Iritis and Uveitis 

In essence, the patient with uveitis complains of unilateral eye pain, blurred vision, and photophobia. On examination, circumcorneal (corneal limbus, at junction of cornea and conjunctiva) injection on closer inspection reveals a tangle of fine ciliary vessels visible through the white sclera. This ciliary flush, or “limbal blush,” is the earliest sign of iritis. Examination under x 10 slit-lamp magnification renders more evident, though a limbal blush is usually evident upon closer, naked-eye, inspection. With increasing severity, the iris and ciliary muscles spasm, producing an irregular, poorly-reactive constricted pupil and a lens which will not focus.¹

Arrange for ophthalmologic consultation or follow-up. If acceptable to the consulting ophthalmologist, dilate the pupil and paralyse ciliary accommodation with 1% cyclopentolate (Cyclogyl) drops just the once; drops that relieve pain of ciliary spasm and help keep the iris away from the lens, where meiosis and inflammation might otherwise cause posterior synechiae (adhesions). A more prolonged  effect can be achieved with the instillation of 1 drop of homatropine 5%, before discharging the patient home. Ensure the patient is reviewed the next day in follow-up. Warn the patient not to shrug-off their “pink eye” and evade follow-up, even if they are feeling better, because of the real possibility of permanent visual impairment. Posterior synechiae can potentiate cataracts and glaucoma. Be mindful that topical-steroid treatment can be problematic if the process is caused by infection, especially the viral infection of herpes keratitis; in which case slit-lamp examination is especially useful. Sometimes, intense conjunctivitis or keratitis may produce a sympathetic (reactive) limbal blush that resolves as the primary process resolves, and requires no additional treatment. More definite, but mild, iritis may also resolve with cycloplegics alone, without need for steroids. All of these conditions, however, mandate ophthalmological referral and follow-up.

Uveitis – An Inflammation of any component of the Uveal Tract

Inflammation of the uveal tract is classified anatomically, anterior involving the iris and ciliary body, posterior involving the choroid. Inflammation of any of these components may also involve other surrounding tissues, such as sclera, retina, and optic nerve. Anterior uveitis always represents a real threat to vision which requires emergency treatment and expert follow-up, because the inflammatory process in the anterior eye can opacify the anterior chamber, deform the iris or lens, scar them together, or extend into adjacent structures.

The aetiology of uveitis is often idiopathic. However, genetic, traumatic, or infectious mechanisms are known to promote or trigger uveitis. Diseases that predispose a patient to uveitis, likely to present to the emergency department, include inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus (SLE), sarcoidosis, tuberculosis, syphilis, and AIDS.

Pathological causes of iritis (uveitis):

• Reiter’s syndrome
• Connective tissue diseases
• Sarcoidosis
• Ankylosing spondylitis
• Juvenile Rheumatoid arthritis
• Vasculitis
• Behcet’s syndrome
• Infections
• Herpes simplex virus infection
• Syphilis
• Leprosy

At one tertiary referral center, the distribution in aetiology among all anatomic forms of uveitis, anterior, intermediate, and posterior, were:

• Idiopathic (34%)
• Seronegative spondyloarthropathies (10.4%)
• Sarcoidosis (9.6%)
• Juvenile rheumatoid arthritis (JRA) (5.6%)
• SLE (4.8%)
• Behçet disease (2.5%)
• AIDS (2.4%)²

Seronegative arthropathies include ankylosing spondylitis, Reiter syndrome, psoriatic arthropathy, and inflammatory bowel disease. In the same study, 51.6% of cases were classified as anterior uveitis, and the aetiological distribution as:

• Idiopathic (37.8%)
• Seronegative arthropathies (21.6%)
• Juvenile Rheumatoid Arthritis (10.8%)
• Herpes virus (9.7%)
• Sarcoidosis (5.8%)
• SLE (3.3%)
• Rheumatoid arthritis (0.9%) 

Posterior uveitis was next most common, with 19.4% of cases, the most common aetiologies being Toxoplasma (24.6%), idiopathic (13.3%), cytomegalovirus (11.6%), SLE (7.9%), and sarcoidosis (7.5%).²

Anatomy of the eye

The eyeball is a highly-stratified organ, structured layers facilitate passage and focus of incident light in its anterior region through cornea and lens, for image interpretation from photosensitive receptors at its back surface, the retina.

