Uveitis – 10 Interesting Facts

What is Uveitis

Uveitis is swelling and irritation in the eye. Most of the time, it affects the middle part of the eye (uvea).

Interesting Facts

  1. Uveitis is sight-threatening inflammation of the uveal tract of the eye. Anterior uveitis typically presents as a painful, red eye with photophobia and distorted vision; eye pain and photophobia are less prominent in more posterior forms of uveitis
  2. Prompt slit lamp examination by an ophthalmologist is imperative for definitive diagnosis
  3. Further assessment, including focused laboratory testing, is required to diagnose associated systemic conditions, both noninfectious (eg, juvenile idiopathic arthritis, spondyloarthropathies, sarcoidosis) and infectious (eg, tuberculosis, syphilis, Lyme disease)
  4. Reactivation of dormant HSV and varicella-zoster virus infection may cause uveitis and may present with acute retinal necrosis and rapid vision loss
  5. Therapy usually initiated with topical corticosteroids, especially for anterior uveitis; more posterior uveitis is more likely to require corticosteroid implants, local injections, or systemic therapy for control
  6. Treat patients with anterior uveitis using a mydriatic or cycloplegic drug to dilate the pupil, reduce pain, and prevent posterior synechiae
  7. Treat uveitis due to HSV, varicella-zoster virus, or cytomegalovirus with antiviral agents
  8. Immunomodulatory agents, such as methotrexate, cyclosporine, and cyclophosphamide, are added for noninfectious causes of uveitis when there is inadequate response to corticosteroids, and may be used in combination
  9. Goal is to place the patient into a durable, steroid-free remission with the eventual discontinuation of all immunomodulatory medication, without relapse of ocular inflammation for at least 5 years
  10. Patients require close monitoring during treatment for development of uveitis complications (eg, angle-closure glaucoma due to synechiae; cystoid macular edema) as well as complications related to treatment (eg, steroid-induced cataract; elevation of intraocular pressure)

There are many types of uveitis:

  • Iritis. This type affects the colored part of the eye.
  • Intermediate uveitis. This type affects the middle of the eye.
  • Posterior uveitis. This type affects the back of the eye.
  • Panuveitis. This type affects all layers of the eye.

Uveitis can affect one eye or both eyes. Over time, the condition may lead to vision loss.

Pitfalls

  • Acute angle-closure glaucoma can present looking much like uveitis; in these cases, the application of mydriatics or cycloplegics could be detrimental
  • Do not use periocular corticosteroid injections in the case of infectious uveitis, especially with toxoplasmosis
  • Avoid periocular corticosteroids in the setting of necrotizing scleritis (inflammation of tissue plane just exterior to choroid) or in patients who have experienced corticosteroid-related elevation in intraocular pressure

Urgent Action

  • Urgent referral to an ophthalmologist if uveitis is suspected based on history and examination

Terminology

Clinical Clarification

  • Uveitis is inflammation of the uveal tract of the eye (ie, choroid, ciliary body, iris) 1
  • Anterior uveitis is the most prevalent form, followed by panuveitis, posterior uveitis, and intermediate uveitis, respectively

Classification

  • Standardization of Uveitis Nomenclature Working Group classification 2
    • Based on anatomic location
      • Anterior (most common)
        • Affects anterior chamber
        • Includes iritis, iridocyclitis, and anterior cyclitis
      • Panuveitis
        • Affects anterior chamber, vitreous body, and retina or choroid
      • Posterior
        • Affects retina, choroid, or both
        • Includes focal, multifocal, or diffuse choroiditis, chorioretinitis, retinitis, and neuroretinitis
      • Intermediate
        • Affects vitreous body
        • Includes pars planitis, posterior cyclitis, and hyalitis
  • Descriptors of uveitis
    • Onset 2
      • Sudden
      • Insidious
    • Duration 2
      • Limited: 3 months’ duration or shorter
      • Persistent: longer than 3 months’ duration
    • Course 2
      • Acute: sudden onset of episode with limited duration
      • Recurrent: episodes are repeated and separated by periods of inactivity without therapy for 3 months’ duration or longer
      • Chronic: persistent; relapse occurs less than 3 months following therapy discontinuation
    • Laterality 3
      • Unilateral
      • Unilateral alternating
      • Bilateral simultaneous
      • Bilateral asynchronous

Diagnosis

Clinical Presentation

History

  • Symptoms vary by type of uveitis, anatomic location, extent of therapy, disease duration, and presence or absence of previous sequelae
  • Commonly encountered symptoms include the following:
    • Acute anterior uveitis
      • Eye pain
      • Marked photophobia
      • Blurred vision
      • Red eye
    • Chronic anterior uveitis
      • Usually presents only with blurred vision and red eye
    • Intermediate or posterior uveitis
      • Distorted or blurred vision
      • Floaters
      • Blind spots
      • Photopsia (flashing lights)
      • Red eye
      • Eye pain and photophobia are uncommon
  • Historical features of an associated inflammatory or infectious process may be present
    • Juvenile idiopathic arthritis (also known as juvenile rheumatoid arthritis)
      • Joint pain and swelling
      • Joint stiffness in the morning
    • Spondyloarthropathy
      • Pain and stiffness in lower back or buttocks
      • Stiffness of the chest and neck
      • Fever
      • Fatigue
    • Sarcoidosis
      • Swollen lymph nodes
      • Weight loss
      • Persistent cough
    • Multiple sclerosis
      • Diplopia
      • Paresthesias
      • Lower extremity weakness that causes difficulty with ambulation
      • Fatigue
      • Lack of coordination
    • Syphilis
      • Genital lesions
      • Rash or mucocutaneous lesions
      • Swollen lymph nodes
      • Weight loss
    • Lyme disease
      • History of erythema migrans following possible tick bite
      • Swollen lymph nodes
      • Muscle and joint aches
      • Fever
      • Chills
    • Toxoplasmosis
      • Flulike symptoms (eg, myalgia, headache, malaise, fatigue)
    • Cytomegalovirus
      • Flulike symptoms (eg, myalgia, headache, malaise, fatigue)
    • Varicella-zoster virus or HSV infection
      • History of chickenpox, genital HSV infection, or oral HSV infection (uveitis is usually caused by reactivation of dormant infection)
    • Tuberculosis
      • Weight loss
      • Fatigue
      • Anorexia
      • Productive cough
      • Night sweats

