INTRODUCTION — Atopic keratoconjunctivitis (AKC) is a chronic, allergic ocular disease that occurs most often in adults with a history of atopic dermatitis (AD). Although less common than other forms of ocular allergy, AKC can cause severe damage to the ocular surface, leading to corneal scarring and vision loss if not treated properly.
The clinical manifestations, pathogenesis, diagnosis, and treatment of AKC are reviewed here. Other forms of allergic ocular disease are discussed elsewhere:
●(See "Vernal keratoconjunctivitis".)
●(See "Giant papillary conjunctivitis".)
EPIDEMIOLOGY — AKC is a chronic, perennial eye disease that typically occurs in patients with a history of atopic dermatitis (AD) [1,2]. The exact prevalence is unknown, although about 4 percent of patients with ocular allergy had AKC in one large study . Among patients with AD, studies have reported varying estimates of how many patients also have AKC, ranging from 20 to 77 percent [4,5]. Approximately 5 percent of patients with AKC do not have AD [6,7].
AKC usually begins in late adolescence or early adulthood, with a peak incidence between 30 and 50 years of age. However, onset of symptoms of AKC has been described between 7 and 76 years of age. AKC has a male:female ratio of 2.4:1 . Personal and family histories are almost always positive for atopy (more commonly AD and asthma than allergic rhinitis) .
PATHOGENESIS — AKC consists of type IV (delayed-type) hypersensitivity reactions and some involvement of type I hypersensitivity.
Tears in patients with AKC contain CD4+ T cells and B cells and increased levels of the cytokines interferon-gamma, tumor necrosis factor-alpha, interleukin (IL)-4, IL-5, and IL-10, and the chemokine eotaxin compared with normal controls [8-11]. Patients with AKC may show dysfunctional cell-mediated immunity and occasionally have lower levels of circulating T cells , although this is not used in diagnosis. Elevated levels of immunoglobulin (Ig)E are observed in the tears and serum of AKC patients compared with normal controls . Allergy testing identifies specific sensitivities in about one-half of patients .
On histology, the conjunctival epithelial layer is thickened in AKC. The conjunctival epithelium and substantia propria of AKC patients show elevated numbers of mast cells and eosinophils; increased fibroblast numbers and collagen amount; and an increased CD4+:CD8+ ratio of T cells compared with normal individuals [8,13-15]. In addition, large numbers of mononuclear cells are present in the substantia propria.
Symptoms and signs — The most commonly reported symptom of AKC is intense itching, which usually occurs perennially, although some patients report seasonal exacerbations [1,13]. Tearing, burning, clear mucus discharge, and redness are also almost always present. Other symptoms include blurry vision, photophobia, and foreign body sensation. Most patients rub their eyes incessantly. Chronic ocular surface inflammation can lead to vision loss.
Physical findings — AKC can involve the eyelid, conjunctiva, and cornea [1,2,16]. There is a wide range of severity, from mild isolated eyelid involvement to sight-threatening corneal involvement. Both eyes are usually involved, although the severity may be asymmetric.
Eyelid changes in AKC are usually quite striking (picture 1). Characteristic findings include:
●Intermittent swelling of the eyelids due to chronic inflammation
●A scaly and indurated appearance to the periocular skin, with flaking dermatitis and a reddened base
Eyelids may become lichenified and woody, developing cicatricial ectropion (lower eyelid turns outward or everts due to scarring) and lagophthalmos (failure to close the eyelids completely). Fissures, loss of eyelashes, lateral canthal ulceration, and ptosis can sometimes develop as well. Eyelid margins may show meibomianitis, keratinization, and punctal ectropion (lacrimal puncta are everted). Coexisting blepharitis caused by staphylococcal bacteria is also common. Over time, the periorbital skin may become hyperpigmented (picture 2) .
