Diseases of the Uvea

Overview

Definition

Uveitis is an inflammation of the uvea, the middle layer of the eye, which comprises the iris, ciliary body, and the choroid.

Anatomy

• Anterior uvea
  • Anterior part of the ciliary body (pars plicata):
    • Controls accommodation by modifying the shape of the lens 
    • Epithelium produces the aqueous humor.
  • Iris: pigmented diaphragm controlling the amount of light entering the eye by mydriasis or miosis
• Intermediate uvea
  • Posterior portion of ciliary body (pars plana)
  • Vitreous chamber: contains the vitreous humor
• Posterior uvea
  • Choroid:
    • Vascular structure that provides support and nutrition to the retina
    • Continuous anteriorly with the ciliary body
  • Retina:
    • Innermost layer
    • Contains photoreceptors that convert light stimuli into nervous impulses

Types

• Anterior uveitis
  • Most common
  • Iritis: iris 
  • Anterior cyclitis: ciliary body 
  • Iridocyclitis: iris and ciliary body 
• Intermediate uveitis
  • Pars planitis: pars plana 
  • Vitreitis/hyalitis: vitreous humor 
• Posterior uveitis
  • Choroiditis: choroid
  • Chorioretinitis/retinochoroiditis: choroid and retina
  • Retinitis: retina
  • Neuroretinitis: retina and optic nerve
• Panuveitis
  • Inflammation of all layers

Epidemiology and Etiology

Epidemiology

• Incidence: 25 cases per 100,000 persons 
• Anterior uveitis, the most prevalent type, accounts for 50% of cases.
• Underlying systemic condition affects racial predisposition:
  • African Americans: sarcoidosis, systemic lupus erythematosus
  • Asians: Behcet’s disease
  • Caucasians: Human leukocyte antigen B27 (HLA-B27) spondyloarthropathy, multiple sclerosis
  • Middle Eastern descent: Behcet’s disease

Etiology

• Viral infections:
  • Herpes simplex virus (HSV) 1 and 2
  • Cytomegalovirus (CMV): found in immunocompromised patients (HIV with low CD4 count)
  • Varicella-zoster virus (VZV)
• Bacterial infections: 
  • Syphilis
  • Tuberculosis (TB)
  • Bartonella henselae (cat scratch disease)
• Fungal infections:
  • Histoplasmosis
  • Blastomycosis
  • Candidiasis
• Parasitic infections:
  • Toxoplasmosis
  • Cysticercosis
  • Onchocerciasis
• Systemic immune-mediated causes:
  • Sarcoidosis
  • Diseases associated with HLA-B27  
    • Unilateral uveitis: ankylosing spondylitis, reactive arthritis 
    • Bilateral uveitis: psoriatic arthritis, Crohn’s disease, ulcerative colitis
  • Juvenile idiopathic arthritis
  • Tubulointerstitial nephritis and uveitis (TINU)
  • Behcet’s disease: frequently a recurrent panuveitis
  • Multiple sclerosis
  • Systemic lupus erythematosus
  • Vogt-Koyanagi-Harada syndrome
• Medications:
  • Rifabutin
  • Fluoroquinolones: moxifloxacin, ciprofloxacin
  • Intravitreal medications: cidofovir, vancomycin
  • BRAF kinase inhibitors: dabrafenib, vemurafenib, trametinib
• No extraocular involvement:
  • Pars planitis: intermediate uveitis affecting the pars plana
  • Sympathetic ophthalmia: inflammation of the contralateral eye after a penetrating injury on the other eye
  • Birdshot uveitis/chorioretinopathy: affects the posterior uvea and is associated with HLA-A29
  • Trauma: includes intraocular surgeries that have self-limited uveitis
• Idiopathic

Pathophysiology

• Risk factors that promote uveitis:
  • Systemic inflammatory disease, especially HLA-B27 syndromes
  • Immunocompromised state
  • Smoking
• Proposed mechanisms:
  • Microbial contamination: In cases of trauma, direct injury and necrosis trigger an inflammatory response at the site.
  • Molecular mimicry: Antigens of infectious or foreign agent(s) cross-reacts with ocular self-antigens.
  • Indirect effect of infection: Foreign antigens of infection stay undetected in ocular tissues and lead to recurrent immune-mediated tissue damage.