Physical examination

  • Ophthalmologic examination (not performed by ophthalmologist)
    • Visual acuity may be decreased
    • Findings on direct visualization of the eye include the following:
      • Small or constricted pupil
      • Pupils may react poorly when iris is adherent to anterior lens capsule
      • Difficulty visualizing iris owing to corneal edema or suspension of cells and protein in aqueous humor
      • Ciliary flush (perilimbal redness)
      • Corneal or scleral thinning (allows underlying pigment to show)
      • Hypopyon (WBCs that have settled to the bottom of the anterior chamber)
      • In children with juvenile idiopathic arthritis and anterior uveitis, the eye tends to be quieter with no or little evidence of inflammation on the ocular surface
    • Measure intraocular pressure (or defer to ophthalmologist)
      • Intraocular pressure typically decreases with uncomplicated uveitis
      • Posterior synechiae, inflammation and swelling of the trabecular meshwork, or physical obstruction of the trabecular meshwork by inflammatory cells may result in acute uveitis–induced glaucoma
  • Slit lamp examination, performed by an ophthalmologist, confirms the presence of inflammatory cells in the aqueous or vitreous body
    • Location of inflammation provides the primary diagnosis of anterior, intermediate, posterior, or panuveitis
    • Additionally, slit lamp examination determines:
      • Clarity of cornea
      • Presence of keratic precipitates (inflammatory deposits on posterior cornea)
      • Presence of posterior synechiae
      • Depth of anterior chamber
      • Number of cells in the anterior chamber and grade of anterior chamber flare
        • Standardization of Uveitis Nomenclature Working Group grading of anterior chamber cells per field (1 mm by 1 mm slit beam) 2
          • Grade 0: fewer than 1 cell per field
          • Grade 0.5+: 1 to 5 cells per field
          • Grade 1: 6 to 15 cells per field
          • Grade 2: 16 to 25 cells per field
          • Grade 3: 26 to 50 cells per field
          • Grade 4: more than 50 cells per field
        • Standardization of Uveitis Nomenclature Working Group grading of anterior chamber flare 2
          • Grade 0: no flare
          • Grade 1+: faint flare
          • Grade 2+: moderate flare (iris and lens detail clear)
          • Grade 3+: marked flare (iris and lens details hazy)
          • Grade 4+: intense flare
      • Number of cells in the vitreous body and grade of vitreous flare
        • Standardization of Uveitis Nomenclature Working Group grading of vitreous cells 2
          • Grade 0: no cells
          • Grade 0.5+: 1 to 10 cells
          • Grade 1+: 11 to 20 cells
          • Grade 2+: 21 to 30 cells
          • Grade 3+: 31 to 100 cells
          • Grade 4+: more than 100 cells
        • Standardization of Uveitis Nomenclature Working Group grading of vitreous flare 2
          • Grade 0: no inflammation present
          • Grade 0.5+: trace inflammation present
          • Grade 1+: mild blurring of the optic nerve and retinal vessels
          • Grade 2+: optic nerve visible, borders blurred markedly
          • Grade 3+: optic nerve head not visible
      • Presence of any other abnormalities
  • Physical features of an associated inflammatory or infectious process may be present
    • Juvenile idiopathic arthritis
      • Joint swelling, most commonly 4 or fewer joints, most often the knees or ankles
      • Refusal to walk, guarding or protecting a joint
    • Spondyloarthropathy
      • Stiffness and reduced range of motion that involves any portion of the vertebral column
      • Sacroiliac joint is most often involved; may also affect shoulders and legs
    • Sarcoidosis
      • Facial sarcoid dermatitis (common)
      • Lymphadenopathy
      • Erythema nodosum involving shins
    • Multiple sclerosis
      • Ataxia
      • Hyperreflexia and spasticity
      • Hemiparesis, paraparesis, or, rarely, monoparesis or quadriparesis
      • Sensory deficit that does not conform to single neural or dermatomal distribution
    • Syphilis
      • Primary syphilis: genital chancres
      • Secondary syphilis: rash on palms or soles; condyloma latum in axillae, mouth, or groin
    • Tuberculosis
      • Abnormalities on lung examination may include rales, rhonchi, and bronchial breath sounds
    • Lyme disease
      • Erythema migrans at site of possible or probable tick bite
        • Appears 3 to 30 days after tick bite, expands to 30 cm diameter or more 4
      • Joint swelling or tenderness
      • Facial or Bell palsy
    • Toxoplasmosis
      • Lymphadenopathy may be only finding in immunocompetent patient
      • Immunocompromised patients have additional findings
        • Signs of focal central nervous system involvement or encephalitis
        • Signs of other organ involvement (eg, signs of pneumonitis or myocarditis; hepatomegaly)
    • Cytomegalovirus
      • Fever, lymphadenopathy, and exudative pharyngitis in immunocompetent patients
        • In immunocompromised patients, additional signs include altered mental status, oral ulcerations, rash, signs of pulmonary or hepatic involvement, and muscle weakness

