Uveitis Disease, Causes, Symptoms, Diagnosis, Treatment

Uveitis

Uveitis Disease is a sight-threatening disease entity with intraocular inflammation that arises from various causes. It may lead to irreversible visual loss if not treated properly in a timely manner. As many as 35% of patients with uveitis exhibit blindness or visual impairment in at least one eye . Uveitis is the fifth most common cause of severe visual loss in the developed world, and up to 20% of legal blindness is due to complications of uveitis , .

Uveitis is a sight-threatening inflammatory eye condition that involves the uveal tissue. It may occur as an isolated idiopathic condition, as a complication of infection, or in association with systemic inflammatory disease. The limited experience of general ophthalmologists in handling uveitis cases may delay initiating proper treatment leading to devastating visual consequences.

Types of Uveitis

Uveitis is classified anatomically into anterior, intermediate, posterior, and panuveitic forms—based on the part of the eye primarily affected.[rx]Prior to the twentieth century, uveitis was typically referred to in English as ophthalmia.”[rx]

  • Anterior uveitis – includes iridocyclitis and iritis. Iritis is the inflammation of the anterior chamber and iris. Iridocyclitis is inflammation of iris and the ciliary body with inflammation predominantly confined to ciliary body. Anywhere from two-thirds to 90% of uveitis cases are anterior in location. This condition can occur as a single episode and subside with proper treatment or may take on a recurrent or chronic nature.
  • Intermediate uveitis – also known as pars planitis, consists of vitritis—which is inflammation of cells in the vitreous cavity, sometimes with snowbanking, or deposition of inflammatory material on the pars plana. There are also “snowballs,” which are inflammatory cells in the vitreous.
  • Posterior uveitis – or chorioretinitis is the inflammation of the retina and choroid.
  • Diffuse uveitis – (also called panuveitis) is inflammation of all areas of the uvea.
  • Pan-uveitis – is the inflammation of all layers of the uvea(Iris, ciliary body and choroid).
  • Juvenile idiopathic arthritis-associated uveitis – This can be classified into those with systemic onset, also known as Still’s disease (these patients rarely have ocular manifestations); polyarticular onset with five or more joints involved (7-14% patients develop acute anterior uveitis), and pauciarticular onset with involvement of less than five joints. This last subtype is commonly associated with anterior uveitis. Subgroups are Type I-ANA positive: presents with chronic iridocyclitis in young girls and Type II recurrent acute anterior uveitis in older boys; 75% are HLA B27 positive.[] Most juvenile idiopathic arthritis (JIA)-associated uveitis presents in the pediatric age group and more commonly in girls. The uveitis is not associated with much cirucmcorneal congestion and hence it is often termed as uveitis with white eye. Complications in the form of complicated cataract and band-shaped keratopathy are common in this uveitic entity mainly because of its late presentation as it’s ignored by the patient and parents because of lack of associated redness and pain.
  • Lens-induced uveitis – The uveitis secondary to lens can present as phacoanaphylactic endophthalmitis which is an immune complex-mediated reaction to lens protein. It presents as a sterile granulomatous uveitis after cataract surgery or after traumatic rupture of the lens capsule. Lens-induced uveitis can be phacogenic uveitis which occurs after exposure to liberated lens protein. It can be also seen along with phacolytic glaucoma in hypermature cataracts in which leakage of lens protein occurs through an intact capsule. There is blockage of the trabecular meshwork by the denatured lens protein leading to secondary glaucoma.[]
  • Intraocular lens (IOL)-related uveitis – Can occur by various mechanisms: mechanical irritation – due to excessive manipulation during surgery; chaffing of the iris by the IOL, Uveitis-Glaucoma- Hyphema (UGH) syndrome is seen in rigid type of anterior chamber (AC) IOL whose footplates erode into the iris root. It can also be secondary to foreign-body reaction to IOL polymers or can present as toxic lens syndrome which is a sterile uveitis due to IOL impurities, metal haptics, poor finish of optic / optic-haptic junction (toxic anterior segment syndrome).[
  • Fuchs heterochromic iridocyclitis – Characterized by idiopathic non-granulomatous anterior uveitis. It is of insidious onset and recurrent in nature. It’s commonly seen in young females, mostly unilateral, and patients commonly present with blurring of vision. As the uveitis is mild, it’s usually not associated with circumcorneal congestion. Classical presentation of uveitis in Fuchs heterochromic iridocyclitis is occasional to 1+ anterior chamber cells, aqueous flare of 1+ to 2+, diffuse white stellate keratic precipitates on the endothelium which are non-pigmented non-confluent in nature. Absence of posterior synechiae is the pathognomic sign of Fuchs heterochromic iridocyclitis.[]

Causes of Uveitis

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Autoimmune disorders associated with noninfectious uveitis.

