Inflammatory uveitic conditions are not caused by infectious agents and are generally treated with corticosteroid or immunosuppressive therapy. They may affect the front (anterior), middle (intermediate), or back (posterior) parts of the eye.
HLA-B27 Associated Uveitis
The HLA-B27 gene is located on short arm of chromosome 6 and is present in 1-8% of general population, varying by race and affecting males more than females. The associated anterior uveitis is often severe with a fibrinoid hypopyon, with a recurrent course, eventually involving both eyes, though usually not simultaneously. HLA B27 diseases are termed seronegative spondyloarthropathies, (“seronegative” referring to a negative rheumatoid factor). These diseases include:
Ankylosing spondilitis: Patients with ankylosing spondylitis have a positive family history, males are more frequent affected (80% males), and 88% are positive for HLA-B27. There is a 25% chance that an HLA-B27 positive patient with AS will develop anterior uveitis. Testing for the HLA B27 test establishes the presence of the gene and CT scan or X-ray will demonstrate changes of the lumbosacral spine or pubic symphysis. Treatment includes physical therapy to help preserve spinal and neck mobility; oral NSAIDS; oral corticosteroids or immunomodulatory agents including methotrexate or tumor necrosis factor alpha antagonists.
Reiter syndrome (reactive arthritis): The diagnostic triad for Reiter syndrome consists of urethritis, conjunctivitis, and arthritis. The condition occurs most frequently in young adults males (90%) and 85-95% are HLA-B27 positive. Reiter syndrome may be triggered by episodes of urethritis caused by Chlamydia or Ureaplasma urealyticum, or by diarrhea or dysentery caused by Campylobacter, Shigella, Salmonella and Yersinia. Arthritis starts within 30 days of infection in 80% of patients. Patients may have a mucopurulent papillary conjunctivitis, severe chronic recurrent acute attacks of iritis (50%), heavy flare, early synechiae, and subepithelial keratitis which may leave scars. Other systemic symptoms include recurrent asymmetric lower extremity migratory polyarthritis, sacroiliitis (1/3), keratoderma blennorrhagia of hands and feet (looks like pustular psoriasis), nail bed pitting, palatal and tongue aphthous ulcers, entesitis, plantar fasciitis, Achilles tendonitis, nonspecific culture-negative urethritis, and circinate balanitis of the distal penis. Treatment includes topical/periocular steroids, cycloplegics/mydriatics, and the possible need for systemic therapy.
Inflammatory bowel disease: Bowel disease may be asymptomatic and follow the onset of iritis. These diseases include ulcerative colitis, in which 5-12% develop acute anterior uveitis, and Crohns disease, in which 2.4% develop acute (mild) anterior uveitis but always with at least one other systemic feature, commonly episcleritis. Ocular findings may include choroidal infiltrates, serous retinal detachments, choroidal leaks, vasculities, cystoid macular edema, or a chronic iridocyclitis. Systemic invovlement includes gastrointestinal symptoms, sacroiliitis in 15% of patients with IBD (60% of them are HLA-B27 positive), ankylosing spondylitis (patients with ulcerative colitis have 30-fold increase in the incidence of AS in comparison with general population), migratory arthriitis, liver derangements, and skin manifestations. Treatment includes topical/periocular steroids, cycloplegics, and often systemic aminosalicylates, corticosteroids, immunomodulators, antibiotics, or anti-TNF agents.
Psoriatic arthritis: Patients with psoriasis but no arthritis do not get uveitis. Psoriasis precedes the inflammatory arthritis, usually by several years. The coexistence of HIV and psoriatic arthritis is characterized by aggressive joints destruction. Systemic findings include ungual psoriasis with pitting, transverse ridges, crumbling, and onycholysis of nails, cutaneous lesions, enthesitis, joint arthritis, sacroiliitis, and spondylitis. Ocular findings include conjunctivitis (20%), keratitis, scleritis (2%), keratoconjunctivitis sicca (dry eye), and iritis (10%). Treatment includes topical/periocular steroids, cycloplegics/mydriatics, and the possible need for systemic therapy.
