INTRODUCTION — Episcleritis is defined by the abrupt onset of inflammation in the episclera of one or both eyes, typically presenting as redness, irritation, and watering of the eye with preserved vision. Most patients with episcleritis have a mild, isolated problem that responds readily to topical therapy alone and does not pose a threat to vision. Indeed, many patients with episcleritis require no treatment per se since the condition typically resolves over a short course. A small fraction of patients with episcleritis have an underlying systemic disease that signifies a serious health concern and that requires additional therapy.
Episcleritis is only one of many potential causes of a red eye, although other causes can generally be distinguished clinically from episcleritis based upon the medical history and the examination of the eye.
The clinical manifestations, diagnosis, and treatment of episcleritis will be reviewed here. The evaluation of the red eye and the clinical manifestations, diagnosis, and treatment of scleritis are discussed separately. (See "The red eye: Evaluation and management" and "Clinical manifestations and diagnosis of scleritis" and "Treatment of scleritis".)
EPIDEMIOLOGY — Approximately 70 percent of cases of episcleritis occur in females . It occurs most frequently in young and middle-aged adults but may affect all age groups. There are no reliable data regarding the true incidence of episcleritis since it is often mistaken for other conditions such as conjunctivitis or "pink eye."
Episcleritis is usually classified as either simple or nodular (picture 1 and picture 2). Simple episcleritis is usually sectoral, confined to a carefully delimited portion of the episclera, but can also be diffuse, involving the entire surface of the eyeball. Nodular episcleritis is raised and thus usually limited to just one area of the eyeball.
The vast majority of episcleritis cases are isolated and are not associated with a known underlying systemic immune-mediated disorder (unlike scleritis, with which the association is much higher). However, episcleritis may be associated with a number of systemic diseases [1-3]:
●Simple episcleritis is observed in association with seronegative spondyloarthritides, inflammatory bowel disease, and certain forms of vasculitis, particularly those associated with antineutrophil cytoplasmic antibodies (ANCA). (See "Reactive arthritis" and "Dermatologic and ocular manifestations of inflammatory bowel disease" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis" and "Overview of the clinical manifestations and classification of spondyloarthritis".)
●Nodular episcleritis is most frequently idiopathic but may be associated with any of the rheumatic conditions, particularly rheumatoid arthritis. Rheumatoid arthritis accounts for approximately 6 percent of all cases of episcleritis, but only a small minority of patients with rheumatoid arthritis develop episcleritis . (See "Ocular manifestations of rheumatoid arthritis".)
Some reports suggest a possible link between use of the bisphosphonate drugs, risedronate and pamidronate, and episcleritis [4,5]. However, a clear cause-and-effect relationship has not been established. Reported occurrence rates are generally less than 1 percent.
PATHOGENESIS — Episcleritis is a clinical diagnosis that can be produced by a variety of systemic immune and nonimmune mechanisms that incite inflammation. The episclera is a thin and highly vascular connective tissue that lies beneath the conjunctiva but is superficial to the sclera (figure 1). Histologic examination reveals widespread vasodilatation, edema, and lymphocytic infiltration .
Immune mechanisms causing episcleritis may involve acute type I hypersensitivity responses caused by immunoglobulin E (IgE)-mediated degranulation of tissue mast cells. It can also be induced by immune complex-mediated reactions (type III hypersensitivity), as occur in some vasculitic diseases, and by systemic infections, such as syphilis or tuberculosis. In granulomatous diseases, the pathophysiology of episcleritis is thought to be mediated by a type IV delayed-type hypersensitivity response, but the underlying antigens are unknown .
A common cause of episcleritis is dry eye syndrome. Dry eye disease can occur in a wide variety of conditions, some only involving the eyes and others in association with systemic disease such as Sjögren's disease, systemic lupus erythematosus, rheumatoid arthritis, or graft versus host disease to name a few. In all of these conditions, the severity of the episcleritis often mirrors the severity of the dry eye disease.
