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Uveitis Treating Intermediate And Posterior UveitisOften confused with other conditions and seen infrequently in most practices, uveitis presents a tough diagnostic challenge.Sharon D. Solomon, MD
Emmett T. Cunningham
Jr., MD, PhD, MPH Incidence and Causes Uveitis affects up to 1 in 1,000 people. Intermediate uveitis refers to inflammation localized primarily in the vitreous cavity, whereas posterior uveitis refers to inflammation involving the retina, choroid or optic nerve. Although both intermediate and posterior uveitis are less common than anterior uveitis, their potential to cause permanent vision loss is far greater. Common causes of vision loss in patients with intermediate and posterior uveitis include cataract, vitreous opacification, cystoid macular edema (CME), direct macular or optic disc involvement, and serous macular detachment. Prompt and appropriate treatment of these forms of uveitis is essential to minimizing the risk of long-term ocular complications and vision loss. Infections, Neoplastic Masquerades Although uveitis is believed in many cases to be “autoimmune” or “endogenous” in origin, both infections and tumors can cause uveitis as well, particularly intermediate and posterior uveitis. The first consideration in evaluating patients with uveitis, therefore, should be to rule out infections and neoplastic masquerades. Infections and malignancies tend to respond poorly to our standard treatment with corticosteroids and non-corticosteroid immunosuppressive agents, and untreated ocular infections and malignancies can produce significant systemic morbidity, and even death. Toxoplasmosis is the most common infectious cause of posterior uveitis. The diagnosis is typically straightforward, since most  patients have a focal retinochoroiditis, often in the setting of
moderate to severe vitreous inflammation and adjacent or nearby retinochoroidal
scars. Other causes of infectious posterior uveitis include: 1) ocular
toxocariasis, which occurs most often in children, tends to be associated with
less vitreous inflammation than toxoplasmosis, and usually produces an elevated
granuloma; and 2) necrotizing herpetic retinitis, which is usually accompanied
by dense vitritis and occlusive retinal vasculitis. Figure 1. Large, yellow, subretinal infiltrates in an elderly white woman with intraocular lymphoma. Consider systemic infections, such as syphilis and tuberculosis, in patients with intermediate and otherwise non-diagnostic forms of posterior uveitis. We tend to test for syphilis in virtually all patients with these forms of uveitis, because the test is risk-free and inexpensive, and because missing a diagnosis of syphilis can have such serious implications for the overall health of the patient. Remember, however, that less specific tests for syphilis, such as the RPR and VDRL, may be negative in up to 30 percent of patients with syphilitic uveitis. The RPR and VDRL may also be falsely positive in patients with collagen-vascular disease. Hence, specific anti-treponemal antibody assays, such as the FTA-ABS or MHA-TP, are the most sensitive and specific single tests for syphilitic uveitis. Similarly, we tend to obtain a chest X-ray in most patients with intermediate and otherwise non-diagnostic forms of posterior uveitis, since this is an inexpensive and low-risk screening test for both tuberculosis and other systemic disorders associated with uveitis, most notably sarcoidosis. We usually reserve purified protein derivative (PPD) skin testing for tuberculosis for those patients with: 1) an abnormal chest X-ray; 2) signs or symptoms suggestive of systemic infection, such as night sweats, persistent cough, recurrent fever, or weight loss; 3) a known exposure to tuberculosis; or 4) a history of travel to regions known to be endemic for this infection. Lyme disease can also cause intermediate or posterior uveitis, but we forego testing unless the patient gives a definite history of tick exposure or of erythema migrans.  Intraocular malignancies are far less common uveitis mimics. In
young children, neoplastic masquerades include retinoblastoma, leukemia and
juvenile xanthogranuloma. Retinoblastoma presents under 3 years of age in 90
percent of children, usually suggested by a milky or chalky-white vitreous, and
retinal or iris infiltrates. An ultrasound or CT scan can sometimes show
calcific densities in these tumors. Figure 2. Multiple snowball vitreous opacities and a moderate-sized snowbank over the inferior retinal periphery in a young patient with bilateral, idiopathic, intermediate uveitis (pars planitis). Ocular leukemia, by contrast, tends to occur at a slightly older age, and may present as anterior uveitis or as yellow-white retinal, subretinal, perivascular, choroidal or optic disc infiltrates. Any patient with leukemia who presents with uveitis should be presumed to have ocular leukemia until proven otherwise. Juvenile xanthogranuloma is a rare disorder that usually appears in the first year of life, and is often suggested by the presence of gray, poorly demarcated iris nodules, often in the setting of one or more raised, orange skin lesions. Both spontaneous hyphema and secondary glaucoma may also occur. Adult patients, particularly those over 50 years of age, are at risk for intraocular lymphoma. While the diagnosis of intraocular lymphoma can be difficult and is often delayed, consider it in all adult patients with uveitis that is partially or transiently responsive to corticosteroid therapy, particularly in the setting of neurologic symptoms or signs. The presence of a serous retinal detachment or of yellow subretinal infiltrates (See Figure 1) is particularly suggestive of this disorder. Evaluation should include a complete neurologic workup, a contrast-enhanced MRI of the brain, and cytological analysis of the cerebrospinal fluid. Treatment Principles The decision to treat