Uveitis refers to inflammation in the uvea, a Latin word for grape , and specifically the vascular middle layer of the eye that involves the iris anteriorly, the ciliary body in the middle, and the choroid posteriorly ( Fig. 1.1 ). It was recognized as a disease entity as early as 1500 BC during the era of Egyptian medicine, and several medicinal extracts were used for treatment of uveitis at that time. Today, uveitis remains a major cause of ocular morbidity, causing approximately 10% of the cases of visual disability in the United States each year. It is estimated to cause 30,000 cases of new-onset legal blindness annually, with an annual prevalence of 58 to 115 per 100,000 population.
Intraocular inflammation is frequently referred to as “uveitis,” even when other structures of the eye are primarily involved—for example, the retina (i.e., retinitis) and sclera (i.e., scleritis). Many uveitic entities are caused by infection, trauma, or neoplasia, but the majority are of unknown etiology and thought to be autoimmune. Some autoimmune uveitic cases are associated with systemic immune-mediated diseases, such as HLA-B27–associated spondyloarthropathies, sarcoidosis, and Behçet disease, whereas others are limited only to the eye without any systemic manifestation—for example, pars planitis and serpiginous choroiditis. The patient’s ocular complaints do not usually suggest a specific anatomic diagnosis; the exception is acute anterior uveitis, which is frequently associated with pain, redness, and photophobia. Most other uveitic entities present with blurred vision, floaters, a blind spot, or cloudiness.
Attempts have recently been made to standardize the nomenclature of uveitis, as well as its description and response to treatment. In 2005 the Standardization of Uveitis Nomenclature (SUN) Working Group (WG), consisting of 79 uveitis experts from 18 countries and 62 clinical centers, published a standardized and internationally accepted terminology for the uveitides, as well as recommendations for the grading of inflammation and development of disease outcomes. Most recently (December 1, 2019), this group met again to adopt and confirm a set of classification criteria for specific uveitic entities, and the results of their work will be published in the near future.
It is important to understand the difference between classification and diagnostic criteria. Classification criteria are standardized definitions that are primarily intended to enable clinical studies with uniform cohorts for research. Consequently, they need to define homogeneous groups that can be compared across studies and geographic areas. In contrast, diagnostic criteria are a set of signs, symptoms, and tests developed for use in routine clinical care to guide the treatment of individual patients. They need to be broad and reflect all the possible different features and sensitivity of a disease that is characteristically heterogeneous. Thus, testing specificity and sensitivity for diagnostic criteria need to be very high, approaching 100%, whereas classification criteria require very high specificity, even with some loss in sensitivity. A detailed discussion of this issue is provided by the American College of Rheumatology and suggests that the difficulty in establishing uniform diagnostic criteria lends support to the proposals of the SUN WG for diagnostic criteria using standard nomenclature, terminology, and testing even though further refinements in diagnostic criteria will undoubtedly be forthcoming.
Because the eye is an extension of the central nervous system (CNS), it makes unique demands on the immune system; it cannot tolerate the full array of immune responses available to other organs. The eye has only one function, to provide sight by the transmission of light to the photoreceptors of the retina, where the light is processed by a complex neural network, and from there, to the visual cortex. This remarkable neurologic function is critical to the survival of the host so that destructive inflammation, even in protection of the eye from infection, is not tolerable. Thus a complex immunoregulatory network to protect the eye from destructive inflammation evolved to prevent immune-mediated injury. This immunologic phenomenon is referred to as immune privilege and is a feature of the CNS and only a few other organs in the body. For example, destruction of a quarter of the liver combating infection would be harmful to the host but would not threaten functional survival of that organ or the host; in contrast, destruction of the fovea (300 to 500 μ) within the center of the retina will cause legal blindness.
A basic understanding of immune privilege is important to appreciate the presentation of intraocular inflammatory diseases such as uveitis. As ophthalmologic specialists, we have the unique ability to observe tissues within an organ (i.e., the eye) during active inflammation; consequently, our specialty has described many different clinical presentations of uveitic entities that are linked to the novel regulation of immunity. Both anatomic and functional factors contribute to the development of immune privilege within the eye, including the blood–retina barrier, absence of lymphatic drainage, soluble immunomodulatory factors, immunomodulatory ligands on the surface of ocular parenchymal cells, chronic activation of the complement system, and tolerogenic parenchymal antigen-presenting cells (APCs). The maintenance of immune privilege involves many different regulatory mechanisms, the details of which are too numerous to discuss in this chapter. Instead, we will briefly mention just three major strategies used by the eye to modify innate and adaptive immune responses within the organ: (1) tissue-associated immunologic ignorance (e.g., the decreased immunogenicity of retinal photoreceptors compared with retinal pigment epithelium [RPE] because of reduced expression of major histocompatibility complex [MHC] antigens on photoreceptors); (2) peripheral tolerance to ocular antigens (e.g., microglia, perivascular macrophages, and dendritic cells within the retina and uvea that can act as tolerogenic APCs); and (3) immunosuppressive microenvironment (e.g., maintained by multiple immunosuppressive soluble factors, surface immune modulators on parenchymal cells, and complement regulatory components). Excellent reviews of ocular immune privilege have recently been published for those interested in further reading on this subject.
Each of the following book chapters present and discuss a different uveitis case. The incidence and prevalence of uveitis differs based on age, sex, anatomic location within the eye, gender, genetic factors, and etiology. Fortunately, although the etiology of a specific uveitic entity is frequently unknown, the characteristic clinical presentation allows a specific diagnosis, frequently confirmed by diagnostic testing, which is important because it provides insight into the likely course of the disease and response to treatment. The large number of idiopathic uveitic entities is partly the result of the fragile nature of ocular tissue, which has hindered the aggressiveness of tissue biopsy, and the value patients place on preservation of sight. However, interventional diagnostic techniques into the anterior chamber, vitreous cavity, and fine needle aspiration biopsy of intraocular tumors are now routinely available, although the limited quantity of fluid or tissue removed limits extensive studies. The recent advances in diagnostic imaging of the eye using optical coherence tomography (OCT) and the advent of new diagnostic laboratory techniques like polymerase chain reaction (PCR), genetic profiling (DNA), and single-cell transcriptomics (RNA) hold promise in providing understanding of the cause of many cases of uveitis that are now considered idiopathic.
The incidence and prevalence of uveitis differ based on age, gender, anatomic location of the inflammatory process (anterior, intermediate, posterior uveitis, panuveitis), type of inflammatory process (acute, chronic, recurrent), geographic location, and etiology (infectious, noninfectious). Anterior uveitis is the most common form, and the underlying cause is usually not identified (30% to 60%), with the disease referred to as idiopathic anterior uveitis . With our newer diagnostic techniques, the etiology of many cases will be determined in the future.
It is our hope that you will find the subsequent case chapters both informative and interesting. They are designed to provide the reader with insight into the fascinating diagnostic and therapeutic field of uveitis.
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