Clinical features — Episcleritis is commonly acute in onset and may be either localized or diffuse; patients usually complain of the abrupt onset of redness, irritation, and watering of the eye [3,7]. Pain is unusual but can be observed with chronic or nodular episcleritis. Vision is not affected.
Physical examination reveals bright red episcleral discoloration caused by vasodilatation of the superficial episcleral vessels and edema of the episclera, without edema or thinning of the sclera (picture 1).
Approximately one-half of cases are bilateral. Bilateral involvement may be associated with an increased likelihood of an underlying inflammatory disease, but not all studies have confirmed this suggestion . Most attacks of simple episcleritis resolve within three weeks, with or without treatment.
In one series of 37 patients with episcleritis, the primary clinical features were as follows :
●The mean age was 45 years, with a range from 9 to 71 years.
●Seventy percent of the patients were female.
●Bilateral disease occurred in 49 percent.
●The great majority of patients (87 percent) had no ocular complications of their episcleritis. Among the five patients with complications, there were three cases of mild anterior uveitis, one case of uveitis and interstitial keratitis, and one case of elevated intraocular pressure.
An important point of this study is that none of the ocular complications were associated with reduced visual acuity. This contrasts with a group of 97 patients with scleritis collected over the same time period, among whom 59 percent had ocular complications and 16 percent had decreased visual acuity .
Patients with episcleritis associated with a systemic illness, but not those with isolated disease, are likely to have extremely high levels of acute phase reactants.
Systemic disease associations — The majority of patients with episcleritis do not have an underlying infectious or systemic inflammatory disease. In a study from a tertiary care medical center, 30 percent of patients had a systemic rheumatic disease and 5 percent had a systemic infection . Among the patients with an underlying systemic condition, the following individual diseases were detected:
●Rheumatoid arthritis – 11 percent of the overall cohort
●Inflammatory bowel disease – 8 percent
●Vasculitis – 5 percent
●Systemic lupus erythematosus – 3 percent
●Other rheumatic disease – 3 percent
●Herpes zoster ophthalmicus – 3 percent
●Lyme disease – 3 percent
Among community-based populations, the proportion of episcleritis patients who have an underlying systemic inflammatory or infectious condition is probably substantially lower.
DIAGNOSIS — The diagnosis of episcleritis should be strongly suspected in a patient with a history of the abrupt onset of redness, irritation, and watering of the eye, often without pain (except in more chronic disease or with nodular episcleritis), and with normal vision. The diagnosis is confirmed on physical examination, where typical findings include bright red episcleral discoloration caused by vasodilatation of the superficial episcleral vessels and edema of the episclera, without edema or thinning of the sclera (picture 1).
A referral to an ophthalmologist should be undertaken, generally within two to three weeks, for a full clinical evaluation, when possible, to minimize chances of a misdiagnosis (eg, labeling an early case of scleritis or an infectious keratitis as episcleritis), which may also require slit-lamp biomicroscopy. Accurate distinction between episcleritis and scleritis is critical. (See 'Differential diagnosis' below.)
Patients should also undergo a thorough history and physical examination at the time of initial diagnosis to determine if symptoms or signs of a related systemic condition may be present, in which case additional evaluation is required. (See 'Recurrent episcleritis or suspected systemic disease' below and 'Differential diagnosis' below.)
POSTDIAGNOSTIC EVALUATION FOR ASSOCIATED CONDITIONS — The extent of the evaluation for underlying conditions depends upon the presenting history and general examination and whether the patient is experiencing their initial episode or a recurrence. (See 'Initial episode of episcleritis' below and 'Recurrent episcleritis or suspected systemic disease' below.)
Initial episode of episcleritis — In a patient with a first episode of episcleritis, the only type of evaluation usually required in addition to a complete eye examination is a thorough general medical history and physical examination.
In a patient with a normal general history and physical examination, the patient should be reassured that the disorder is probably benign, and that additional investigations are needed only if episcleritis recurs or new symptoms develop. However, more extensive evaluation is required in patients with recurrent episcleritis, evidence of other ocular disease, or abnormal findings on the general history and physical examination.
