Tips for the Treatment of Uveitis

The right protocol can prevent permanent vision loss.

MARIANA CABRERA, MD • THOMAS ALBINI, MD

The diagnosis and treatment of intraocular inflammation is often challenging. Many different etiologies can present with similar findings, with at least one-third of patients not having a specific etiologic or further differentiated diagnosis.¹ In this article, we present five tips to avoid some of the most common mistakes made by ophthalmologists when treating posterior uveitis.

TIP #1: ALWAYS EXCLUDE AN INFECTIOUS CAUSE

Many infectious forms of uveitis can masquerade as noninfectious uveitis. If these patients are treated with systemic immunosuppression, or even worse with intravitreal steroids, the results can be dismal.

Syphilis has intraocular manifestations in the secondary, and less frequently in the tertiary, phase. It can manifest as a granulomatous or nongranulomatous anterior uveitis, vitritis, chorioretinitis (posterior placoid chorioretinitis), or optic neuritis.² Frequently, small white retinal precipitates may be seen lying on top of the retina (Figure 1).

Figure 1. Syphilitic chorioretinitis. Small white retinal precipitates may be seen lying on top of the retinal vessels.
PREVIOUSLY PUBLISHED IN RAHMAN HT, YEH S. DIFFUSE INFILTRATIVE SYPHILITIC RETINITIS IN AN HIV-POSITIVE PATIENT. J OPHTHALMIC INFLAMM INFECT. 2011;1:123.

Every uveitis patient requires a fluorescent treponemal antibody absorption (FTA-ABS) test or syphilis antibody test. A Venereal Disease Research Laboratory (VDRL) test or rapid plasma reagent (RPR) test is highly sensitive in the secondary phase but may return a false negative, especially but not exclusively in immunocompromised patients (called the prozone effect, due to a large number of antibodies preventing the aggregation in the test). It is also negative in 20-30% of cases of tertiary syphilis.

FTA-ABS is useful because it remains positive in all stages of the disease, and the percentage of false negative results is minimal, but it provides no information on disease activity. Hence, obtaining both tests will identify a patient with syphilis at virtually any stage. Because of the likelihood of missing tertiary syphilis with the VDRL or RPR, if only one test can be obtained, the FTA-ABS or syphilis antibody test is better.

Tuberculosis can also present with myriad manifestations in both the anterior and posterior segment, and it has been dubbed “the great simulator.” Risk factors in the developed world include immigration from an endemic area, history of exposure, granuloma, and vasculitis with perivascular pigment hypertrophy.

A type of multifocal choroiditis very similar to a serpiginous chorioretinopathy has been identified to be secondary to tuberculosis.³ The distinguishing feature is that the lesions are multifocal, may be accompanied by significant vitritis and, as expected, do not respond well to immunosuppression therapy.

Patients should have a purified protein derivative or quantiFERON-TB test (Qiagen, Valencia, CA) in cases of immunosuppression or previous Bacille Calmette-Guerin vaccine. Extraocular signs of active tuberculosis are very often absent, making it essential for the ophthalmologist to make the final call on whether the patient must be treated for active extrapulmonary tuberculosis.

Toxoplasmosis does not always manifest with the characteristic area of retinitis. Intraocular inflammation may precede the area of retinitis, or the inflammation may render it impossible to view. It can manifest as neuroretinitis and may even have an appearance similar to acute retinal necrosis. In countries with a high prevalence of toxoplasmosis, it should be borne in mind, especially in cases of unilateral inflammation.

Although rare, endogenous endophthalmitis is a cause of inflammation that requires a high degree of suspicion. The diagnosis can be fairly straightforward in patients with clear risk factors, such as fungal meningitis, HIV/AIDS, and prolonged stays in the intensive care unit.⁴ However, there may be other risk factors that must be investigated, such as intravenous drug use, because the substances used to dilute the drugs may be responsible. An example of this phenomenon is lemon juice, which is used to dilute crack cocaine and has been linked to Candida endophthalmitis (Figure 2).

Figure 2. Candida endophthalmitis in an intravenous drug user who used lemon juice to dilute crack cocaine.

Most importantly, if the inflammation is not responding as anticipated to steroids or other immunomodulatory therapy, the physician should ensure again that an infectious cause has not been missed.

TIP #2: DO NOT MISS ACTIVE INFLAMMATION

Many chronic posterior uveitides have subclinical smoldering inflammation, which leads to complications such as macular edema, retinal atrophy, and scarring and can end in irreversible vision loss.

