The Wills Eye Manual

Chapter 12. Uveitis

APPROACH TO UVEITIS

Uveitis is not a single disease but a collection of 30 to 40 different disorders that may be characterized by clinical symptoms, anatomic location, morphology, presence or absence of key anatomic findings (such as ciliary flush, keratic precipitates [KP], iris nodules, synechiae, snowballs, snowbanks, retinal vasculitis, macular edema, and optic neuropathy), and response to treatment. A thorough history and review of systems with a complete examination will typically narrow the differential diagnosis to a much more manageable number of possibilities on which the workup should be based. There is no one “uveitis workup.” The use of a “shotgun" approach to diagnostic testing is not only not cost-effective but will often lead to incorrect diagnoses and treatment based on a misunderstanding of the sensitivity, specificity, and positive and negative predictive values of a given test.

The Standardization of Uveitis Nomenclature Working Group has emphasized the clinical presentation of the disease, laterality, and the anatomic location of inflammation in the evaluation of patients with uveitis.

• The history defines the course of the disease.

 Onset (sudden versus insidious)

 Duration

 Limited (<3 months) versus persistent (>3 months).

 Course

 Acute (sudden onset and limited duration).

 Recurrent (flare-ups occurring >3 months after stopping therapy).

 Chronic (persistent or flaring up <3 months after stopping therapy).

 Note that by these criteria, the term "acute or chronic" has no meaning, and uveitis controlled with medication should be considered "suppressed" and not "in remission."

 Laterality

 Unilateral.

 Unilateral/alternating (bilateral and nonsimultaneous).

 Bilateral and simultaneous.

 Anatomic location

 Anterior: cells limited to the anterior chamber (iritis) or with some anterior vitreous involvement (iridocyclitis)

 Anterior chamber cells must be greater than vitreous cells.

 Isolated anterior uveitis should NEVER be diagnosed without assessment of the retina.

 Intermediate uveitis: Cells in the vitreous cavity (vitritis) without chorioretinal involvement; may have anterior chamber cells

 Vitreous cells must be greater than anterior chamber cells.

 Posterior: isolated retinitis, choroiditis, or both

 Retinochoroiditis: primarily retinal with secondary choroidal involvement.

 Chorioretinitis: primarily choroidal with secondary retinal involvement.

 There may be posterior vitreous cells.

 Optic disc edema and hyperemia may be present.

 Neuroretinitis.

 Retinal vasculitis

 Venous.

 Arterial.

 Mixed venous/arterial.

 Lesions in posterior uveitis should be characterized by:

 Color

 White lesions are usually retinal.

 Yellow lesions are usually choroidal.

 Pigmented lesions usually indicate long-standing disease.

 Presence or absence of hemorrhage

 Presence or absence of retinal vasculitis

 Border appearance: creamy versus granular versus sharply defined

 Pattern

 Focal or paucifocal.

 Multifocal.

 Morphology

 Placoid.

 Punched-out.

 Serpiginous.

 Amoeboid.

 Ovoid.

 Punctate.

• Panuveitis: concurrent anterior, intermediate, and posterior uveitis.

NOTE: Macular edema and peripheral retinal vasculitis do not by themselves define posterior uveitis (e.g., pars planitis may have cystoid macular edema [CME], peripheral vascular sheathing and leakage, and optic disc edema but it is still an intermediate uveitis).

Hypopyon (layering of white blood cells in the anterior chamber)

 Usually white, flat-topped.

 Bloody hypopyon often suggests herpetic uveitis.

 Shifting hypopyon (changes with head position) suggests Behcet disease.

Consider different causes of or predisposing factors to uveitis (recognizing there may be substantial overlap)

 Infectious.

 Systemic inflammatory disease.

• Vascular disorders.

 Host immune status.

 Genetic.

 Drug-induced.

 Trauma.

 Environmental.

The principles of the uveitis workup should be as follows:

1. Distinguish infectious from noninfectious uveitis.

2. Distinguish purely ocular disease from uveitis associated with systemic conditions.

3. Consider masquerade syndromes (e.g., retained intraocular foreign body, tumors, chronic retinal detachment, etc.).

4. Obtain additional testing only if the results will influence the differential diagnosis, medical or surgical management, prognosis, or referral patterns.

5. Recognize that up to 40% of uveitis is undifferentiated (the term preferred to “idiopathic,” since nearly all noninfectious uveitis has no known cause) and explain this to patients.

6. Imaging, like laboratory testing, should be based on the disease and not used indiscriminately. Testing may include:

 Optical coherence tomography (OCT).

 Intravenous fluorescein angiography (IVFA).

 Indocyanine green angiography (ICGA).

 Fundus autofluorescence (FAF).

 OCT angiography.

 Visual field testing.

• Electrophysiology.

12.1 Anterior Uveitis (Iritis/Iridocyclitis)

Symptoms

 Acute: Pain, redness, photophobia, consensual photophobia (pain in the affected eye when a light is shone in the fellow eye), excessive tearing, and decreased vision.

 Chronic: Decreased vision (from cataract, vitreous debris, CME, or epiretinal membrane [ERM]) and floaters. May have periods of exacerbations and remissions with few acute symptoms (e.g., juvenile idiopathic arthritis [JIA]).

Signs

Critical

TABLE 12.1.1

Grading of Anterior Chamber Cells

Grade

Cells in 1 x 1 mm Field

0

<1

0.5+

1 to 5

1 +

6 to 15

2+

16 to 25

3+

26 to 50

4+

>50

TABLE 12.1.2

Grading of Anterior Chamber Flare

Grade

Description

0

None

1 +

Faint

2+

Moderate (iris/lens details clear)

3+

Marked (iris/lens details hazy)

4+

Intense (fibrin/plastic aqueous)

 Cells and flare in the anterior chamber (see Tables 12.1.1 and 12.1.2) and ciliary flush.

Keratic Precipitates

 Fine KP: Herpes simplex or varicella zoster virus, cytomegalovirus (CMV), Fuchs heterochromic iridocyclitis (FHIC).

 Small, nongranulomatous KP (NGKP): HLA-B27-associated, trauma, masquerade syndromes, JIA, Posner-Schlossman syndrome (glaucomatocyclitic crisis), drug-induced. Granulomatous uveitides such as sarcoidosis can present with NGKP; the reverse rarely occurs.

 Granulomatous KP (large, greasy, “mutton-fat”; mostly on the inferior cornea): Sarcoidosis, syphilis, tuberculosis (TB), JIA- associated, sympathetic ophthalmia, lens-induced, Vogt- Koyanagi-Harada (VKH) syndrome, and others.

 CMV uveitis often has characteristic “coin-shaped" KP not found in other herpetic uveitides.

 The location of KP can be helpful diagnostically.

 Diffuse KP are characteristic of FHIC and herpetic uveitides.

 KP underneath areas of stroma opacification suggest herpes simplex or, less often, varicella zoster keratouveitis.

 Granulomatous KP in an inferior peripheral crescent underneath areas of stromal haze (often with fine, deep stromal vascularization) are highly suggestive of sarcoidosis.

 Granulomatous KP in Arlt triangle (apex near central cornea, base at inferior limbus) are nonspecific.

 “Crenated" KP are translucent and discrete, usually medium-large lesions characteristic of regressed granulomatous anterior uveitis.

Other. Low intraocular pressure (IOP) more commonly seen (secondary to ciliary body hyposecretion), elevated IOP can occur (e.g., herpetic, lens-induced, FHIC, Posner-Schlossman syndrome), fibrin (e.g., HLA-B27 or endophthalmitis), hypopyon (e.g., HLA-B27, Behcet disease, infectious endophthalmitis, rifabutin-induced, tumor), iris nodules (e.g., sarcoidosis, syphilis, TB), iris atrophy (e.g., herpetic, oral fourth-generation fluoroquinolones), iris heterochromia (e.g., FHIC), iris synechiae (especially HLA-B27, sarcoidosis), band keratopathy (especially JIA in younger patients, any chronic uveitis in older patients), uveitis in a “quiet eye” (consider JIA, FHIC, and masquerade syndromes), and CME (see Figure 12.1.1).

FIGURE 12.1.1 Anterior uveitis with posterior synechiae.

Differential Diagnosis

 Intermediate or panuveitis with spillover into the anterior chamber: Mainly floaters and decreased vision, positive fundoscopic findings (see 12.3, Posterior Uveitis).

 Traumatic iritis. See 3.5, Traumatic Iritis.

 Posner-Schlossman syndrome: Recurrent episodes of very high IOP and minimal inflammation. Many cases are caused by herpetic uveitis (herpes simplex virus [HSV], varicella zoster virus [VZV], and CMV). See 9.8, Glaucomatocyclitic Crisis/Posner- Schlossman Syndrome.

 Drug-induced uveitis (e.g., rifabutin, cidofovir, sulfonamides, pamidronate, systemic fluoroquinolones [especially moxifloxacin], biologic drugs, cancer immunotherapy [checkpoint inhibitors], and some chemotherapeutic drugs).

 Sclerouveitis: Uveitis secondary to scleritis; typically presents with profound pain and tenderness to palpation. See 5.7, Scleritis.

 Contact lens-associated red eye (CLARE): Red eye, corneal edema, epithelial defects, iritis with or without hypopyon, hypoxic subepithelial or stromal infiltrates (often multiple) may be present.

 Infectious keratouveitis: Corneal infiltrate is present. See 4.11, Bacterial Keratitis.

 Infectious endophthalmitis: History of recent ocular surgery (including intravitreal injections), penetrating trauma, systemic infections (e.g., urinary tract infections), recent bowel or dental surgery, and skin wounds. Signs and symptoms include pain, hypopyon, fibrinous anterior chamber reaction, vitritis, decreased vision, and red eye; may have an endogenous source with fever, elevated white blood cell count. See 12.13 to 12.16, Endophthalmitis Sections.

 Schwartz-Matsuo syndrome: Pigment released from a chronic retinal detachment clogs the trabecular meshwork, resulting in elevated IOP.

 Tumor: Retinoblastoma and juvenile xanthogranuloma in children, primary intraocular lymphoma in elderly, metastatic disease in all ages, and others.

 Pseudouveitis from pigment dispersion syndrome. Other findings include Krukenburg spindle and iris transillumination defects. Pigment cells in the anterior chamber are smaller than white blood cells and may disappear when viewed with a red- free light.

Etiology

 Undifferentiated (idiopathic) (30% to 50% of anterior uveitis has no identifiable cause or disease association).

 HLA-B27-associated uveitis: Systemic associations include ankylosing spondylitis, reactive arthritis (Reiter syndrome), psoriatic arthritis, and inflammatory bowel disease.

NOTE: Bilateral acute recurrent alternating anterior uveitis is very characteristic of HLA-B27 uveitis.

 Lens-induced uveitis: Immune reaction to the lens material, often secondary to incomplete cataract extraction, trauma with lens capsule damage, or hypermature cataract. See 9.12, Lens-Related Glaucoma.

 Postoperative iritis: Anterior chamber inflammation following intraocular surgery. Rule out acute endophthalmitis, retained lens fragments, iris chafing, or recurrence of preexisting anterior uveitis (e.g., HLA B27-associated uveitis). A small percentage of patients (especially African-Americans) with well-positioned posterior chamber intraocular lenses (IOL) may have a low-grade, steroid-responsive anterior uveitis that recurs when low-dose topical steroids are tapered off. Endophthalmitis must be considered if severe inflammation and pain are present. See 12.14, Chronic Postoperative Uveitis.

 Uveitis-glaucoma-hyphema (UGH) syndrome: Usually secondary to irritation from an IOL (particularly a closed-loop anterior chamber lens or single-piece IOL in ciliary sulcus). A milder variant with iris chafing but no hyphema can occur (look for iris transillumination defects in an undilated pupil). See 9.16, Postoperative Glaucoma.

 Behcet disease: Young adults, acute simultaneous bilateral shifting hypopyon and iritis, aphthous ulcers, genital ulcerations, erythema nodosum, retinal vasculitis (arteries and/or veins), and hemorrhages, may have recurrent episodes.

 VKH disease: acute unilateral or bilateral anterior uveitis occurs in chronic VKH disease.

 Lyme disease: May have a history of a tick bite and rash. See 13.3, Lyme Disease.

 Anterior segment ischemia: Unilateral. Flare out of proportion to a cellular reaction. Corneal edema is common. Pain. Secondary to carotid insufficiency, tight scleral buckle, or previous extraocular muscle surgeries.

 Tubulointerstitial nephritis and uveitis (TINU) syndrome: Uncommon but frequently underdiagnosed; usually bilateral nongranulomatous uveitis in children and young adults, female predilection. May be precipitated by oral nonsteroidal antiinflammatory drug (NSAID) therapy. Systemic symptoms include abdominal pain, fatigue, and malaise. Urinary beta-2 microglobulin, urinary casts, and increased serum creatinine helpful diagnostically.

 Toxoplasmosis: granulomatous unilateral anterior uveitis, posterior synechiae, and mutton-fat KP in Arlt triangle typically present. Occurs only with concurrent toxoplasmic retinitis.

 Other rare infectious etiologies of anterior uveitis: Mumps, influenza, adenovirus, measles, chlamydia, leptospirosis, Kawasaki disease, rickettsial disease, chikungunya virus, and others. Ask about recent travel history.

Chronic

 JIA: Usually occurs in young girls with pauciarticular arthritis (<4 joints involved); may be painless and asymptomatic with minimal injection. Usually bilateral. Iritis may precede typical arthritis. Positive antinuclear antibody (ANA), negative rheumatoid factor, and increased erythrocyte sedimentation rate (ESR) are most commonly seen. Associated with glaucoma, cataracts, band keratopathy, and CME. Uveitis less commonly occurs in polyarticular and rarely in systemic JIA (Still disease).

 Chronic iridocyclitis of children: Usually occurs in young girls; it is similar to JIA in signs and symptoms but lacks arthritis.

 FHIC: Floaters with or without blurred vision and glare, but few other symptoms, diffuse iris stromal atrophy often causing a lighter-colored iris with transillumination defects and blunting of the iris architecture. Gonioscopy may reveal fine vessels that cross the trabecular meshwork. Fine, stellate KP over the entire corneal endothelium, and mild anterior chamber reaction. Vitreous opacities, glaucoma, and cataracts are common, but macular edema and posterior synechiae are absent. Topical corticosteroids not helpful. Cataract surgery may cause anterior chamber hemorrhage from rupture of fine angle vessels, but outcomes are usually excellent.

 Sarcoidosis: More common in African-Americans and Scandinavians. Usually bilateral; can have extensive posterior synechiae and conjunctival or iris nodules. See 12.6, Sarcoidosis.

 HSV/VZV/CMV: May be chronic or acute and recurrent. Diffuse KP, increased IOP, and iris atrophy (transillumination defects). History of a unilateral recurrent red eye, occasionally history of skin vesicles, or history of shingles. Corneal scars associated with decreased corneal sensation may be present. HSV and VZV anterior uveitis usually require long-term oral acyclovir, valacyclovir, or famciclovir; CMV anterior uveitis usually requires oral valganciclovir. All three types usually require chronic low-dose topical corticosteroids for suppression.

 Syphilis: Anterior and intermediate uveitis are most common. May have a maculopapular rash, iris roseola (vascular papules on the iris), and interstitial keratitis with ghost vessels in late stages. Inflammation of any ocular structure may occur. Placoid chorioretinitis is virtually pathognomonic. Neurosyphilis can cause meningismus. See 12.12, Syphilis.

 TB: “Sticky” uveitis with extensive posterior synechiae, usually bilateral. Positive protein derivative of tuberculin (PPD) and/or interferon-gamma release assay (IGRA) (e.g., QuantiFERON-TB Gold), typical chest radiograph findings (helpful but not necessary for diagnosis; most TB uveitis occurs in patients without pulmonary TB), occasionally phlyctenular or interstitial keratitis, and sometimes signs of posterior uveitis. See 12.3, Posterior Uveitis.

 Others: Leprosy, brucellosis, and other infectious causes.