Postinfectious (reactive) arthritis
Behcet's disease is diagnosed by the classic triad of hypopyon iritis (often painless), aphthous oral ulcers, and genital ulcers. There is an increased incidence of HLA-B5 or subset B51 in this disease, with young males from age 15 to 55 being most frequently affected. The disease is rare in the US; more common in Japan, Mediterranean countries, and the mideast. Systemic findings include: generalized occlusive vasculitis of unknown cause, recurrent aphthous ulcers (98%), mucosal ulcers, nodular genital lesions with central ulceration, skin lesions of erythema nodosum and pseudofolliculitis (pustular vasculitis), nondestructive recurrent arthritis (60%), and 25% with stroke, confusional state, or meningoencephalitis, due to neuro-Behcet’s. Ocular findings typically start 2-3 years after systemic presentation and include: asymmetric bilateral eye disease (50-70%), posterior involvement more common than anterior in men, recurrent noncoagulable hypopyon iritis (10%), and common posterior findings of vasculitis ultimately leading to vision loss (sheathing, retinal necrosis, CME, vitritis, serous RD, ischemic optic neuropathy, CRVO). The vasculitis tends to be hemorrhagic and involves both arteries and veins. Prognosis for Behcet's uveitis: the risk of visual loss is higher in males and higher in patients with skin lesions, arthritis, and/or posterior uveitis. The disease is chronic and recurrent over 10-20 years before burning out in some patients. In the U.S., only 25% end up with Va worse than 20/200. Treatment includes oral NSAIDs, steroids, chlorambucil and other immunosuppressives (such as cyclosporine, azathioprine, methotrexate, CellCept, cyclophosphomide, anti-TNFa, and interferon 2a). Colchicine and thalidomide may be used for patients with mucus membrane disease.
Posner-Schlossman (glaucomatocyclitic crisis)
Posner-Schlossman syndrome is a rare condition, and a diagnosis of exclusion. It usually presents as a unilateral, mild, acute iritis with elevated intraocular pressure. Recurrences are common and the episodes are usually self limited. It is associated with HLA-Bw54 gene locus and there may be an association with herpetic trabeculitis. Clinical findings include markedly increased intraocular pressure, corneal edema, fine keratic precipitates, low grade anterior chamber reaction, and a slightly dilated pupil. Episodes last from several hours to days and recurrences are common and always occur in the same eye. Diagnosis is one of exclusion, but one first needs to rule out herpetic uveitis. Treatment typically includes topical steroids and aqueous suppressants to control IOP.
Tubulointerstitial Nepritis and Uveitis Syndrome (TINU)
TINU occurs predominantly in adolescent girls (11-20 years) and women in their early 30s, the mean age of presentation is 21. Patients may present with ocular findings, acute uveitis, before the development of systemic symptoms and Acute Interstitial Nephritis. Ocular findings include anterior uveitis more severe in recurrent diseas with development of fibrin, posterior sinechiae, larger KPs, and, rarely, hypopyon. Posterior segment findings may include vitreous floaters, optic nerve swelling, and retinal exudates. Systemic findings include fever, weight loss, anorexia, arthralgias, myalgias, rash, and tubulointerstitial nephritis. Diagnosis is based on tests of renal function, urinalysis, liver function, and kidney biopsy. Anterior uveitis usually respond to topical steroids and nephritis usually respond to oral prednisone.
Lens Induced Uveitis
Normally, the immune system tolerates native lens proteins very well because they are sequestered in the lens capsule. However once the lens proteins leave the confines of the capsular bag from traumatic release of lens material (phacoanaphylactic) or release of proteins from hypermature cataract (phacolytic), they can induce an immune response. A severe granulomatous uveitis, including a hypopyon, may occur. If lens injury is limited, the granulomatous reaction can be zonal. Glaucoma can occur as a result of inflammation, or from clogging of the trabecular meshwork with lens particles. Infectious endophthalmitis must be ruled out. Treatment includes topical and oral corticosteroids, cycloplegics, and surgical removal fo the lens material.