Eyeball components: Cornea and Retina L: direction of incident light

Presentation

History

Symptoms of uveitis depend on several variables: the most important variables are type (location)—anterior, posterior, intermediate—and duration of symptoms, whether acute or chronic.

Important elements of the medical history that should suggest uveitis as the cause of ocular pain include:

• A history of autoimmune disease such as inflammatory bowel disease, SLE, and sarcoidosis
• Sexually transmitted diseases, particularly syphilis and chlamydia
• Tuberculosis
• AIDS

While most cases of uveitis are idiopathic, a history focused on identifying a potential underlying systemic cause, especially in young adult men—those with conjunctivitis, urethritis, and a polyarthritis suggestive of reactive arthritis—is necessary to determine if workup is needed.

Acute anterior uveitis presents with:

• Pain that generally develops over a few hours or days except in cases of trauma
• Redness
• Photophobia
• Excessive lacrimation
• Blurred vision  

Chronic anterior uveitis presents primarily as blurred vision and mild redness. Patients have little pain or photophobia except during an acute episode. Posterior uveitis presents with blurred vision and floaters, with the notable absence of symptoms of anterior uveitis—i.e. the absence of pain, redness, and photophobia. The presence of symptoms of posterior uveitis together with pain suggest either anterior chamber involvement, bacterial endophthalmitis, or posterior scleritis. An intermediate uveitis, alternatively, presents as painless floaters and decreased vision (similar to posterior uveitis) with minimal photophobia or external inflammation. Patients with panuveitis may present with any or all of these symptoms.

Posterior uveitis presents with:

• Blurred vision, floaters
• Absence of symptoms of anterior uveitis: i.e. nil pain, or redness, or photophobia

Symptoms of posterior uveitis and pain suggest anterior chamber involvement, bacterial endophthalmitis, or posterior scleritis. Intermediate uveitis may present similarly to posterior uveitis: i.e., with painless floaters and decrease in vision and minimal photophobia or external inflammation. A panuveitis may present with any or all these symptoms.

Consider also, while examining the patient, for complications from a uveitis:

An acute rise in intraocular pressure secondary to pupillary block (posterior synechiae), inflammation, or topical corticosteroid use is the single most important complication. Examine all patients presenting with a red eye with a slit lamp to detect the presence of cells or flare. Consider all other causes of a red eye  before uveitis is diagnosed. An acute rise in intraocular pressure can lead to optic nerve atrophy and permanent vision loss.

Where the local eye symptoms are suggestive of a possible uveitis, consider that this may be the presentation of an underlying systemic disease, albeit some 50% of patients have idiopathic uveitis that is not associated with any other clinical syndrome.

• Acute non-granulomatous uveitis is associated with diseases related to human leukocyte antigen B27 (HLA B27), including ankylosing spondylitis, inflammatory bowel disease, reactive arthritis, psoriatic arthritis, and Behçet disease. Herpes simplex, herpes zoster, Lyme disease, and trauma also are associated with acute non-granulomatous uveitis.
• Chronic non-granulomatous uveitis is associated with juvenile rheumatoid arthritis, chronic iridocyclitis of children, and Fuchs heterochromic iridocyclitis.
• Chronic granulomatous uveitis is observed with sarcoidosis, syphilis, and tuberculosis.
• Posterior uveitis is found in such diseases as toxoplasmosis, ocular histoplasmosis, syphilis, sarcoidosis, and in immunocompromised hosts with CMV or candidal or herpetic infection. Embolic retinitis also may cause posterior uveitis.