For example, patients with early birdshot chorioretinopathy may complain of unspecific symptoms, such as flashes and floaters, without a significant decrease in vision. Fundus examination may reveal minimal vitreous inflammation and faint white spots in the fundus, which may be missed. If the inflammation is left untreated, patients will present with complications such as cystoid macular edema, optic atrophy, and neovascularization.

Vogt-Koyanagi-Harada syndrome consists of four phases. The prodromal phase has no ophthalmic manifestations. The majority of patients present during the acute uveitic stage, which lasts a few weeks and presents with anterior uveitis plus the characteristic serous detachments.

Even after the detachments resolve, patients will require either prolonged oral corticosteroids (slow taper over six months) or long-term steroid-sparing immunosuppression, because aggressive treatment has been shown to reduce the rate of complications and recurrences.⁵ Even in the absence of vitritis/anterior uveitis, findings on optical coherence tomography show that depigmentation of the fundus may indicate a chronic inflammatory process that results in chorioretinal atrophy.⁶

Serpiginous chorioretinopathy presents with variable anterior chamber and vitreous cellular reaction, with the latter presenting in approximately one-third of cases. Active choroiditis appears ophthalmoscopically as well-circumscribed, gray-white, geographically shaped lesions at the level of the retinal pigment epithelium and choriocapillaris, involving the peripapillary region or macula and progressing in a characteristic serpentine fashion.

Examining the borders of the lesions is crucial to determine whether immunosuppression is adequate. Autofluorescence is valuable for comparing the shape of the lesions, and in many cases, active borders are hyperautofluorescent.⁷

TIP #3. DO NOT FORGET LYMPHOMA/OBTAINING A BIOPSY

Although rare, primary intraocular lymphoma should be borne in mind in all adult patients. In situations in which the degree of vitreous inflammation is severe (often forming sheets of cells), but scarring and other sequelae of inflammation are disproportionately mild, primary intraocular lymphoma should be suspected. Subretinal deposits are also seen frequently and can strongly suggest this diagnosis.

It is important to remember that the yield of a vitreous biopsy in these cases is low and may need to be performed several times, sometimes even requiring a chorioretinal biopsy if the vitreous does not yield the diagnosis.

A vitreous biopsy is a useful tool in patients with inflammation unresponsive to treatment. In these cases, a vitreous biopsy has a diagnostic yield of approximately 60%.8 Occult infections can also be identified. Figure 3 shows a patient with postsurgical endophthalmitis due to Mycobacterium fortuitum, which could only be diagnosed through direct aspiration of the lesions.

Figure 3. Mycobacterium fortuitum endophthalmitis post-pars plana vitrectomy. Pathogen identification could only be possible after direct aspiration of the precipitates in the retina.

TIP #4: IF INDICATED, DO NOT HESITATE TO USE STEROID-SPARING AGENTS

The mainstay of therapy for uveitis remains corticosteroids. This treatment can consist of a short course of high-dose corticosteroids to control acute, severe inflammation, or in patients with chronic inflammation, systemic corticosteroids may be required initially to control the symptoms, followed by long-term corticoid-sparing immunosuppression.

In cases of acute sight-threatening inflammation (such as bilateral serous retinal detachment), intravenous methylprednisolone may be used at a dose of 500-1,000 mg/day for three days, followed by oral corticosteroid therapy. Initial therapy should be 0.5 to 1 mg/kg/day of prednisone, followed by a slow taper when the inflammation has been controlled.

It is imperative that the corticosteroids not be tapered too quickly to prevent rebound inflammation. There are several taper schemes, but in general, if 40 mg or more are used, the dose should be decreased by 10 mg every one to two weeks; if 20-40 mg are used, decrease by 5 mg/day every one to two weeks; and if 20-10 mg are used, decrease by 2.5 mg/day every one to two weeks. If the disease recurs, a higher dose should be used for another month and slowly tapered again.⁹

Complications with systemic steroids include altered mood (and in severe cases psychosis), systemic hypertension, elevated blood glucose, leukocytosis, hypokalemia, acne, osteoporosis, avascular necrosis of the hip, weight gain, and pancreatitis. Prolonged use in children should be avoided, because delayed growth has been observed even with 0.4 mg/kg of prednisone and can be permanent.¹⁰

Cataract formation with systemic steroids is dose- and length-dependent; 83% of patients will develop cataracts if taking corticosteroids (even maintenance doses) for more than four years.¹¹ Blood pressure and blood glucose should be monitored every three months and bone density and cholesterol levels on an annual basis. Calcium and vitamin D supplementation is advised, as well as weight-bearing exercises.