Systemic immune-mediated causes of uveitis Uveitis syndromes confined primarily to the eye
(i) Ankylosing spondylitis (i) Acute posterior multifocal placoid pigmentary epitheliopathy
(ii) Behçet’s disease (ii) Acute retinal necrosis
(iii) Blau syndrome (iii) Autosomal dominant neovascular inflammatory vitreoretinopathy
(iv) Crohn’s disease (iv) Birdshot choroidopathy
(v) Drug or hypersensitivity reaction (v) Fuchs heterochromic cyclitis
(vi) Interstitial nephritis (vi) Glaucomatocyclitic crisis
(vii) Juvenile idiopathic arthritis (vii) Immune recovery uveitis
(viii) Kawasaki’s disease (viii) Iridocorneal endothelial syndrome
(ix) Multiple sclerosis (ix) Leber’s stellate neuroretinitis
(x) Neonatal onset multisystem inflammatory disease (x) Multifocal evanescent white dot syndrome
(xi) Psoriatic arthritis (xi) Pars planitis
(xii) Reactive arthritis (xii) Punctate inner choroidopathy
(xiii) Relapsing polychondritis (xiii) Serpiginous choroidopathy
(xiv) Sarcoidosis (xiv) Subretinal fibrosis and uveitis syndrome
(xv) Sjögren’s syndrome (xv) Sympathetic ophthalmia
(xvi) Sweet syndrome (xvi) Trauma
(xvii) Systemic lupus erythematosus
(xviii) Ulcerative colitis
(xix) Vasculitis
(xx) Vitiligo
(xxi) Vogt-Koyanagi-Harada syndrome

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Auto Immuno Causes

  • The most common form of uveitis is acute anterior uveitis (AAU). It is most commonly associated with HLA-B27, which has important features: HLA-B27 AAU can be associated with ocular inflammation alone or in association with systemic disease.
  • HLA-B27 AAU has characteristic clinical features including male preponderance, unilateral alternating acute onset, a non-granulomatous appearance, and frequent recurrences, whereas HLA-B27 negative AAU has an equivalent male to female onset, bilateral chronic course, and more frequent granulomatous appearance.[rx] Rheumatoid arthritis is not uncommon in Asian countries as a significant association of uveitis.[rx]

Noninfectious or Autoimmune Causes

  • Behçet disease
  • Crohn’s disease
  • Fuchs heterochromic iridocyclitis
  • Granulomatosis with polyangiitis
  • HLA-B27 related uveitis
  • Juvenile idiopathic arthritis
  • Sarcoidosis
  • Spondyloarthritis
  • Sympathetic ophthalmia
  • Tubulointerstitial nephritis and uveitis syndrome

Infectious Causes

Uveitis may be an immune response to fight an infection inside the eye. While representing the minority of patients with uveitis, such possible infections include:

  • brucellosis
  • herpesviruses
  • leptospirosis
  • Lyme disease
  • presumed ocular histoplasmosis syndrome
  • syphilis
  • toxocariasis
  • toxoplasmic chorioretinitis
  • tuberculosis
  • Zika fever[rx]

Associated with Systemic Diseases

Systemic disorders that can be associated with uveitis include:[rx][rx]

  • ankylosing spondylitis
  • Behçet’s disease
  • chronic granulomatous disease
  • enthesitis
  • inflammatory bowel disease
  • juvenile rheumatoid arthritis
  • Kawasaki’s disease
  • multiple sclerosis
  • polyarteritis nodosa
  • psoriatic arthritis
  • reactive arthritis
  • sarcoidosis
  • systemic lupus erythematosus
  • Vogt–Koyanagi–Harada disease
  • Whipple’s disease

Drug Related Side Effects

  • Rifabutin, a derivative of Rifampin, has been shown to cause uveitis.[rx]
  • Several reports suggest the use of quinolones, especially Moxifloxacin, may lead to uveitis.[rx]
  • All of the widely[rx] administered vaccines have been reported to cause uveitis.