Workup

1. Obtain a thorough history and review of systems. Specifically ask about fevers, chills, fatigue, malaise, cough, shortness of breath, joint pain/swelling/stiffness, diarrhea, blood in urine/stool, skin rashes, and oral or genital ulcers.

TABLE 12.1.3

Suggested Diagnostic Workup for Anterior Uveitis

Ankylosing spondylitis

HLA B27, SI joint films, rheumatology consult

Reactive arthritis

HLA B27, SI joint films (if symptomatic), swab for Chlamydia

Psoriatic arthritis

HLA B27, rheumatology and/or dermatology consult

Lyme disease

Lyme antibody immunofluorescent assay (e.g., ELISA)

Juvenile idiopathic arthritis or any suspect uveitis in children

Rheumatoid factor, antinuclear antibodies, HLA-B27, radiographs of affected joints, urinalysis and renal function tests, rheumatology consult

Sarcoidosis

Chest radiograph and/or chest CT, PPD or IGRA, ACE, lysozyme

Syphilis

RPR or VDRL, FTA-ABS or treponemal-specific assay; HIV testing if

 

positive

Ocular ischemic syndrome

Intravenous fluorescein angiography, carotid Doppler studies

NOTE: Autoimmune diseases are less common in the very young and very old—consider masquerades.

2. Complete ocular examination, including an IOP check, gonioscopy, and a dilated fundus examination. The vitreous should be evaluated for cells.

3. A laboratory workup may be unnecessary in certain situations:

 First episode of a mild, unilateral, nongranulomatous uveitis with a history and examination that is not suggestive of systemic disease or herpetic uveitis.

 Uveitis in the setting of known systemic disease such as sarcoidosis or the use of medicines known to cause uveitis (e.g., rifabutin).

 Clinical findings are classic for a particular diagnosis (e.g., herpetic keratouveitis, FHIC, and toxoplasmosis).

4. In all other situations requiring laboratory or diagnostic testing, a targeted workup is recommended. If too many tests are ordered unnecessarily, a portion of them may come back false-positive and confuse the diagnosis. See Table 12.1.3. However, if a patient presents with bilateral, granulomatous, or recurrent uveitis without a suspected diagnosis, our practice is to at least evaluate for sarcoidosis, syphilis, and TB (in at-risk patients). Consider additional workup as needed based on history and examination.

 Syphilis testing (see 12.12 Syphilis).

 PPD and/or IGRA. Limit use of TB testing to patients:

 At risk of TB (e.g., immigrants from high-risk areas such as India, human immunodeficiency virus [HIV]-positive patients), homeless patients, or prisoners).

 If immunosuppressive therapy (especially biologics) are being considered.

 If anti-inflammatory therapy is not working.

 Chest radiograph or chest CT to rule out sarcoidosis and pulmonary tuberculosis.

 Angiotensin-converting enzyme (ACE) ± lysozyme (questionable utility).

 Lyme antibody (consider in endemic areas).

 HLA-B27 (in acute unilateral or bilateral alternating anterior uveitis; especially if hypopyon is present; ask about symptoms of a seronegative spondyloarthropathy).

 Anterior chamber paracentesis for polymerase chain reaction (PCR) testing for suspected herpes virus-associated anterior uveitis (HSV, VZV, and CMV) and toxoplasmosis.

• Serologic tests for infectious diseases have a low positive predictive value due to high seroprevalence in the general population, but negative tests (e.g., IgM and IgG for Toxoplasma gondii) may help to rule out the disease.

NOTE: In children with uveitis, sarcoidosis and syphilis are much less common and no lab test should be ordered routinely except as indicated by the history and findings. Evaluation for systemic disease by a pediatric rheumatologist may be warranted (e.g., JIA and TINU).

Treatment

1. Cycloplegic (e.g., cyclopentolate 1% t.i.d. for mild to moderate inflammation; atropine 1% b.i.d. to q.i.d. for severe inflammation).

2. Topical steroid (e.g., prednisolone acetate 1%) q1-6h, depending on the severity of inflammation. Most cases of moderate to severe acute uveitis require q1-2h dosing initially. Difluprednate 0.05% may allow less frequent dosing than prednisolone acetate. Consider a loading dose (prednisolone acetate 1% one drop every minute for 5 minutes at bedtime and awakening) or fluorometholone 0.1% ophthalmic ointment at night. If the anterior uveitis is severe, unilateral, and is not responding to topical steroids, then consider periocular repository steroids (e.g., 0.5 to 1.0 mL subtenon injection of triamcinolone 40 mg/mL). See Appendix 10, Technique for Retrobulbar/Subtenon/Subconjunctival Injections.

NOTE: The periocular use of triamcinolone is off-label and must be discussed with patients. A trial of topical steroids at full strength for several weeks may help identify patients at risk of a significant IOP increase from steroids. Additionally, periocular depot steroids should be used with extreme caution in patients with scleritis because of possible scleral melting.

3. If there is no improvement on maximal topical and repository steroids, or if the uveitis is bilateral and severe, consider systemic steroids, or immunosuppressive therapy. Consider referral to a uveitis specialist and rheumatologist.

NOTE: Prior to giving periocular depot steroids, it is important to rule out infectious causes; oral steroids in such cases may be helpful starting 1 to 2 days after initiation of treatment for the underlying infection.

4. Treat secondary glaucoma with aqueous suppressants. Avoid pilocarpine. Glaucoma may result from:

 Cellular blockage of the trabecular meshwork. See 9.7, Inflammatory Open Angle Glaucoma.

 Secondary angle closure from synechiae formation. See 9.4, Acute Angle Closure Glaucoma.

 Neovascularization of the iris and angle. See 9.14, Neovascular Glaucoma.

 Steroid-response. See 9.9, Steroid-Response Glaucoma.

 Although topical prostaglandins may rarely cause uveitis, they should be tried if other medical management is ineffective before considering glaucoma surgery.

5. If an exact etiology for the anterior uveitis is determined, then additional ocular and/or systemic management may be indicated.

 Ankylosing spondylitis: Often requires systemic anti-inflammatory agents (e.g., NSAIDs such as naproxen). Consider consulting rheumatology, physical therapy, and cardiology (increased incidence of cardiomegaly, conduction defects, and aortic insufficiency).

 Inflammatory bowel disease (IBD): Often benefits from systemic steroids, sulfadiazine, or other immunosuppressive agents. Obtain a medical or gastrointestinal consult.

 Reactive arthritis (previously known as Reiter syndrome): If urethritis is present, then the patient and sexual partners are treated for chlamydia (e.g., single-dose azithromycin 1 g p.o.). Obtain medical and/or rheumatology or urology consult.

 Psoriatic arthritis: Consider a rheumatology and/or dermatology consult.

 Glaucomatocyclitic crisis: See 9.8, Glaucomatocyclitic Crisis/Posner-Schlossman Syndrome.

 Lens-induced uveitis: Usually requires removal of the lens material. See 9.12, Lens-Related Glaucoma.

 Herpetic uveitis: Herpes simplex typically requires topical or oral antivirals and steroid drops for nonepithelial corneal disease. Herpetic iridocyclitis benefits from topical steroids and systemic antiviral medications (e.g., acyclovir, valacyclovir, or famciclovir); topical antivirals are usually ineffective for uveitis due to poor intraocular penetration. See 4.15, Herpes Simplex Virus and 4.16, Herpes Zoster Ophthalmicus/Varicella Zoster Virus.

 UGH syndrome: See 9.16, Postoperative Glaucoma.

 Behcet disease: See 12.7, Behcet Disease.

 Lyme disease: See 13.3, Lyme Disease.

 JIA: Topical steroids can be useful acutely for reducing cells and flare, but should be minimized for long-term therapy to reduce the risk of cataract and glaucoma, both of which are more common in children. Systemic steroid therapy in children may cause growth suppression and should be avoided if possible. Prolonged cycloplegic therapy may be required and necessitate appropriate refractive correction. Consultation with rheumatology, pediatrics, and/or a uveitis specialist is useful as immunomodulatory therapy (e.g., methotrexate, adalimumab, and infliximab) is often needed. Regular follow up is essential, as flares may be asymptomatic; recurrent or chronic disease can lead to irreversible damage and various sequelae including synechiae, glaucoma (or hypotony), CME, epiretinal membrane, and cataract formation.

NOTE: Cataract surgery in patients with JIA-associated uveitis has a high complication rate. Avoid cataract surgery if possible until the patient is inflammation-free for at least 3 months. An IOL may be placed in select circumstances and is preferable to aphakia in well-controlled disease.

 Chronic iridocyclitis of children: Same as JIA.

 FHIC: Usually does not respond to or require steroids (a trial of steroids may be attempted, but they should be tapered quickly if there is no response); cycloplegics are not necessary.

NOTE: Patients with FHIC usually do well with cataract surgery; however, they may develop a hyphema.

 Sarcoidosis: See 12.6, Sarcoidosis.

 Syphilis: See 12.12, Syphilis.

 Tuberculosis: Refer the patient to an internist, infectious disease specialist, or public health officer for consideration of systemic treatment. Patients with ocular TB frequently have no pulmonary disease but still require systemic four-drug antituberculous therapy. Concomitant oral steroids or methotrexate may be necessary.

Follow Up

1. Every 1 to 7 days in the acute phase, depending on the severity; every 1 to 3 months when stable.

2. At each visit, the anterior chamber reaction and IOP should be evaluated.

3. A vitreous and fundus examination should be performed for all flare-ups, when vision is affected, or every 3 to 6 months. Macular edema is a frequent cause of decreased vision even after the uveitis is controlled; OCT can be very useful.

4. If the anterior chamber reaction has resolved, then the steroid drops can be slowly tapered with intermittent examinations to ensure that the inflammation does not return during the taper (usually one drop per day every 3 to 7 days [e.g., q.i.d. for 1 week, then t.i.d. for 1 week, then b.i.d. for 1 week, etc.]). Steroids are usually discontinued following the taper when the anterior chamber is quiet. Occasionally, long-term, low-dose steroids every day or every other day are required to keep the inflammation from recurring. Punctal occlusion techniques may increase the potency of the drug and decrease systemic absorption. The cycloplegic agents also can be tapered off as the anterior chamber reaction improves and no new posterior synechiae are noted.

NOTE: Topical steroids should be tapered slowly to prevent severe rebound inflammation. If oral steroids are used, consider concurrent calcium 600 mg with vitamin D 400 units twice a day to reduce the risk of osteoporosis. In patients with very severe disease, note that doses of prednisone >60 mg/d increase the risk of ischemic necrosis of bone, and a three-day course of intravenous methylprednisolone 1 g/d for 3 days should be considered instead. Regular monitoring of glucose, blood pressure, lipids, and bone density should be done by a primary care doctor or rheumatologist if long-term oral steroid therapy is necessary.

12.2 Intermediate Uveitis

Symptoms

Painless floaters and decreased vision. Minimal photophobia or external inflammation. Most often bilateral and classically affects patients aged 15 to 40 years.

Signs

(See Figure 12.2.1.)

FIGURE 12.2.1 Pars planitis/intermediate uveitis with snowballs.

Critical. Vitreous cells and cellular aggregates floating predominantly in the inferior vitreous (snowballs). Younger patients may present with vitreous hemorrhage. White exudative material over the inferior ora serrata and pars plana (snowbank) is suggestive of pars planitis.

NOTE: Snowbanking is typically in the inferior vitreous and can often be seen only with indirect ophthalmoscopy and scleral depression.

Other. Peripheral retinal vascular sheathing, peripheral neovascularization, mild anterior chamber inflammation, CME, posterior subcapsular cataract, band keratopathy, secondary glaucoma, ERM, and exudative retinal detachment. Posterior synechiae in pars planitis are uncommon and, if present, usually occur early in the course of the disease. Choroidal neovascularization is rare.

Etiology

 Pars planitis (>70%). Autoimmune disease of unknown cause in teenagers and young adults; insidious onset; bilateral but may be asymmetric; no clear gender predilection. CME most common cause of vision loss; vitreous hemorrhage may cause acute vision loss.

 Sarcoidosis. See 12.6, Sarcoidosis.

 Multiple sclerosis. See 10.14, Optic Neuritis.

 Lyme disease. See 13.3, Lyme Disease.

 Syphilis. See 12.12, Syphilis.

 TINU: Rare cause of uveitis, mostly in young females but wide age distribution. Ocular disease usually follows renal disease but occasionally precedes or is concurrent. More commonly presents as anterior uveitis. Requires co-management with a nephrologist; eye disease may linger long after resolution of nephritis.

 Primary intraocular lymphoma: intermediate uveitis may be the initial manifestation. Ask about neurologic symptoms in older patients; low threshold for CNS imaging. Referral to a retina specialist or an ocular oncologist for diagnostic pars plana vitrectomy and send the undiluted specimen to an experienced ocular cytopathologist; consider testing for interleukin-10 and MYD88 mutation. Oral steroids prior to biopsy may decrease the yield.

 Toxocariasis. See 12.3, Posterior Uveitis and 8.1, Leukocoria.

 Others: IBD, Bartonellosis (cat-scratch disease), Whipple syndrome, primary Sjogren syndrome, etc.

 Masquerade syndromes include retinoblastoma in children, old vitreous hemorrhage, and asteroid hyalosis.

Workup

1. Complete ocular examination. Includes gonioscopy to evaluate for possible neovascularization.

2. Appropriate workup may include chest radiograph and/or chest CT, PPD and/or IGRA, ACE ± lysozyme, RPR or VDRL, and FTA- ABS or treponemal-specific assay. Obtain urinary beta-2 microglobulin, hemoglobin, creatinine, and urinalysis if TINU is suspected.

3. Consider IVFA and/or OCT to document CME or retinal vasculitis.

4. Consider lab testing for Lyme disease, toxoplasmosis, and catscratch disease in the appropriate clinical context. In older individuals, consider workup for malignancy/lymphoma.

5. Consider magnetic resonance imaging (MRI) of the brain ± orbits with gadolinium to evaluate for demyelinating lesions if the review of systems is positive for current or previous focal neurologic deficits. Refer to a neurologist for multiple sclerosis workup if necessary.

Treatment

Treat all vision-threatening complications (e.g., CME and vitritis) in symptomatic patients with active disease. Mild vitreous cell in the absence of symptoms, CME, or vision loss may be observed in cases of noninfectious intermediate uveitis.

1. Topical prednisolone acetate 1% or difluprednate 0.05% q1-2h. Consider subtenon steroid (e.g., 0.5 to 1.0 mL injection of triamcinolone 40 mg/mL). May repeat the injections every 6 to 8 weeks until the vision and CME have stabilized. Slowly taper the frequency of injections. Subtenon steroid injections must be used with caution in patients with steroid-induced glaucoma. See Appendix 10, Technique for Retrobulbar/Subtenon/Subconjunctival Injections.

2. If there is minimal improvement after three subtenon steroid injections 1 to 2 months apart, consider systemic steroids (e.g., prednisone 40 to 60 mg p.o. daily for 4 to 6 weeks), tapering gradually according to the patient’s response. High-dose systemic steroid therapy should last no longer than 2 to 3 months, followed by a taper to no more than 5 to 10 mg/d. Other options include sustained-release steroid implants (e.g., dexamethasone 0.7 mg intravitreal implant; fluocinolone acetonide 0.19 or 0.59 mg intravitreal implant) and immunomodulatory therapy (e.g., antimetabolites, calcineurin inhibitors, and anti-tumor necrosis factor agents), usually in conjunction with rheumatology.

NOTE: In bilateral cases, systemic steroid therapy may be preferred to periocular injections. However, in children and adolescents, growth suppression (in addition to the usual complications of long-term systemic steroids) is a major concern.

3. Transscleral cryotherapy to the area of snowbanking should be considered in patients who fail to respond to either oral or subtenon corticosteroids and who have neovascularization.

4. Pars plana vitrectomy may be useful in cases refractory to systemic steroids or to treat vitreous opacification, tractional retinal detachment, ERM, and other complications. Additionally, vitreous biopsy through a pars plana vitrectomy may be indicated in cases of suspected masquerade syndromes, especially intraocular lymphoma.