Causes and Risk Factors

Causes

  • Anterior uveitis
    • Associated with comorbid systemic disease
      • Juvenile idiopathic arthritis–associated uveitis (12%-30% of these patients develop uveitis; 90% within 4 years of diagnosis) 5
      • Ankylosing spondylitis with HLA-B27–associated uveitis
      • Psoriatic arthritis
      • Relapsing polychondritis
      • Rheumatoid arthritis
      • Behçet disease (systemic vasculitis with oral, genital, and/or gastrointestinal ulcers, arthritis, and erythema nodosum with uveitis)
      • Reactive arthritis
      • Inflammatory bowel disease
      • Multiple sclerosis
      • Sarcoidosis
      • Systemic lupus erythematosus
    • Associated with local ocular disease
      • Posttraumatic uveitis
      • Fuchs heterochromic iridocyclitis
    • Infectious
      • Cytomegalovirus
      • HSV
      • Varicella-zoster virus
      • Syphilis
      • Tuberculosis
      • Lyme disease
    • Idiopathic
  • Intermediate uveitis
    • Associated with comorbid systemic disease
      • Multiple sclerosis
      • Sarcoidosis
      • Behçet disease
      • Systemic lupus erythematosus
    • Associated with local ocular disease
      • Primary ocular lymphoma
    • Infectious
      • Syphilis
      • Lyme disease
    • Idiopathic
  • Posterior uveitis
    • Infectious (most common)
      • Toxoplasmosis
      • Cytomegalovirus retinitis
      • Lymphoreticulosis (also called cat scratch disease)
      • Syphilis
      • Tuberculosis
      • Lyme disease
    • Associated with comorbid systemic disease
      • Systemic lupus erythematosus
      • Sarcoidosis
      • Behçet disease
    • Associated with local ocular disease
      • Primary ocular lymphoma
      • Inflammatory chorioretinopathy of unknown origin (also called white dot syndrome)
  • Panuveitis
    • Infectious
      • Syphilis
      • Acute retinal necrosis as a result of HSV reactivation
      • Tuberculosis
    • Associated with comorbid systemic disease
      • Behçet disease
    • Associated with local ocular disease
      • Sympathetic ophthalmia (bilateral diffuse granulomatous uveitis affecting both eyes after trauma occurs in 1 eye)

Risk factors and/or associations

Age
  • Peak incidence is between ages 20 and 59 years 6
  • Children account for 5% to 15% of cases 5
    • Pediatric uveitis is more common in anterior location than in posterior location 7
Genetics 3
  • Anterior uveitis occurring in patients with spondyloarthropathy is commonly associated with the HLA-B27 gene
  • A minority of patients with HLA-B27–associated anterior uveitis do not have an associated spondyloarthropathy
Other risk factors/associations
  • History of smoking is associated with all subtypes of uveitis
  • Medications associated with uveitis (1% of uveitis cases associated with drug or vaccine toxicity) 1 8
    • Anterior
      • Cidofovir, intravenous: 17% to 89% risk of uveitis 6
      • Cidofovir, intravitreal: 26% to 52% risk 6
      • Prostaglandin analogues, topical: 0.9% to 4.9% risk 6
      • Bisphosphonates: less than 1% risk 6
      • Moxifloxacin, oral: rare
      • Sulfonamides: rare
    • Intermediate
      • Anti–vascular endothelial growth factor: 1% to 5% of treated eyes 6
    • Any location
      • Rifabutin: 14% to 64% risk 6
      • Bacille Calmette-Guérin: rare

Diagnostic Procedures

Primary diagnostic tools

  • If uveitis is suspected with history and physical examination findings, promptly refer to ophthalmologist to confirm diagnosis 3
  • Identify underlying infectious or inflammatory disorder using focused strategy 3
    • Suggestive medical and ophthalmic history and physical examination findings may give clues to a specific underlying cause; recognition of these patterns can be used to direct further diagnostic work-up 3
      • Juvenile idiopathic arthritis: unilateral, chronic, anterior uveitis
      • Spondyloarthropathy-associated: unilateral or unilateral alternating, recurrent, anterior uveitis
      • Sarcoidosis-associated: bilateral or unilateral, chronic, uveitis of any location
    • Obtain focused laboratory and imaging tests to determine underlying infection or inflammatory disorder 3
      • Test adolescents and adults with confirmed anterior uveitis for HLA-B27 status 6
      • Test adolescents and adults for evidence of syphilis and, where exposure is likely, Lyme disease 3
      • Test patients who are immunosuppressed, who have recent exposure to or high-risk (based on country of origin) of tuberculosis, and/or who have slit lamp choroidal appearance suggestive of tuberculosis 3
      • Evaluate patients with any organ abnormality suggestive of sarcoidosis (eg, lungs, skin, liver, lymph nodes) by chest radiography and by hepatic enzyme testing; refer for biopsy if findings are positive 3
    • In patients with uveitis and known juvenile idiopathic arthritis, obtain antinuclear antibody testing; a positive test result predicts risk for chronic anterior uveitis 3
  • Slit lamp examination and indirect ophthalmoscopy by an ophthalmologist can confirm the diagnosis 1
    • Additional diagnostic testing performed by an ophthalmologist includes 2:
      • Fluid sampling or biopsy for microscopy, cytology, culture, or polymerase chain reaction to identify infectious or neoplastic causes of uveitis
      • Fluorescein or indocyanine green angiography is typically performed in cases of intermediate and posterior uveitis to evaluate compromise in retinal vascular circulation, and identify choroidal disease 3

