström's or multiple myeloma. Basic evaluation should include a medical review of systems, testing for high blood pressure and diabetes for all patients, and sedimentation rate, carotid Doppler and cardiac sonogram should always be obtained for retinal arterial disease (RAO). After a basic evaluation, many patients with RAO or retinal venous disease (RVO) are said to have idiopathic conditions. In recent years, there have been a large number of papers citing possible associations of RAO and RVO with abnormalities of plasma proteins. Are these associations real? Which should be considered and looked for in which patients? It will be some years before we can offer clear guidance on this subject, and there is a strong need for large prospective studies with contemporaneous well-matched control groups. Until these studies are available, in this chapter we summarize the pertinent literature and offer some thoughts on whether and how patients with RAO and RVO who do not have obvious causes after a "basic" evaluation should be worked up. [ABSTRACT FROM AUTHOR]

Idiopathic juxtafoveolar retinal telangiectases (IJRT) were classified by Gass and Oyakawa in 1982 using biomicroscopic and fluorescein angiographic data [6]. This classification was updated by Gass and Blodi in 1993 [5], who subdivided IJRT into three groups (Table 22.1.1). Group 1 IJRT are unilateral in most cases and characterized by dilated retinal capillaries and abnormal leakage leading to an easily visible exudation. Group 2 IJRT are mostly bilateral and characterized by late staining on fluorescein angiography with minimal exudation. Later in the disease process retinal pigment epithelial proliferation or secondary subretinal neovascularization may develop. In Group 3 changes are based on bilateral capillary occlusion. These changes lead to easily visible telangiectasis, parafoveolar capillary occlusion and minimal exudation. [ABSTRACT FROM AUTHOR]

The grading of diabetic retinopathy is based on the concept that a hierarchy of stages can be defined, where the higher the grade, the higher the risk of suffering visual loss. The grading scale reflects the natural course of the disease in its unrelenting and most devastating form. In reality, diabetic retinopathy can regress both spontaneously and after therapeutic intervention. To construct or validate a grading scale, rates of progression to visual loss or another endpoint that is meaningful to the patient must be measured. Grading scales constructed for scientific and regulatory purposes, such as the study of new interventions, are made with the purpose of achieving maximum sensitivity for change in retinopathy. Interventional trials may then result in selected grades being validated and found useful for guiding interventions such as photocoagulation for proliferative diabetic retinopathy or diabetic macular edema. The timely identification of patients who reach interventional thresholds is the purpose subserved by simpler grading scales used in clinical screening practice. [ABSTRACT FROM AUTHOR]

Retinopathy of prematurity (ROP) was first noted in the late 1940s in preterm infants and described as retrolental fibroplasia, a total retinal detachment seen as white mass behind the lens. The disease was subsequently associated with excessive oxygen use [12, 14, 52]. Oxygen supplementation was curtailed with a decrease in ROP but with an increase in cerebral palsy and death. Supplemental oxygen is now delivered to premature infants to maintain adequate blood levels, but it is monitored carefully [37]. [ABSTRACT FROM AUTHOR]

In most cases (97%) neovascular glaucoma is caused by ischemia [5]. The most common underlying diseases are proliferative diabetic retinopathy and proliferative retinopathy after central retinal vein occlusion (CRVO). Rare types of neovascular glaucoma are of non-ischemic nature (e.g., tumor-induced, inflammatory disease) but should be separated because of different treatment strategies (Table 17.1). [ABSTRACT FROM AUTHOR]