Recurrent episcleritis or suspected systemic disease — Both routine and specialized serologic assays, a plain radiograph of the chest, and other testing, which may be dictated by specific findings that raise suspicion of particular underlying conditions, are important in the evaluation of patients suspected of having an underlying rheumatic or infectious illness.
When to refer — When a systemic disorder is suspected based upon the presence of symptoms or findings in addition to episcleritis, further laboratory testing should be obtained and the patient should be evaluated by their primary care clinician to determine if consultation with a rheumatologist or other specialist is most appropriate and for further evaluation and management (see 'Basic tests' below and 'Specialized serologic assays' below and 'Imaging' below and 'Other testing' below). However, most patients lack any features suggesting an underlying systemic disorder, such as a systemic rheumatic disease, inflammatory bowel disease, or an infectious disorder; thus, consultation and further testing is usually not required.
Basic tests — The following routine tests should be sent for all patients who are suspected, based upon their medical history or other systemic features, of having a systemic disease as the cause of their episcleritis [3,8]:
●Complete blood count – Patients with systemic conditions frequently have abnormalities of the white blood cell count, platelet count, or hematocrit.
●Serum chemistry profile – This should include creatinine, blood urea nitrogen, electrolytes, albumin, total protein, and aminotransferases.
●Urinalysis with microscopy – Urinalysis with microscopic examination of the urine sediment is essential to excluding glomerulonephritis and other renal disorders.
●Acute phase reactants – Patients with episcleritis associated with a systemic illness, but not those with isolated disease, are likely to have extremely high acute phase reactant levels. Both the erythrocyte sedimentation rate and serum C-reactive protein should be measured.
We do not advise an exhaustive systemic immunological workup unless either the medical history or review of systems are suggestive of a non-ocular immune-based disorder; or unless the patient has recurrent episcleritis, which is associated with an increased chance of an associated systemic disease.
Specialized serologic assays — Blood tests we usually obtain in patients suspected of an associated systemic disorder and which are targeted to specific systemic inflammatory diseases associated with episcleritis include:
●Rheumatoid factor – A positive rheumatoid factor assay is a nonspecific result, but extremely high titers of rheumatoid factor are usually found in the setting of rheumatoid vasculitis. (See "Rheumatoid factor: Biology and utility of measurement" and "Clinical manifestations and diagnosis of rheumatoid vasculitis".)
●Antibodies to cyclic citrullinated peptides – Antibodies to cyclic citrullinated peptides (anti-CCP antibodies) have a high specificity for rheumatoid arthritis. (See "Biologic markers in the assessment of rheumatoid arthritis".)
●Antineutrophil cytoplasmic antibodies – Antineutrophil cytoplasmic antibody (ANCA) assays are positive in most patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) and in a smaller proportion of patients with eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss). Patients with inflammatory bowel disease may also have ANCA.
If an immunofluorescence assay for ANCA is positive in either a cytoplasmic or perinuclear pattern (ie, C-ANCA or P-ANCA), then further investigation through specific enzyme immunoassays is important. Among the vasculitides, only antibodies to proteinase-3 (C-ANCA) or myeloperoxidase (one of a variety of P-ANCAs) have specific associations with GPA, MPA, and EGPA. Patients with inflammatory bowel disease typically have P-ANCAs that are directed against non-myeloperoxidase antigens, assays for which are not widely clinically available. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)
●Antinuclear antibody testing – Antinuclear antibody (ANA) testing is useful for the exclusion of connective tissue diseases related to systemic lupus erythematosus. A positive ANA assay should be followed by a rheumatology consultation and possibly by additional serologic testing to determine the specific disease responsible for the ANA positivity. Additional testing may include serum complement levels (C3, C4), antibodies to double-stranded DNA, and antibodies to the Ro, La, Sm, or RNP antigens. (See "Measurement and clinical significance of antinuclear antibodies".)
Imaging — A chest radiograph should be performed in patients suspected of having a systemic condition. Any abnormality detected on chest radiograph should be defined more completely by a computed tomography (CT) scan of the chest.