White Dot Syndromes

Occasionally, uveitis is not associated with a systemic condition: the inflammation is confined to the eye and has unknown cause. In some of these cases, the presentation in the eye is characteristic of a described syndrome, which are called white dot syndromes, and include the following diagnoses:

  • acute posterior multifocal placoid pigment epitheliopathy
  • birdshot chorioretinopathy
  • multifocal choroiditis and panuveitis
  • multiple evanescent white dot syndrome
  • punctate inner choroiditis
  • serpiginous choroiditis
  • acute zonal occult outer retinopathy

Masquerade Syndromes

Masquerade syndromes are those conditions that include the presence of intraocular cells but are not due to immune-mediated uveitis entities. These may be divided into neoplastic and non-neoplastic conditions.

Non-neoplastic

  • retinitis pigmentosa
  • intraocular foreign body
  • retinal detachment
  • juvenile xanthogranuloma

Neoplastic

  • retinoblastoma
  • lymphoma
  • malignant melanoma
  • leukemia
  • reticulum cell sarcoma

Symptoms of Uveitis

Anterior uveitis

  • Burning of the eye
  • Redness of the eye
  • Blurred vision
  • Photophobia
  • Irregular pupil
  • Blacked out sclera
  • Headaches
  • Signs of anterior uveitis include dilated ciliary vessels, presence of cells and flare in the anterior chamber, and keratic precipitates (“KP”) on the posterior surface of the cornea. In severe inflammation there may be evidence of a hypopyon. Old episodes of uveitis are identified by pigment deposits on lens, KPs, and festooned pupil on dilation of pupil.
  • Busacca nodules, inflammatory nodules located on the surface of the iris in granulomatous forms of anterior uveitis such as Fuchs heterochromic iridocyclitis (FHI).[rx]
  • Synechia

Intermediate Uveitis

Most common

  • Floaters, which are dark spots that float in the visual field
  • Blurred vision

Intermediate uveitis normally only affects one eye. Less common is the presence of pain and photophobia.[rx]

Posterior Uveitis

Inflammation in the back of the eye is commonly characterized by:

  • Floaters
  • Blurred vision
  • Photopsia or seeing flashing lights

Diagnosis of Uveitis

In other cases, investigations which may be advised:

  • Complete Blood Count – Baseline, Leucocytosis in infectious etiology

  • Erythrocyte sedimentation rate (ESR) – Nonspecific indication of a systemic disease.

  • Mantoux test – Nonspecific test. Indicates prior exposure to tubercle bacilli.

  • Venereal disease research laboratory test (VDRL) – Nonspecific screening test for syphilis.

  • Treponema pallidum hemagglutination test (TPHA) – Highly specific for syphilis.

  • Human leukocyte antigen (HLA) B27 – To be done in patients with recurrent attacks of anterior uveitis, positivity of HLA B27 helps the clinician in counselling the patient for recurrent attacks of uveitis which are more severe and more frequent in nature.

  • Antinuclear Antibodies – Collagen vascular disease.

  • Serum Angiotensin Converting Enzyme – Assay Active sarcoidosis. However it can be normal in patients with sarcoidosis and it can be physiologically elevated in chronic smokers and in children. Interpretation of serum ACE test has to be done in conjunction with clinical findings.

  • Chest X-ray – Tuberculosis, Calcified hilar lymphadenopathy in Sarcoidosis;

  • Sacroiliac joint X-ray – Ankylosing Spondylitis

  • High resolution CT scan chest – Sarcoidosis

  • Tridot analysis for HIV – Any unusual presentation of uveitis.

The above listed tests have to be done on a tailored basis and not all the tests are usually required in all patients with anterior uveitis. Similarly, in selected cases with keratouveitis, the aqueous humor study for Herpes Simplex Virus or other viruses can be carried out using polymerase chain reaction (PCR) study.

Specific disease entities in anterior uveitis

A. Non-infectious cause

  • Idiopathic – Isolated inflammation of the anterior segment. Non-granulomatous and may have seasonal variation. Accounts for 50% of cases.

  • Ankylosing spondylitis (HLA B27) related iridocyclitis – More common in males, and has a younger age of onset. Can be associated with systemic features.[–] It is believed to be triggered by gram-negative bacilli, which interact with HLA B27.[–]

  • Ocular features – unilateral, recurrent, acute iridocyclitis. Ocular features do not correlate with the severity of systemic disease.

  • Systemic features – sacroilitis with morning stiffness that improves with exercise.