Intravitreal injection was reported by Ohm in 1911 as a technique to introduce air for retinal tamponade and repair of retinal detachment [28]. Intravitreal administration of pharmacotherapies dates to the mid-1940s with the use of penicillin to treat endophthalmitis [34, 35]. Since that time, use of the intravitreal injection technique has steadily increased, with its usage being focused primarily on the treatment of retinal detachment [7, 32], endophthalmitis [8, 31], and cytomegalovirus (CMV) retinitis [13, 43]. The increasing confidence in the efficacy and safety of intravitreal injections, in conjunction with the development of additional pharmacotherapies, has led to a recent rapid increase in the use of this technique for the administration of various pharmacotherapies (e.g., ranibizumab [6], pegaptanib sodium [9, 41, 42]) for age-related macular degeneration (AMD) and intravitreal triamcinolone for macular edema associated with a variety of etiologies, such as diabetic retinopathy [21], central retinal vein occlusion [10, 36], branch retinal vein occlusion [5, 17, 30, 37], uveitis [2, 44], and birdshot retinochoroidopathy [22]. [ABSTRACT FROM AUTHOR]

No advance in the treatment of vitreoretinal diseases has been as significant as the introduction of pars plana vitrectomy by Machemer in 1971 [44]. The closed system allowed for a safe intraocular manipulation and constant viewing of the retina. During the past few decades the instrumentation has advanced, but the same principles still apply. [ABSTRACT FROM AUTHOR]

Cryotherapy has a long history in the treatment of retinal vascular disease. Freezing the retina to create inflammation in the area of application began as early as 1918, when Schöler applied solid carbon dioxide to the sclera and described choroidal inflammation [9]. In the treatment of proliferative retinopathy, cryotherapy today has largely been replaced by laser photocoagulation. However, the transscleral mode of application renders cryotherapy particularly useful in the case of hazy media or cataracts. It is also useful in treating more peripheral lesions that cannot be easily visualized at a slit lamp. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) with verteporfin has significantly improved functional outcome in the treatment of choroidal neovascularization (CNV) in various clinical disorders [86]. While CNV due to age-related macular degeneration [4, 53, 76-80, 84] and pathologic myopia [83, 85] was the primary focus, several studies showed that the treatment effects of PDT were not only restricted to these two underlying disorders. Recently, several clinical studies observed PDT as a treatment modality of CNV due to ocular histoplasmosis syndrome [52, 55, 68], choroiditis [71, 89], angioid streaks [31, 37, 68], Stargardt's disease [81], symptomatic choroidal hemangioma [30, 61, 82] and other causes [15, 72]. While PDT has become an established treatment modality for various choroidal disorders, its role in the treatment of retinal diseases remains to be determined. [ABSTRACT FROM AUTHOR]

Today light coagulation is a common treatment procedure and the basis of treatment in many retinal diseases. Its origins go back to Meyer-Schwickerath 1949 [46], who initially used sunlight as an energy source. However, sunlight was unsuitable for several reasons. A system of several mirrors and a long exposure time were necessary. The dependence on the weather forecast was an obvious problem. With the development of xenon high pressure lamps (Fig. 13.1) at the beginning of the 1950s, enough power for light coagulation of the ocular fundus became available [34]. Much scientific work was published at this time which showed the therapeutic effect of the light coagulation and which led to a wider experience [47, 48]. The main focuses of clinically based xenon coagulation were retinopexy and the treatment of proliferative diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Retinal vascular diseases, in particular diabetic retinopathy and retinal venous occlusive disorders, are important causes of visual loss and blindness. Other important retinal vascular diseases which can affect visual function include arterial occlusive disease, parafoveal telangiectasis, Coat's disease, vasculitides, macroaneurysms, and hypertensive retinopathy. Despite the various etiologies and underlying pathogenic processes, the mechanisms of visual loss are frequently similar among these diseases. One such common final pathway is the development of occlusions of the microcirculation (capillaries) with attendant retinal ischemia. The most frequent sequela, however, is a compromise in retinal vascular permeability leading to leakage and exudation with accumulation of fluid, lipid, and proteins within the retina [40] or in the subretinal space. Structural alterations are also a frequent outcome of retinal vascular disease. These changes include the development of cystoid spaces in the retina and vitreomacular traction. [ABSTRACT FROM AUTHOR]

