Byline: Narsing. Rao
Uveitis, also referred to as intraocular inflammation, is a complex inflammatory process, involving primarily the uveal tract, with or without the involvement of adjacent intraocular structures. The underlying cause of the intraocular inflammation may reside in the uveal tract, retina, lens, or other ocular tissues. Uveitis is a leading cause of blindness in both developed and developing countries, including India. Although the inflammation can be due to a variety of causes - infections, systemic diseases, organ-specific autoimmune processes (primarily to T-cell-mediated Th2 and or Th17 processes), trauma, and primary or secondary ocular neoplasm presenting with clinical features of uveitis - the resulting uveal inflammation usually presents with similar symptoms that affect the patient's vision. Most patients with uveitis are diagnosed accurately and the disease is subclassified as granulomatous or nongranulomatous anterior, intermediate, posterior or pan uveitis; but determining the proper underlying etiology can be a challenge. The current issue, containing several articles from leaders in the field of uveitis, provides a clinically valid and prudent approach to determining the underlying causes of uveitis and lays out the current medical and surgical interventions that can be used to preserve vision and prevent blindness.
About 25% of blindness in India and other developing countries is attributed to uveitis and its complications, such as secondary cataract, glaucoma, cystoid macular edema, or retinal photoreceptor or optic nerve damage. However, it is unclear how often these complications are associated with various uveitis entities, classified either by the anatomic location of the inflammation or by the etiology of the uveitis. Generally, public health reports reflecting the burden of blindness do not consider that uveitis may also be an important cause of cataract or glaucoma or of retinal damage. This leads to a serious underestimation of the significance of uveitis as a cause of blindness. Moreover, recent cutting-edge basic science research reveals that intraocular inflammation is the underlying source leading to two other major causes of blindness: Age-related macular degeneration and diabetic retinopathy.
In developed countries, in contrast, the incidence of blindness from uveitis varies from 3% to 10%. In Europe, the incidence is estimated to be between 3% and 7%; and in United States, recent figures from California reveal that 10% of blindness is due to uveitis. The remarkable difference in the incidence of blindness between developing and developed countries could be due to differences in socioeconomic conditions or access to medical care or to other disparities; but it is clear that the causes of uveitis differ in developed and developing countries, and such etiologic differences could play a significant role in the high levels of blindness that occur in developing countries. Infections are a leading cause of uveitis in India and other developing countries, whereas idiopathic uveitis, believed to be an organ-specific immune inflammatory process, is a leading cause in developed countries.
Since most infections can be prevented or treated satisfactorily, the blindness resulting from uveitis in India could be dramatically reduced by early and proper etiologic diagnosis and treatment rather than treating all uveitis patients with nonspecific corticosteroid treatment. A good example of how uveitis-related blindness can be prevented is intraocular tuberculosis. Since tuberculosis is endemic in India and since about 10% of uveitis in India is caused by localization of this infection to the eye, early diagnosis and appropriate medical intervention with antituberculosis agents could prevent much of the visual morbidity caused by uveitis. Other infectious and parasitic diseases that may cause uveitis in India include dengue fever, chicken guinea, and other viral infections, protozoa and nematode, and trematode parasites.
In the current issue, Babu and Rathinam present an algorithmic approach to arrive at the proper etiologic diagnosis and to proceed with investigations to support the diagnosis. As the authors point out, the demographic features must be taken into consideration in this algorithmic approach. Such an approach was first introduced in the United States over 3 decades ago and was found useful in a clinical setting with patients presenting with typical features of various uveitis entities. However, several infectious and noninfectious uveitis entities do not have the typical expected clinical presentations; their presentations may vary. Similarly, several uveitis entities can present with virtually identical clinical features even though the underlying cause may be different. Thus, in addition to this algorithmic approach, ophthalmologists should entertain a wide differential diagnosis to arrive at a proper diagnosis in timely manner.
Ancillary and laboratory investigations play important roles in supporting the etiologic diagnosis of uveitis, as stated clearly in two articles, one by Gupta, Gupta and the second by Majumdar, Sudharshan and Biswas. In most instances, a careful clinical history and a thorough ophthalmic examination, combined with a systemic examination, will clinch the diagnosis; additional investigations are ordered to support the clinical diagnosis. For instance, the clinical details of a patient presenting with bilateral posterior or panuveitis with exudative retinal detachment and signs of meningismus are usually sufficient to arrive at a diagnosis of Vogt-Koyanagi-Harada disease. The findings of investigations such as fluorescein angiography and ultrasonography lend support to the clinical diagnosis; but patients with such clear clinical features rarely actually require additional investigations. Both of these articles correctly emphasize that the investigations are meant primarily to support the clinical diagnosis or to help in differential diagnosis. A few infectious entities manifest with clinical features that mimic various clinical entities, for example, syphilis and intraocular tuberculosis. The latter entity is important in areas that are endemic for tuberculosis; thus, recommending a Mantoux test and/or a a interferon release assay for tuberculosis is important either to exclude a diagnosis of intraocular tuberculosis or to establish such a diagnosis before treating a patient with high-dose systemic corticosteroids.