Other testing — Additional specialized testing (eg, endoscopic procedures to exclude inflammatory bowel disease in a patient with severe episcleritis) is mandated only if there are nonocular morbidities or elements in the medical history and physical examination suggestive of a particular condition.
DIFFERENTIAL DIAGNOSIS — Other disorders that may cause a red eye and other features that can resemble elements of episcleritis include subconjunctival hemorrhage, conjunctivitis, blepharitis, keratitis, scleritis, acute anterior uveitis, and acute angle-closure glaucoma. These conditions can generally be distinguished from episcleritis based upon the history and examination of the eye. The evaluation and differential diagnosis of the red eye is described in detail separately. (See "The red eye: Evaluation and management".)
Among the most important and most common conditions to distinguish from episcleritis are:
●Scleritis – Episcleritis must be distinguished from scleritis, a potentially dangerous cause of a red eye. In contrast to episcleritis, which is characteristically associated with bright red episcleral discoloration and not with pain (picture 1), classic cases of scleritis present with intense ocular pain, photophobia, and a deep-red or purplish scleral hue. In addition, in episcleritis, there is no edema or thinning of the sclera. Such changes in the sclera are readily visible with the aid of a slit-lamp biomicroscope. (See "Clinical manifestations and diagnosis of scleritis".)
In cases that are not classic, the distinction between these two disorders may be difficult on gross (unmagnified) physical examination alone. In such cases, the application of phenylephrine eye drops leads to swift, transient resolution of episcleral redness, permitting more careful evaluation of the underlying sclera.
●Conjunctivitis – Episcleritis must also be distinguished from conjunctivitis, a much more common cause of a red eye. Patients with all types of conjunctivitis (bacterial, viral, allergic) complain of morning crusting and daytime redness and discharge. Crusting and discharge (other than tearing from irritation) are not present in patients with episcleritis alone. (See "Conjunctivitis".)
In conjunctivitis, the erythema or injection of the eye is diffuse, involving the bulbar (globe) conjunctiva for 360 degrees as well as the palpebral or tarsal conjunctiva (the mucus membrane on the inner surface of the lids) (picture 3). If the conjunctival injection is localized rather than diffuse, episcleritis is more likely.
●Herpes keratitis – In contrast to herpetic keratitis, an important cause of a red eye and which can lead to severe ocular damage, episcleritis is usually not associated with pain. Herpes keratitis has an acute onset with variable symptoms of pain, visual blurring, and watery discharge. However, if there is any question about the diagnosis, immediate consultation with an ophthalmologist for a slit-lamp examination is essential before the start of therapy. (See "Herpes simplex keratitis".)
●Uveitis – A red eye is typical of both episcleritis and anterior uveitis, although episcleritis and uveitis can generally be distinguished from each other and other causes of a red eye on ophthalmic examination. In iritis (anterior uveitis), the redness is primarily noted at the limbus (the junction between the cornea and the sclera), in association with a constricted pupil and pain. The evaluation and differential diagnosis of uveitis is discussed in detail separately. (See "Uveitis: Etiology, clinical manifestations, and diagnosis".)
TREATMENT — Episcleritis is not sight-threatening and, in most patients, is an episodic, self-limited process; thus, symptomatic relief should be the goal of therapy. Indeed, many patients with episcleritis require no treatment per se since the condition typically resolves over a short course. For the achievement of symptomatic relief, there are four levels of therapy that we successively employ in the following sequence, depending upon the adequacy of the response to the initial and subsequent intervention:
●Topical nonsteroidal antiinflammatory drugs (NSAIDs)
For some of these treatment modalities, a handful of randomized clinical trials have been performed.
Initial therapy with topical lubricants — For initial management in patients bothered by their episcleritis, we suggest the application of topical lubricants. Any over-the-counter preparation of artificial tears (eg, Refresh Plus or Bion Tears) will suffice, provided it is used four to six times daily. In patients who require more frequent use for symptomatic relief, we suggest the use of preparations that do not contain preservatives in order to avoid preservative-induced toxicity. Preservative-free preparations can be used as frequently as required and for as long as the patient remains symptomatic.