Examination

Evaluate vital signs and check visual acuity and extraocular movement. Perform a funduscopic examination and measure intraocular pressure. Most importantly, perform a slit-lamp examination. Findings of the examination of the lids, lashes, and lacrimal ducts are normal. The conjunctival examination reveals 360° perilimbal injection, which increases in intensity as it approaches the limbus. Differentiate this condition from conjunctivitis, in which the pattern is reversed, with the most severe inflammation at a distance from the limbus. Visual acuity may be decreased in the affected eye. Extraocular movement is generally normal.

On the pupillary examination, the patient may experience direct photophobia when the light is directed into the affected eye, as well as consensual photophobia when light is directed into the uninvolved eye. Consensual photophobia is helpful in distinguishing between iritis and more superficial causes of photophobia, such as conjunctivitis. In the latter, direct, but not consensual, photophobia is noted. Pupillary miosis is common.

Findings on Physical Examination:

• Normal lids, lashes, and lacrimal ducts
• Full-circle 360-degree perilimbal injection, of increasing in intensity as it approaches the limbus
  • this is the reverse of the pattern seen in conjunctivitis, where the most severe inflammation occurs at distance from the limbus
• Visual acuity may be decreased in the affected eye
• Extraocular movement is generally normal
• Direct photophobia, when light is directed into the affected eye, together with a consensual photophobia, when light is directed into the uninvolved eye
  • consensual photophobia is typical of iritis, while a photophobia from more superficial causes, such as conjunctivitis, is direct but not consensual
• Pupillary miosis is common

Eye Inspection by Slit-lamp magnification is the most important aspect of the examination:

• Examine the cornea via direct illumination with a broad beam at 30-40° angle between viewing microscope and light source.
• Examine the epithelium for abrasions, edema, ulcers, or foreign bodies.
• Inspect the stroma for deep ulcers and edema.
• So angling the slit lamp beam, allows identification of fine particulates floating around in the anterior chamber. Keratitic precipitates (white blood cells) on the endothelium are a hallmark of iritis.
• Ciliary flush, a violaceous ring around the cornea, is highly indicative of intraocular inflammation.
• Corneal edema and vitreous haze, large collection of inflammatory cells in the vitreous, may be observed.
• Intraocular pressure may be normal or slightly decreased, in the acute phase, owing to decreased aqueous humour production; pressure may, however, become elevated as the inflammation subsides.
• Opacities of the lens (cataracts) may be present but are not specific for uveitis.
• Small stellate keratic precipitates with fine filaments in a patient with Fuchs heterochromic iridocyclitis.

The most important structure to examine is the anterior chamber. Examine the anterior chamber using a vertically and horizontally short beam. Normally, the aqueous humour in the anterior chamber is optically clear. In uveitis, an increase in the protein content of the aqueous causes an effect upon examination known as flare, which is similar to that produced by a moving projector beam in a dark smoky room. White or red blood cells may be observed; layering of white blood cells in the anterior chamber is called hypopyon.

Cell and Flare video

Document the amount of blood cells in the anterior chamber, according to the grading: “0” if none; “1⁺ or Faint” if barely detectable; “2⁺ or Moderate” where clear iris and lens detail; “3⁺ or Moderate” for hazy iris and lens detail; “4⁺ or Intense” where there are fibrin deposits or coagulated aqueous.

Formulate a Differential Diagnoses:

• Acute Angle-Closure Glaucoma in Emergency Medicine
• Acute Conjunctivitis (Pink Eye)
• Corneal Ulcer/Abrasion and Ulcerative Keratitis
• HSV Keratitis
• Intraocular Foreign Body (IOFB)
• Scleritis
• Ultraviolet Keratitis

Workup and Diagnosis

The workup should be tailored to the patient according to the history or to signs and symptoms that suggest a certain aetiology.

Laboratory Studies:

Laboratory studies are unlikely to be helpful in cases of mild, unilateral non-granulomatous uveitis in the setting of trauma or in the context of known systemic disease, or where the history and physical are not suggestive of systemic disease. Where the history and the physical examination findings are unremarkable in the presence of bilateral uveitis, granulomatous uveitis, or recurrent uveitis, a nonspecific workup is indicated.

