UVEITIS

UVEITIS

Current Diagnosis

• The most common form of uveitis is anterior uveitis.

•   Anterior uveitis is commonly idiopathic.

•   Posterior uveitis is most likely infectious.

• In any form of uveitis, syphilis, tuberculosis, and Lyme disease need to be ruled out.

• In immunosuppressed individuals, the uveitis is most likely infectious: the patient’s HIV status needs to be determined, because a positive status completely changes the diagnostic approach.

• The key to correct diagnosis is a good history, including a thorough review of systems and a careful ophthalmologic examination as well as dilated funduscopy; laboratory and radiographic investigations, sometimes including aqueous or vitreous polymerase chain reaction or cytologic studies, are frequently necessary.

• Involvement of an ophthalmologist with expertise in the diagnosis and treatment of uveitis is mandatory.

Current Therapy

• Uveitis resulting from a systemic infection (e.g., syphilis, Lyme disease, tuberculosis) needs to be treated as a central nervous system infection.

• Idiopathic anterior uveitis or anterior uveitis related to an autoimmune disease responds to topical corticosteroids (e.g., prednisolone acetate [Pred Forte] 1% 1 drop every 2 hours while awake3) and cycloplegia (e.g., homatropine [Isopto Homatropine]1 2% 1 drop three times daily).

• Periocular steroids (posterior or anterior sub-Tenon’s steroid injection) is useful in the management of severe anterior uveitis and in intermediate uveitis.

• Intraocular triamcinolone acetonide injection (Kenalog)1 or implantation of a sustained-release dexamethasone implant (Ozurdex) or fluocinolone acetonide implant (Retisert) is reserved for cases of severe uveitis.

• Oral steroids (prednisone 1–2 mg/kg PO) can be effective in cases of severe uveitis that is unresponsive to topical, periocular, and intraocular steroids.

• Systemic immunosuppressants can control uveitis unresponsive to steroids or be used as steroid-sparing agents. Some specific uveitides mandate systemic immunosuppression as first-line treatment.

• Commonly used immunosuppressants are azathioprine (Imuran),1 methotrexate (Trexall),1 cyclosporine (Neoral),1 and mycophenolate mofetil (CellCept).1

• Anti-tumor necrosis factor-α agents are increasingly being used for the treatment of severe uveitis unresponsive to steroids or requiring steroid-sparing agents.

1 Not FDA approved for this indication.

1 Not FDA approved for this indication.

Uveitis refers to intraocular inflammation: it comprises multiple disease entities, some of which are caused by infectious agents and some of which are immune mediated. Uveitis can be classified by the predominant anatomic location of the inflammation: if it is in the anterior chamber, it is an anterior uveitis (previously known as iritis or iridocyclitis); if it is in the vitreous, it is an intermediate uveitis; and if it is in the retina or choroid, it is a posterior uveitis. In panuveitis, inflammation involves all of these sites. Uveitis is said to be limited if it lasts less than 3 months or persistent if it lasts longer than 3 months.

Clinical Features and Diagnosis

Anterior Uveitis

Anterior uveitis is the most commonly encountered type. It typically manifests with sudden-onset severe photosensitivity, pain, blurred vision, and red eye. Clinical examination documents decreased vision, limbal injection, keratic precipitates (cells and protein on the corneal endothelium), and an anterior chamber reaction (white cells and flare- increased light scatter in the anterior chamber caused by the increased protein concentration resulting from inflammation-induced vascular permeability). The anterior uveitis associated with juvenile idiopathic arthritis in children may be asymptomatic.

Anterior uveitis is commonly idiopathic but may be associated with human leukocyte antigen (HLA) B27; other HLA-B27 conditions, such as ankylosing spondylitis, Achilles tendonitis, plantar fasciitis, and dactylitis, should be sought. Anterior uveitis may also be associated with psoriatic arthropathy, Reiter’s syndrome (although conjunctivitis is its most common feature), inflammatory bowel disease (which is also associated with intermediate uveitis), or sarcoidosis. Rheumatoid arthritis does not cause uveitis, although it may cause scleritis. In a patient with prior intraocular surgery or recent trauma, postoperative infectious endophthalmitis is a possibility. Infectious causes such as tuberculosis, syphilis, and Lyme disease need to be excluded, because they are curable. Viral infections (e.g., herpes simplex virus, varicella- zoster virus) can lead to an anterior uveitis, but they more frequently cause keratitis. Other rare associations are possible.

A good history, including a very thorough systems review combined with a good clinical examination including dilated funduscopy (to rule out retina or choroid involvement) by an ophthalmologist with expertise and interest in uveitis is mandatory for appropriate diagnosis and management.

A first occurrence of anterior uveitis that readily responds to topical corticosteroids (see later discussion) does not require further investigation unless there is strong suggestion of an associated systemic disorder based on the history and general physical examination. Investigation for anterior uveitis that is recurrent or is unresponsive to topical corticosteroids should be tailored based on the clinical examination findings but should not neglect to rule out syphilis, tuberculosis, Lyme disease, and HIV.