Associated and complicating conditions
●Infectious and herpetic ulcers
●Ocular infection with Staphylococcus aureus
●Corneal thinning disorders (eg, keratoconus) and corneal perforation 
●Retinal detachment (presenting with symptoms of increased floaters, flashes, or black curtains in the eye) (see "Approach to the adult with acute persistent visual loss", section on 'Retinal detachment')
EVALUATION AND DIAGNOSIS — The diagnosis should be suspected in a patient with a history of atopic dermatitis (AD) who presents with ocular itching and eyelid dermatitis. Generalists should examine the skin, eyes, and eyelids. AKC is typically bilateral, so unilateral disease should prompt consideration of other disorders.
A general skin examination should be performed if the diagnosis of AD (eczema) has not already been established. Dry skin and severe itching are the cardinal signs of AD. Acute AD is characterized by intensely itchy erythematous papules and vesicles with exudation and crusting, whereas subacute or chronic lesions present as dry, scaly, or excoriated erythematous papules (picture 5). Skin thickening from chronic scratching (lichenification) and fissuring may develop over time (picture 6). (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)
When to refer — All patients with suspected AKC, regardless of severity, should be referred to an ophthalmologist. Every patient requires a thorough ophthalmologic examination to ensure that corneal and conjunctival pathology, in particular, is identified and managed appropriately. A thorough slit-lamp examination of the cornea, bulbar, and palpebral conjunctiva will be performed by the ophthalmologist. In moderate-to-severe cases, patients are then referred to a cornea and external disease specialist.
Ocular examination — Definitive diagnosis is made by an ophthalmologist, based on characteristic signs and symptoms. There are no established diagnostic criteria or laboratory tests for AKC.
Signs of chronic ocular surface inflammation include (picture 4):
●Tarsal papillary hypertrophy
Upon slit-lamp evaluation, the papillary hypertrophy in AKC is most prominent in the inferior fornix. In addition, papillae may form adjacent to the cornea as perilimbal gelatinous hyperplasia. Subepithelial fibrosis is common, but forniceal shortening and symblepharon (adhesion of the eyelid to the globe) may also form.
Giant papillae may be detected on the conjunctival lining of the lower tarsus and inferior fornix. Giant papillae may also be present on the conjunctival lining of the upper eyelids. However, this finding is common in many other ocular diseases and with contact lens use or foreign body (eg, exposed suture), so if the majority of the papillae are on the upper eyelids, these other conditions should be considered.
DIFFERENTIAL DIAGNOSIS — There are four other main types of ocular allergy: seasonal allergic conjunctivitis, perennial allergic conjunctivitis, vernal keratoconjunctivitis (VKC), and giant papillary conjunctivitis. Of these, VKC is the primary disorder in the differential diagnosis of AKC. Other disorders that may resemble mild AKC include toxic conjunctivitis, blepharitis, and rosacea.
●VKC – VKC most often occurs in prepubertal boys from warm climates. The peak incidence of VKC is between 7 and 12 years of age. Symptoms are most often seasonal initially, and the upper tarsus (eyelid) is predominantly affected. In contrast, AKC usually affects adults, and symptoms are present perennially, although there may be seasonal exacerbations if the patient has coexisting seasonal allergies. Patients with VKC often develop giant papillae on the conjunctival lining of the upper eyelid, whereas the papillary hypertrophy in AKC is more prominent in the inferior fornix. Both VKC and AKC can affect the cornea and threaten sight, and referral to an ophthalmologist is indicated. VKC is discussed in more detail separately. (See "Vernal keratoconjunctivitis".)
●Toxic conjunctivitis – Toxic conjunctivitis is not allergic in nature, but it is frequently confused with allergic ocular disease. It develops with protracted use of topical medications, mostly due to preservatives. It is not associated with atopic dermatitis (AD). This disorder is discussed in detail separately. (See "Toxic conjunctivitis".)