NOTE:

1. Some physicians delay steroid injections for several weeks to observe whether the IOP increases on topical steroids (steroid response). If a marked steroid response is found, depot injections should be avoided.

2. Intravitreal preservative-free triamcinolone acetonide and the dexamethasone or fluocinolone acetonide implants are more effective for uveitic macular edema than periocular triamcinolone.

3. Intravitreal anti-VEGF drugs (e.g., ranibizumab, bevacizumab, and aflibercept) are effective in the treatment of uveitic CME but only if the uveitis itself is suppressed.

4. Oral acetazolamide 250 mg two to four times a day can reduce CME but is often not well tolerated due to nausea, diarrhea, fatigue, malaise, anorexia, or hypokalemia.

5. Topical NSAIDs are usually not effective in patients with uveitic CME.

6. Cataracts are a frequent complication of intermediate uveitis. If cataract extraction is performed, the patient should ideally be free of inflammation for 3 months preceding the operation. Consider starting the patient on oral prednisone 60 mg daily 2 to 5 days prior to surgery and tapering the prednisone over the next 1 to 4 weeks. Aggressive perioperative use of topical NSAIDS (e.g., ketorolac 0.5% q.i.d.) and topical steroids (e.g., prednisolone acetate 1% q2h or difluprednate 0.05% six times a day) starting 2 to 5 days preoperatively and continued for at least 4 to 6 weeks postoperatively may reduce the risk of pseudophakic CME and recurrent uveitis. Consider a combined pars plana vitrectomy at the time of cataract surgery if significant vitreous opacification is present.

Follow Up

1. In the acute phase, patients are re-evaluated every 1 to 4 weeks, depending on the severity of the condition.

2. In the chronic phase, re-examination is performed every 3 to 6 months. Monitor for neovascularization, CME, ERM, glaucoma, and cataract.

Other Causes of Vitreous Cells

 Ocular ischemia.

 Spillover from anterior uveitis.

 Masquerade syndromes: Always consider these in the very old or very young patients.

 Large cell lymphoma: Persistent vitreous cells in patients >50 years old, which usually do not respond completely to systemic steroids. Yellow-white subretinal infiltrates, retinal edema and hemorrhage, anterior chamber inflammation, or neurologic signs may be present.

 Malignant melanoma: A retinal detachment and associated vitritis may obscure the underlying tumor. See 11.36, Choroidal Nevus and Malignant Melanoma of the Choroid.

 Retinitis pigmentosa: Vitreous cells and macular edema may accompany waxy pallor of the optic disc, "bone-spicule" pigmentary changes, and attenuated retinal vessels. See 11.28, Retinitis Pigmentosa and Inherited Chorioretinal Dystrophies.

 Rhegmatogenous retinal detachment (RRD): A small number of pigmented anterior vitreous and anterior chamber cells frequently accompany an RRD. Uveitis due to chronic retinal detachment (Schwartz-Matsuo syndrome) is one of the masquerade syndromes. See 11.3, Retinal Detachment.

 Retained intraocular foreign body (IOFB): Persistent inflammation after a penetrating ocular injury. May have iris heterochromia. Diagnosed by indirect ophthalmoscopy, gonioscopy, B-scan ultrasonography (US), US biomicroscopy (UBM), or computed tomography (CT) scan of the globe. See 3.15, Intraocular Foreign Body.

 Retinoblastoma: Almost always occurs in young children. May also present with a pseudohypopyon and vitreous cells. One or more elevated white retinal lesions are usually, but not always, present. See 8.1, Leukocoria.

 Leukemia: Unilateral retinitis and vitritis may occur in patients already known to have leukemia. Prompt laboratory testing (complete blood count [CBC] with differential) and anterior chamber paracenteses (if there is anterior uveitis) for histology and immunostaining usually diagnostic.

 Amyloidosis: Retrolenticular footplate-like deposits, vitreous globules, or vitreous membranes without any signs of anterior segment inflammation. Serum protein electrophoresis and diagnostic vitrectomy confirm the diagnosis. Rare.

 Asteroid hyalosis: Small, white, refractile particles (calcium soaps) adherent to collagen fibers and floating in the vitreous. Usually asymptomatic and of no clinical significance.

Workup

1. Complete history and review of systems: Ask about systemic disease or infection, skin rash, tattoos, intravenous drug abuse, indwelling catheter, risk factors for AIDS, recent eye trauma or surgery, travel (particularly to Ohio-Mississippi River Valley, Southwestern United States, New England, or Middle Atlantic area), and exposures (e.g., tick bite).

2. Complete ocular examination, including IOP measurement and careful ophthalmoscopic examination. Indirect ophthalmoscopy with scleral depression of the ora serrata.

3. Consider IVFA for diagnosis or therapeutic planning.

4. Blood tests (any of the following may be obtained, depending on the suspected diagnosis, but a “shotgun” approach is inappropriate): Toxoplasma titer, ACE level, serum lysozyme, RPR or VDRL, FTA-AbS or treponemal-specific assay, ESR, ANA, ANCA, HLA-B51 (Behcet disease), HLA-A29 (birdshot retinochoroidopathy), Toxocara titer, IGRA ± PPD, and/or Lyme antibody. In neonates or immunocompromised patients, consider checking titers for HSV, VZV, CMV, and rubella virus. Cultures of blood and i.v. sites may be helpful when infectious etiologies are suspected. PCR techniques are available for HSV, VZV, CMV, and Toxoplasma.

5. Chest radiograph or CT.

6. CT/MRI of the brain and lumbar puncture when either lymphoma is suspected or there is any potential for central nervous system (CNS) involvement from an HIV-associated opportunistic infection.

7. Diagnostic vitrectomy when appropriate (see individual sections).

8. See individual sections for more specific guidelines on workup and treatment.

12.3 Posterior and Panuveitis

Symptoms

Blurred vision and floaters. Scotomas and metamorphopsia are common. Photopsias are often present in posterior uveitis. Pain, redness, and photophobia are often present due to anterior chamber inflammation.

NOTE: Panuveitis describes a pattern of severe, diffuse inflammation of both anterior and posterior segments. Often bilateral. Endophthalmitis or posterior scleritis should be considered in patients with posterior uveitis and significant pain.

Signs

Critical. Cells in the posterior vitreous, vitreous haze, retinal or choroidal inflammatory lesions, and retinal vasculitis (sheathing and exudates around vessels).

Other. Anterior and intermediate uveitis (indicative of panuveitis), retinal neovascularization, CME, ERM, and choroidal neovascular membranes.

Differential Diagnosis

Panuveitis

Possible etiologies are listed below:

 Sarcoidosis: See 12.6, Sarcoidosis.

 Syphilis: See 12.12, Syphilis.

 VKH syndrome: See 12.11, Vogt-Koyanagi-Harada Syndrome.

 Behcet disease: See 12.1, Anterior Uveitis (Iritis/Iridocyclitis) and 12.7, Behcet Disease.

 Lens-induced uveitis: See 9.12, Lens-Related Glaucoma.

 Sympathetic ophthalmia: See 12.18, Sympathetic Ophthalmia.

 Tuberculosis: Produces varied clinical manifestations. The diagnosis is usually made by ancillary laboratory tests and response to antituberculosis therapy. Miliary tuberculosis may produce multifocal, small, yellow-white choroidal lesions. Most patients have concomitant anterior granulomatous or nongranulomatous uveitis.

 Tattoo-associated uveitis: Anterior, intermediate, or panuveitis mimicking sarcoidosis; associated with induration and itching of tattooed but not adjacent skin. Posterior synechiae and resistance to steroid therapy are common. Often requires immunosuppressive therapy. Removal of preexisting tattoos not usually effective and often not feasible.

White Dot Syndromes

FIGURE 12.3.1 Fundus photographs of right (A) and left (B) eye showing creamy yellow subretinal lesions in APMPPE. Note a pigmented choroidal nevus along the inferotemporal arcade in the left eye.

 Acute posterior multifocal placoid pigment epitheliop athy (APMPPE): Acute visual loss in young adults, often after a viral illness. Multiple, creamy yellow-white or gray, plaque-like subretinal lesions in both eyes (see Figure 12.3.1A and B). Lesions block early and stain late on IVFA. Usually spontaneously improves over weeks to months without treatment. May be associated with a cerebral vasculitis (consider MRA if the patient has a headache or other neurologic symptoms), in which case, systemic steroids are indicated.

 Multiple evanescent white dot syndrome (MEWDS): Photopsias and acute unilateral visual loss, often after a viral illness and usually in young women. May have a shimmering scotoma. Uncommonly bilateral, sequential, or recurrent. Characterized by multiple, small white lesions deep in the retina or at the level of the retinal pigment epithelium with foveal granularity and occasionally vitreous cells. Fluorescein angiography may show a classic perifoveal “wreath-like” pattern. There is often an enlarged blind spot on formal visual field testing. Vision typically returns to normal within 6 to 8 weeks without treatment.

 Birdshot retinochoroidopathy: Usually middle-aged patients with multiple bilateral, oval, creamy-yellow spots deep to the retina, approximately 1 mm in diameter, scattered throughout the fundus but most prominent in inferior quadrants. A mild to moderate vitritis is present. Retinal vasculitis, CME, and optic nerve edema may be present. ICG angiography shows characteristic hypofluorescent spots but fluorescein angiography often shows only retinal vasculitis, CME, and “quenching" of dye. Positive HLA-A29 in 95% to 100% of patients. Early systemic immunosuppression is often recommended.

 Multifocal choroiditis with panuveitis: Visual loss in young myopic women more often than men, typically bilateral. Multiple, small, round, and pale inflammatory lesions (similar to histoplasmosis) are located at the level of the pigment epithelium and choriocapillaris. Unlike histoplasmosis, vitritis occurs in 98% of patients. The lesions can occur in the macula and midperiphery and frequently respond to oral or periocular steroids, but typically recur with tapering, so that immunosuppressive therapy is often necessary. Choroidal neovascularization (CNV) occurs in about 1/3 of patients, and so patients should return for urgent evaluation if they have decreased vision or metamorphopsia.

 Punctate inner choroidopathy: Blurred vision, paracentral scotoma, and/or photopsias, usually in young myopic women. Multiple, small round yellow-white spots predominantly in posterior pole with minimal intraocular inflammation. Lesions become well-demarcated atrophic scars within weeks. CNV may develop in up to 40% of patients. Systemic immunosuppression is usually indicated.

 Serpiginous choroidopathy: Typically bilateral, recurrent chorioretinitis characterized by acute lesions (yellow-white subretinal patches with indistinct margins) bordering old atrophic scars. The chorioretinal changes usually extend from the optic disc outward; however, one-third may begin in the macula. Patients are typically aged 30 to 60 years. CNV may develop. Systemic immunosuppression is usually indicated. Must be distinguished from the “serpiginous” pattern of tuberculous chorioretinitis.

 Toxocariasis: Typically unilateral. Usually occurs in children. The most common presentations are a macular granuloma (elevated white retinal/subretinal lesion) with poor vision, unilateral intermediate uveitis with peripheral granuloma, or endophthalmitis. A peripheral lesion may be associated with a fibrous band extending to the optic disc, sometimes resulting in macular vessel dragging. A severe vitritis and anterior uveitis may be present. A negative undiluted Toxocara titer in an immunocompetent host usually rules out this disease. See 8.1, Leukocoria.

 Presumed ocular histoplasmosis syndrome: Punched-out chorioretinal scars, peripapillary atrophy, CNV is common.

Vitreous cells are absent. See 11.24, Ocular Histoplasmosis.

Retinitis

 CMV retinitis: White patches of necrotic retina with granular borders, often mixed with retinal hemorrhage. Vascular sheathing (secondary frosted branch angiitis) in about 20% of eyes. Vitritis and anterior uveitis are usually mild. Seen in immunocompromised patients (most commonly in advanced HIV/AIDS, but also inherited or iatrogenic disorders of the immune system; rarely after periocular or intravitreal steroid injections) and congenitally infected neonates. See 12.9, Cytomegalovirus Retinitis.

 Acute retinal necrosis (ARN): Unilateral or bilateral peripheral white patches of thickened necrotic retina with vascular sheathing that progress rapidly. Marked vitritis and anterior uveitis are typically present. See 12.8, Acute Retinal Necrosis.

 Progressive outer retinal necrosis (PORN): Clinically similar to ARN, but may not have vitreous cells. Involves the posterior pole or optic nerve early, and classically spares the vessels. Occurs exclusively in severely immunocompromised patients, especially advanced HIV/AIDS, with rapid progression over several days. See 12.8, Acute Retinal Necrosis.

 Toxoplasmosis: Unilateral retinal lesion may or may not be associated with an adjacent pigmented chorioretinal scar or clumps of scars. Focal dense vitritis over an area of white retinitis constitutes the “headlight in a fog” morphology. See 12.5, Toxoplasmosis.

 Candida: Early discrete drusen-like choroidal lesions progressing to yellow-white, fluffy retinal, or preretinal lesions. See 12.17, Candida Retinitis/Uveitis/Endophthalmitis.

Vasculitis

Retinal sheathing around vessels. Branch retinal vein and branch retinal artery occlusions may occur.

 Periphlebitis (predominantly veins)

 Sarcoidosis: Yellow "candlewax" exudates around veins.

 Syphilis.

 Pars planitis: Most prominent in the inferior periphery, neovascularization may be present.

 Eales disease: Peripheral neovascularization and/or avascular retina.

 Multiple sclerosis.

 Birdshot retinochoroidopathy.

 Arteritis (predominantly arteries)

 Giant cell arteritis.

 Polyarteritis nodosum.

 Frosted branch angiitis.

 Churg-Strauss disease.

 ARN.

 Idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN).

 Susac syndrome.

 Both arteries and veins

 Systemic lupus erythematosus.

 Granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis).

 Behcet disease.

 HLA-B27-associated (rare).

Postsurgical/Trauma

See 12.13, Postoperative Endophthalmitis; 12.14, Chronic Postoperative Uveitis; 12.15, Traumatic Endophthalmitis; and 12.18, Sympathetic Ophthalmia.

Other Infectious Causes of Posterior Uveitis

 Cat-scratch disease: Unilateral stellate macular exudates, optic nerve swelling, vitreous cells, and positive Bartonella serology. See 5.3, Parinaud Oculoglandular Conjunctivitis.

 Diffuse unilateral subacute neuroretinitis: Unilateral visual loss in children and young adults, caused by a nematode. Optic nerve swelling, vitreous cells, and deep gray-white retinal lesions are present initially, but may be subtle. Later, optic atrophy, narrowing of retinal vessels, and atrophic pigment epithelial changes develop. Vision, visual fields, and ERG deteriorate with time. Treatment is to laser nematode.

 Lyme disease: Produces varied forms of posterior uveitis. See 13.3, Lyme Disease.

 Nocardia, Coccidioides species, Aspergillus species, Cryptococcus species, meningococcus, ophthalmomyiasis, onchocerciasis, and cysticercosis (seen more commonly in Africa and Central and South America).

12.4 Human Leukocyte Antigen-B27- Associated Uveitis

Symptoms

Acute pain, blurred vision, and photophobia. Associated systemic complaints may include lower back, cervical, or heel pain (typically worse on awakening), arthritis, oral ulcers, pain with urination, gastrointestinal complaints, and rashes.

Signs

Critical. Recurrent, unilateral (or alternating bilateral) nongranulomatous anterior uveitis.

Other. Severe anterior chamber reaction with cell, flare, and fibrin. Most common cause of unilateral hypopyon. Tendency to form posterior synechiae early. Ciliary flush. More common in men than women.

Differential Diagnosis

 Other hypopyon uveitides: Behcet disease (posterior involvement more common than in HLA-B27), infectious endophthalmitis, retinoblastoma, metastatic tumors, drug-induced (e.g., rifabutin), sarcoidosis, and masquerade syndromes.

 Idiopathic anterior uveitis.

Types of HLA-B27 Disease

 HLA-B27-associated uveitis without systemic disease.

 Ankylosing spondylitis: Young adult men, often with lower back pain or stiffness, abnormalities on sacroiliac spine radiographs, increased ESR, positive HLA-B27, and negative rheumatoid factor (seronegative spondyloarthropathy).