Kawasaki's Disease (Mucocutaneous Lymph Node Syndrome)
Kawasaki disease is a systemic vasculitis of unknown etiology, occurs in children of all races but is more prevalent in Japan. It is primarily an illness of children younger than 5 years old, although reports of older patients exist. Its epidemiogical and clinical manifestations imply that an infection is the cause, but bacterial, viral and serologic studies failed to confirm such an etiology. The disease is characterized by erythematous and desquative exanthem, oral mucocal erythema, conjunctivitis, fever, cervical adenopathy. Ocular findings include a bilateral conjunctivitis without marked discharge. and mild transient bilateral anterior uveitis, usually without ocular sequelae. Topical steroids and short acting cycloplegics are the only eye therapy necessary. Systemic treatment includes aspirin and intravenous immunoglobulin.
Traumatic Anterior Uveitis (Iritis)
Traumatic iritis is commonly associated with corneal abrasion and hyphema formation. Intraocular foreign body should always be ruled out by complete dilated examination, B-scan ultrasound or CT scan. In patients with a concern for infection due to the corneal abrasion, topical NSAIDs can be used to control the inflammation until the epithelial defect is fully healed. Treatment depends on the degree of iritis and patient's symptoms (cycloplegics, topical NSAIDs, topical steroids).
Anterior segment findings of a chronic granulomatous iridocyclitis is the characteristic presentation. Other presentations include granulomas of the eyelids, lacrimal gland, conjunctiva and extraocular muscles, episcleritis or scleritis, and iris nodules. Sarcoidosis may also cause an intermediate uveitis or vitritis. Posterior segment findings are less frequent than anterior segment involvement, and may include so-called "candlewax drippings", vascular sheathing (venules, not arterioles), vitreous snowballs, cystoid macular edema, disc edema, choroidal and retinal granulomas and glaucomatous changes, which carry a poor prognosis. Diagnosis is established through blood testing for ACE level, lysozyme, as well as chest x-ray, CT scan, or gallium scan. Biopsies may be performed to confirm the presence of granulomas. Treatment begins with topical, periocular, and systemic steroids, and cycloplegics. Systemic immunomodulatory therapy is used for patients who are intolerant or fail to respond to systemic corticosteroids. Anti-TNF agents have been shown to be effective for sarcoid associated uveitis as well.
Fuchs Heterochromic Iridocyclitis
Fuchs uveitis syndrome usually presents with mild unilateral symptoms, median age at presentation is 20-40 year old. 3-5% of cases have bilateral involvement. The etiology remains unclear; an association with ocular toxoplasmosis and herpes simplex virus has been suggested. The disease is under-diagnosed and often over treated. Findings include stellate keratic precipitates, fine thin vessels in the anterior chamber angle, and minimal cellular reaction. There may be diffuse iris stromal atrophy, heterochromia, glaucoma, cataracts, and cystoid macular edema. Usually no treatment is required, aside from treating the cataract or glaucoma that may result.
Multiple Sclerosis (MS)
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease that affects the central nervous system (CNS). Disease onset usually occurs in young adults and is more common in women. The prevalence ranges between 2 and 150 per 100,000 depending on the country or specific population. MS affects the white matter in the brain and spinal cord, which helps the neurons carry nerve impulses. MS may take several forms, with new symptoms occurring either in discrete attacks (relapsing forms) or slowly accumulating over time (progressive forms). Ocular findings include a uveitis that is generally bilateral, may be granulomatous, and intermediate or diffuse. Double vision (diplopia) may occur as a result of third or sixth nerve palsies. Weakness of the medial rectus muscle is usually part of intra-nuclear ophthalmoplegia that is caused by lesions in the medial longitudinal fasciculus. Nystagmus is also common and Horner’s syndrome is occasionally present. Optic neuritis may lead to vision loss and decreased color vision and contrast sensitivity. Bilateral INO in a young patient is nearly pathognomonic for MS. Treatment of MS associated intermediate uveitis is the same as for those with idiopathic disease. Optic neuritis can be treated with high dose intravenous methylprednisone which appears to lessen the risk of recurrence and prevents the development of MS during the first two years. Immunosuppressive agents may be indicated if recalcitrant to aforementioned treatments.