Laboratory

  • HLA-B27 testing 3
    • Obtain in all patients with acute anterior uveitis (particularly if recurrent)
    • High correlation of HLA-B27 positivity with spondyloarthropathy
  • Syphilis test 3
    • Use specific test (eg, treponemal pallidum particle agglutination, fluorescent treponemal absorption)
    • Nonspecific test results (usually used to screen; eg, VDRL test, rapid plasma reagin) are negative in one-third of syphilitic uveitis cases
  • Lyme disease testing 3
    • Test if patient resides in or has visited an area where Lyme disease is endemic
    • Screen for antibodies (eg, ELISA for IgM or IgG)
    • If assay result is positive, confirm with Western blot test
  • Tuberculosis testing 3
    • Indicated in patients who are from an endemic area, who are immunosuppressed, or who have a clinical finding that suggests tuberculosis (eg, serpiginouslike tuberculous choroiditis)
    • Methods include interferon-γ release assay and PPD tuberculin skin test
  • Liver function testing 3
    • Indicated in all patients with suggestive history and physical examination to screen for hepatic involvement of sarcoidosis
    • Obtain ALT and AST
  • Antinuclear antibody testing 3
    • Determine presence of antinuclear antibodies by immunofluorescent staining or serologic testing for antibody titers
    • Positive antinuclear antibody result often occurs in children with juvenile idiopathic arthritis; these patients are also at high risk for anterior uveitis

Imaging

  • Chest radiograph 3
    • Indicated for all patients with suggestive history and physical examination to screen for sarcoidosis, which has lung involvement in 90% of cases 3
    • Typical findings in patients with sarcoidosis include bilateral hilar adenopathy and interstitial disease

Differential Diagnosis

Most common

  • Acute angle-closure glaucoma
    • Presents with photophobia and acute onset of painful red eye
    • Severely decreased visual acuity
    • Pupil is usually fixed and mid-dilated
    • Intraocular pressure is 40 mm Hg or above (not elevated in uncomplicated uveitis) 9
    • Slit lamp examination will usually reveal the absence of inflammation
    • Acute angle-closure glaucoma can present looking much like uveitis; in these cases, the application of mydriatics or cycloplegics could be detrimental
  • Acute conjunctivitis
    • Conjunctival inflammation, typically presents with a mildly uncomfortable red eye
    • Itching and burning with a foreign-body sensation
    • Pus is present to varying degrees, mainly in bacterial conjunctivitis
    • Redness typically caused by conjunctival injection; no ciliary flush
    • Slit lamp examination will reveal the absence of inflammation beyond that seen in the conjunctivae
  • Corneal abrasion
    • Epithelial layer of the cornea is lost owing to contact with a foreign object
    • Sudden onset of pain or foreign body sensation, photophobia, reflex lacrimation, and visual impairment
    • History of trauma or foreign body
    • Examination reveals conjunctival injection, lid edema, and haziness of the cornea
    • Diagnosis confirmed by corneal epithelial defect on fluorescein staining, or foreign body that is on the corneal surface, embedded in the cornea, or on inner side of upper lid
  • Corneal ulceration
    • Inflammatory or infectious disruption of the epithelial layer of the cornea
    • Can be caused by infection, trauma, or systemic disease
    • Presents with acute pain, foreign body sensation, redness, photophobia, and blepharospasm
    • Visual impairment may be present if ulcer is central or large
    • Examination reveals eyelid swelling, hyperemia predominant in limbal region, and clouding of cornea
    • Diagnosis is confirmed by corneal defect with clear borders and gray ulcer base on fluorescein staining and slit lamp examination
    • Urgent ophthalmology referral is indicated
  • Intraocular foreign body
    • History of a foreign object entering eye
    • Pain and visual loss may be absent
    • Small entry wound may be seen
    • Object identified on slit lamp examination of dilated eye
    • Perform gonioscopy if there is concern for a foreign body in the angle

Treatment

Goals

  • Preserve visual acuity
  • Manage both ocular and systemic disease
  • Aim to place the patient into a durable, steroid-free remission with eventual discontinuation of all immunomodulatory medication, without relapse of ocular inflammation for at least 5 years 2

Disposition

Recommendations for specialist referral

  • Immediately refer all patients with suspected or known uveitis to an ophthalmologist
    • Differential diagnoses include several entities that could be exacerbated if corticosteroids, mydriatics, or cycloplegics are administered
  • Ophthalmologist should consult or refer to a rheumatologist or hematologist when the management of uveitis requires immunomodulatory therapies and provider experience/training in the use of these drugs is lacking
  • Ophthalmologist should consult an infectious disease specialist for diagnostic and/or therapeutic advice when ophthalmologic features are atypical or disease is rapidly progressive

Treatment Options

Use stepladder approach for therapy 2

  • Begin with the lowest effective, but appropriately aggressive, therapy for the specific disease presentation
  • Advance up the ladder, using more aggressive treatments if needed, owing to intolerance or lack of effectiveness. Early recognition of an ineffective therapy is important
  • Medical management represents the lower rungs of the ladder and therapeutic vitrectomy tops the ladder, reserved only for vitritis or cystoid macular edema that is unresponsive to medical management
    • Initially, give corticosteroids
      • Exact preparation used is determined by the location of inflammation (eg, topical corticosteroid drops for anterior uveitis, periocular injection for posterior uveitis)
      • Give mydriatics or cycloplegics concurrently with corticosteroids for symptom relief of anterior uveitis
    • Next, administer immunomodulatory agents for patients with sight-threatening uveitis or those intolerant of or resistant to corticosteroids
    • Finally, surgical management is indicated for visually significant vitritis or the complication of cystoid macular edema that is resistant to medical therapy
    • For infectious uveitis, specific therapies may include:
      • Antiviral therapy for uveitis caused by HSV, varicella-zoster virus, or cytomegalovirus
        • Acute anterior uveitis caused by HSV is treated with oral acyclovir; continued prophylactic therapy after initial treatment may be beneficial 10
        • Treat uveitis caused by HSV-related or varicella-zoster–related acute retinal necrosis with high-dose IV acyclovir followed by 6 or more weeks of oral antiviral therapy 11
        • Treat uveitis caused by acute retinal necrosis in an immunocompromised patient with IV ganciclovir instead of acyclovir, until cytomegalovirus infection is ruled out 11
      • Select treatment for uveitis caused by toxoplasmosis in consultation with an infectious disease specialist
      • Base therapies for other specific pathogens on the identified pathogen; consultation with an infectious diseases specialist may be helpful