A small randomized trial found similar effects on the signs and symptoms of episcleritis with artificial tears or topical ketorolac (an NSAID) . In this trial, involving treatment of 38 eyes in 37 patients for three weeks, 50 percent improvement in redness and pain was achieved within about four to six days in both groups.
Topical NSAIDs for persistent discomfort despite lubricants — In patients with significant discomfort, in whom topical lubricants are inadequate, we suggest a topical NSAID (eg, diclofenac ophthalmic drops two to four times daily for several weeks). It is important to exclude dry eyes or other ocular surface epithelial disorders before committing patients to topical NSAIDs, given the potential toxicity of these medications to such eyes. We do not use a topical NSAID as primary therapy, because they are often not needed and can cause ocular toxicity, especially in patients with ocular surface disease, such as dry eyes, who may develop non-healing epithelial defects .
Resistant to lubricants and topical NSAIDs — For patients who require therapy beyond topical NSAIDs, we suggest topical glucocorticoids (eg, fluorometholone acetate [0.1 percent] or prednisolone acetate [1 percent], four times daily). These medications are sufficient in more than 80 percent of cases. It is extremely important to emphasize that chronic glucocorticoid use is associated with a significantly increased risk of cataracts, glaucoma, secondary infection, and corneoscleral thinning. The use of topical glucocorticoids should be directed by an ophthalmologist and should be employed only when the patient remains highly symptomatic despite optimal use of other treatments.
A randomized, double-blind clinical trial indicated that fluorometholone acetate (0.1 percent) and prednisolone acetate (1 percent) were comparable in efficacy in the treatment of external ocular inflammation (conjunctivitis, episcleritis, and scleritis) .
●Oral NSAIDs – In patients who do not respond to topical therapies, or in those with recurrent disease despite such therapy, we suggest an orally administered NSAID. Therapy should be initiated with low doses (eg, naproxen 220 mg twice daily, ibuprofen 400 mg three times daily, or indomethacin 25 mg three times daily). Dose escalation, particularly of indomethacin, should be limited in older patients. These interventions have not been formally compared with other therapies, but in our experience patients usually respond to these medications with improvement in symptoms and findings.
●Oral glucocorticoids – Rarely, all the above strategies may fail in patients with nodular episcleritis. In such cases, a brief course of oral prednisone starting at 0.5 to 0.75 mg/kg daily with a quick taper over one to two weeks can help the resolution.
PROGNOSIS — Most patients with episcleritis have a mild, isolated problem that responds readily to topical therapy alone and does not pose a threat to vision, and many patients require no treatment since the condition typically resolves over a short course. A small fraction of patients with episcleritis have an underlying systemic disease that signifies a serious health concern and that requires additional therapy.
Although episcleritis does not produce significant ocular complications and does not impair vision, mild complications including corneal infiltrates and low-grade uveitis may rarely occur. (See 'Clinical features' above.):
●Small peripheral corneal infiltrates, visible only with the slit-lamp biomicroscope, are a rare occurrence, sometimes occurring despite treatment. These infiltrates represent inflammation within the stroma of the cornea. The changes are small, localized, and nonprogressive and do not affect vision. Patients with significant limbal or corneal inflammation should be followed more carefully to ensure that they do not progress to frank scleritis.
●Some patients develop transient low-grade anterior uveitis with severe attacks . Uveitis, defined as intraocular inflammation, is best diagnosed at the slit lamp by an ophthalmologist; however, the onset of photophobia, pain, and decreased vision should alert the clinician that uveitis has complicated a case. These patients may benefit from a short course of topical glucocorticoids. (See "Uveitis: Treatment".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Uveitis".)
SUMMARY AND RECOMMENDATIONS
●Definitions – Episcleritis is usually classified as either simple or nodular. Simple episcleritis is usually sectoral, confined to a carefully delimited portion of the episclera, but can also be diffuse, involving the entire surface of the eyeball (picture 1). Nodular episcleritis is raised and thus usually limited to just one area of the eyeball (picture 2). Nodular episcleritis is most frequently idiopathic but may be associated with any of the rheumatic conditions. Seventy percent of episcleritis patients are women. (See 'Epidemiology' above.)