Pars Planitis/Idiopathic Intermediate Uveitis
Pars planitis is idiopathic intermediate uveitis that usually affects persons in the second to third decades of life. The course of this disease is variable and ranges from a self-limited disease to a severe course. The most frequent complaint is decreased visual acuity. Histopathologic and clinical findings suggest an autoimmune etiology. There are no systemic associations, by definition. Ocular findings include vitritis (bilateral in 80%), peripheral retinal vasculitis, optic nerve edema, pars plana exudation, macular edema, cyclitic membranes, and optic nerve neovascularization. Treatment includes periocular and systemic corticosteroids, or immunosuppressive therapy.
Lymphoma of the Central Nervous System (CNS)
We suspect lymphoma in patients whose vitreitis is chronic, uni- or bilateral, nongranulomatous, and associated with infiltrates in the retina or choroid. If patients with IU develop such infiltrates, we order a CNS MRI, refer the patient for lumbar puncture, and strongly consider vitreous biopsy if syphilis testing is negative.
Presumed Ocular Histoplasmosis Syndrome (POHS)
POHS is a non-infectious immunologic response to the fungus Histoplasma capsulatum. The organism is found worldwide and is endemic to the Midwestern states of the United States. The organism is found in soil and readily inhaled. The lesions are commonly found in the lungs with old calcific lesions on chest x-rays. Immunologic response to the histoplasmosis antigen with the classic triad of punched out peripheral chorioretinal lesions ("histo spots"), peripapillary atrophy, and an asymmetric maculopathy from the presence of choroidal neovascular membrane. Classic findings of ocular histoplasmosis can be seen in 1.6% to 12.9% of the population in endemic areas. The disease will most commonly occur during the third and fourth decade with males more likely to present with bilateral macular involvement. In patients without macular lesions, the risk of CNV is roughly 2%, while the risk of CNV is 25% in patients with macular lesions. Peripapillary changes in histoplasmosis occur due to underlying choroiditis with line of pigment bordering the optic disc. Treatment is directed at controlling the neovascular membranes that develop as a part of this disease, typically with laser or intravitreal injections of anti-VEGF agents.
This disease is not uncommon in uveitis referral practices. The classic description of Birdshot was made by Ryan and Maumanee in 1980, although it had previously been observed and termed vitiliginous choroidopathy by Gass. The disease commonly presents in patients in the 4th to 6th decades with slowly progressive lost of vision. It is somewhat more common in females than males, and is associated with the HLA-A29 haplotype. The hallmark of the disease is the characteristic fundus findings. Confirmatory diagnostic testing may include checking for the HLA-A29 haplotype, fluorescein angiography, indocyanine green angiography, and electroretinogram (ERG). Treatment involves establishing immediate control of the disease with corticosteroids and then maintaining control typically with steroid-sparing immunosuppression. Patients may require intravitreal corticosteroid implants for disease control.
Vogt-Koyanagi Harada Syndrome (VKH)
Vogt Koyanagi Harada Syndrome (VKH) is autoimmune disorder in which the immune system target appears to be melanocytes. The disease is systemic, although the ocular involvement is the most devastating of all organs involved. The disease is principally found in darkly pigmented individuals, the typical patient being an Asian or native American between 30 and 50 years of age. Females are slightly more affected. The HLA-DR4, subtype 0405 is disproportionately represented among affected patients. This disorder shares many of the clinical features of sympathetic ophthalmia, except for the history of ocular injury or surgery, and in the fact that SO appears to spare the choriocapillaris pathologically. Treatment requires establishing immediate control with combination of pulse intravenous corticosteroids, periocular corticosteroid and oral corticosteroids. Long-term control is with immunomodulatory therapy primarily, often with inflximab, although cyclosporine, mycophenolate, azathioprine and methotrexate have also been used with varying degrees of success.
Multifocal Choroiditis and Panuveitis (MCP)
First described by Nozik and Dorsch in 1973, multifocal choroiditis and panuveitis (MCP) has a female:male ratio of nearly 4:1. The disease is in the middle of a continuum including Punctate Inner Choroidopathy (PIC), Multifocal Choroiditis Panuveitis (MCP) and Subretinal Fibrosis and Uveitis Syndrome (SFU). Most significant vision loss is associated with the development of choroidal neovascularization. Treatment involves immediate control with corticosteroids and long-term control with immunomodulation.