Certain tests, not necessarily required at the primary encounter, may be ordered by the consulting ophthalmologist, to be followed and further coordinated by the primary care physician:

• Complete blood cell (CBC) count
• Erythrocyte sedimentation rate (ESR)
• Antinuclear antibody (ANA)
• Rapid plasma reagin (RPR)
• Venereal disease research laboratory (VDRL)
• Purified protein derivative (PPD)
• Lyme antibody titre
• HLA-B27 testing for ankylosing spondylarthroses
• Chest radiography, to assess for sarcoidosis or tuberculosis
• Urinalysis, for red blood cells or casts
• Infectious workup, e.g., HIV, toxoplasmosis, depending on the presentation

Imaging Studies

Chest radiography may be performed to assess for sarcoidosis or tuberculosis as the underlying cause of uveitis.

Treatment

Emergency Department Care

The main goals in the emergency department are to correctly diagnose uveitis, to provide analgesia, and to refer the patient to an ophthalmologist for possible initiation of topical steroids. Although the patient’s eye is erythematous and cells are present in the anterior chamber, antibiotics are not indicated. Patients with possible uveitis should be examined by an ophthalmologist within 24 hours. Referral is paramount.

Long-Term Monitoring

Follow-up care with an ophthalmologist within 24 hours is imperative. In the acute phase, cases of uveitis are monitored every 1-7 days with slit-lamp examination and intraocular pressure measurements. The ophthalmologist tapers steroids and cycloplegics.  When the condition is stable, patients are monitored every 1-6 months.

Two sustained-release corticosteroid vitreous implants, fluocinolone acetonide (Retisert, Yutiq) and dexamethasone (Ozurdex), have been approved by the FDA for the treatment of inflammation-induced cases of panuveitis, intermediate uveitis, and posterior uveitis. These implants preclude risks associated with systemic steroids and reduce the need for immunosuppressive agents while providing continuous therapy (approximately 30-36 months).  The installation and monitoring of these treatment modalities should be managed by an ophthalmologist.

Management

Uveitis has no standard treatment regimen. The initial course of management is step-wise, starting with cycloplegics and corticosteroid drops to control pain and reduce inflammation. Progression to immunosuppressive agents is often necessary after consideration of the baseline aetiology; this therapy would be initiated by a primary care physician only in consultation with an ophthalmologist and after consideration of both physician and patient factors. Topical steroid-eye drops and sustained-release steroid implants are the only FDA-approved medications for uveitis; all other medications used are off-label use, with sparse and mostly equivocal supporting evidence for all treatment modalities.

Before initiating therapy, be mindful that supporting evidence for any treatment is sparse.  Check the intraocular pressure and rule out a herpes simplex virus (HSV) keratitis before starting topical corticosteroids. Initiate steroid treatment only in consultation with an ophthalmologist.

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Background Information

Uveitis is inflammation of the uveal tract, an orbital tract inclusive of iris, ciliary body, and choroid. The iris regulates the amount of light that enters the eye, the ciliary body produces aqueous humour and supports the lens, and the choroid provides oxygen and nourishment to the retina.

Classification of Uveitis based upon anatomic location

Type	Primary Site of Inflammation	Manifestation
Anterior uveitis	Anterior chamber	Iritis, iridocyclitis, anterior cyclitis
Intermediate uveitis	Vitreous	Vitreitis, hyalitis,  pars planitis
Posterior uveitis	Choroid	Choroiditis / chorioretinitis / retinochoroiditis / retinitis / neuroretinitis
Panuveitis	Anterior chamber, vitreous, and/or choroid	All of the above

Uveitis, particularly posterior uveitis, is a common cause of preventable blindness; uveitis is considered a sight-threatening condition. Anterior uveitis is the form most likely to present to the emergency department. Inflammation limited to the iris, is an iritis. If the ciliary body is also involved, that is iridocyclitis.