Development of novel molecular biology techniques in the 1970s and 1980s furnished scientists with new tools to advance the study and treatment of human disease. Progress in the understanding of bacterial and viral biology led to innovations in molecular cloning and chimeric plasmid construction. Advances in nucleic acid sequencing allowed researchers to gain a better understanding of genes and the ability to study gene mutations. Unraveling the minutiae of molecular events involved in gene transcription and translation furthered the analysis of cellular pathways and their complex interrelationships. Production of proteins ex vivo allowed physicians to treat diseases such as diabetes with synthetic human insulin, ending the dependency on animal sources. [ABSTRACT FROM AUTHOR]

Fluorescein is one of the most potent artificial dyes. It was first synthesized in 1871 by Adolf von Baeyer, a German chemist who in 1905 received the Nobel Prize in chemistry for his work on organic dyes. [ABSTRACT FROM AUTHOR]

The human eye is supplied by two vascular systems: the retinal and the uveal vessels. The uveal vascular system consists of the iris, the ciliary body and the choroid. The outer layers of the retina including the photoreceptors are nourished by the choroid, whereas the inner layers of the retina including the retinal ganglion cells are supplied by the retina. Approximately 65% of the oxygen consumed by the retina is delivered from the choroid. [ABSTRACT FROM AUTHOR]

Proper retinal function requires the presence of a well-defined blood-retinal barrier (BRB). In many of the leading causes of medical blindness this BRB is compromised. Indeed, retinopathy of prematurity and age related macular degeneration both include production of aberrant vessels with poor barrier properties. Further, diabetic retinopathy, the leading cause of blindness in working age adults, involves progressive vision loss and is closely associated with macular edema [117]. Increased fluid accumulation, as well as lipid and albumin deposits, is believed to be the result of the breakdown of the BRB that normally controls the neuronal environment. Barrier dysfunction results in increased permeability which diagnostically indicates progressive retinopathy [32]. This chapter will review the normal physiology of the BRB, the changes that occur through the course of diabetic retinopathy, and the known underlying molecular mechanisms that may lead to barrier dysfunction. Elucidating the mechanisms of barrier dysfunction in diabetic retinopathy will further our understanding of its pathogenesis and provide future therapeutic targets. [ABSTRACT FROM AUTHOR]

Oxygen cannot passively diffuse for more than a radius of 100 µm around capillaries. As a result, adequate O2 supply to each cell depends on effective regulation of the integrity and function of the vascular network. On the other hand, high O2 tissue levels would result in reactive oxygen species (ROS) generation and cellular damage. Therefore, an optimal O2 concentration is needed to avoid hypoxia or ROS-mediated cellular injury. The retinal tissue is very active metabolically and, therefore, exquisitely dependent on adequate O2 supply for its function [4]. The delivery of oxygen to the retina is dependent not only on systemic blood pressure, hemoglobin content and integrity of local vasculature, but on the level of intraocular pressure and local autoregulatory mechanisms as well. Hypoxia and its sequelae are implicated in the pathogenesis of most retinal diseases, especially those that involve pathologic neovascularization. This is due to the potent stimulation of production of vascular endothelial growth factor (VEGF), mediated by the hypoxia-inducible factor (HIF)-1 pathway, in response to hypoxia. [ABSTRACT FROM AUTHOR]

Much of the effort to understand diabetic retinopathy has focused on vascular pathology. Due to the influence of diabetes on systemic physiology, it is thought that many changes in retinal vascular cells likely stem from direct biochemical disruptions such as hyperglycemia. Other contributing factors may include circulating cytokines, advanced glycation end products, cholesterol, albumin, and electrolytes, and more complex functional changes such as reduced elasticity in erythrocytes and other blood cells. These and other changes could be responsible for generating the vascular pathologies that have been well established in diabetic retinopathy. There is increasing evidence, however, for involvement of the neural elements of the retina, the neurons and glial cells, and it is no longer clear if the pathological changes in these cells result from vascular dysfunction, such as the reduction in effectiveness of the blood-retinal barrier, or if diabetic physiology induces neural pathology, which in turn gives rise to vascular changes. A third possibility is that early vascular and neural responses to diabetes are independent phenomena that are triggered by different factors. [ABSTRACT FROM AUTHOR]