  • Reiter’s syndrome – Young males in the age group of 15-35 years. The classical triad consists of arthritis, urethritis and conjunctivitis. Acute non-granulomatous, recurrent uveitis is the hallmark. Other ocular features are mucopurulent conjunctivitis, subepithelial keratitis. Other systemic features are keratoderma blenorrhagica, balanitis, and aphthous stomatitis.[,]

  • Inflammatory bowel disease – Crohn’s disease, ulcerative colitis and Whipple’s disease may present with acute recurrent iridocyclitis.[,]

  • Psoriatic arthritis – Patients have recurrent acute iridocyclitis. Systemic features: psoriatic skin changes and seronegative, erosive arthritis in the small joints.[,]

Treatment of Uveitis

Uveitis is typically treated with glucocorticoid steroids, either as topical eye drops (prednisolone acetate) or as oral therapy.[rx] Prior to the administration of corticosteroids, corneal ulcersmust be ruled out. This is typically done using a fluoresence dye test.[rx] In addition to corticosteroids, topical cycloplegics, such as atropine or homatropine, may be used. Successful treatment of active uveitis increases T-regulatory cells in the eye, which likely contributes to disease regression.[rx] In some cases an injection of posterior subtenon triamcinolone acetate may also be given to reduce the swelling of the eye. [rx]

Antimetabolite medications, such as methotrexate are often used for recalcitrant or more aggressive cases of uveitis. Experimental treatments with Infliximab or other anti-TNF infusions may prove helpful. The anti-diabetic drug metformin is reported to inhibit the process that causes the inflammation in uveitis.[rx] In the case of herpetic uveitis, anti-viral medications, such as valaciclovir or aciclovir, may be administered to treat the causative viral infection.[rx]

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Pharmacologic Treatment of Viral Retinitis and Uveitis

Drug Route Side effects Viral coverage
Acyclovir Intravenous: 1500 mg/m2/day divided Q8h x 14 days followed by
Oral: 800 mg five times a day for 6 weeks (also dose for viral anterior uveitis)
Prophylactic dose: 400 mg PO BID-TID		 GI symptoms, hypersensitivity reactions, renal or CNS dysfunction (requires renal dosing) HSV-1, HSV-2, VZV, EBV ≫ CMV
Valacyclovir (prodrug) Oral: 1 g (viral anterior uveitis)-2 g (viral retinitis) Q8h x 6 weeks
Prophylactic dose: 1 g PO BID		 Similar to acyclovir HSV-1, HSV-2, VZV≫ CMV
Ganciclovir Intravenous: 500 mg Q12h x 14 days
Intravitreal: 2–5 mg/0.1 mL, 3x/week
Topical gel: 0.15% Applied 4x/day x 3 months for CMV anterior uveitis
Intravitreal surgical implant:lasts 8 months (no longer available)		 Anemia, thrombocytopenia, granulocytopenia HSV-1, CMV ≫VZV, HSV-2
Valganciclovir Oral: 900 mg BID x 3–6 weeks
Prophylactic dose: 450 mg PO BID		 HA, GI symptoms, bone marrow suppression, anemia, renal dysfunction HSV-1, CMV≫VZV, HSV-2
Foscarnet Intravenous: 40–60 mg/kg Q8h x 3 weeks
Intravitreal: 2.4 mg/0.1 mL every 3–4 days		 HA, GI symptoms, renal or CNS toxicity uncommonly HSV-1, HSV-2, VZV>CMV
Famciclovir (prodrug) Oral: 500 mg Q8h HA, GI symptoms, rash HSV-1>HSV-2>VZV
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Treatment of Uveitis

Anterior uveitis can generally be managed by medical therapy and requires surgical intervention only if structural complications supervene and those can be either secondary glaucoma or secondary cataract. The general goals of medical management are:

  • Relief of pain and photophobia

  • Elimination of inflammation

  • Prevention of structural complications such as synechiae, secondary cataract and glaucoma

  • Preservation or restoration of good visual function.

However, one needs to remember the potential side-effects and long-term iatrogenic complications secondary to the use of steroid therapy. The risk-benefit ratio should be analyzed on a case-to-case basis.

Noninfectious anterior uveitis is treated using the following drugs.[–]

Corticosteroids

Corticosteroids are the drug of choice in the treatment of anterior uveitis. Steroids act by modifying and decreasing the inflammatory response in the eye. They inhibit both the cycloxygenase pathways of inflammatory response. Topical corticosteroids if administered as frequent doses, can achieve adequate therapeutic levels in the anterior chamber. However, if topical alone is inadequate, periocular and systemic administrative routes should be considered.