Corticosteroids 2

  • Initial therapy in stepladder approach to treatment
  • Topical steroids are preferred to manage anterior uveitis, and may be helpful in managing mild to intermediate uveitis
    • Initial treatment using a high dose of topical corticosteroids is recommended, then taper as inflammation subsides
    • The more potent the topical corticosteroid, the greater the risk of steroid-induced glaucoma
  • All forms of corticosteroids place the patient at risk for cataracts and glaucoma
    • Some patients have a genetic predisposition to open-angle glaucoma with steroid usage
  • Corticosteroids also may be given locally by periocular injection or intravitreal injection, as determined by the type and location of uveitis
    • Periocular injection 2
      • Recommended therapy for intermediate or posterior uveitis
      • Depot or aqueous forms of periocular injection are used in the following settings:
        • Patient has uveitis that is more posterior, or
        • Patient is nonadherent to topical or systemic administration of corticosteroids, or
        • Patient is poorly responsive to previous topical or systemic administration
      • Injection is placed directly into the inferotemporal or superotemporal quadrant, or along the orbital floor
      • Do not use periocular corticosteroid injections in the case of infectious uveitis, especially toxoplasmosis
      • Avoid periocular corticosteroids in the setting of necrotizing scleritis (inflammation of tissue plane just exterior to choroid) or in patients who have experienced corticosteroid-related elevation in intraocular pressure
    • Intravitreal placement
      • Frequently used to treat acute inflammation that is not adequately responsive to periocular injections 2
      • Also used as bridge therapy to corticosteroid-sparing systemic immunomodulatory therapy
  • Sustained-release forms of implantable corticosteroids 2
    • Indicated in patients intolerant of or not adequately responsive to systemic steroids or immunomodulatory therapy, or in patients with severe unilateral or bilateral noninfectious uveitis that is severe or resistant to therapy
      • Placed by surgical fixation or intravitreal injection
      • Greater risk of cataract and glaucoma owing to prolonged corticosteroid activity
      • Inserts are FDA approved for treatment of posterior noninfectious uveitis
  • Systemic corticosteroid therapy 2
    • Give oral corticosteroids for chronic uveitis that is vision threatening, for which topical steroids are inadequate, or for patients requiring systemic therapy for another disease
      • Treat patients on high-dose corticosteroids with an additional proton pump inhibitor or an H₂-receptor blocker
      • Immunomodulatory therapy and bone preservation therapy are recommended for oral corticosteroid therapy that exceeds 3 months’ duration or when more than 5 mg prednisone per day is required to control inflammation
    • Severe, noninfectious posterior uveitis or panuveitis may require pulsed IV methylprednisolone for 3 days, followed by a prednisone taper 2

Mydriatic and cycloplegic agents 2

  • Most patients with anterior uveitis receive therapy with a cycloplegic drug to dilate the pupil
    • Cycloplegics paralyze the ciliary body and break up or prevent posterior synechiae formation, relieving photophobia and pain
    • Mydriatics not only dilate the pupil, but also guard against posterior synechiae
      • Best used as part of a tapering process in a patient who is responding well to corticosteroid therapy, since mydriatics blur vision less than cycloplegics
      • Allow patient to resume normal activities more rapidly
  • Use atropine with caution in infants and children owing to systemic absorption and the ease of fatal overdosage 12

Immunomodulatory therapy

  • Second step in the treatment stepladder 2
  • Uses immunosuppressive chemotherapeutic agents as antiinflammatory and corticosteroid-sparing therapy 2
  • Indicated for sight-threatening uveitis and in patients resistant to or intolerant of corticosteroids 2
  • 28% to 59% of patients with noninfectious uveitis will experience a visual loss that requires treatment beyond corticosteroids 1
  • Subdivided into the following drug types: 2
    • Antimetabolites (eg, methotrexate, azathioprine, mycophenolate mofetil)
      • Used most frequently; methotrexate is preferred in children 5
    • Biologic response modifiers (eg, infliximab, adalimumab)
    • Inhibitors of T-lymphocyte signaling (eg, cyclosporine)
    • Alkylating agents (eg, cyclophosphamide, chlorambucil)
      • Increased risk of hematologic malignancies
  • Uveitis is controlled in 50% to 70% of cases using immunomodulatory therapy 1
  • Good clinical response is expected within 3 months of therapy initiation; if response is inadequate at maximum dose, substitute immunomodulatory therapy or give a combination of immunomodulatory therapy agents 2
  • If clinical response is good after 24 months, no breakthroughs of inflammation occur, and the patient is totally free of corticosteroids in any form, immunomodulatory therapy may be tapered; if no breakthrough inflammation occurs during taper, immunomodulatory therapy may be discontinued 2
  • Refer to rheumatologist or immunologist when experience and training in the use of these drugs is lacking

NSAIDs 2

  • Topical NSAIDs are indicated to manage postoperative inflammation and cystoid macular edema, as well as cystoid macular edema that continues after uveitis is resolved
  • Systemic NSAIDs may be used to prevent acute, chronic, or recurrent iridocyclitis, particularly in patients who are HLA B-27–positive with recurrent nongranulomatous anterior uveitis