Clinical Presentation and Diagnosis

Clinical presentation

• Anterior uveitis:
  • Unilateral or bilateral 
  • Pain, photophobia, redness, excessive tearing, and reduced visual acuity
  • Constricted or irregular pupil: from posterior synechia (iris adhesions to anterior lens)
• Intermediate and posterior uveitis:
  • Not usually with pain or redness
  • Reduced visual acuity, floaters, visual field defect
• Panuveitis: presents with any of the aforementioned symptoms

Diagnosis

Diagnosis is made by dilated fundus examination and slit-lamp examination. Scleral depression is an additional maneuver to visualize structures posterior to the lens.

Findings

• Anterior uveitis:
  • Leukocytes in anterior chamber
  • “Flare”: protein accumulation in the aqueous humor from vascular changes
  • Keratic precipitates: hallmark of iritis 
  • Ciliary flush: diffuse redness at the limbus
  • Hypopyon: layering of leukocytes in the anterior chamber of the eye 
  • Findings that indicate complications:
    • Cataract 
    • Glaucoma
    • Band keratopathy: calcium deposits of the cornea
    • Synechiae formation 
• Intermediate uveitis:
  • Vitreous haze: inflammatory cells and protein in the vitreous humor
  • “Snowballs”: large inflammatory collection in the vitreous humor
  • “Snowbank”: pars plana exudates
  • Cystoid macular edema: cyst-like areas of fluid in the macula
• Posterior uveitis:
  • Focal chorioretinal spots
  • Retinal whitening
  • Retinal detachments
  • Optic nerve edema

Additional laboratory and radiographic imaging are indicated when extraocular signs and symptoms are attributable to a causative disease (e.g., sarcoidosis, syphilis).

Management

Infectious uveitis

• Treatment directed toward the causative agent
• Antibiotics (i.e., trimethoprim/sulfamethoxazole for toxoplasmic chorioretinitis) or antivirals (i.e., acyclovir for herpetic uveitis)

Noninfectious uveitis

• Anterior uveitis:
  • Topical steroids: dose-dependent on disease severity
  • Cycloplegic agent (cyclopentolate):
    • Relieves pain by preventing pupillary muscle spasm
    • Prevents synechiae formation
• Intermediate or posterior uveitis:
  • Not responsive to topical medication
  • Periocular or intraocular injection of glucocorticoids
• Systemic therapy or immunosuppressants
  • For cases that cannot be treated with local injection or resistance to initial therapy
  • Oral glucocorticoids
  • Antimetabolites (methotrexate, azathioprine, mycophenolate)
  • Anti-tumor-necrosis factor (TNF)-alpha (adalimumab)
• Intraocular glucocorticoid–releasing implant
  • For resistant posterior uveitis
  • Long-lasting effect, up to 3 years
  • Complications: endophthalmitis, cataract formation, ocular hypertension

Differential Diagnosis

• Conjunctivitis: inflammation of the conjunctiva, the outer lining of the eye. Etiology can be infectious or non-infectious. Patients present with redness and discharge on 1 or both eyes. Bacterial conjunctivitis often has purulent discharge, whereas viral causes have watery discharge.
• Subconjunctival hemorrhage: appearance of demarcated areas of extravasated blood just beneath the surface of the eye. The condition is asymptomatic and may occur spontaneously or with Valsalva–associated mechanisms (e.g., coughing, sneezing, or vomiting). Diagnosis is confirmed by normal acuity and the absence of discharge, photophobia, or foreign body sensation. Subconjunctival hemorrhage typically resolves within 1–2 weeks.
• Retinal detachment: separation of the retina from the retinal pigment epithelium resulting in rapid photoreceptor damage. Symptoms include painless vision changes such as sudden flashes of light, floaters, worsening peripheral vision, or having a shadow in the field of vision. Retinal detachment is an emergency requiring corrective surgery.
• Vitreoretinal lymphoma: most common intraocular lymphoproliferative disorder and 1 of the masquerade syndromes that presents a diagnostic dilemma. Patients have gradual visual impairment with floaters. Gold standard of diagnosis is cytopathologic examination of ocular fluid or chorioretinal biopsy.