Topical drops are the commonest and easiest method with the least side-effects. A number of topical ophthalmic corticosteroids are available:[–]

  • Prednisolone acetate 0.125% and 1%

  • Betamethasone 1%

  • Dexamethasone sodium phosphate 0.1% (also available in 0.05% ointment form)

  • Fluorometholone 0.1% and 0.25% (also available in 0.1% ointment form)

  • Loteprednol

  • Rimexolone 1%

The choice of topical steroid should be based on the severity of uveitis; in cases with severe AC reaction topical steroid with strong potency such as prednisolone acetate should be preferred whereas in cases with mild anterior uveitis weak topical steroid such as betamethasone or dexamethasone can be applied. In steroid responders one should try and avoid steroid as far as possible and can use topical non-steroidal anti-inflammatory drugs (NSAIDs) like flubriprofen or weak steroids or steroids with least propensity to raise IOP such as rimexolone 1%.

Periocular injection is indicated where maximum concentration of the drug is required for a longer time with minimal side-effects. The drugs which can be considered for periocular injections are dexamethasone or triamcinolone acetonide. Posterior subtenon’s injection is recommended in intermediate and posterior uveitis.

Systemic corticosteroids are indicated when the anterior uveitis is not responding to topical drugs alone or if the disease is recurrent and bilateral. If there is any component of posterior uveitis, one may need to start oral corticosteroids early itself. The guidelines for oral corticosteroids therapy are:

  • Use enough, soon enough, often enough, and long enough to secure the desired results.

  • Start with high dose and taper according to the clinical response.

  • Suppress inflammation till the pathogenic effect ends.

  • The dose of steroid should be planned but in accordance to the response of the disease.

The level of aggression in terms of treatment is based on the putative diagnosis and the clinical manifestations. Traumatic iritis does not require extensive treatment whereas juvenile rheumatoid arthritis requires more aggressive and more prolonged treatment,[] the further decision regarding the aggressiveness of therapy should also be based on the degree of inflammation, duration of inflammation, history of previous uveitis and how was the response to treatment, risk of structural damage and response to initial treatment.

Mydriatics/cycloplegics

These are given as supportive measures. They cause paresis of the iris and ciliary muscle and keep the pupils mobile, thereby preventing the formation of synechiae. A short-acting mydriatic/cycloplegic preparation is usually preferred. All cycloplegic agents are cholinergic antagonists which work by blocking neurotransmission at the receptor site of the iris sphincter and ciliary muscle. Cycloplegics serve three purposes in the treatment of anterior uveitis

  • To relieve pain by immobilizing the iris

  • To prevent adhesion of the iris to the anterior lens capsule (posterior synechia), which can lead to iris bombe and elevated IOP

  • To stabilize the blood-aqueous barrier and help prevent further protein leakage (flare).

  • Cycloplegic agents useful in treating anterior uveitis are:

  • Atropine, 0.5%, 1%, 2%

  • Homatropine, 2%, 5%

  • Cyclopentolate, 0.5%, 1%, 2%.

  • Phenylephrine, 2.5%, is an adrenergic agonist that causes dilation by direct stimulation of the iris dilator muscle. Because phenylephrine has neither a cycloplegic nor anti-inflammatory effect and may cause a release of pigment cells into the AC, it is generally not recommended as an initial part of the therapeutic regimen. Phenylephrine may, however, help break recalcitrant posterior synechia.

Non-steroidal anti-inflammatory drugs

These work by inhibition of arachidonic acid metabolism and include drugs such as indomethacin, flurbiprofen and diclofenac sodium. However, when used alone, their efficacy in treating acute intraocular inflammation has not been established.

Immunosuppressive agents

These are used mainly in corticosteroid-resistant cases or as steroid-sparing agents. They are usually not used in acute anterior uveitis except in a few cases like JIA-associated iridocyclitis and Behcet’s disease. The immunosuppressives commonly used are methotrexate or azathioprine. One needs to start immunosuppressive in conjunction with the internist. Patients needs to be educated about the side-effects of immunosuppressives and should be strictly asked for regular blood and systemic examinations as and when required.

Diseases Associated with Uveitis

Uveitis can be associated with many diseases including

  • AIDS
  • Ankylosing spondylitis
  • Behcet’s syndrome
  • CMV retinitis
  • Herpes zoster infection
  • Histoplasmosis
  • Kawasaki disease
  • Multiple sclerosis
  • Psoriasis
  • Reactive arthritis
  • Rheumatoid arthritis
  • Sarcoidosis
  • Syphilis
  • Toxoplasmosis
  • Tuberculosis
  • Ulcerative colitis
  • Vogt Koyanagi Harada’s disease

References

Uveitis Disease