Uveitis

Etiology can be divided into idiopathic, infectious, and noninfectious causes. Infectious causes include herpes simplex virus (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV), HIV, Lyme disease, toxoplasmosis, tuberculosis (TB), syphilis, and histoplasmosis.[12] HSV and VZV are the most common viral causes of uveitis worldwide.[13][14] Endemic viruses (e.g., Chikungunya, dengue, Ebola, Zika virus) are less frequent, but are important emerging causes of viral uveitis.[13][14]

Noninfectious causes include seronegative arthropathies, inflammatory bowel disease, autoimmune disorders, sarcoidosis, multiple sclerosis, and eye trauma.

Onset and duration of the ocular symptoms offer clues to the etiology. Acute uveitis, characterized by sudden onset (over hours or days) and limited duration (≤3 months' duration), is seen in certain uveitis-associated diseases. Most forms of anterior uveitis present acutely, and acute anterior uveitis is the most common form of acute uveitis. Common causes of acute anterior uveitis include human leukocyte antigen (HLA)-B27-associated disorders, systemic disease (e.g., sarcoidosis, Behçet disease), infection, drug reactions, and trauma. Acute anterior uveitis may also be idiopathic, or mimicked by a masquerade syndrome.[15] Post-surgical bacterial endophthalmitis (a form of infectious panuveitis) also usually presents acutely.

Chronic uveitis is defined as persistent uveitis (>3 months' duration) characterized by relapse within 3 months of therapy termination.[2] Several types of uveitis, such as juvenile idiopathic arthritis (JIA), tuberculous uveitis, and Fuchs heterochromic cyclitis, may present this way. Common causes of chronic anterior uveitis include systemic disease (e.g., JIA, sarcoidosis), Fuchs heterochromic cyclitis, infection, chronic idiopathic anterior uveitis, and postoperative inflammation. Chronic anterior uveitis is not associated with HLA-B27.[15] Chronic intermediate uveitis is often idiopathic, or may be associated with multiple sclerosis, sarcoidosis, syphilis, Lyme disease, or ocular lymphoma.[16] Chronic posterior uveitis may be caused by an infection, including syphilis, TB, Lyme disease, or fungal, viral, or parasitic infection. It may be associated with many systemic diseases, including sarcoidosis, Behçet disease, or Vogt-Koyanagi-Harada syndrome, or it may be associated with ocular syndromes such as sympathetic ophthalmia or birdshot chorioretinopathy.[16]

Recurrent uveitis, characterized by repeated episodes separated by disease inactivity ≥3 months, whether on or off treatment, may be seen in many types of chronic uveitis, including Fuchs heterochromic cyclitis and sarcoid-associated uveitis.

Possible causes classified by location and type include:

Anterior uveitis
- Granulomatous
  - Infectious: viral (HSV and VZV), TB, syphilis, Lyme disease
  - Autoimmune: sarcoidosis, Vogt-Koyanagi-Harada syndrome, granulomatosis with polyangiitis, sympathetic ophthalmia

Nongranulomatous
- HLA-B27-associated anterior uveitis, JIA associated anterior uveitis, traumatic iritis, postoperative inflammation
- With associated iris atrophy: viral (HSV, VZV, Epstein-Barr virus, CMV), syphilis, Fuchs heterochromic iridocyclitis
- With associated keratitis: viral (HSV, VSV), sarcoidosis, syphilis, systemic lupus erythematosus (SLE)
- With associated scleritis: viral (HSV, VSV), sarcoidosis, syphilis, SLE, granulomatosis with polyangiitis, polyarteritis nodosa, relapsing polychondritis.

Intermediate uveitis
- Infectious: Lyme disease, syphilis
- Autoimmune: sarcoidosis, inflammatory bowel disease, multiple sclerosis, pars planitis.