In the past few decades, our knowledge of the mechanisms underlying retinal vasoproliferation has increased greatly (see Chapters 2, 3.1, 3.2 and 3.3). While vasoproliferation was once considered to be mainly a consequence of ischemia, current evidence also supports a contribution of inflammatory mechanisms. Inflammation is also highly related to vascular leakage in diseases that are known to result in retinal and macular edema. Recently, inflammatory mechanisms have gained interest with respect to the retinal pathology following ischemia, as well as in diseases such as diabetic retinopathy (DR) and sickle cell retinopathy (see Chapter 27.1). In this chapter, the discussion will focus on the published data relating to the inflammatory mechanisms in ischemic retinal diseases such as DR. The definition of inflammation in this setting is the involvement of any leukocyte-mediated pathology in the course of the disease. [ABSTRACT FROM AUTHOR]

Neovascular diseases of the eye include retinopathy of prematurity (ROP), proliferative diabetic retinopathy (PDR), and the exudative or "wet" form of age-related macular degeneration (ARMD). Together these diseases affect all age groups and are the leading causes of vision impairment in developed nations [77]. [ABSTRACT FROM AUTHOR]

The vasculature is the first organ to arise during development. Blood vessels run through virtually every organ in the body, ensuring metabolic homeostasis by supplying oxygen and nutrients and removing waste products. Consequently, a dysfunction of blood vessels compromises normal organ performance. This in turn may lead to congenital or acquired diseases, disability or even death. The lymphatic system develops in parallel but secondary to the blood vascular system. It serves an essential function in absorbing and transporting tissue fluid and extravasated proteins and cells back to the venous circulation. Understanding the principles of how blood and lymph vessels form and which angiogenic factors are involved might provide novel attractive opportunities for treatment of angiogenic disorders. [ABSTRACT FROM AUTHOR]

The circulatory system evolved so that nutrients and chemicals required for cellular function can be efficiently transferred from central organs to the extremities. Because of its importance to the growth and survival of other tissues, the circulatory system forms during early stages of development, and its correct development and early function is absolutely critical for survival of the embryo. During development, blood vessel formation occurs by three processes, the initial formation of vessels from yolk sacs during early embryogenesis, and by the distinct processes of vasculogenesis and angiogenesis during subsequent development [33, 35]. [ABSTRACT FROM AUTHOR]

The densely cellular retina with its intricate arrangement of neurons requires highly specialized circulations to meet its demanding metabolic requirements without compromising its extracellular space, which is a highly defined microenvironment conducive to neurotransmission, phototransduction and the complex interaction of metabolites, growth factors and vasoactive agents. The retinal circulation, which supplies the inner retina, is observed ophthalmoscopically as a regular geometrically arranged network of vessels and their three-dimensional complexity reflects the cellular density of the retinal neuropile. The caliber of directly viewed vessels is determined by the size of the red cell column, as the vessel walls and peripheral plasma layer are virtually transparent. The vessels accordingly appear wider during fluorescein angiography as dye mixes with the luminal plasma. As the vessel walls sclerose with age, stress or disease processes they become visible, due to reflected light on ophthalmoscopy, and obscure the red cell column to varying degrees. Abnormalities of the retinal circulation are key pointers to retinal dysfunction and disease and frequently highlight perturbations of the systemic circulation, e.g., diabetes, hypertension, and sickle cell disease. [ABSTRACT FROM AUTHOR]

Although no randomized, prospective studies have been performed, evidence suggests that in general uveal tumor biopsy with the 25-gauge vitreous cutter produces a larger sample than FNAB and more quickly and safely than transscleral incisional biopsy or using the 20-gauge vitrectomy system. Early results are encouraging, but it is likely that results will improve with further refinements of the technique and developments in laboratory methods. [ABSTRACT FROM AUTHOR]

The current treatment of macular oedema remains unsatisfactory. The dissection of the molecular mechanisms responsible for the formation of macular oedema will lead to the identification of specific therapeutic targets, and the successful application of this knowledge will result in the generation of more effective treatment modalities. [ABSTRACT FROM AUTHOR]