 IBD: Crohn disease and ulcerative colitis. Chronic diarrhea, bloody stool, and crampy abdominal pain. Patients who have IBD and are HLA B27-negative may be more likely to get sclerokeratitis or peripheral ulcerative keratitis than uveitis.

 Reactive arthritis (Reiter syndrome): Young adult men, conjunctivitis, urethritis, polyarthritis, occasionally keratitis, increased ESR, and positive HLA-B27. May have recurrent episodes. Arthritis tends to involve the lower extremities.

 Psoriatic arthritis: Characteristic skin findings with arthritis typically involving the upper extremities.

NOTE: Over half of patients presenting with HLA-B27-positive acute anterior uveitis have an underlying seronegative spondyloarthropathy, and of those, over half are diagnosed only after the onset of uveitis.

Workup

1. HLA-B27 to confirm the diagnosis.

2. Ankylosing spondylitis: Sacroiliac spine radiographs or CT scan show sclerosis and narrowing of the joint spaces; ESR often elevated but nonspecific.

3. IBD: A medicine or gastroenterology consult.

4. Reactive arthritis: Conjunctival and urethral swabs for chlamydia if indicated. Consult medicine or rheumatology.

5. Psoriatic arthritis: A rheumatology or dermatology consult.

Treatment

See 12.1, Anterior Uveitis (Iritis/Iridocyclitis). Patients with HLA-B27 uveitis often suffer multiple recurrences. For particularly severe relapsing cases, consider longer-term steroid-sparing immunomodulatory therapy, often in conjunction with rheumatology.

12.5 Toxoplasmosis

Symptoms

Blurred vision and floaters. May have redness and photophobia. Pain depends on the severity of associated iridocyclitis.

Signs

(See Figure 12.5.1.)

FIGURE 12.5.1 Toxoplasmosis.

Critical. New, unilateral white retinal lesion often associated with an old pigmented chorioretinal scar. There is a moderate to severe focal vitreous inflammatory reaction directly over the lesion. Scar may be absent in cases of newly acquired toxoplasmosis.

Other

 Anterior: Mild anterior chamber spillover may be present, increased IOP in 10% to 20%.

 Posterior: Vitreous debris, optic disc swelling due to peripapillary lesions often with edema extending into the retina, neuroretinitis with/without macular star, optic neuritis with significant vitritis, retinal vasculitis, rarely retinal artery or vein occlusion in the area of the inflammation. Kyrieleis arteritis is periarterial exudate accumulation, which may occur near the retinitis or elsewhere in the retina; IVFA does not show vascular occlusion. Chorioretinal scars are occasionally found in the uninvolved eye. CME may be present.

NOTE: Toxoplasmosis is the most common cause of posterior uveitis and accounts for approximately 90% of focal necrotizing retinitis.

Toxoplasmosis can also develop in the deep retina (punctate outer retinal toxoplasmosis) with few to no vitreous cells present. More common in HIV- infected patients. See SPECIAL CONSIDERATION IN IMMUNOCOMPROMISED PATIENTS at the end of this section.

Differential Diagnosis

See 12.3, Posterior Uveitis, for a complete list. The following rarely may closely simulate toxoplasmosis.

TABLE 12.8.1

Cytomegalovirus (CMV) Retinitis Versus Acute Retinal Necrosis (ARN) Versus

Progressive Outer Retinal Necrosis (PORN) Versus Toxoplasmosis

• Syphilis (See 12.12, Syphilis) and tuberculosis.

 Toxocariasis: Usually affects children. Chorioretinal scars are not typically seen. See 12.3, Posterior Uveitis and 8.1, Leukocoria.

 ARN. See 12.8, Acute Retinal Necrosis (see Table 12.8.1).

 PORN. See 12.8, Acute Retinal Necrosis (see Table 12.8.1).

Workup

See 12.3, Posterior Uveitis, for work-up recommendations when the diagnosis is in doubt.

1. History: risk factors include handling or eating raw meat (e.g., venison), exposure to cats or especially kittens (sources of acquired infection), and hunters who dress their own game. Inquire about risk factors for HIV in atypical cases (e.g., multifocal retinitis). Water- and air-borne outbreaks of toxoplasmosis reported.

2. Complete ocular examination, including a dilated fundus evaluation.

3. Serum anti-Toxoplasma antibody titer to indicate remote (IgG) or recent (IgM) infection (usually not necessary). IgM is found approximately 2 weeks to 6 months after initial infection, after which only IgG remains positive.

4. PCR testing from aqueous or vitreous specimens for Toxoplasma gondii is more specific than serologic testing.

The high population seropositivity reduces the positive predictive value of a positive titer, but a negative titer makes the diagnosis unlikely.

NOTE: Request a 1:1 dilution because any titer of serum antibodies is significant in the setting of classic fundus findings.

5. Toxoplasma antibody titers and PCR may be performed on anterior chamber taps or through diagnostic vitrectomy in equivocal cases.

6. Consider RPR or VDRL, FTA-ABS or treponemal-specific assay, PPD or IGRA, chest radiograph or CT, and a Toxocara ELISA when the diagnosis is uncertain.

7. Consider HIV testing in atypical cases or high-risk patients. See below.

Treatment

1. Mild peripheral retinochoroiditis.

 Self-limited in immunocompetent patients. May consider observation only for peripheral lesions.

 Treat elevated IOP with antiglaucoma medications and anterior uveitis with topical cycloplegic (e.g., cyclopentolate 1% to 2% t.i.d.) with or without topical steroid (e.g., prednisolone acetate 1% q2h).

2. Treatment usually recommended for lesions in the macula, within 2 to 3 mm of the disc, threatening a large retinal vessel, associated with severe vitritis causing decreased vision, or disease in an immunocompromised patient. Immunocompromised patients may require extended treatment.

 Classic first-line triple therapy (for 4 to 6 weeks):

 Pyrimethamine, 200 mg p.o. load (or two 100 mg doses p.o. 12 hours apart), and then 25 to 50 mg p.o. daily. Do not give pyrimethamine to pregnant or breastfeeding women (spiramycin 1 g p.o. t.i.d. for women who seroconvert in pregnancy).

 Folinic acid 10 mg p.o. every other day (to minimize bone marrow toxicity of pyrimethamine).

 Sulfadiazine 2 g p.o. load and then 1 g p.o. q.i.d. Expensive and difficult to obtain; trimethoprim/sulfamethoxazole 160 mg/800 mg twice daily may be substituted as described below.

 Prednisone may be added 20 to 60 mg p.o. daily beginning at least 24 hours after initiating antimicrobial therapy and tapered 10 days before stopping antibiotics. Periocular steroids should not be given.

Systemic steroids should only rarely be used in immunocompromised patients. Before systemic steroid use, evaluation of fasting blood sugar/hemoglobin A1C and studies to rule out tuberculosis are prudent.

NOTE: Due to potential bone marrow suppression, a CBC must be obtained once per week while a patient is taking pyrimethamine. If the platelet count decreases below 100,000, then reduce the dosage of pyrimethamine and increase the folinic acid. Patients taking pyrimethamine should not take vitamins that contain folic acid. The medication should be given with meals to reduce anorexia.

3. Alternate regimens:

• Clindamycin 150 to 450 mg p.o. t.i.d. to q.i.d. (maximum 1.8 g/d) may be used alone, with pyrimethamine as the alternative therapy (if the patient is sulfa allergic), or as an adjunct (quadruple therapy). Patients on clindamycin should be warned about pseudomembranous colitis, and the medication should be stopped if diarrhea develops. Intravitreal injection of clindamycin (0.1 mg/0.1 mL) can be effective for macular-threatening cases, or when the patient is intolerant to systemic medication. Combined intravitreal clindamycin (0.1 mg/0.1 mL) and dexamethasone (0.4 mg/0.1 mL) have been reported helpful.

 Atovaquone 750 mg p.o. q.i.d., used as an alternative similar to clindamycin.

 Trimethoprim/sulfamethoxazole (160 mg/800 mg) one tablet p.o. b.i.d., with or without clindamycin and prednisone.

 Azithromycin loading dose 1 g (day 1) and then 250 to 500 mg daily. May be used alone or in combination with pyrimethamine (50 mg daily).

 Spiramycin 400 mg p.o. t.i.d. may be considered in cases of pregnancy, but must be obtained from CDC.

 Anterior segment inflammation is treated as above.

4. Vitrectomy has been used for nonclearing dense vitritis or other complications.

5. Maintenance therapy (if the patient is immunosuppressed)

 Trimethoprim/sulfamethoxazole 160 mg/800 mg one tablet p.o. three times a week.

or

 If sulfa-allergic (common in HIV-infected patients), may use clindamycin 300 mg p.o. q.i.d.

6. Prophylaxis: In a patient with a history of toxoplasmosis undergoing cataract or refractive surgery, consider using trimethoprim/sulfamethoxazole b.i.d. during the perioperative period.

Follow Up

In 3 to 7 days for blood tests and/or ocular assessment, and then every 1 to 2 weeks on therapy.

SPECIAL CONSIDERATION IN IMMUNOCOMPROMISED PATIENTS

Vitritis usually much less prominent. Adjacent retinochoroidal scars may not be present. The lesions may be single or multifocal, discrete or diffuse, and unilateral or bilateral. CNS imaging is essential because of high association with CNS disease (e.g., toxoplasmic encephalopathy in HIV patients). Diagnostic vitrectomy may be necessary because of the multiple simulating entities and the variability of laboratory diagnostic tests. Systemic steroids for ocular toxoplasmosis should be used very cautiously in patients with AIDS.

12.6 Sarcoidosis

Symptoms

Unilateral or bilateral ocular pain, photophobia, and decreased vision. May have an insidious onset, especially in older patients with chronic disease. Systemic findings may include shortness of breath, parotid enlargement, fever, arthralgias, and rarely neurologic symptoms including cranial nerve palsy. Most common in the 20- to 50-year age group. Most common in African Americans and Scandinavians.

Signs

Critical. Iris nodules, large mutton-fat KP (especially in Arlt triangle), and sheathing along peripheral retinal veins (candlewax drippings).

Other. Conjunctival nodules, enlargement of the lacrimal gland, dry eyes, posterior synechiae, glaucoma, cataract, intermediate uveitis, CME, vitritis, round and pale choroidal lesions that may simulate multifocal choroiditis or birdshot retinochoroidopathy, chorioretinitis, optic nerve granuloma, optic disc or peripheral retinal neovascularization (see Figure 12.6.1).

FIGURE 12.6.1 Sarcoid choroidal granuloma.

Systemic. Tachypnea, facial nerve palsy, enlargement of salivary or lacrimal glands, bilateral symmetric hilar adenopathy on chest radiograph or CT, erythema nodosum (erythematous, tender nodules beneath the skin, often found on the shins), lupus pernio (a dusky purple rash on nose and cheeks), arthritis, lymphadenopathy, hepatosplenomegaly.

NOTE: Uveitis, secondary glaucoma, cataracts, and CME are the most common vision-threatening complications of ocular sarcoidosis.

Differential Diagnosis

• Other causes of mutton-fat KP and iris nodules include syphilis, tuberculosis, sympathetic ophthalmia, tattoo-associated uveitis, and lens-related uveitis. See 12.1, Anterior Uveitis (Iritis/Iridocyclitis).

 Intermediate uveitis may be idiopathic or secondary to sarcoid, multiple sclerosis, Lyme disease, and others. See 12.2, Intermediate Uveitis.

 Posterior uveitis with multiple chorioretinal lesions may be from birdshot retinochoroidopathy, intraocular lymphoma, syphilis, sympathetic ophthalmia, multifocal choroiditis, VKH syndrome, and others. See 12.3, Posterior Uveitis.

Workup

The following are the tests that are obtained when sarcoidosis is suspected clinically. See 12.1, Anterior Uveitis (Iritis/Iridocyclitis) and 12.3, Posterior Uveitis, for other uveitis workup.

1. Chest radiography: May reveal bilateral and symmetric hilar adenopathy and/or infiltrates indicative of pulmonary fibrosis, but may be normal in many patients and a negative result does not rule out sarcoidosis. Chest CT is more sensitive but more expensive. In cases of unilateral or atypical lung disease, consider malignancy.

2. Serum ACE: Elevated in 60% to 90% of patients with active sarcoidosis. Similar to chest radiography, a normal level does not rule out sarcoidosis, and elevation is not specific. HIV, tuberculosis, histoplasmosis, and leprosy may also present with elevated ACE. Patients with underlying lung disease (e.g., COPD) or patients on oral steroids and/or ACE inhibitors may have falsely low ACE levels. ACE levels in children are less helpful in diagnosis.

3. Tissue biopsy: Definitive diagnosis requires demonstration of noncaseating granulomatous inflammation. Obtain biopsy of accessible affected lesions, including lymph nodes or edges of skin plaques or nodules. Sarcoid granulomas are not present in erythema nodosum and these lesions should not be sampled. An acid-fast stain and a methenamine-silver stain may be performed to rule out tuberculosis and fungal infection. A nondirected conjunctival biopsy in the absence of visible lesions has a low yield and is not recommended. Indurated areas of tattooed skin with concurrent uveitis may suggest tattoo-associated uveitis; skin biopsy may show noncaseating granulomas while the chest X-ray (CXR) is normal.

4. PPD or IGRA: Useful for differentiating tuberculosis from sarcoidosis when pulmonary findings are present. Up to 50% of sarcoidosis patients are anergic and have no response to PPD or controls.

5. Other: Some authors recommend serum and urine calcium levels, liver function tests, and a serum lysozyme. A positive result on one of these tests in the absence of chest radiographic or other findings is usually not helpful in diagnosis. A serum lysozyme may be useful in children, in whom ACE levels are often normal.

If laboratory and chest radiographic studies suggest sarcoidosis or in the setting of a negative workup but a high clinical suspicion of the disease, the following tests should be considered:

1. Chest CT is more sensitive than CXR.

2. Whole-body gallium scan is sensitive for sarcoidosis. A “panda sign” indicates involvement of lacrimal, parotid, and submandibular glands. A “lambda sign” indicates involvement of bilateral hilar and right paratracheal lymph nodes. A positive gallium scan and an elevated ACE level are 73% sensitive and 100% specific for sarcoidosis. Cost and inconvenience are drawbacks.

3. Referral to a pulmonologist for pulmonary function tests and transbronchial lung biopsy.

4. The risks of an invasive diagnostic test or radiation exposure must be weighed against the impact the results will have on treatment.

Treatment

Refer patients to an internist or pulmonologist for systemic evaluation and medical management. Consider early referral to a uveitis specialist in complicated cases. A poor visual outcome has been reported with posterior uveitis, glaucoma, delay in definitive treatment, or presence of macula-threatening conditions such as CME.

1. Anterior uveitis:

 Cycloplegic (e.g., cyclopentolate 1% t.i.d. or atropine 1% b.i.d.).

 Topical steroid (e.g., prednisolone acetate 1% q1-6h).

2. Posterior uveitis:

 Supplement calcium with vitamin D (e.g., 600 mg with 400 iU) once or twice daily and consider a histamine type 2 receptor (H2) blocker (e.g., ranitidine 150 mg p.o. b.i.d.) or proton pump inhibitor (e.g., pantoprazole 40 mg daily).

 Periocular steroids (e.g., 0.5 to 1.0 mL injection of triamcinolone 40 mg/mL) may be considered instead of systemic steroids, especially in unilateral or asymmetric cases. Can repeat injection every 3 to 4 weeks. See Appendix 10, Technique for Retrobulbar/Subtenon/Subconjunctival Injections.

3. Immunosuppressives (e.g., methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, cyclophosphamide, and infliximab) have been used effectively as steroid-sparing agents. Decisions regarding therapy should be individualized given known side effect profiles of each regimen.

NOTE: Topical steroids alone are inadequate for the treatment of posterior uveitis.

4. CME: See 11.14, Cystoid Macular Edema.

5. Glaucoma: See 9.7, Inflammatory Open Angle Glaucoma; 9.9, Steroid-Response Glaucoma; 9.4, Acute Angle Closure Glaucoma; or 9.14, Neovascular Glaucoma, depending on the etiology of the glaucoma.