patients with intermediate and posterior uveitis is often difficult, and has to take numerous factors into account, including the natural history and severity of the disorder, and whether or not there is concurrent systemic involvement. Many patients with mild intermediate uveitis, in particular, maintain good vision without therapy. In fact, we tend to follow patients with vision of 20/30 or better and no complications, even though they may complain of floaters, or have snowball vitreous opacities and a snowbank (See Figure 2). We recommend treatment, however, once the vision has decreased to 20/40 or less due to either vitreous inflammation or CME (See Figure 3), or for patients who develop retinal neovascularization. Corticosteroids are the primary and best therapy for most forms of uveitis, at least in the short term. While most patients with uveitis and CME will require periocular or oral corticosteroids, we often try two to four weeks of intensive topical therapy, because uveitic CME will occasionally respond to drops, and because topical corticosteroids can help identify those patients who are prone to developing ocular hypertension before giving a periocular injection. For patients with uveitic CME who don’t develop corticosteroid-induced ocular hypertension,  we prefer periocular injections, whenever possible, to systemic
corticosteroids, since injections avoid so many of the systemic side effects of
oral medications. We also prefer the posterior sub-Tenon’s approach for
injecting corticosteroids over the orbital floor technique. It is less painful,
there is very little risk of subcutaneous fat atrophy and the sub-Tenon’s
approach allows more directed and closer application of corticosteroids to the
posterior globe. Figure 4. Occlusive retinal vasculitis in a patient with Behçet’s disease. There is also an epiretinal membrane temporal to the fovea, and moderate optic disc pallor. We tend to reserve oral corticosteroids for those patients who cannot tolerate an injection, for example, very young children who require only a short course of treatment, or for whom an injection might be otherwise contraindicated, such as patients with a history of corticosteroid-induced ocular hypertension. By contrast, we use oral corticosteroids almost exclusively in patients with uveitis in the setting of systemic disease. Examples include sarcoidosis with pulmonary involvement, Vogt-Koyanagi-Harada’s disease, or Behçet’s disease, particularly when the retina is involved (See Figure 4). While corticosteroids are unparalleled for their prompt and potent anti-inflammatory and immunosuppressive effects, they can’t be used indefinitely. Prolonged corticosteroid use is associated with a number of ocular and systemic complications, including ocular hypertension, cataract, weight gain, systemic hypertension, diabetes mellitus and bone loss, just to name a few. We try, therefore, to have all of our patients on less than 0.15 mg/kg/day (approximately 10 mg per day for a 70 kg adult) of prednisone within three months of initiating treatment. For those patients who cannot be tapered effectively, or who have a chronic disease, such as Behçet’s disease or sympathetic ophthalmia, we often add a systemic non-corticosteroid immunosuppressive agent. Many such agents are available, and the choice of an appropriate medication is complicated. In general, the so-called anti-metabolites, those medications that inhibit nucleotide incorporation into RNA and DNA, such as methotrexate, azathrioprin and the newer mycophenalate mofetil (Cellcept), provide less risk for the patient but are also less potent. Inhibitors of intracellular T-cell signaling, such as cyclosporine and tacrolimus (FK-506), are more potent, but can have notable side effects, including hypertension and renal toxicity. Cytotoxic agents, such as cyclophosphamide and chlorambucil, are most potent of all, but carry the very real risks of infertility, irreversible bone marrow suppression, delayed formation of hematopoietic malignancies and, in the case of cyclophosphamide, hair loss, hemorrhagic cystitis and bladder cancer. The choice of a particular agent has to be tailored, therefore, both to the patient and to his or her particular disease. That stated, we often choose Methotrexate as our first-line corticosteroid-sparing immunosuppressive agent in patients for whom it is otherwise not contraindicated. Methotrexate is particularly useful in children, where it has a long safety record for the treatment of juvenile rheumatoid arthritis. We typically start with 7.5-10 mg per week, and increase the dose over four to six weeks to 15-25 mg per week, the usual therapeutic dose in adults. We then try again to taper the corticosteroids. Non-corticosteroid immunosuppressive agents, such as cyclosporine, may be needed in a more severe uveitis. We usually reserve cyclophosphamide and chlorambucil agents for life-threatening and severe, vision-threatening inflammatory disorders. Using Consultants Treatment of intermediate and posterior uveitis can be challenging. Most ophthalmologists see relatively few patients with these disorders, and the consequences of incomplete or inappropriate treatment can be very serious for the patient. For these reasons, most patients with moderate to severe uveitis should be comanaged with a uveitis specialist, and with a physician skilled in the use of systemic corticosteroids and non-corticosteroid immunosuppressive agents, such as a rheumatologist. With a systemic and team-oriented approach, most forms of intermediate and posterior uveitis can be well-controlled. Dr. Solomon is at the Wilmer Eye Institute, Johns Hopkins University, School of Medicine. Dr. Cunningham is director of the Uveitis Service at the Francis I. Proctor Foundation and the Department of Ophthalmology, UCSF. Contact him at (415) 476-1442, or by e-mail: emmett@itsa.ucsf.edu.
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