An immunosuppressive drug should be considered if an adequate response in not seen with two to four weeks of high-dose corticosteroids or if, after three months of adequate treatment and taper, the disease in not controlled on less than 10 mg of prednisone per day.

Additionally, in some diseases, immunosuppressive drugs are indicated at presentation because of their poor natural history. These conditions include Behçet disease with posterior involvement, serpiginous choroidopathy, sympathetic ophthalmia, and birdshot chorioretinopathy. Some authors recommend early immunosuppressive drugs in multifocal choroiditis with panuveitis and Vogt-Koyanagi-Harada syndrome.

Immunosuppressive drugs can be divided into antimetabolites (methotrexate, azathioprine, mycophenolate mofetil, leflunomide), T-cell inhibitors (cyclosporine, tacrolimus), and alkylating agents (cyclophosphamide and chlorambucil). Antimetabolites, the most commonly used of these agents, take approximately eight weeks to reach their full effect, so it is important to taper steroids slowly to coincide with the effect of the chosen immunosuppressive.

Biologics are medications manufactured with recombinant DNA and designed to target specific inflammatory pathways based on disease pathogenesis. They include monoclonal antibodies to proteins such as cytokines (such as tumor necrosis factor α), cell adhesion molecules, and cytokine receptors. They are increasingly being used in uveitis. Infliximab (Remicade, Janssen Biotech, Horsham, PA) is now considered first-line therapy for the ophthalmic manifestations of Behçet disease, and the results have been better than using corticosteroids or conventional immunosuppressive therapy.¹²

TIP # 5. CONSIDER SUSTAINED-RELEASE STEROIDS

Although extremely important in the treatment of uveitis, particularly uveitic CME, caution must be taken when performing intravitreal injections of triamcinolone acetonide. Side effects include cataract, ocular hypertension (approximately 30% of patients develop an intraocular pressure higher than 21 mm Hg),¹³ glaucoma, retinal detachment, vitreous hemorrhage, and endophthalmitis, which occurs at a rate of between 0.1% and 0.9%.

However, triamcinolone injections result in repeated peaks and troughs of activity, and the risk of endophthalmitis increases with numerous injections. Sustained-release corticosteroids may offer a more effective treatment option.

Ozurdex (Allergan, Irvine, CA) is a biodegradable polymer implant that contains 700 µg of dexamethasone, which is released to the vitreous cavity over a six-month period, until it dissolves completely. Peak response is seen in the first four months. It is administered via a 22-gauge injecting applicator through the pars plana and in an office setting. It is a useful tool, particularly in cases of CME or vasculitis, as well as in vitrectomized eyes in which the effect duration of triamcinolone is significantly decreased.^14,15

If a longer and more potent effect is desired, Retisert (Bausch + Lomb, Rochester, NY) is a fluocinolone acetonide–containing, nonbiodegradable implant. It is inserted through a pars plana sclerotomy and secured by a suture in the sclera (must be performed in the operating room). It releases fluocinolone acetonide for up to three years.

However, it has a high rate of ocular hypertension, necessitating incisional glaucoma surgery in 30% to 40% of eyes — in contrast to less than 1% in patients with serial Ozurdex injections. Prospective, randomized data have shown equivalent efficacy of Retisert monotherapy and standard systemic steroid-sparing immunosuppression.

Ruling out infectious causes is particularly important when intraocular steroids are used. Several reports exist of reactivation of syphilis and toxoplasmosis secondary to intravitreal triamcinolone injection, which may have devastating consequences.^16,17 Reports of new onset cytomegalovirus retinitis secondary to intravitreal injection have also been published.¹⁸

CONCLUSION

Although uveitis remains a vision-threatening disease, more treatment options are available than ever before to treat it effectively. Prompt diagnosis of infectious causes and control of damaging inflammation are important early steps in management. It is also important to exclude malignancy.

Steroids are still a very effective treatment for uveitis, although the spectrum of side effects is well known. Today, the retinal physician can consider steroid-sparing treatments, such as biologics, as well as the newer sustained-release steroid implants. This expanded armamentarium offers better options for both physician and patient. RP

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