6. Retinal neovascularization: May require panretinal photocoagulation.

7. Orbital disease is managed with systemic steroids as described previously.

8. Optic nerve granulomas require consultation with a neuroophthalmologist and treatment with systemic steroids.

9. Pulmonary disease, facial nerve palsy, CNS disease, and renal disease require systemic steroids and management by an internist or neurologist.

Follow Up

1. Patients are re-examined in 1 to 7 days, depending on the severity of inflammation. The steroid dosages are adjusted in accordance with the treatment response. Slowly taper the steroids and cycloplegic agent as the inflammation subsides. Monitor IOP and re-evaluate the fundus at each visit.

2. Patients with quiescent disease are seen every 3 to 6 months.

3. Patients being treated with steroids or systemic immunosuppression are monitored every 2 to 6 weeks, pending clinical response.

4. Poor response to steroid treatment should prompt a workup for other causes of uveitis or referral to a subspecialist.

12.7 Behcet Disease

Symptoms

Sudden onset of bilateral decreased vision, floaters, and photophobia.

Pain is usually mild or moderate.

Signs

Critical. Painful oral aphthous ulcers (well-defined borders with a white yellow necrotic center, often with surrounding erythema, found in 98% to 100% of patients) at least three times per year and two of the following: genital ulcers, skin lesions, positive Beh^etine (pathergy) test (formation of a local pustule that appears 48 hours after skin puncture with a needle), and eye lesions. May have other skin findings including erythema nodosum, pseudofolliculitis, palpable purpura, superficial thrombophlebitis, or dermographism.

Other. Other systemic manifestations include arthritis, hemoptysis from pulmonary artery involvement, renal involvement, gastrointestinal disease with bowel ulceration, epididymitis, and neuro-Beh^et (e.g., vasculitis, encephalitis, cerebral venous thrombosis, neuropsychiatric symptoms).

Ocular Signs

• Anterior: Bilateral hypopyon and anterior chamber reaction; scleritis occasionally reported.

NOTE: Patients with Behpet disease almost never have fibrin even if the anterior chamber reaction is severe, thus the hypopyon appears mobile (“shifting”) in contrast to HLA-B27- associated uveitis.

• Posterior: Vitritis, retinal vasculitis affecting both arteries and veins, venous obstruction, arterial attenuation, retinal neovascularization, focal necrotizing retinitis, waxy optic nerve pallor, and retinal detachment.

Epidemiology

Age 20 to 40 years; especially Japanese, Turkish, or Middle Eastern descent.

Differential Diagnosis

 Sarcoidosis: May occasionally present with oral ulcers. See 12.6, Sarcoidosis.

 HLA-B27: Usually unilateral or bilateral alternating uveitis. Severe fibrinous uveitis. Oral ulcers are less painful and severe. See 12.4, Human Leukocyte Antigen-B27-Associated Uveitis.

 ARN: Confluent retinal whitening in the periphery. More pain than Behcet disease. See 12.8, Acute Retinal Necrosis.

 GPA: Nephritis, orbital inflammation, sinus, and pulmonary inflammation.

 Syphilis. See 12.12, Syphilis.

 Systemic lupus erythematosus and other collagen vascular diseases.

Workup

 Chest radiograph or CT, ACE level, PPD or IGRA, RPR or VDRL, and FTA-ABS or treponemal-specific assay.

 Consider HLA-B27 in young men with a positive review of systems suggesting seronegative spondyloarthropathy.

 Granular-staining cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) if GPA is suspected.

 Consider HLA-B51 and HLA-DR5 testing for Behcet disease (positive and negative predictive values are uncertain).

 Consider Beh^etine (pathergy) test. The test is considered positive if there is development of a papule of 2 mm or more in size 48 hours after 5-mm deep skin prick with a 20-gauge needle.

Treatment

If untreated, bilateral blindness often develops within 3 to 4 years. Death may result from CNS involvement. Proper referral for immunosuppressive therapy is critical.

1. Topical corticosteroids (e.g., prednisolone acetate 1% q1-6h depending on severity of inflammation) and cycloplegics (e.g., atropine 1% b.i.d.) for anterior inflammation.

2. Systemic corticosteroids should be started (prednisone 1 mg/kg p.o. daily or intravenous methylprednisolone sodium succinate 1 g daily for 3 days, followed by prednisone). Steroids delay the onset of blindness but do not alter the long-term outcome. Prior to systemic immunosuppressive therapy, it is important to rule out syphilis, tuberculosis, and hepatitis.

3. All patients with Behcet disease and posterior uveitis should be referred to a specialist for initiation of immunosuppressive therapy. TNF-antagonists such as infliximab or adalimumab are now considered first-line therapy for Behcet disease. Calcineurin inhibitors (tacrolimus and cyclosporine) and antimetabolites (e.g., mycophenolate mofetil, methotrexate, and azathioprine) can be used, but take 1 to 2 months to achieve the full effect.

Follow Up

Daily during acute episodes to monitor inflammation and IOP. Refer to a uveitis specialist for further follow up.

12.8 Acute Retinal Necrosis

Symptoms

Blurred vision, floaters, ocular pain, and photophobia. Affected patients are usually immunocompetent.

Signs

(See Figure 12.8.1.)

FIGURE 12.8.1 Acute retinal necrosis.

Critical. The American Uveitis Society criteria include one or more foci of retinal necrosis with discrete borders in the peripheral retina, rapid progression of disease in the absence of antiviral therapy, circumferential spread, evidence of occlusive vasculopathy with arterial involvement, and prominent inflammatory reaction in the anterior chamber and vitreous. If untreated, the circumferential progression of necrosis may become confluent and spread posteriorly. The macula is typically spared early in the disease course.

Other. Anterior chamber reaction; KP; conjunctival injection; episcleritis or scleritis; increased IOP; sheathed retinal arterioles and sometimes venules, especially in the periphery; retinal hemorrhages (minor finding); optic disc edema; delayed RRD occurs in approximately 70% of patients secondary to large irregular posterior breaks. Usually begins unilaterally but may involve the second eye in one-third of cases within weeks to months. An optic neuropathy with disc edema or pallor sometimes develops.

Etiology

ARN is a clinical syndrome caused by the herpes virus family: VZV (older patients), HSV (younger patients), or rarely, CMV or Epstein- Barr virus (EBV).

Differential Diagnosis

See 12.3, Posterior Uveitis.

 CMV retinitis (Table 12.8.1).

 PORN: Rapidly progressive retinitis characterized by clear vitreous and sheet-like opacification deep to normal-looking retinal vessels, and occasional spontaneous vitreous hemorrhage. PORN is usually found in immunocompromised individuals and frequently leads to rapid bilateral blindness due either to the infection itself or to secondary retinal detachment, making prompt diagnosis and treatment essential. Unlike ARN, pain and vitritis are minimal and macular involvement occurs early.

 Syphilis.

 Toxoplasma chorioretinitis.

 Behcet disease.

 Sarcoidosis.

 Fungal or bacterial endophthalmitis.

 Large cell lymphoma. Consider in patients >50 years of age with refractory unilateral vitritis, yellow-white subretinal infiltrates, and absence of pain.

Workup

See 12.3, Posterior Uveitis, for a nonspecific uveitis workup.

1. History: Risk factors for AIDS or other immunocompromised states (iatrogenic, autoimmune, malignancy, or genetic)? If yes, the differential diagnosis includes CMV retinitis and PORN. Ask about history of shingles (especially zoster ophthalmicus) or herpes simplex infections. Head trauma (including neurosurgery) and ocular surgery may precipitate ARN. Rarely, ARN can follow periocular or intravitreal corticosteroid injections. Most patients have no identifiable precipitating factors.

2. Complete ocular examination: Evaluate the anterior chamber and vitreous for cells, measure IOP, and perform a dilated retinal examination using indirect ophthalmoscopy; gentle scleral depression as necrotic retina has an increased risk of retinal detachment.

3. Consider a CBC with differential, RPR or VDRL, FTA-ABS or treponemal-specific assay, ESR, Toxoplasma titers, PPD or IGRA, and chest radiograph or CT to rule out other etiologies.

4. Consider HIV testing.

5. Anterior chamber paracentesis for herpes virus and Toxoplasma PCR to confirm the causative virus is highly specific but sensitivity may vary. See Appendix 13, Anterior Chamber Paracentesis.

6. Consider IVFA to identify retinal vasculitis and areas of ischemia.

7. MRI of the brain and orbits in cases of suspected optic nerve dysfunction.

8. CT or MRI of the brain and lumbar puncture if large cell lymphoma, tertiary syphilis, or encephalitis is suspected.

Treatment

NOTE: All patients with ARN should be referred to a specialist.

1. Prompt inpatient or outpatient treatment. The goal is to decrease the incidence of disease in the fellow eye. Treatment does not reduce the rate of retinal detachment in the first eye.

2. Oral antivirals (valacyclovir 1 to 2 g t.i.d. or famciclovir 500 mg t.i.d. preferred; acyclovir 800 mg five times per day second-line option as it achieves lower intravitreal levels) with supplemental intravitreal injections with foscarnet (2.4 mg/0.1 mL) or ganciclovir (2 mg/0.1 mL) given one to two times per week. Alternative therapy includes intravenous acyclovir 10 mg/kg t.i.d. for 5 to 14 days (requires dose adjustment for renal insufficiency) with supplemental intravitreal injections as noted above, followed by oral valacyclovir 1 g t.i.d. or acyclovir 400 to 800 mg five times per day. Either of these regimens is maintained for up to 14 weeks from the onset of infection. Involvement of the second eye typically starts within 6 weeks of initial infection. Published literature suggests that primary treatment with oral antivirals in conjunction with the above intravitreal injections has similar efficacy as intravenous therapy. Stabilization and early regression of retinitis are usually seen within 4 days. The lesions may progress during the first 48 hours of treatment. The ideal duration of oral antiviral therapy remains unproven, but since replicating virus in the anterior chamber can be found up to 2 months after the onset of disease, a minimum of 2 months of therapy is recommended, and some experts recommend lifetime therapy to reduce the risk of second- eye involvement (especially if the first eye becomes nonfunctional).

3. Topical cycloplegic (e.g., atropine 1% t.i.d.) and topical steroid (e.g., prednisolone acetate 1% q2-6h) in the presence of anterior segment inflammation.

4. The benefits of antiplatelet therapy (e.g., aspirin 81 to 650 mg daily) to minimize vascular thrombosis and help prevent further retinal ischemia remain unproven.

5. Systemic steroids may be considered, particularly when the optic nerve is thought to be involved. Steroids are usually delayed at least 24 hours after the initiation of antiviral therapy, or when regression of retinal necrosis is evident. A typical oral corticosteroid regimen is prednisone 60 to 80 mg/d for 1 to 2 weeks followed by a taper over 2 to 6 weeks. Subtenon injection of triamcinolone (40 mg/1 mL) can be considered after adequate loading of antiviral therapy but may interfere with the clearance of virus by the eye.

6. See 9.7, Inflammatory Open Angle Glaucoma, for increased IOP.

7. Consider prophylactic barrier laser photocoagulation posterior to active retinitis to wall off or prevent subsequent RRD (efficacy unclear).

8. Pars plana vitrectomy, with long-acting gas or silicone oil, is the best way to repair the associated complex RRD. Proliferative vitreoretinopathy is common.

Follow Up

1. Patients are seen daily initially and are examined every few weeks to months for the following year; examination of both eyes is essential.

2. A careful fundus evaluation is performed at each visit to rule out retinal holes that may lead to a detachment. If barrier laser demarcation has been done and the retinitis subsequently crosses the posterior margin, consider applying additional laser therapy.

3. Pupillary evaluation should be performed, and optic neuropathy should be considered if the retinopathy does not explain the amount of visual loss.

12.9 Cytomegalovirus Retinitis

CMV is the most frequent ocular opportunistic infection in patients with AIDS, but is 80% to 90% less common in the era of combination antiretroviral therapy (cART). CMV is almost never seen unless the CD4+ count is <100 cells/mm3. Because active retinitis is often asymptomatic, patients with CD4+ counts <100 cells/mm3 should be seen at least every 3 to 6 months. May also be seen in other immunocompromised states (e.g., leukemia and post-transplant). Local ocular immunosuppression (regional steroid injections) may precipitate CMV retinitis in otherwise healthy patients.

Symptoms

Scotoma or decreased vision in one or both eyes, floaters, or photopsias. Pain and photophobia are uncommon. Often asymptomatic.

Signs

Critical

FIGURE 12.9.1 CMV retinitis.

 Indolent form: Peripheral granular opacities with or without hemorrhage. The absence of hemorrhage does not rule out CMV retinitis.

 Fulminant form: Confluent areas of necrosis with prominent hemorrhage, starting along the major retinal vascular arcades. Progressive retinal atrophy may also indicate active CMV (see Figure 12.9.1).

Other. Anterior uveitis with nongranulomatous, stellate KP almost always present but mild. Vitritis is usually mild. Retinal pigment epithelial (RPE) atrophy and pigment clumping result once the active process resolves. RRD occurs in approximately one-third of patients with CMV retinitis with increased risk when >25% of the retina is involved.

Workup

1. History and complete ocular examination.

2. Consider anterior chamber paracentesis with viral PCR in equivocal cases. See Appendix 13, Anterior Chamber Paracentesis.

3. Refer the patient to an internist or an infectious disease specialist for systemic evaluation and treatment.

Treatment

See Table 12.9.1 for treatment details.

TABLE 12.9.1

Therapy for CMV Retinitis

aCompared with intravitreal therapy alone, there is a decreased risk of mortality (50%), systemic disease (90%), and fellow eye involvement (80%) in patients treated with systemic anti-CMV therapy. Moreover, the risk of retinitis progression is significantly greater in eyes treated with intravitreal therapy alone.

bCompared with i.v. ganciclovir, there is an increased risk of systemic disease (30%) and fellow eye involvement (50%) after 6 months. However, the relapse-free interval is greatly increased.

cDuring the induction phase, 500 mL of normal saline is used for each dose. During maintenance, 1000 mL of saline should be used.

1. Oral therapy with valganciclovir 900 mg p.o. b.i.d. for induction (21 days), followed by 900 mg p.o. daily for maintenance. Alternatively, intravenous ganciclovir 5 mg/kg b.i.d. or foscarnet 90 mg/kg b.i.d. (adjusting for renal function) may be used, followed by oral therapy valganciclovir (900 mg p.o. b.i.d. to complete 3-week induction, then 900 mg p.o. daily). Patients with progression of retinitis despite induction or who have disease that threatens the macula may benefit from intravitreal antiviral injections, but systemic therapy is still necessary to prevent the involvement of the fellow eye. The goal of treatment is quiescent retinitis (nonprogressive areas of RPE atrophy with a stable opacified border).

2. Under the direction of an internist or infectious disease specialist, HAART should be initiated or optimized; immune recovery with sustained CD4+ counts >200 cells/mm3 results in decreased risk of retinal detachment, second-eye involvement, antiviral resistance, and mortality. Also, monitor for toxicity of anti-CMV therapy (valganciclovir and ganciclovir cause bone marrow toxicity; foscarnet is nephrotoxic and can cause electrolyte abnormalities and seizures; intravenous ganciclovir and foscarnet require placement of an indwelling catheter, which may cause line infection and sepsis).

3. Small, macula-sparing RRDs may be treated with laser demarcation, but multiple retinal breaks are typical and may be missed; pars plana vitrectomy with silicone oil is indicated for most detachments, especially those involving the macula.

4. Primary prophylaxis (prevention of CMV retinitis) with oral valganciclovir in high-risk patients is usually not recommended because of potential toxicity except in transplant patients.

Follow Up

1. Ganciclovir resistance (reflected by positive blood or urine CMV cultures) may occur with prolonged treatment.

2. All currently available anti-CMV therapy is virostatic, not virocidal, and almost all patients eventually relapse if not treated with HAART. Serial fundus photographs helpful for comparison.

3. Relapse is defined as recurrent or new retinitis, movement of opacified border, or expansion of the atrophic zone.

4. Relapse can occur from resistance or subtherapeutic intraocular drug levels. Reinduction with the same medication is the first line of treatment.