Posterior uveitis
- Infectious: toxoplasmosis chorioretinitis, toxocariasis, acute retinal necrosis, CMV retinitis, syphilis
- Autoimmune: serpiginous choroiditis, acute posterior multifocal placoid pigment epitheliopathy, birdshot chorioretinopathy, multifocal choroiditis.
Panuveitis
- Infectious: syphilis, bacterial or fungal endophthalmitis (traumatic or endogenous)
- Autoimmune: sarcoidosis, Vogt-Koyanagi-Harada syndrome, Behçet disease, SLE, granulomatosis with polyangiitis.

One study found that 49.4% of patients with anterior uveitis tested positive for the HLA-B27 antigen.[10] Posterior uveitis is associated with localized infections or systemic infection, or systemic inflammatory disease. Rarely, uveitis can be caused by a previous eye injury or underlying neoplasm.

Insults to ocular structures, such as trauma or infection, lead to an inflammatory response within the uvea. Traumatic eye injury results in ocular inflammation due to a breakdown of the blood-brain barrier. Release of potent inflammatory mediators (prostaglandins and leukotrienes) leads to vascular leakage and the influx of inflammatory cells. Uveitis may also result from infectious disease. Micro-organisms cause intraocular damage either by direct lysis of host cells or by producing endotoxins or exotoxins toxic to the ocular microenvironment. These breakdown products induce the recruitment of host inflammatory cells (neutrophils and macrophages) and associated production of free radicals and enzymes to eliminate the infectious organism. In the process, further tissue damage occurs. Ocular inflammation is also associated with immunologic disorders. An autoimmune attack begins with an antigen-specific immune response (T cells and B cells) to ocular antigens. Autoantibodies may bind specific antigens, as in peripheral ulcerative keratitis and ocular cicatricial pemphigoid, and complement is activated and macrophages are recruited to the site. This leads to direct tissue damage. In contrast, an autoimmune response may lead to immune complex formation and deposition in the blood vessels and activation of the immune response. Immune complexes appear to be involved in SLE, granulomatosis with polyangiitis (formerly known as Wegener granulomatosis), and other vasculitides. Finally, an autoimmune uveitis can occur via a cell-mediated mechanism in which autoreactive T-cells recognize self-antigen and lead to tissue damage by direct infiltration and production of cytokines, amplifying the immune response.

Anatomic classification based on International Uveitis Study Group (IUSG)[1]

Anterior uveitis (iris and anterior ciliary body)

Iritis
Anterior cyclitis
Iridocyclitis

Intermediate uveitis (posterior ciliary body-pars plana)

Posterior cyclitis
Hyalitis
Basal retinochoroiditis

Posterior uveitis (predominantly choroid)

Focal, multifocal, or diffuse choroiditis
Retinochoroiditis
Neurouveitis

Panuveitis (all segments involved)

Anatomic classification of uveitis based on Standardization of Uveitis Nomenclature (SUN) for reporting clinical data[2]

Anterior uveitis (inflammation of the anterior chamber); includes iritis, iridocyclitis, anterior cyclitis
Intermediate uveitis (inflammation of the vitreous); includes pars planitis, posterior cyclitis, hyalitis
Posterior uveitis (inflammation of the retina and choroid); includes focal or diffuse choroiditis, chorioretinitis, retinochoroiditis, retinitis, neuroretinitis, retinal vasculitis
Panuveitis (inflammation of the anterior chamber, vitreous, and retina or choroid)

SUN descriptors of uveitis[2]

Onset

Sudden
Insidious

Duration

Limited (≤3 months' duration)
Persistent (>3 months' duration)

Course

Acute (sudden onset and limited duration)
Recurrent (repeated episodes separated by disease inactivity ≥3 months, whether on or off treatment)
Chronic (persistent uveitis with relapse in <3 months, whether on or off treatment)

Pathophysiology

Classification

Anatomic classification based on International Uveitis Study Group (IUSG)[1]

Anatomic classification of uveitis based on Standardization of Uveitis Nomenclature (SUN) for reporting clinical data[2]

SUN descriptors of uveitis[2]