After anatomical classification, uveitis is further described by:

• Onset: sudden vs insidious
• Duration: limited, under 3 months duration; persistent, above 3 months duration
• Course: acute, recurrent, or chronic
• Laterality: unilateral vs bilateral

The distribution of general uveitis cases by anatomic site of disease has been found to differ significantly between community-based practice, where 90.6% is anterior, 1.4% intermediate, 4.7% posterior, and 1.4% panuveitis, and university referral practice that see anterior disease in 60.6%, intermediate disease in 12.2%, posterior uveitis in 14.6%, and a panuveitis in 9.4% (p < 0.00005).

Pathophysiology and Epidemiology

The mechanism for traumatic uveitis is thought to be a combination of microbial contamination and accumulation of necrotic products at the site of injury, stimulating the body to mount an inflammatory response in the anterior segment of the eye. For the infectious aetiologies of uveitis, it is postulated that an immune response directed against foreign molecules or antigens injures the uveal tract vessels and cells. Where uveitis is found in association with autoimmune disorders, the mechanism may be a hypersensitivity reaction involving immune complex deposition within the uveal tract.

The approximate estimated annual incidence of uveitis in the United States ranges from 25-52 cases per 100,000 persons per year. Finland has one of the highest annual incidences of uveitis, probably because of the high frequency of HLA-B27 spondyloarthropathy among the population. Racial predisposition to uveitis relates to underlying systemic disease:

• Whites: HLA-B27, multiple sclerosis
• Blacks: Sarcoidosis, SLE
• Mediterranean/Middle Eastern descent: Behçet disease
• Asians: Behçet disease

In general, uveitis has no sexual predisposition except in cases secondary to systemic disease, such as JRA and SLE. Most people who develop uveitis are aged 20-50 years. No deaths due to iritis or uveitis have been reported. Morbidity from uveitis results from the formation of posterior synechiae (adhesions between the iris and the lens) that may lead to high intraocular pressure and subsequent optic nerve loss. Blindness may result from inadequate treatment. Complications of medications, specifically topical steroids, may include glaucoma, cataracts, and potential vision deterioration. Generally, with appropriate treatment, the prognosis for iritis and uveitis is a good one.

Medication

Aim to reduce pain and inflammation, using cycloplegics and corticosteroids. Corticosteroid eye drops remain the standard of care for uveitis since the early 1950s. Despite sparse evidence supporting their use, topical corticosteroids are the only medications approved by the FDA to treat uveitis. Uveitis is a diagnosis of exclusion and corticosteroids should only be initiated in conjunction with an ophthalmologist, as adverse steroids effects include increased intraocular pressure, cataract formation, steroid-induced glaucoma, and an increased risk of herpes keratitis.²

Studies comparing non-steroidal anti-inflammatory (NSAID) eye drops to placebo and corticosteroids have not demonstrated benefit; their use as an alternative to corticosteroids not supported by evidence. Potassium-sparing drugs are indicated when chronic steroid use is required to control inflammation. Approximately half of patients with uveitis need more than corticosteroid treatment to prevent vision loss.

Ocular Anticholinergic Agents

These agents block nerve impulses to the pupillary sphincter and ciliary muscles, easing pain and photophobia.

• Cyclopentolate 0.5-2% (Cyclogyl): Induces cycloplegia in 25-75 min and mydriasis in 30-60 min. Effects last as long as 1 d; however, duration may be less in setting of severe anterior chamber reaction. For this reason, Cyclogyl less attractive for treating uveitis than homatropine.
• Homatropine (Isopto Homatropine, Homatropaire): Induces cycloplegia in 30-90 min and mydriasis in 10-30 min. Effects last 10-48 h for cycloplegia and 6 h to 4 d for mydriasis, but duration may be less in setting of severe anterior chamber reaction. Homatropine is agent of choice for uveitis.²

Ocular Corticosteroids

These agents decrease inflammation. Corticosteroid treatment often is initiated only after consultation with an ophthalmologist.