5. Clinical resistance is defined as persistent or progressive retinitis despite induction level medication for 6 weeks. Laboratory confirmation is possible for low-grade UL97 (viral phosphotransferase) or high-grade UL54 (viral DNA polymerase) mutations.

6. If resistance is recognized, a change in therapy from one antiviral to the other is indicated. Consider intravenous cidofovir 5 mg/kg once weekly for 2 weeks and then 3 to 5 mg/kg every 2 weeks. Cidofovir itself may cause uveitis and renal impairment and must be given with probenecid to reduce the nephrotoxicity. Intravitreal cidofovir is contraindicated because of the high risk of uveitis and hypotony. Cross-resistance can occur since all three anti-CMV drugs are CMV DNA polymerase inhibitors.

7. Discontinuation of anti-CMV maintenance therapy may be considered in select patients receiving HAART who have CD4+ counts >100 cells/mm3 for greater than 6 months and completely quiescent CMV retinitis. In these patients, whose immune system can control CMV, stopping maintenance therapy may prevent drug toxicity and drug-resistant organisms. In iatrogenically immunosuppressed patients, cessation or reduction in dosage of immunosuppressive drugs may be required for long-term control of CMV retinitis.

8. Immune recovery uveitis (IRU): Occurs in previously immunocompromised patients (HIV/iatrogenic) with CMV after the CD4+ count or immune system reconstitutes. In the presence of a functioning immune system, the CMV antigens elicit an inflammatory response that is predominantly posterior (e.g., vitritis, papillitis, CME, and ERM). Treatment may require topical, periocular, or intraocular steroids. Antivirals should be continued to avoid reactivation of CMV in cases of borderline CD4+ counts.

12.10 Noninfectious Retinal

Microvasculopathy/HIV Retinopathy

Noninfectious retinopathy is the most common ocular manifestation of HIV/AIDS. About 50% to 70% of patients with AIDS have this condition.

Symptoms

Rarely symptomatic (focal scotomata and decreased contrast).

Signs

Cotton-wool spots, intraretinal hemorrhages, and microaneurysms. An ischemic maculopathy may occur with significant visual loss in 3% of affected patients.

Workup

HIV retinopathy is a marker of low CD4+ counts. Look for concomitant opportunistic infections (see 12.9, Cytomegalovirus Retinitis). Rule out the other causes for unexplained cotton-wool spots (see 11.5, Cotton-Wool Spot).

Treatment

No specific ocular treatment is necessary, but the retinopathy resolves with cART and increased CD4+ counts.

Follow Up

Patients with CD4+ counts <50 should be examined every 3 to 4 months.

12.11 Vogt-Koyanagi-Harada Syndrome

Autoimmune disease featuring inflammation of melanocytecontaining tissues.

Symptoms

Decreased vision, photophobia, pain, and red eyes; accompanied or preceded by a headache, stiff neck, nausea, vomiting, fever, and malaise. Hearing loss, noise causing ear pain, and tinnitus frequently occur. Typically bilateral.

NOTE: Harada disease refers to isolated ocular findings without associated systemic signs of VKH syndrome.

Signs

Diagnostic criteria include the following:

 (1) no history of ocular trauma, (2) no evidence of other disease processes, (3) bilateral anterior or panuveitis, (4) neurologic/auditory findings (usually occur before ocular disease), and (5) dermatologic findings (usually occur after ocular disease).

 Complete VKH includes criteria 1 to 5, incomplete VKH includes criteria 1 to 3 and either 4 or 5, and probable VKH (isolated ocular disease) includes criteria 1 to 3.

(See Figure 12.11.1.)

Critical

FIGURE 12.11.1 Vogt-Koyanagi-Harada (VKH) disease.

FIGURE 12.11.2 IVFA of VKH.

 Anterior: Anterior chamber flare and cells, granulomatous (mutton-fat) KP, perilimbal vitiligo (e.g., depigmentation around the limbus).

 Posterior: Bilateral serous retinal detachments with underlying choroidal thickening, vitreous cells, opacities, and optic disc edema.

 Systemic (four phases):

 Prodromal: loss of high-frequency hearing, tinnitus, meningismus, encephalopathy, and hypersensitivity of the skin to touch.

 Uveitic: acute ocular findings (see preceding bullets).

 Convalescent: alopecia, vitiligo, poliosis, "sunset glow" fundus (yellow-orange appearance of the fundus due to depigmentation of the RPE and choroid).

 Chronic recurrent: recurrence of anterior uveitis, subretinal fibrosis, neovascularization, glaucoma, and cataract.

 IVFA: Multiple pinpoint leaking areas of hyperfluorescence at the level of the retinal pigment epithelium (see Figure 12.11.2).

Other

 Anterior: Iris nodules, peripheral anterior or posterior synechiae, scleritis, hypotony, or increased IOP from the forward rotation of ciliary processes.

 Posterior: Sunset glow fundus (mottling and atrophy of the retinal pigment epithelium after the serous retinal detachment resolves), retinal vasculitis, choroidal neovascularization, and chorioretinal scars.

 Systemic: Neurologic signs, including loss of consciousness, paralysis, and seizures.

Epidemiology

Typically, patients are aged 20 to 50 years, female (77%), and have pigmented skin (especially Asian, Middle Eastern, Hispanic, or Native American).

Differential Diagnosis

See Table 12.11.1 for the differential of serous retinal detachments and 12.3, Posterior Uveitis. In particular, consider the following:

TABLE 12.11.1

Differential Diagnosis of Serous Retinal Detachments

Harada Disease

Malignant hypertension

Toxemia of pregnancy

Disseminated intravascular coagulopathy

Idiopathic uveal effusion syndrome

Sympathetic ophthalmia

Posterior scleritis

Central serous chorioretinopathy

Choroidal tumors (including metastases)

Choroidal neovascularization

Congenital optic disc pit

Nanophthalmos

 Sympathetic ophthalmia: History of trauma or surgery (especially repeated vitreoretinal procedures) in the contralateral eye. Usually no systemic signs. See 12.18, Sympathetic Ophthalmia.

 APMPPE: Ophthalmoscopic and IVFA features may be very similar, but there is less vitreous inflammation and no anterior segment involvement. See 12.3, Posterior Uveitis.

 Posterior scleritis: Typically unilateral, not typically associated with neurologic or dermatologic findings. Associated with an ultrasonographic "T" sign.

 Systemic arterial hypertension and pregnancy-related hypertension: Acute elevation in blood pressure can produce multifocal serous retinal detachments.

 Other granulomatous panuveitides (e.g., syphilis, sarcoidosis, and tuberculosis).

Workup

See 12.3, Posterior Uveitis, for a nonspecific uveitis workup.

1. History: Neurologic symptoms, hearing loss, or hair loss? Previous eye surgery or trauma?

2. Complete ocular examination, including a dilated retinal evaluation.

3. CBC, RPR or VDRL, FTA-ABS or treponemal-specific assay, ACE, PPD or IGRA, blood pressure, and possibly chest radiograph or CT to rule out similar-appearing disorders.

4. Consider B-scan ultrasonography to rule out posterior scleritis.

5. Consider a CT or MRI of the brain with or without contrast in the presence of neurologic signs to rule out a CNS disorder.

6. Lumbar puncture during attacks with meningeal symptoms for cell count and differential, protein, glucose, VDRL, Gram and methenamine-silver stains, and culture. CSF pleocytosis is often seen in VKH and APMPPE.

7. Consider IVFA to evaluate for pinpoint leaking areas of hyperfluorescence at the level of the retinal pigment epithelium.

Treatment

Inflammation is initially controlled with steroids; the dose depends on the severity of the inflammation. In moderate to severe cases, the following regimen can be used. Steroids are tapered very slowly as the condition improves.

1. Topical steroids (e.g., prednisolone acetate 1% qlh).

2. Systemic steroids (e.g., prednisone 60-80 mg p.o. daily or intravenous methylprednisolone sodium succinate 1 g daily for 3 days followed by oral therapy) with concurrent calcium/vitamin D supplementation and antiulcer prophylaxis.

3. Topical cycloplegic (e.g., cyclopentolate 1% t.i.d. or atropine 1% b.i.d.).

4. Treatment of any specific neurologic disorders (e.g., seizures or coma).

5. For patients who cannot tolerate or are unresponsive to long-term oral steroids, consider immunosuppressive agents (e.g., antimetabolites, calcineurin inhibitors, cytotoxic agents, and TNF- alpha inhibitors).

Follow Up

1. Initial management may require hospitalization if intravenous corticosteroids are initiated.

2. Weekly, then monthly re-examination is performed, watching for recurrent inflammation and increased IOP.

3. Steroids are tapered very slowly, and most patients should be transitioned to steroid-sparing immunosuppressants for longterm management. Inflammation may recur up to 9 months after the steroids have been discontinued. If this occurs, steroids should be reinstituted.

12.12 Syphilis

ACQUIRED SYPHILIS

Signs

Systemic. Most patients with syphilis will never develop ocular involvement. A history of sexually transmitted disease, HIV, or high- risk sexual activity should be elucidated. Men who have sex with men are at an increased risk.

 Primary: Chancre (ulcerated, painless lesion), regional lymphadenopathy.

 Secondary: Skin or mucous membrane lesions, generalized lymphadenopathy, constitutional symptoms (e.g., sore throat, fever), and symptomatic or asymptomatic meningitis.

 Latent: No clinical manifestations.

 Tertiary: Cardiovascular disease (e.g., aortitis), CNS disease (e.g., meningovascular disease, general paresis, and tabes dorsalis).

Ocular

FIGURE 12.12.1 Fundus photographs of the right (A) and left (B) eye showing placoid retinopathy in secondary syphilis.

 Primary: A chancre may occur on the eyelid or conjunctiva, madarosis (loss of lashes or eyebrows).

 Secondary: Uveitis (posterior and panuveitis more common than anterior), optic neuritis, chorioretinitis, serous retinal detachments, retinitis, retinal vasculitis, conjunctivitis, dacryoadenitis, dacryocystitis, episcleritis, scleritis, interstitial keratitis, and others. See Figure 12.12.1A and B.

 Tertiary: Optic atrophy, old chorioretinitis, interstitial keratitis, chronic anterior uveitis, Argyll Robertson pupil (see 10.3, Argyll Robertson Pupil), in addition to signs seen in secondary disease.

NOTE: Presentations strongly suggestive of syphilis include the following: patchy hyperemia of the iris with fleshy, pink nodules near the iris sphincter; acute posterior placoid chorioretinitis (multifocal white placoid lesions in the posterior pole); and punctate inner retinitis (superficial punctate creamy white lesions).

Differential Diagnosis

See 12.1, Anterior Uveitis (Iritis/Iridocyclitis) and 12.3, Posterior Uveitis.

Workup

See 12.1, Anterior Uveitis (Iritis/Iridocyclitis) and 12.3, Posterior Uveitis, for general uveitis workup recommendations.

1. Complete ophthalmic examination, including pupillary and dilated fundus examination. Palmar skin lesions are common and easily assessed in the clinic.

2. The “reverse algorithm” should be used, with treponemal testing done first to confirm the disease, and (if reactive) then nontreponemal testing to allow for assessment of treatment response. Treponemal testing with enzyme immunoassay (EIA), chemiluminescent immunoassays (CIA), FTA-ABS, or Treponema pallidum microhemagglutination assay (MHA-TP) tests are highly sensitive and specific in all but the primary stage of syphilis, during which ocular involvement is very rare. Quantitative nontreponemal tests such as RPR or VDRL are then done to assess the activity of the infection and are then repeated periodically after treatment to confirm resolution of infection. Once reactive, treponemal tests do not normalize and cannot be used to assess the patient’s response to treatment.

3. VDRL and RPR should not be used for screening as false-negative results can occur in early primary, latent, or late syphilis due to low sensitivity. False-negatives are also possible due to interference from excessively high titers (prozone reaction). Falsepositive results can occur due to viral illnesses, pregnancy, and test cross-reactivity with autoimmune or collagen vascular diseases. RPR and VDRL titers are used to follow treatment response.

4. In a patient with findings consistent with syphilis but no documented history of treatment, a positive treponemal test with a negative nontreponemal test still mandates treatment.

5. HIV testing is indicated in any patient with syphilis because of the relatively aggressive course in HIV-infected individuals as well as the high frequency of co-infection.

6. Patients should be evaluated for concomitant sexually transmitted diseases, with notification sent to the local health department when indicated.

7. Lumbar puncture with VDRL or FTA testing, protein, and cell count with differential should be performed in all cases of confirmed syphilitic uveitis, which should be considered consistent with neurosyphilis. Persistently stable or elevated CSF VDRL titers are concerning for incomplete treatment or reinfection.

Treatment Indications

In the presence of uveitis consistent with syphilis:

1. Treponemal testing negative: Syphilis unlikely, consider retesting if there is high suspicion and/or evaluating for other causes of uveitis.

2. Treponemal testing positive and nontreponemal testing negative:

 If appropriate past treatment cannot be documented, treatment for syphilis is indicated.

 If appropriate past treatment can be documented, treatment for syphilis is not indicated if another cause is identified and the patient responds to therapy for that condition.

3. Treponemal testing positive and nontreponemal testing positive: Treat for syphilis.

NOTE: Patients with concurrent HIV and active syphilis may have negative serologies (both treponemal and nontreponemal) because of their immunocompromised state. These patients manifest aggressive, recalcitrant syphilis and should be treated with neurosyphilis dosages over longer treatment periods. Consultation with infectious disease is recommended. Treatment of their comorbid HIV infection is paramount.

Treatment

1. Syphilitic uveitis represents a breakdown of the blood-brain (ocular) barrier and should be treated as neurosyphilis: Aqueous crystalline penicillin G 3 to 4 million units q4h for 10 to 14 days, followed by benzathine penicillin 2.4 million units intramuscularly (i.m.) weekly for 3 weeks.

2. If anterior segment inflammation is present, treatment with a cycloplegic (e.g., cyclopentolate 1% b.i.d.) and topical steroid (e.g., prednisolone acetate 1% q2h) should be started.

3. Oral steroids may be started 24 to 48 hours after induction of penicillin therapy and may speed visual recovery, but ultimately, have not been shown to affect final visual outcomes. Oral steroids may also help prevent systemic inflammatory complications associated with the Jarisch-Herxheimer reaction.

NOTE:

 Incomplete response to i.m. penicillin is possible, while a full course of i.v. therapy is virtually always effective; therefore, i.v. therapy is considered definitive therapy.

 Treatment for chlamydial infection with a single dose of azithromycin 1 g p.o. is typically indicated.

 Therapy for penicillin-allergic patients should be done in consultation with an infectious disease specialist. The CDC recommends admission and penicillin desensitization for patients who have a serious penicillin allergy and have neurosyphilis. Alternative regimens include ceftriaxone 2 g i.v./i.m. daily for 10 to 14 days or doxycycline 200 mg p.o. b.i.d. for 21 to 28 days. Notably, cephalosporins have a small risk for cross-reactivity in patients with a penicillin allergy.

Follow Up

1. Uveitis (negative CSF VDRL): Repeat serum VDRL/RPR testing q3 months after treatment. If a titer of 1:8 or more does not decline fourfold within 6 months, the titer increases fourfold, or clinical symptoms or signs of syphilis persist or recur, then repeat lumbar puncture checking VDRL and retreatment may be indicated. If a pretreatment VDRL/RPR titer is <1:8, retreatment is indicated only when the titer increases or when signs of syphilis recur.

2. Uveitis and neurosyphilis (positive CSF VDRL): Requires follow up with an infectious disease specialist. Repeat lumbar puncture should be performed every 6 months for 2 years, less frequently if the cell count returns to normal sooner. The cell count should decrease to a normal level within this period, and the CSF VDRL titer should decrease fourfold within 6 to 12 months. A significantly elevated CSF protein decreases more slowly. Failure of these indices to improve is concerning for incomplete treatment or reinfection.