●Etiology – The majority of patients with episcleritis do not have an underlying infectious or systemic inflammatory disease. The most common association, when one is present, is with a systemic rheumatic disease; inflammatory bowel disease, vasculitis, systemic infections, and other conditions may be seen. (See 'Systemic disease associations' above.)
●Diagnosis – The diagnosis of episcleritis should be strongly suspected in a patient with a characteristic clinical manifestations, including a history of the abrupt onset of redness, irritation, and watering of the eye, often without pain (except in more chronic disease or with nodular episcleritis), and with normal vision. The diagnosis is confirmed on physical examination, where typical findings include bright red episcleral discoloration caused by vasodilatation of the superficial episcleral vessels and edema of the episclera, without edema or thinning of the sclera (picture 1). Approximately one-half of cases are bilateral. (See 'Clinical manifestations' above and 'Diagnosis' above.)
A referral to an ophthalmologist for a full clinical evaluation should be undertaken, when possible, to minimize chances of a misdiagnosis. In a patient with a first episode of episcleritis, the only type of evaluation required in addition to a complete eye examination is a thorough history and physical examination.
Additional investigations beyond the initial clinical evaluation are needed only if episcleritis recurs, if there is evidence of other ocular disease, or if there are abnormal findings on the general history and physical examination. Both routine and specialized serologic assays are important in the evaluation of patients suspected of having an underlying rheumatic or infectious illness. (See 'Diagnosis' above and 'Postdiagnostic evaluation for associated conditions' above.)
●Differential diagnosis – Episcleritis must be distinguished carefully from scleritis, conjunctivitis, uveitis, and herpetic keratitis, and from other causes of red eye. (See 'Differential diagnosis' above.)
•Asymptomatic – For patients not bothered by the presence of episcleritis, treatment is generally not needed because symptoms and findings typically resolve over several weeks. (See 'Treatment' above.)
•Initial management – For initial management in patients bothered by the presence of episcleritis, we suggest artificial tear preparations that do not contain preservatives, such as Refresh Plus or Bion Tears (Grade 2B). (See 'Initial therapy with topical lubricants' above.)
•Refractory to topical lubricants – In patients in whom topical lubricants are inadequate, particularly those with significant discomfort, we suggest a topical nonsteroidal antiinflammatory drug (NSAID; eg, diclofenac ophthalmic drops two to four times daily for several weeks) (Grade 2C). It is important to exclude dry eyes or other ocular surface epithelial disorders before committing patients to topical NSAIDs, given the potential toxicity of these medications to such eyes. (See 'Topical NSAIDs for persistent discomfort despite lubricants' above.)
•Refractory to topical NSAIDs – In patients who remain highly symptomatic despite optimal use of topical lubricants and topical NSAIDs, we suggest topical glucocorticoids (eg, fluorometholone acetate [0.1 percent] or prednisolone acetate [1 percent], four times daily) (Grade 2C). Chronic glucocorticoid use is associated with a significantly increased risk of cataracts, glaucoma, secondary infection, and corneoscleral thinning; the use of topical glucocorticoids should be directed by an ophthalmologist. (See 'Resistant to lubricants and topical NSAIDs' above.)
•Refractory to topical agents – In patients who do not respond to topical therapies, or in those with recurrent disease despite such therapy, we suggest an orally administered NSAID (Grade 2C). Therapy should be initiated with low doses (eg, naproxen 220 mg twice daily, ibuprofen 400 mg three times daily, or indomethacin 25 mg three times daily). (See 'Resistant disease' above.)
●Prognosis – Most patients with episcleritis have a mild, isolated problem that responds to topical therapy alone and does not pose a threat to vision. Ocular complications are uncommon in episcleritis and are usually mild. However, a minority have an underlying systemic disease that requires additional therapy. In some patients, episcleritis is an early presentation of a more severe and destructive ocular immune problem such as scleritis. (See 'Prognosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John Stone, MD, who contributed to an earlier version of this topic review.
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