Intermediate Uveitis

Intermediate uveitis typically manifests in a young or middle-aged adult with pain, photosensitivity, blurred vision, and floaters. The most important finding on clinical examination is a vitreitis (white cells in the vitreous and vitreous haze).

Intermediate uveitis is commonly idiopathic (pars planitis) or may be associated with tuberculosis, sarcoidosis, Lyme disease, syphilis, inflammatory bowel disease, or, rarely, multiple sclerosis. Intraocular lymphoma should be considered in patients older than 50 years of age who have vitreitis. Investigation of intermediate uveitis is mandatory, because it is usually unresponsive to topical corticosteroid drops.

Posterior Uveitis

Posterior uveitis is commonly infectious. Patients complain of visual loss and floaters. Clinical signs include decreased visual acuity, vitreous cells and haze, and some of the following: retinal infiltrates, serous retinal detachment, retinal hemorrhage, chorioretinal scars, choroidal granulomas, venular sheathing, or arteriolar sheathing.

The most common cause of posterior uveitis is Toxoplasma retinochoroiditis. Viral infections such as varicella-zoster or herpes simplex can uncommonly cause acute retinal necrosis, and cytomegalovirus retinitis can be devastating in immunocompromised individuals. Tuberculosis, Lyme disease, and syphilis are bacterial causes of posterior uveitis. Pneumocystis jirovecii (formerly called Pneumocystis carinii) and Cryptococcus can cause a choroiditis in the immunocompromised individual. Sarcoidosis can also cause posterior uveitis. There is a plethora of well-defined posterior uveitides without associated systemic findings (e.g., serpiginous chorioretinitis). Intraocular lymphoma can masquerade as posterior uveitis and needs be considered in older patients.

Unless a clinical diagnosis is possible (e.g., in Toxoplasma chorioretinitis), further investigations are required. If a rapid plasma reagin test is negative, a diagnostic vitrectomy should be considered in all patients and is mandatory in immunocompromised patients; otherwise, tailored laboratory and radiographic investigations need to be performed.

Panuveitis

Panuveitis combines the signs and symptoms of anterior and posterior uveitis, although early in the course one location may predominate.

Bacterial or fungal endophthalmitis needs be considered. Vogt- Koyanagi-Harada syndrome is a common cause in the Far East and in patients of Native American ancestry. Adamantiades-Behçet syndrome, sympathetic ophthalmia, tuberculosis, syphilis, and, rarely, Lyme disease need be considered, among others.

Sequelae and Complications of Uveitis

Uncontrolled uveitis can be a blinding condition. Visual loss results commonly from cystoid macular edema or from cataracts, glaucoma, band keratopathy, hypotony maculopathy, macular scar, macular necrosis, or retinal detachment.

Current Treatment

Almost all of the medications employed in the treatment of uveitis are used off-label (FDA approved for an indication other than the treatment of uveitis).

Anterior Uveitis

If photosensitivity is a prominent complaint, topical cycloplegia affords considerable relief. Homatropine (Isopto Homatropine) 2% or 5%, scopolamine (Isopto Hyoscine) 0.25%, or tropicamide (Mydriacyl) 1% may be used. Cyclopentolate (Cyclogyl) should be avoided, because it has chemoattractant properties in vitro. Topical cycloplegia is also necessary with severe anterior uveitis to prevent posterior synechiae.

Topical corticosteroid drops are the first line of treatment for anterior uveitis (e.g., prednisolone acetate [Pred Forte] 1% 1 drop every 2 hours while awake).3 Patient education to ensure compliance is of paramount importance. Difluperdnate 0.05% (Durezol) is also being used with increasing frequency.

After 1 to 2 weeks, a slow taper of the drops is commenced (administer four times daily for 7–10 days, then taper by 1 drop every 7–10 days), provided that the anterior chamber cells have resolved. If there is an increase in activity during the taper, an increase in the dosing frequency to re-achieve a complete response, followed by a slower taper, is performed. Occasionally, patients have to be maintained for the long term on topical prednisolone; this is acceptable, provided that no adverse side effects occur.

If there is incomplete response to prednisolone acetate 1% given every 2 hours or if the drops cannot be tapered without recurrence and investigations are negative, the next step to be considered could be a sub-Tenon’s (under the conjunctiva) injection of 0.5 to 1.0 mL triamcinolone acetonide 40 mg/mL (Kenalog),1,6,* which forms a depot providing continuous steroid release for up to 6 months; alternatively, oral corticosteroids (usually prednisone) may be used in patients with especially severe bilateral uveitis, although this is uncommon. For the rare severe anterior uveitis that is unresponsive to these treatments or to decreases in the steroid dose, immunosuppressant medications such as methotrexate,1 cyclosporine,1 or mycophenolate mofetil1 or an anti-tumor necrosis factor-α (anti-TNF-α) agent such as infliximab1 may be given (see later discussion for recommended doses).