CONGENITAL SYPHILIS

Ocular signs include bilateral interstitial keratitis, secondary cataracts, salt-and-pepper chorioretinitis, and chronic anterior uveitis. Hutchinson triad of congenital syphilis includes peg-shaped widely spaced incisors, interstitial keratitis, and deafness. Serologic testing is similar to acquired syphilis above. Standard treatment is with penicillin G, but dosing should be managed by a pediatrician or an infectious disease specialist.

12.13 Postoperative Endophthalmitis

ACUTE (DAY[S] AFTER SURGERY)

Symptoms

Sudden onset of decreased vision and increasing eye pain after surgical procedure.

Signs

(See Figure 12.13.1.)

FIGURE 12.13.1 Postoperative endophthalmitis with hypopyon.

Critical. Hypopyon, fibrin, severe anterior chamber reaction, vitreous cells and haze, and decreased red reflex.

Other. Eyelid edema, corneal edema, intense conjunctival injection, chemosis (all are highly variable).

Organisms

• Postcataract extraction:

 Most common: Staphylococcus epidermidis.

 Common: Staphylococcus aureus, Streptococcal species (except Pneumococcus).

 Less common: Gram-negative bacteria (species including Pseudomonas, Aerobacter, Proteus, Klebsiella, Bacillus, Enterobacter, Haemophilus influenzae, Escherichia coli) and anaerobes.

 Bleb associated: Streptococcus or Gram-negative infections.

 Postvitrectomy: S. epidermidis.

 Postintravitreal injection: S. epidermidis and oral flora (notably streptococcal species).

Differential Diagnosis

 Toxic anterior segment syndrome (TASS): Occurs 6 to 24 hours after cataract surgery. Diffuse corneal edema with KP. Due to endotoxin from surgical instruments or fluids. Usually responds to intensive topical steroid and cycloplegic therapy but may require endothelial keratoplasty or penetrating keratoplasty for persistent corneal edema.

 Acute noninfectious uveitis flare: Ask about history of previous uveitis; HLA-B27-associated anterior uveitis may be precipitated by trauma, including surgery.

 Sterile (noninfectious) endophthalmitis (e.g., following intravitreal triamcinolone acetonide or anti-VEGF injection).

 Lens-particle uveitis (retained lens fragment in the angle or vitreous or retained lens cortex in the capsular bag).

 See 12.14, Chronic Postoperative Uveitis.

Workup

1. Complete ocular history and examination. Look for wound/bleb leak, exposed suture, vitreous to wound, blepharitis, or other predisposing factors for endophthalmitis.

2. Consider B-scan US if there is limited view to the posterior segment, which may confirm marked vitritis and/or membrane formation and establishes a baseline against which the success of therapy can be measured.

3. If vision is light perception postcataract extraction, a diagnostic (and therapeutic) vitrectomy is often indicated. Cultures (blood, chocolate, Sabouraud, and thioglycolate) and smears (Gram and Giemsa stains) should be obtained and intravitreal antibiotics are given. If vision is hand motion or better, vitreous aspiration or an anterior chamber paracentesis if the vitreous specimen cannot be obtained of 0.2 mL is performed and variably sent for culture. See Appendix 13, Anterior Chamber Paracentesis.

Treatment

1. Prevention: Preparation of the conjunctiva with 5% povidone- iodine in all cases and the eyelids for incisional eye surgery prior to surgery has been proven to reduce the risk of endophthalmitis. Intraoperative (e.g., intracameral) antibiotics have also been shown to reduce endophthalmitis risk. While perioperative use of topical broad-spectrum antibiotics may decrease bacterial load, it has not been proven to lower the rates of endophthalmitis and may promote antibiotic resistance.

2. Anterior chamber or vitreous tap for Gram stain, culture, and sensitivities along with timely intravitreal injections using broadspectrum antibiotics (often vancomycin and ceftazidime, amikacin if penicillin allergic). See Appendix 11, Intravitreal Tap and Inject and Appendix 12, Intravitreal Antibiotics. Consider intravitreal steroids (e.g., dexamethasone 0.4 mg/0.1 mL) in select cases with severe vitreous inflammation.

3. Consider admission to hospital for observation.

4. Consider intensive topical steroids (e.g., prednisolone acetate 1% q1h around the clock) for control of anterior segment inflammation.

5. Consider intensive topical fortified antibiotics (e.g., vancomycin and tobramycin, q1h around the clock for 24-48 hours) in the setting of filtering blebs, wound leaks, or exposed sutures. See Appendix 9, Fortified Topical Antibiotics/Antifungals.

6. Atropine 1% b.i.d. to t.i.d.

7. For postcataract extraction endophthalmitis, immediate pars plana vitrectomy is beneficial if visual acuity on presentation is light perception. Vitrectomy for other causes of endophthalmitis (bleb-related, posttraumatic, or endogenous) may be beneficial in select cases.

8. Systemic antibiotics may be considered. Intravenous antibiotics are not routinely used. Consider i.v. fluoroquinolones (e.g., moxifloxacin) in special circumstances (e.g., bleb-related endophthalmitis or trauma). Some oral antibiotics (e.g., moxifloxacin 400 mg p.o. daily) may reach therapeutic vitreous levels and could be considered as alternatives to intravenous antibiotics.

9. Subconjunctival antibiotics (vancomycin and ceftazidime) were used in the Endophthalmitis Vitrectomy Study; however, their use has become less common.

Follow Up

1. Monitor the clinical course q12-24h early on.

2. Relief of pain is a useful early sign of response to therapy.

3. Early prednisone 60 mg p.o. daily for 5 days was part of the Endophthalmitis Vitrectomy Study protocol. However, its use depends on the causative organism, the patient’s comorbidities (e.g., diabetic), as well as the severity and duration of the disease. Once the infection is sterilized, postendophthalmitis inflammation may be significant and should be treated with aggressive topical and occasionally oral steroids.

4. After 48 hours, patients should show clinical improvement (e.g., relief of pain, decreased inflammation, and decreased hypopyon).

Consider reinjecting antibiotics if there is no improvement or if Gram stain shows an unusual organism. Consider vitrectomy if the patient is deteriorating.

5. The antibiotic regimen is refined according to the treatment response, culture results, and culture sensitivity.

6. If the patient is responding well, topical antibiotics and steroids may be slowly tapered. Close outpatient follow up is warranted.

SUBACUTE (WEEKS TO MONTHS AFTER SURGERY)

Symptoms

Variable. Insidious decreased vision, increasing redness, and pain.

Signs

Critical. Anterior chamber and vitreous inflammation, lens capsular plaque, hypopyon; clumps of fibrinous exudate in the anterior chamber, on the iris surface, or along the pupillary border; vitreous abscesses; and vitritis.

Other. Variable conjunctival injection, KP, corneal edema, and blebitis.

Organisms

 S. epidermidis or other common bacteria (e.g., streptococci with a filtering bleb).

Cutibacterium acnes (formerly Propionibacterium acnes), or other rare, indolent bacteria: Recurrent, anterior uveitis, may have a hypopyon and granulomatous KP, but with minimal conjunctival injection and pain. A white plaque or opacities on the lens capsule may be evident. Only a transient response to steroids.

 Fungi (Aspergillus, Candida, Cephalosporium, Penicillium species, and others).

Differential Diagnosis

 Lens-particle uveitis: Perform gonioscopy and dilated exam to look for retained lens fragment(s) in angle or vitreous.

 IOL-induced uveitis (iris chafing): Look for iris transillumination and IOL decentration. Most common with one-piece acrylic IOL (thick, square-edge haptics) in the sulcus and with any lens that impinges on the iris or ciliary body.

 See 12.14, Chronic Postoperative Uveitis.

Workup

1. Complete ocular history and examination.

2. Aspiration of vitreous for smears (Gram, Giemsa, and methenamine-silver) and cultures (blood, chocolate, Sabouraud, thioglycolate, and a solid medium for anaerobic culture).

See Appendix 11, Intravitreal Tap and Inject. Intravitreal antibiotics are given as described previously. See Appendix 12, Intravitreal Antibiotics.

NOTE: C. acnes will be missed unless proper anaerobic cultures are obtained and held for extended culture (14 days).

Treatment

1. Initially treat as acute postoperative endophthalmitis, as described previously, but do not start steroids.

2. Immediate pars plana vitrectomy is beneficial if visual acuity on presentation is light perception within 6 weeks after cataract surgery. Prompt vitrectomy for endophthalmitis due to other procedures has not been studied in a large randomized trial.

3. If a fungal infection is suspected, administer intravitreal amphotericin B (5 to 10 μg/0.1 mL) or intravitreal voriconazole (100 μg/0.1 mL).

4. Removal of the intraocular lens and capsular remnants may be required for diagnosis and treatment of C. acnes endophthalmitis, which may be sensitive to intravitreal penicillin, cefoxitin, clindamycin, or vancomycin.

5. If S. epidermidis is isolated, intraocular vancomycin (including irrigation of the capsular bag) alone may be sufficient.

6. Antimicrobial therapy should be modified in accordance with culture results, sensitivity testing, clinical course, and tolerance of therapeutic agents.

7. A vitrectomy with limited capsulectomy of the capsular plaque may be considered if vitreous aspiration cultures are negative or if the clinical response is incomplete. In cases with an incomplete response, removal of the entire capsule and IOL, along with intravitreal antibiotics, should be considered.

Follow Up

1. Dependent on the organism.

2. In general, follow up is as described previously for acute postoperative endophthalmitis.

12.14 Chronic Postoperative Uveitis

Routine postoperative inflammation is typically mild, responds promptly to steroids, and usually resolves within 6 weeks. Consider the following etiologies when postoperative inflammation is atypical.

Etiology

 Severe intraocular inflammation in the early postoperative course:

 Infectious endophthalmitis: Deteriorating vision, pain, fibrin, or hypopyon in the anterior chamber, vitritis. See 12.13, Postoperative Endophthalmitis.

 Retained lens material: A severe granulomatous inflammation with mutton-fat KP, resulting from an hypersensitivity reaction to lens protein exposed during surgery and may result in elevated IOP. See 9.12, Lens-Related Glaucoma.

 Aseptic (sterile) endophthalmitis: A severe noninfectious postoperative uveitis caused by intraoperative injections (e.g., triamcinolone acetonide) or excess tissue manipulation, especially of vitreous manipulation, during surgery. A hypopyon and a mild vitreous cellular reaction may develop. Usually not characterized by profound or progressive pain or visual loss. A fibrinoid reaction is typically absent. Eyelid swelling and chemosis are atypical. Conjunctival injection is often absent. Usually resolves with topical steroid therapy.

 TASS: An acute, sterile inflammation following uneventful surgery that develops rapidly within 6 to 24 hours. Characterized by anterior chamber cell and flare, possibly with fibrin or hypopyon, and severe corneal edema in excess of what would be expected following surgery. IOP may be increased. May be caused by any material placed in the eye during surgery including irrigating or injected solutions (e.g., due to the presence of a preservative or incorrect pH or concentration of a solution) or improperly cleaned instruments.

 Acute iridocyclitis flare: HLA-B27-associated and herpetic uveitis flares can be triggered by surgical trauma.

 Persistent postoperative inflammation (e.g., beyond 6 weeks):

 Poor compliance with topical steroids.

 Steroid drops tapered too rapidly.

 Retained lens material.

 Iris or vitreous incarceration in the wound.

 UGH syndrome: Irritation of the iris or ciliary body by an IOL. Increased IOP and red blood cells in the anterior chamber accompany the anterior segment inflammation. See 9.16, Postoperative Glaucoma.

 Retinal detachment: Often produces a low-grade anterior chamber reaction. See 11.3, Retinal Detachment.

 Sub-acute endophthalmitis (e.g., C. acnes and other indolent bacteria, fungal, or partially treated bacterial endophthalmitis).

 Epithelial downgrowth: Corneal or conjunctival epithelium grows into the eye through a corneal wound and may be seen on the posterior corneal surface and iris. The iris may appear flattened with loss of detail because of the spread of the membrane across the anterior chamber angle onto the iris. Large cells may be seen in the anterior chamber, and glaucoma may be present. The diagnosis of epithelial downgrowth can be confirmed by observing the immediate appearance of white spots after medium-power argon laser treatment to the areas of iris covered by the membrane. An anterior chamber tap may also reveal many epithelial cells.

 Preexisting chronic uveitis: See 12.1, Anterior Uveitis (Iritis/Iridocyclitis).

 Sympathetic ophthalmia: Diffuse granulomatous inflammation in both eyes, after penetrating trauma or surgery. See 12.18, Sympathetic Ophthalmia.

Workup and Treatment

1. History: Is the patient taking the steroid drops properly? Did the patient stop the steroid drops abruptly? Was there a postoperative wound leak allowing epithelial downgrowth? Previous history of uveitis?

2. Complete ocular examination of both eyes, including a slit lamp assessment of the anterior chamber reaction, a determination of whether vitreous or residual lens material is present in the anterior chamber, and an inspection of the lens capsule looking for capsular opacities (e.g., C. acnes capsular plaque). Perform gonioscopy (to evaluate for iris or vitreous to the wound or small retained lens fragments), an IOP measurement, vitreous evaluation for inflammatory cells, and a dilated posterior and peripheral fundus examination (to rule out retained lens material in the inferior pars plana, retinal detachment, or signs of chorioretinitis).

3. Obtain B-scan US when the fundus view is obscured. Consider UBM to assess the IOL position, for iris-IOL contact, and to evaluate for retained lens material.

4. When concerned for subacute postoperative endophthalmitis: A vitreous tap should be performed (see Appendix 11, Intravitreal Tap and Inject) with anaerobic cultures, using both solid media and broth to isolate atypical organisms such as C. acnes (routine cultures also are obtained; see 12.13, Postoperative Endophthalmitis). The anaerobic cultures should be incubated in an anaerobic environment as rapidly as possible and held for an extended incubation period (14 days).

5. Consider an anterior chamber paracentesis for diagnostic smears and cultures. See Appendix 13, Anterior Chamber Paracentesis.

6. Consider diagnostic medium-power argon laser treatment to areas of iris with suspected epithelial downgrowth.

In the setting of a capsular plaque, transient improvement in inflammation with steroids, and a negative work up, surgery may be required to diagnose and treat subacute endophthalmitis such as C. acnes. Initially, a vitrectomy with limited capsulectomy of the capsular plaque and injection of intravitreal antibiotics should be considered. Removal of the entire capsule and IOL may be required if there is an incomplete response as it usually successfully eradicates the infection.

See 12.1, Anterior Uveitis (Iritis/Iridocyclitis); 12.3, Posterior Uveitis; 12.13, Postoperative Endophthalmitis; and 12.18, Sympathetic Ophthalmia for more specific information on diagnosis and treatment.

12.15 Traumatic Endophthalmitis

This condition constitutes an emergency requiring prompt attention.

Symptoms and Signs

Similar to 12.13, Postoperative Endophthalmitis. An occult or missed IOFB must be ruled out. See 3.15, Intraocular Foreign Body.

NOTE: Patients with Bacillus endophthalmitis may have a high fever, leukocytosis, proptosis, a corneal ring ulcer, and rapid visual deterioration.

Organisms

Staphylococcus species, Streptococcus species, Gram-negative species, fungi, Bacillus species, and others. Mixed flora may be present. Understanding the mechanism of injury is helpful in predicting the type of infecting organism (e.g., penetrating trauma from organic matter increases the risk of fungal infection).

Differential Diagnosis

 Phacoanaphylactic inflammation: A sterile hypersensitivity reaction as a result of exposed lens protein associated with anterior chamber reaction, KP, and sometimes elevated IOP. See 9.12, Lens-Related Glaucoma.

 Lens cortex: Fluffed up and hydrated cortical lens material, especially in younger patients with soft nuclei after violation of the lens capsule, associated with large anterior chamber lens particles, but no KP.

 Sterile inflammatory response from a retained IOFB, blood in the vitreous, retinal detachment, or as a result of surgical manipulation.

Workup

Same as for 12.13, Postoperative Endophthalmitis, in addition to an orbital CT scan (axial, coronal, and parasagittal views) with thin 1-mm cuts and B-scan US to evaluate for IOFB.