• Prednisolone 1% (Pred Forte, Omnipred): Strongest steroid of its group and best choice for uveitis. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Corticosteroid Ophthalmic Implants

Corticosteroid ophthalmic implants preclude risk associated with systemic steroids and provide continuous therapy for 30-36 months.

• Fluocinolone intravitreal implant (Retisert, Yutiq): The implants are surgically inserted by the ophthalmologist and indicated for chronic, non-infectious uveitis of posterior segment of eye. Retisert releases 0.6 mcg per day initially; amount released decreases after the first month to 0.3-0.4 mcg per day over some 30 months. Yutiq releases at a rate of 0.25 mcg per day over about 36 months duration.
• Dexamethasone intravitreal implant (Ozurdex): The implant is surgically inserted by the ophthalmologist and indicated for chronic, non-infectious uveitis of posterior segment of eye.²

Tumour Necrosis Factor Blockers

Consider the expert panel recommendations from The American Uveitis Society for the off-label use of biologic agents, such as tumour necrosis factor alpha (TNF-α) inhibitors, in ocular inflammatory disorders, including: use of infliximab or adalimumab early in the treatment of patients with vision-threatening ocular manifestations of Behçet disease; use of infliximab or adalimumab as second-line therapy in children with vision-threatening uveitis secondary to juvenile idiopathic arthritis for whom methotrexate therapy is ineffective or not tolerated; use of infliximab and possibly adalimumab as second-line treatment for patients with vision-threatening chronic uveitis caused by seronegative spondyloarthropathy; use of infliximab or adalimumab for vision-threatening corticosteroid-dependent disease in patients for whom first-line therapy has failed; use of infliximab or adalimumab before etanercept in treatment of ocular inflammatory disease, or switching of patients using etanercept to either infliximab or adalimumab.

• Infliximab (Remicade): Infliximab is a chimeric IgG1κ monoclonal antibody that binds specifically to the soluble and transmembrane forms of TNF-α and inhibits the binding of TNF-α to its receptors.
• Adalimumab (Humira): Adalimumab is a recombinant human IgG1 monoclonal antibody that is specific for human TNF. It reduces inflammation and inhibits progression of structural damage.²

Causes of Uveitis – Summary ⁴

A working list of causes of a uveitis in their approximate order of frequency showing that, the cause of a uveitis remains, in most cases, unknown.

Causes of anterior uveitis:

• idiopathic or postsurgical (most common)
• trauma
• spondyloarthropathies
• juvenile idiopathic arthritis
• herpes virus infection: herpes simplex virus (HSV); varicella zoster virus (VZV); or cytomegalovirus (CMV)

Causes of intermediate uveitis:

• Idiopathic
• Multiple sclerosis
• Sarcoidosis
• Tuberculosis (TB)
• Syphilis
• Lyme disease (in endemic regions)

Causes of posterior uveitis (retinitis):

• Idiopathic
• Toxoplasmosis
• CMV (immunocompromised)
• HSV /VZV
• Sarcoidosis

Causes of panuveitis:

• Idiopathic
• Sarcoidosis
• TB

Infrequently, systemic drugs cause uveitis (usually anterior). Examples include sulfonamides, bisphosphonates, rifabutin, cidofovir, and checkpoint inhibitors such as nivolumab and ipilimumab. 

References

1. Feied, Craig; Smith, Mark; Handler, Jon and Gillam, Michael. “Iritis (uveitis),” National Center for Emergency Medicine Informatics (NCEMI). http://www.ncemi.org/as_ncemi/signup.htm.
2. Monalisa N Muchatuta and Gil Z Shlamovitz. “Iritis and Uveitis.” EMedicine. Medscape. Jan 15, 2019. Available at https://emedicine.medscape.com/article/798323-overview.
3. Neill, A. L. The A to Z of Major Organs., 162
4. RCPA Manual. “Iritis (uveitis).” The Royal College of Pathologists of Australasia. Feb 2, 2015. Available at http://www.rcpa.edu.au/Library/Practising-Pathology/RCPA-Manual/Items/Clinical-Problems/I/Iritis-(uveitis).