Drug therapy

  • Mydriatics and cycloplegics 2
    • Atropine sulfate (topical atropine must be used with caution in infants and children as this lethal dose is weight-dependent)
      • Atropine Sulfate Ophthalmic drops, solution; Children and Adolescents: 1 drop to affected eye(s) 2 to 3 times daily; 1 to 2 drops once daily also used. For ointment, apply small amount in conjunctival sac of affected eye(s) 1 to 2 times daily.
      • Atropine Sulfate Ophthalmic drops, solution; Adults: 1 to 2 drops to affected eye(s) up to 4 times daily. For ointment, apply small amount in conjunctival sac of affected eye(s) 1 or 2 times daily.
    • Homatropine hydrobromide
      • Homatropine Hydrobromide Ophthalmic drops, solution; Children >= 6 years: 1 drop into eye(s) 2—3 times per day. Monitor for anticholinergic toxicity.
      • Homatropine Hydrobromide Ophthalmic drops, solution; Adults and Adolescents: 1—2 drops into eye(s) q3—4h.
  • Topical corticosteroids 2
    • Dexamethasone
      • Dexamethasone Sodium Phosphate Ophthalmic drops, solution; Adults, Adolescents, and Children: Instill 1 or 2 drops of 0.1% ophthalmic solution in the affected eye(s) every hour during the day and every 2 hours at night; reduce application to every 4 hours (while awake) once a favorable response occurs. Later, further reduction in dosage to 1 drop 3 or 4 times daily may suffice to control symptoms.
    • Prednisolone
      • Prednisolone Acetate Ophthalmic drops, suspension; Infants†, Children†, and Adolescents†: Not FDA-approved. However, pediatric patients commonly receive dosing as in product labels: 1 to 2 drops in the affected eye(s) 2 to 4 times daily or 2 drops in the affected eye(s) 4 times per day. During the initial 24 to 48 hours, may increase dose frequency if necessary. If signs and symptoms fail to improve after 2 days, re-evaluate. Once the condition is responding, lower dosage may be used, but care should be taken not to discontinue therapy prematurely. In chronic conditions, withdrawal of treatment should be carried out by gradually decreasing the frequency of applications.
      • Prednisolone Acetate Ophthalmic drops, suspension; Adults: 1 to 2 drops in the affected eye(s) 2 to 4 times daily or 2 drops in the affected eye(s) 4 times per day. During the initial 24 to 48 hours, may increase dose frequency if necessary. If signs and symptoms fail to improve after 2 days, re-evaluate. Once responding, lower dosage may be used, but care should be taken not to discontinue therapy prematurely. In chronic conditions, withdrawal of treatment should be carried out by gradually decreasing the frequency of applications.
    • Difluprednate
      • Difluprednate Ophthalmic drops, emulsion; Adults: Instill 1 drop into the affected eye(s) 4 times daily for 14 days; taper as indicated.
  • Oral corticosteroids 2
    • Prednisone
      • Prednisone Oral tablet; Children and Adolescents: 0.14 mg/kg/day to 2 mg/kg/day PO or 4 mg/m2/day to 60 mg/m2/day PO, given in 1 to 4 divided doses. NOTE: Topically applied corticosteroids are as effective as systemic corticosteroids for anterior ocular inflammation.
      • Prednisone Oral tablet; Adults: 5 mg to 60 mg PO per day in 1 to 4 divided doses, depending upon disease being treated. NOTE: Topically applied corticosteroids are as effective as systemic corticosteroids for anterior ocular inflammation.
    • Methylprednisolone
      • Methylprednisolone Oral tablet; Children: 0.5 to 1.7 mg/kg/day PO, given in divided doses every 6 to 12 hours.
      • Methylprednisolone Oral tablet; Adults: 4 to 48 mg/day PO, administered in 4 divided doses. Adjust to condition severity and response.
  • Regional corticosteroids 2
    • Hydrocortisone
      • Hydrocortisone Sodium Succinate Solution for injection; Adults: 50 to 125 mg placed subconjunctivally or below Tenon space.
    • Methylprednisolone
      • Methylprednisolone Sodium Succinate Solution for injection; Adults: 40 to 125 mg placed subconjunctivally or below Tenon space.
    • Triamcinolone
      • Triamcinolone Diacetate Suspension for injection; Adults: 40 mg placed subconjunctivally or below Tenon space.
  • Sustained release devices for corticosteroid implant 2
    • Dexamethasone
      • Dexamethasone Implant; Adults: Inject the implant containing 0.7 mg dexamethasone in a solid polymer delivery system intravitreally. Monitor the patient for elevated intraocular pressure and endophthalmitis.
    • Fluocinolone
      • Fluocinolone Acetonide Implant tablet; Adults: Surgically insert 1 implant tablet (0.59 mg fluocinolone acetonide) into the posterior segment of the affected eye. The implant releases fluocinolone acetonide at an initial rate of 0.6 mcg/day, decreasing over the first month to 0.3 to 0.4 mcg/day at steady state, and lasting 30 months.
  • Systemic corticosteroid for pulsed therapy 2
    • Methylprednisolone
      • Methylprednisolone sodium succinate; Adults: 1 gram IV every 24 hours for 3 days. Follow with gradual taper of oral prednisone, starting at 1 mg/kg/day. 2
  • Topical NSAIDs 2
    • Diclofenac
      • Diclofenac Sodium Ophthalmic drops, solution; Adults: 1 drop to the affected eye(s) 4 times per day.
    • Ketorolac
      • Ketorolac Tromethamine Ophthalmic drops, solution; Adults: Instill 1 drop into affected eye(s) 3 times daily.
    • Bromfenac
      • Bromfenac Sodium 0.09% Ophthalmic drops, solution; Adults: One drop instilled into affected eye(s) once daily.
  • Systemic NSAIDs 2
    • Indomethacin
      • Regular release formulatuon
        • Indomethacin Oral capsule; Adults: 25 to 50 mg PO 3 to 4 times daily.
      • Extended release formulation
        • Indomethacin Oral capsule, extended-release; Adults: 75 mg PO twice daily.
    • Naproxen
      • Naproxen Oral tablet; Adults: 250 to 500 mg PO twice daily.
  • Immunomodulatory therapy 2
    • Antimetabolites
      • Methotrexate 2
        • Oral
          • Methotrexate Sodium Oral tablet; Adults: 7.5 to 15 mg PO once/week. Dose may be adjusted gradually to achieve optimal response; MAX: 25 mg/week.
        • Injectable
          • Recommended for higher doses or for those who have significant gastrointestinal discomfort with oral dosing.
          • Methotrexate Solution for injection; Adults: 7.5 to 15 mg subcutaneously given as a single weekly dose.
          • Methotrexate Sodium Solution for injection; Adults: 25 mg IM given as a single weekly dose.
      • Azathioprine 2
        • Azathioprine Oral tablet; Adults: 1 to 3 mg/kg/day PO, given in 1 or 2 divided doses.
      • Mycophenolate mofetil 2
        • Mycophenolate Mofetil Oral tablet; Adults: 1 to 3 gram PO twice daily.
    • Calcineurin inhibitors (T-lymphocyte signaling inhibitors)
      • Cyclosporine 2
        • Cyclosporine Oral capsule; Adults: 2.5 to 5 mg/kg/day PO in divided doses.
      • Tacrolimus
        • Tacrolimus Oral capsule; Adults: In patients with refractory uveitis, 0.1—0.15 mg/kg/day PO in 2 divided doses for 12 weeks was effective.
    • Biologic response modifiers
      • Infliximab
        • Infliximab (Murine) Solution for injection; Adults: Loading dose at 0, 2 and 4 weeks of 5 to 20 mg/kg/day IV, then every 4 weeks until 6 months after steroid-free remission has been achieved; then taper with 3 infusions at 6, 8, 10, and 12 week intervals before withdrawal. 2
      • Adalimumab
        • Adalimumab Solution for injection; Adults: 80 mg subcutaneously initially (administered as two 40-mg injections on day 1), followed by 40 mg subcutaneously every other week starting 1 week after the initial dose. In clinical trials, all patients received prednisone concurrently.
    • Alkylating agents
      • Chlorambucil
        • Chlorambucil Oral tablet; Adults: Doses of 0.1 to 0.2 mg/kg PO once daily for 1 year have been recommended.
      • Cyclophosphamide
        • Oral
          • Cyclophosphamide Oral capsule; Adults: 1 to 2 mg/kg/day PO in addition to corticosteroids, especially if there is major organ system involvement.
        • Intravenous
          • Cyclophosphamide Solution for injection; Adults: 0.5—1 g/m2 IV monthly in addition to corticosteroids, especially if there is major organ system involvement.
  • Antimicrobials
    • Antiviral agents
      • Uveitis caused by HSV-related or varicella-zoster–related acute retinal necrosis
        • Acyclovir
          • Acyclovir Sodium Solution for injection; Adults: 10 to 12 mg/kg every 8 hours (with normal renal function) for 7 to 10 days until stable, then convert to oral antiviral therapy (acyclovir, valacyclovir, or famciclovir) for 6 weeks minimum. 11
      • Uveitis associated with acute retinal necrosis in an immunocompromised patient, until cytomegalovirus infection can be excluded 13
        • Ganciclovir-valganciclovir combination
          • First, give ganciclovir, then follow with valganciclovir
            • Ganciclovir Sodium Solution for injection; Adults: 5 mg/kg/dose IV every 12 hours for 14 to 21 days. 13
            • Valganciclovir Hydrochloride Oral tablet; Adults: 900 mg PO every 24 hours for maintenance therapy.