Treatment

1. Consider hospitalization.

2. Management for a ruptured globe or penetrating ocular injury if present. See 3.14, Ruptured Globe and Penetrating Ocular Injury.

3. Removal of an intraocular foreign body in traumatic endophthalmitis is paramount in controlling the infection. See 3.15, Intraocular Foreign Body.

4. Intravitreal antibiotics (e.g., ceftazidime 2.2 mg in 0.1 mL and vancomycin 1 mg in 0.1 mL; clindamycin 1 mg in 0.1 mL or amikacin 0.4 mg in 0.1 mL may also be considered for anaerobic coverage, especially if high concern for Bacillus, intraocular foreign body, or when there is a penicillin allergy). Intravitreal aminoglycosides should be used with caution, given their potential risk of macular infarction. These medications may be repeated every 48 to 72 hours as needed. See Appendix 12, Intravitreal Antibiotics.

5. Systemic antibiotics (e.g., ciprofloxacin 400 mg i.v. q12h or moxifloxacin 400 mg p.o. or i.v. daily; and cefazolin 1 g i.v. q8h). Consider an infectious disease consult for guidance in specific cases. May need to adjust dose for renal insufficiency and for children.

6. The benefit of pars plana vitrectomy is unknown for traumatic endophthalmitis without IOFB. However, pars plana vitrectomy reduces the overall infectious and inflammatory burden and provides sufficient material for diagnostic culture and pathologic investigation.

7. Give tetanus toxoid 0.5 mL intramuscularly if immunization is not up-to-date. See Appendix 2, Tetanus Prophylaxis.

8. Steroids are typically not used until fungal organisms are ruled out, although recent reports have demonstrated that topical steroids may not be as deleterious as previously thought. Topical and oral steroids may be used at the discretion of the physician to control postinfection inflammation once the infection is sterilized.

Follow Up

Same as for 12.13, Postoperative Endophthalmitis.

12.16 Endogenous Bacterial Endophthalmitis

Symptoms

Decreased vision in an acutely ill (e.g., septic) or recently hospitalized patient, the immunocompromised, a patient with an indwelling catheter, an intravenous drug user, or in a patient with a history of a recent systemic procedure (e.g., heart valve replacement or repair). No history of recent intraocular surgery.

Signs

Critical. Chorioretinitis, vitreous cells and debris, anterior chamber cell and flare, and/or a hypopyon.

Other. Iris microabscesses, absent red reflex, retinal inflammatory infiltrates, flame-shaped retinal hemorrhages with or without white centers, retinal/subretinal/choroidal abscesses, corneal edema, eyelid edema, chemosis, conjunctival injection, and panophthalmitis with orbital involvement (proptosis, restricted ocular motility). May be bilateral.

Organisms

Bacillus cereus (especially in i.v. drug users), streptococci, Neisseria meningitidis, S. aureus, H. influenzae, Klebsiella in East Asia, and others.

Differential Diagnosis

• Endogenous fungal endophthalmitis: May see fluffy, white vitreous opacities. Organisms include Aspergillus and Candida. See 12.17, Candida Retinitis/Uveitis/Endophthalmitis.

• Viral retinitis: one or more foci of retinal whitening with variable levels of vitreous inflammation. See 12.8 Acute Retinal Necrosis.

 Retinochoroidal infection (e.g., toxoplasmosis and toxocariasis): Yellow or white retinochoroidal lesions.

 Noninfectious posterior or intermediate uveitis (e.g., sarcoidosis and pars planitis). Unlikely to get the first episode coincidentally during sepsis.

 Neoplastic conditions (e.g., large cell lymphoma and retinoblastoma).

Workup

1. History: Duration of symptoms? Systemic symptoms of underlying disease or infection? Indwelling catheter? Intravenous drug use? Immunocompromised? Recent medical procedures?

2. Complete ocular examination, including a dilated fundus evaluation.

3. B-scan US if there is no view to the fundus to assess for vitritis, abscesses.

4. Complete medical workup by an infectious disease specialist.

5. Chest X-ray; cultures of blood, urine, all indwelling catheters, and i.v. lines; Gram stain of any discharge. Consider a transesophageal or transthoracic echocardiogram to rule out endocarditis. A lumbar puncture is indicated when meningeal signs are present.

Treatment

All treatment should be coordinated with an internal medicine physician.

1. Hospitalize the patient.

2. Broad-spectrum (i.v. and/or oral) antibiotics are started after appropriate smears and cultures are obtained. Antibiotic choices vary according to the suspected source of septic infection (e.g., gastrointestinal tract, genitourinary tract, and cardiac) and are determined in consultation with an infectious disease specialist. Dosages recommended for meningitis and severe infections are used. If oral antibiotics are used, confirm that the regimen includes antibiotics with good vitreous penetration.

NOTE: Intravenous drug users are given an aminoglycoside and clindamycin to eradicate Bacillus cereus.

3. Topical cycloplegic (e.g., atropine 1% b.i.d. to t.i.d.).

4. Topical steroid (e.g., prednisolone acetate 1% q1-6h titrated to the degree of anterior segment inflammation).

5. Consider intravitreal antibiotics if there is significant or worsening vitreous involvement (e.g., ceftazidime 2.2 mg in 0.1 mL and vancomycin 1 mg in 0.1 mL; clindamycin 1 mg in 0.1 mL, or amikacin 0.4 mg in 0.1 mL may also be considered for anaerobic coverage, especially if there is high concern for Bacillus, intraocular foreign body, or when there is a penicillin allergy). Intravitreal aminoglycosides, including amikacin, may cause macular infarction. The timing of intravitreal antibiotics is controversial although they offer higher intraocular concentrations. Consider intravitreal antifungal agents, if clinically suspicious. See Appendix 11, Intravitreal Tap and Inject, and Appendix 12, Intravitreal Antibiotics.

6. Consider pars plana vitrectomy if severe or nonresponsive to initial therapy. Vitrectomy offers the benefits of reducing infective and inflammatory load and providing sufficient material for diagnostic culture and pathologic study. Additionally, intravitreal antibiotics may be administered at the time of surgery.

7. Periocular antibiotics (e.g., subconjunctival or subtenon injections) are sometimes used. See Appendix 10, Technique for Retrobulbar/Subtenon/Subconjunctival Injections.

Follow Up

1. Daily in the hospital.

2. Peak and trough levels for many antibiotic agents are obtained every few days. Renal function needs monitoring during aminoglycoside therapy. The antibiotic regimen is guided by the culture and sensitivity results, as well as the patient’s clinical response to treatment. Intravenous antibiotics are maintained for at least 2 weeks (pending identification of clinical source and response to treatment).

12.17 Candida Retinitis/Endophthalmitis

Symptoms

Decreased vision, floaters, and pain that is often bilateral. Patients typically have a history of recent hospitalization, recent abdominal surgery, being immunocompromised, possessing a long-term indwelling line or catheter (e.g., for hyperalimentation, hemodialysis, or antibiotics), or using intravenous drugs.

Signs

(See Figure 12.17.1.)

FIGURE 12.17.1 Candida chorioretinitis with vitreous involvement.

Critical. Discrete, multifocal, yellow-white, choroidal to chorioretinal fluffy lesions from one to several disc diameters in size. With time, the lesions increase in size, break into the vitreous, and appear as “cotton balls” or a “string of pearls".

Other. Vitreous cell and haze, vitreous abscesses, retinal hemorrhages with or without pale centers, anterior chamber cells, and hypopyon. A retinal detachment may develop.

Differential Diagnosis

The following should be considered in immunocompromised patients.

 CMV retinitis: Multifocal areas of granular retinal whitening with a minimal to mild vitreous reaction, more likely to be associated with retinal hemorrhage. See 12.9, Cytomegalovirus Retinitis.

 Toxoplasmosis: Yellow-white retinal lesions often with an adjacent chorioretinal scar. See 12.5, Toxoplasmosis.

 Pneumocystis choroidopathy: Rare manifestation of widely disseminated Pneumocystis carinii infection. Usually in AIDS patients. Often asymptomatic. History of P. carinii and treatment with aerosolized pentamidine. Multifocal, yellow, round, deep choroidal lesions approximately one-half to two-disc diameters in size, located in the posterior pole. No vitritis. Patients are often cachectic. Treatment is with i.v. trimethoprim/sulfamethoxazole or i.v. pentamidine in conjunction with an infectious disease specialist.

 Others: Herpes viral retinitis; Nocardia, Aspergillus, and Cryptococcus species; Atypical Mycobacterium, coccidioidomycosis, and others.

Workup

1. History: History of bacteremia or fungemia? Underlying medical conditions? Medications? Indwelling catheter? Intravenous drug use? Other risk factors for immunocompromised state?

2. Skin examination for signs of intravenous drug injection.

3. Most clinicians recommend that all patients with candidemia have a complete, dilated fundoscopic examination (ideally within 72 hours), as ocular involvement may be asymptomatic. A repeat fundoscopic examination is recommended 2 weeks after the initial negative examination.

4. Blood, urine, and catheter tip fungal cultures; these often need to be repeated several times and may be negative despite ocular candidiasis. Blood cultures may need to be held a full 7 days and may take 3 to 4 days to become positive for Candida species.

5. Consider vitrectomy to obtain a specimen and remove opacified vitreous. Cultures and smears can confirm the diagnosis. Amphotericin B 5 to 10 pg in 0.1 mL or voriconazole 50 to 100 pg in 0.1 mL is injected into the vitreous cavity after the procedure.

6. Baseline CBC, renal function tests, and liver function tests.

Treatment

1. Suspected fungal endophthalmitis without a clear source should be considered evidence of a disseminated infection and requires further systemic evaluation and workup.

2. Hospitalize all unreliable patients, systemically ill patients, or those with moderate to severe vitreous involvement.

3. An infectious disease specialist should be consulted for systemic workup to evaluate for a source and other sites of involvement.

4. Typically, chorioretinitis without vitreous involvement can be successfully treated with systemic therapy alone with one of the following regimens: Fluconazole 800 mg p.o. loading dose followed by 400 to 800 mg p.o. daily. Alternatively, voriconazole 400 mg i.v. b.i.d. daily for 2 doses followed by 300 mg i.v. or p.o. b.i.d. may also be considered in fluconazole-resistant species. For fluconazole- and voriconazole-resistant species, liposomal amphotericin B (3 to 5 mg/kg i.v. daily) is recommended. Therapy should be guided by cultures and sensitivities. Other agents that may be used include caspofungin, itraconazole, and micafungin.

5. Intravitreal injection of antifungal agents as above (voriconazole or amphotericin B) if there is vitreous involvement. Depending on the response and location of retinal involvement (anterior versus posterior), injections may be repeated.

6. Topical cycloplegic agent (e.g., atropine 1% b.i.d. to t.i.d.).

7. See 9.7, Inflammatory Open Angle Glaucoma, for IOP control.

Follow Up

1. Patients are seen daily early on. Visual acuity, IOP, and the degree of anterior chamber and vitreous inflammation are assessed.

2. Patients receiving azole antifungals require liver function tests every 1 to 2 weeks and as clinically indicated. Patients receiving amphotericin require monitoring of electrolytes, kidney function, and CBC as directed by an infectious disease specialist.

12.18 Sympathetic Ophthalmia

Symptoms

Bilateral eye pain, photophobia, decreased vision, and red eyes. A history of penetrating trauma or intraocular surgery (most commonly vitreoretinal surgery) to one eye (usually 4 to 8 weeks before, but ranges from days to decades, with 90% occurring within 1 year). Sympathetic ophthalmia is rare (the literature estimates an annual incidence of 0.03/100,000 people).

Signs

Critical. Suspect anytime there is inflammation in the uninvolved eye after unilateral ocular trauma or surgery. Bilateral severe anterior chamber reaction with large mutton-fat KP; may have asymmetric involvement with typically more reaction in uninjured eye. Posterior segment findings include small depigmented nodules at the level of the retinal pigment epithelium (corresponding to Dalen-Fuchs nodules histopathologically) and diffuse thickening of the choroid. Signs of previous injury or surgery in one eye are usually present. In developed countries, repeated vitreoretinal procedures following ocular trauma are the most common risk factors.

Other. Nodular infiltration of the iris, peripheral anterior synechiae, neovascularization of the iris, occlusion, and seclusion of the pupil, cataract, exudative retinal detachment, and papillitis. The earliest sign may be loss of accommodation, or a mild anterior or posterior uveitis in the uninjured eye.

Differential Diagnosis

 VKH syndrome: Similar signs, but no history of ocular trauma or surgery. Other systemic symptoms. See 12.11, Vogt-Koyanagi-Harada Syndrome.

 Phacoantigenic (formerly phacoanaphylaxis) endophthalmitis: Severe anterior chamber reaction from injury to the lens capsule. The contralateral eye is uninvolved. See 9.12, Lens-Related Glaucoma.

 Sarcoidosis: Often associated systemic symptoms involving the lungs or skin, elevated ACE level, or characteristic pulmonary changes on chest CT. May cause a bilateral granulomatous panuveitis. See 12.6, Sarcoidosis.

 Syphilis: Positive treponemal and reflex nontreponemal testing. May cause bilateral granulomatous panuveitis. See 12.12, Syphilis.

 Tuberculosis: Positive PPD or IGRA with possible characteristic findings on CXR or chest CT. May cause bilateral granulomatous panuveitis.

 Multifocal choroiditis with panuveitis: Usually bilateral, with no history of trauma.

Workup

1. History: Any prior eye surgery or injury? History of sexually transmitted disease or high-risk sexual activity? Difficulty breathing?

2. Complete ophthalmic examination, including a dilated retinal examination.

3. Assess for any systemic findings to rule out VKH (e.g., neurologic, skin, or auditory changes).

4. CBC, EIA, or another treponemal testing followed by reflex, nontreponemal testing if positive.

5. Chest radiograph and/or CT chest to evaluate for tuberculosis and sarcoidosis.

6. IVFA or B-scan ultrasound, or both, to help confirm the diagnosis.

Treatment

1. Prevention: Historically enucleation of a blind, traumatized eye within 14 days of the trauma has been recommended to reduce the risk of sympathetic ophthalmia. However, this has limited support in the literature and should only be performed if the eye has been deemed unsalvageable. Once sympathetic ophthalmia develops, enucleation of the sympathizing eye appears to have no benefit.

2. Initial treatment with high dose oral steroids (e.g. prednisone 1 mg/kg p.o. daily) with calcium/vitamin D supplementation and gastric ulcer prophylaxis may be used initially to control ocular inflammation.

3. However long-term local or systemic immunosuppression is essential in most cases. Local control can be achieved with intravitreal steroid implants (e.g., dexamethasone 0.7 mg intravitreal implant or the fluocinolone acetonide 0.19 or 0.59 mg intravitreal implants). Inflammatory control can also be achieved with steroid-sparing systemic immunosuppression. The choice of specific local or systemic immune suppression should be made in conjunction with a uveitis specialist and individualized for each patient.

4. Cycloplegic (e.g., cyclopentolate 1% b.i.d.) for active anterior chamber inflammation.

5. Topical steroids for active anterior chamber inflammation (e.g., prednisolone acetate 1% q1-2h or difluprednate 0.05% q2h), which are tapered slowly as the inflammation improves.

6. Periocular or intravitreal steroids (e.g., subconjunctival triamcinolone acetate 40 mg in 1 mL) may be used to aid in local control prior to pursuing long-term options. See Appendix 10, Technique for Retrobulbar/Subtenon/Subconjunctival Injections.

Follow Up

1. Every 1 to 7 days initially, to monitor the effectiveness of therapy and IOP.

2. As the condition improves, the follow-up interval may be extended to every 3 to 4 weeks.

3. Oral steroids may be used initially to quell inflammation with rapid, sequential initiation of long-term local or steroid-sparing systemic immunosuppression to allow for tapering of oral steroids. The goal should be to slowly taper oral prednisone to 5 mg or less by 3 months to avoid the adverse effects of systemic steroids. Because of the possibility of recurrence, periodic checkups are important.

4. The long-term prognosis in patients treated with immunosuppressive therapy can be good, with 81% of eyes seeing ≥20/40 at the final follow up.