The so called "tailored approach" is a prudent tactic for ordering laboratory investigations in support of a clinical diagnosis of uveitis. The investigations should be directed either to support the clinical diagnosis or to differentiate one uveitis entity from another with a similar presentation. Thus, clinical history and findings should be overriding factors in obtaining proper laboratory test results. As pointed out by Majumdar et al ., routine ordering of laboratory tests should be avoided without a proper clinical basis. Irrelevant test results could complicate the issue, not only supporting a clinical diagnosis, but also leading to unnecessary additional investigations and/or delaying proper treatment. There must be a clear indication for ordering certain tests; it is advisable to avoid ordering nonrelevant tests. For example, a patient presenting with recurrent unilateral anterior uveitis with subepithelial corneal scarring and with no systemic changes requires a corneal sensation test or anterior chamber polymerase chain reaction (PCR) test for herpes viral DNA to support a clinical diagnosis of herpetic uveitis rather than a human leukocyte antigen (HLA) B27 test. A positive HLA-B27 is irrelevant to support the diagnosis in this patient, and the patient may not even have ankylosing spondylitis.
Recent advances in ocular immunology and the development of clinically relevant animal models of uveitis provided a clear understanding of the immunopathology of uveitis, the role of cytokines, and methods of modulating the cytokine genes that are involved in induction and perpetuation of uveitis. Such advances led to the introduction of novel uveitis treatments using biological agents that target proinflammatory cytokines such as tumor necrosis factor alpha (TNF a ) and other cytokines. Interestingly, several rhematological diseases share proinflammatory cytokines with uveitis. Monoclonal antibodies have been developed using genetic engineering techniques to neutralize TNF a ; these anti-TNF a monoclonal antibodies were first introduced in the treatment of rheumatological diseases and were found to help minimize or eliminate symptoms related to rheumatoid arthritis and other related diseases. Subsequently, these same monoclonal antibodies were used to treat recalcitrant uveitis, uveitis related to Behcet's disease, and other uveitis entities with remarkable improvement in the uveal inflammation. However, these biological agents are associated with significant side effects, including reactivation of latent tuberculosis and exacerbation of demyelinating diseases; the treatment can even lead to the development of malignancy and suppression of the immune system, resulting in the development of various opportunistic systemic infections. Such significant side effects dictate that in noninfectious uveitis, these biological agents should be tried only when classic treatment with corticosteroids and other immunosuppressive drugs fails to control the intraocular inflammation. In the current issue, Mahendradas and Murthy discuss classic and evolving systemic and local treatments for uveitis. Since idiopathic uveitis is an organ-specific inflammation localized to the eye, local drug delivery is a good option. However, slow corticosteroid-releasing intraocular implants are associated with complications such as cataract and glaucoma. Ocular toxoplasmosis, a similarly localized retinal infection with secondary uveal inflammation, can be managed with intravitreal delivery of clindamycin. These are positive developments in the management of uveitis.
Surgical interventions in uveitis are primarily directed at management of complications, including cataract development, glaucoma, epiretinal membrane formation, and cystoid macular edema. Murthy, Reddy and Sangwan summarize indications for surgical interventions with a primary goal of visual rehabilitation. It is interesting that the authors state the importance of surgical approaches in establishing an etiologic diagnosis. Although biopsy of iris and choroid is a rare indication in either the diagnosis and or management of uveitis, in clinically suspected cases of primary intraocular lymphoma, a combined retina-choroid biopsy is indicated since the lymphoma cells are preferentially localized at the level of Retinal Pigment Epithelium (RPE) or the subretinal space or may involve the retina.
Advances in ocular imaging techniques, including optical coherence tomography, autofluorescence, and wide-field imaging techniques make this an exciting period indeed in the diagnosis and treatment of uveitis entities. Furthermore, the introduction of PCR analysis of ocular fluids has provided a positive impact in establishing or supporting an etiologic diagnosis of infectious uveitis. Local drug delivery and introduction of biological agents have provided novel approaches to the management of recalcitrant uveitis. Combining the medical treatment of uveitis with a surgical approach to accomplish visual rehabilitation should help to reduce blindness caused by uveitis and related intraocular inflammations.
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