Nondrug and supportive care

Procedures
3-port pars plana vitrectomy 2

General explanation

  • A portion of the vitreous body is removed via the pars plana

Indication

  • Visually significant vitritis or cystoid macular edema not responsive to medical management
  • Limited vitrectomy may be required to place intraocular corticosteroid implants

Comorbidities 6

  • Systemic inflammatory disease may be associated with uveitis, especially in anterior location
  • Uveitis may be an initial presentation of an inflammatory or autoimmune disease that has not yet been diagnosed

Special populations

  • Pregnant women 14
    • Uveitis activity is lessened during pregnancy, significantly decreasing from the time of midpregnancy onward; tends to relapse in the postpartum period
    • Certain drugs—particularly immunosuppressants—are contraindicated in pregnancy, including:
      • Methotrexate
      • Cyclophosphamide
      • Mycophenolate mofetil
    • Suggested approach to the treatment of uveitis in pregnancy is as follows:
      • Taper and cease systemic treatments during pregnancy
      • Treat flare-ups with topical corticosteroids, corticosteroids placed below the Tenon space, or sustained-release corticosteroids placed intravitreally
      • Additional local injections placed prophylactically are considered for those with sight-threatening disease, but injections must be balanced with increased risk of steroid-induced elevation of intraocular pressure and cataract formation in younger patients
      • Restart systemic therapies after delivery, giving consideration to breastfeeding status
        • Patients with chronic sight-threatening uveitis may be managed best with sustained-release inserted corticosteroid devices, especially for those considering multiple children

Monitoring

  • Monitor patients receiving corticosteroid therapy in the following ways 1:
    • Measure blood pressure and blood glucose every 3 months
    • Obtain blood cholesterol, lipid profile, and bone mineral density measurements annually
    • Recommend adequate calcium and vitamin D intake 1
      • 1500 mg calcium daily
      • 800 units vitamin D daily
  • Regularly monitor patients on immunomodulatory therapy for efficacy of therapy and evidence of toxicity 2
    • Depending on the medication, schedule visits every 6 to 8 weeks 2
    • Obtain full interval history with review of symptoms
    • Order CBC with differential, liver function tests, and renal function tests
  • Screen patients in whom biologic response modifiers are being considered before and during therapy for latent infection (eg, hepatitis, tuberculosis) 2
    • As appropriate, obtain anti-HAV IgM, anti-HBc IgM, HBsAg, and anti-HCV tests
    • Tuberculin skin test or interferon-γ release assay
      • Obtain chest radiograph to look for signs of active disease for patients with positive test results
      • Obtain sputum examination for acid-fast bacilli if there are chest radiograph abnormalities or respiratory symptoms
  • Monitor patients who are treated with an alkylating agent to assure blood leukocyte counts remain in the range of 3000 to 4500 cells per high-power field 2
    • Obtain CBC with differential weekly for chlorambucil and at least biweekly for cyclophosphamide
    • Encourage patients receiving cyclophosphamide to drink 8 or more large cups of water daily to prevent the accumulation of toxic acrolein in the bladder (causing cystitis) 2
    • Obtain urinalysis monthly to look for epithelial sloughing, casts, or evidence of hemorrhage
  • Evaluate all patients who are treated for uveitis by slit lamp examination and by measurement of intraocular pressure at each ophthalmologic or optometric visit