It cannot be overemphasized that a severe “anterior uveitis,” especially with a hypopyon, occurring after recent intraocular surgery or trauma should alert the physician to the possibility of endophthalmitis. Emergent anterior chamber and vitreous cultures need to be obtained, and intravitreous nonpreserved vancomycin (Vancocin) 1.0 mg/0.1 mL6 and ceftazidime (Fortaz) 2.25 mg/0.1 mL6 must be injected.

The main side effects of topical steroid use are cataract formation and ocular hypertension, which can lead to glaucoma. Untreated uveitis can cause the same side effects; therefore, inflammation needs be controlled promptly, and then the corticosteroids need to be tapered off as soon as possible without precipitating a recurrence.

Topical steroid use also predisposes to cornea infection, including reactivation of herpes simplex or varicella-zoster keratitis.

Intermediate Uveitis, Posterior Uveitis, and Panuveitis

Uveitis associated with systemic infection (e.g., syphilis, Lyme disease) is treated in consultation with an infectious disease specialist, because intraocular involvement is considered central nervous system involvement. Adjuvant topical corticosteroids and mydriatics can afford relief without jeopardizing cure in most cases (as for anterior uveitis).

Ocular toxoplasmosis, the most common posterior uveitis, is self- limited. Treatment is required in cases in which the optic nerve or macula is threatened or the vitreitis is particularly severe. Treatment consists of pyrimethamine (Daraprim) (loading dose 50 mg, then 25 mg twice daily), sulfadiazine (1 g four times daily), and folinic acid (Leucovorin)1 5 mg three times weekly. More recently, clindamycin (Cleocin)1 150 to 300 mg PO four times daily or trimethoprim- sulfamethoxazole1 (Bactrim DS 800 mg sulfamethoxazole/160 mg trimethoprim twice daily) have been found to be equally efficacious and are more widely used. Prednisone 40 mg/day is added 24 to 48 hours later. Treatment duration is usually 30 to 40 days, with a prednisone taper guided by the clinical response.

For intermediate uveitis, posterior uveitis, or panuveitis not associated with systemic infection, treatment options are to be considered in the following order:

1.   Periocular steroids (posterior sub-Tenon’s injection of triamcinolone acetonide)1 are commonly efficacious for intermediate uveitis.

2.   Oral corticosteroids are very efficacious but have ocular as well as systemic side effects. If the uveitis cannot be controlled with less than prednisone 10 mg after 6 months of treatment, one of the other options needs to be considered.

3.   In severe cases of intermediate, posterior, or panuveitis, intravitreous triamcinolone acetonide (Kenalog or Triessence 4 mg1,*), an injectable dexamethasone implane (Ozurdex), or a fluocinolone implant (Retisert) can be used; intravitreous long- acting steroid treatment has similar efficacy to systemic immunosuppression; the former has ocular complications (cataract formation, glaucoma), and the latter carries the risk of systemic side effects.

4.   Systemic immunosuppression with azathioprine (Imuran)1 up to 2.5 to 4 mg/kg/day, cyclosporine (Neoral)1 2.5 to 5.0 mg/kg/day in 2 divided doses, tacrolimus (Prograf)1 0.15 to 0.30 mg/kg/day, mycophenolate mofetil (CellCept)1 500 to 1000 mg twice daily, methotrexate (Trexall)1 (12.5 to 25 mg weekly, or an anti-TNF-α agent (e.g., infliximab [Remicade])1 have all been used with success as steroid-sparing agents or to control uveitis that is poorly responsive to corticosteroids alone.

There are specific uveitis entities that mandate the use of immunosuppression as first-line treatment (together with steroids initially). These include Wegener’s retinal vasculitis, Adamantiades- Behçet’s syndrome, sympathetic ophthalmia, and possibly birdshot choroidopathy, uveitis related to Vogt-Koyanagi-Harada syndrome, and serpiginous chorioretinitis.

References

1.     Harper S.L., Chorich L.J., Foster C.S. Diagnosis of uveitis. In: Foster C.S., Vitale A., eds. Diagnosis and Treatment of Uveitis. Philadelphia: WB Saunders; 2002:79–97.

2.     Jabs D.A., Rosenbaum J.T., Foster C.S., et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: Recommendations of an expert panel. Am J Ophthalmol. 2000;130:492–513.

3.     Nussenblatt R.B. Philosophy, goals and approaches to medical therapy. In: Nussenblatt S.M., Whitcup S.M., eds. Uveitis, Fundamentals and Clinical Practice. ed 3rd Philadelphia: Mosby; 2004:95–136.

4.     The Standardization of Uveitis Nomenclature (SUN) working group. Standardization of uveitis nomenclature for reporting clinical data: Results of the first international workshop. Am J Ophthalmol. 2005;140:509–516.

3  Exceeds dosage recommended by the  manufacturer.

6  May be compounded by  pharmacists.

* Kenalog is commercially available as 40 mg/mL. Special compounding is needed for the concentration of 4 mg/mL.

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