Complications and Prognosis

Complications

  • Complications of disease
    • Vision loss
      • A long-term study of 1076 patients revealed 19% of eyes treated for uveitis experienced visual loss 15
      • Higher likelihood in nonanterior uveitis and when cystoid macular edema develops
    • Cystoid macular edema
      • Chronic inflammation may affect the competence of the blood-retinal barrier; causes the perimacular blood vessels to leak, forming fluid-filled cystoid spaces
      • NSAIDs are first line therapy
    • Synechiae formation
      • Frequent complication of anterior uveitis
      • Causes irregular pupil
    • Acute angle-closure glaucoma
      • May occur in anterior uveitis if posterior synechiae develop
    • Hypotony
      • Defined by intraocular pressure less than 6 to 8 mm Hg 16
      • Occurs in approximately 8% to 10% of eyes with severe uveitis 16
      • May be more common in juvenile idiopathic arthritis–associated uveitis and in children overall
    • Neovascularization of the retina
      • May develop in any patient with uveitis; most common in patients with pars planitis, sarcoid panuveitis, and retinal vasculitis
      • Treatment is photocoagulation by laser for some cases (eg, ischemic retinal neovascularization) and antiinflammatory therapy for those with chronic inflammation
  • Complications of treatment
    • Cataract
      • Known side effect of corticosteroid therapy in all forms and may develop in more than 90% of patients treated with sustained-release corticosteroid implants within 2 years of placement 1
      • Therapy involves surgical removal of the cataract, with efforts to have the inflammation controlled before surgery 17
        • Anterior chamber cells must be eliminated and the eye should be quiet for at least 3 months without the need for corticosteroids
    • Glaucoma
      • Known side effect of corticosteroids in all forms and is known to develop in up to 60% of patients treated with a corticosteroid implant within 2 years of placement 1
      • Therapy involves medication (eg, prostaglandin analogs, β-adrenergic blocking agents, α₂-adrenergic blocking agents) or surgical treatment (eg, trabeculectomy)
    • Ischemic necrosis of bone
      • Doses of prednisone (or equivalent) exceeding 20 mg daily for more than 6 months are associated with a 15% to 20% risk of ischemic necrosis of bone 1
      • Treatment ranges from NSAID therapy, reduced weight-bearing, and range-of-motion exercises, to surgical treatment (eg, osteotomy, bone graft, total joint replacement)
    • Sterile hemorrhagic cystitis
      • Occurs during cyclophosphamide therapy due to buildup of toxic acrolein in the bladder
      • Urinalysis will reveal casts, epithelial sloughing, or evidence of hemorrhage
      • Immediate referral to a urologist is required

Prognosis

  • Children 5
    • 9.2% are legally blind at time of diagnosis
    • Worse visual outcomes are associated with cystoid macular edema and hypotony (intraocular pressure less than 6-8 mm Hg)
    • Panuveitis and posterior uveitis are associated with a greater risk of loss of visual acuity
    • In juvenile idiopathic arthritis patients, prognosis of uveitis is worsened when patient is male, when synechiae are present at first visit, and when the interval is shorter between onset of arthritis and onset of uveitis
  • All patients
    • Infectious uveitis carries a worse overall prognosis than noninfectious uveitis
    • Of patients with noninfectious uveitis, 28% to 59% will develop loss of vision requiring treatment beyond corticosteroids 1
    • Most visual disability is related to intermediate uveitis, posterior uveitis, and panuveitis

Screening and Prevention

Screening

At-risk populations

  • Patients with juvenile idiopathic arthritis 18

Screening tests

  • Ocular examination using a slit lamp within 1 month of receiving the diagnosis 19
  • Perform follow-up ophthalmologic screening as indicated in the guidelines of the International League of Associations for Rheumatology, based on risk category and classification, intervals ranging from 3 months to 12 months 20

Follow these instructions at home:

  • Take over-the-counter and prescription medicines only as told by your doctor.
  • Follow instructions for safely putting eye drops in your eyes.
  • Drink enough fluid to keep your pee (urine) pale yellow.
  • Follow instructions from your doctor about what activities are safe for you.
  • Do not use any products that contain nicotine or tobacco, such as cigarettes and e-cigarettes. If you need help quitting, ask your doctor.
  • Keep all follow-up visits as told by your doctor. This is important.

Contact a doctor if:

  • Your symptoms do not get better.

Get help right away if:

  • You cannot see as much as you did before.
  • You have more redness in one eye or both eyes.
  • Light bothers your eyes a lot.
  • You have pain in your eye.
  • You have aching in your eye.

Summary

  • Uveitis is swelling and irritation in the eye. Most of the time, it affects the middle part of the eye (uvea).
  • Uveitis can affect one eye or both eyes. Over time, the condition may lead to vision loss.
  • Follow instructions for safely putting eye drops in your eyes.
  • Keep all follow-up visits as told by your doctor. This is important.

Sources

1: Dunn JP: Uveitis. Prim Care. 42(3):305-23, 2015

Cross Reference

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