●Blepharitis – Blepharitis is a common inflammatory disorder of the eyelids, which presents with chronic eye irritation, often accompanied by eye redness (picture 7). Characteristic waxy scaling in the eyelashes may be present. Symptoms may flare episodically. Blepharitis is associated with seborrhea and facial rosacea, whereas most patients with AKC have AD. (See "Blepharitis".)
●Ocular rosacea – Ocular rosacea presents with burning, itching, foreign body sensation, dryness, tearing, or photophobia. The most common findings in patients with ocular rosacea are blepharitis, eyelid margin telangiectasias, and conjunctival hyperemia. Some patients may have cutaneous rosacea (erythematous rash and telangiectasias in the malar areas), but others may not. The eyelids in patients with rosacea are erythematous, whereas the eyelids in AKC are more thickened and hyperpigmented.
COMPLICATIONS — Complications of AKC include several forms of cataracts, which may result from AKC itself or from corticosteroid therapy. Vision loss may result from corneal scarring and chronic corneal ulceration. Other less predictable complications are discussed above. (See 'Associated and complicating conditions' above.)
TREATMENT — The treatment of AKC includes basic eye care as well as topical and sometimes systemic medications. Our approach in adults and children is similar, although data in children are lacking [18-20].
Our approach — All patients should be evaluated by an ophthalmologist and counseled in basic eye care. We usually begin treatment with dual-action agents (ie, agents with both mast cell-stabilizing and antihistamine actions). If symptoms do not improve sufficiently, a brief course of topical corticosteroids is the next step. For patients who have trouble controlling symptoms when topical corticosteroids are reduced, we add topical calcineurin inhibitors as steroid-sparing agents. Most patients have adequate control with these measures over time, but a small percentage require systemic immunosuppressive therapies.
Basic eye care — There are several general measures that are helpful to most patients:
●Patients should not rub their eyes, because rubbing can cause mechanical mast cell degranulation and worsening of symptoms, which requires thorough patient education.
●Cool compresses can help reduce eyelid and periorbital edema.
●Frequent use of refrigerated artificial tears throughout the day can help patients with concomitant dry eye.
Mild disease — The primary topical agents used in mild AKC are antihistamines with mast cell-stabilizing properties, corticosteroids, and calcineurin inhibitors.
Antihistamines/mast cell stabilizers — Topical antihistamines with mast cell-stabilizing properties are typically used as daily, long-term prophylactic therapy, based on their efficacy in other allergic eye diseases. Stabilization of mast cells prevents release of histamine and other proinflammatory mediators from mast cells in the ocular tissues. There are no randomized trials or observational studies using these drugs in AKC. Specific medications include olopatadine (Patanol, Pataday, Pazeo [brand names]), alcaftadine (Lastacaft [brand name]), bepotastine (Bepreve [brand name]), azelastine hydrochloride (Optivar [brand name]), epinastine (Elestat [brand name]), ketotifen fumarate (generic, Ketotifen [brand name]), and emedastine (Emadine [brand name]). Ketotifen fumarate and olopatadine are available without a prescription (in the United States).
Dosing is twice per day for most products. Pataday, Pazeo, and Lastacaft (brand names) are once-daily preparations. It may take two to three weeks to see the full effect of these agents and for symptoms to subside.
Common side effects include stinging and burning upon instillation. Patients may find it helpful to refrigerate the drops and/or use refrigerated artificial tears before using these medications. Other adverse effects include headache and increased ocular dryness.
Additional therapies for resistant disease — Additional therapies for symptoms that persist despite a mast cell stabilizer/antihistamine include topical corticosteroids and calcineurin inhibitors.
Topical corticosteroids — For patients who do not respond to two or three weeks of consistent therapy with a mast cell stabilizer/antihistamine, pulse therapy with topical corticosteroids is appropriate. Topical corticosteroids are used to gain control of the inflammation so that mast cell stabilizers/antihistamines and artificial tears have a greater chance of working. Patients should be referred to an ophthalmologist for this therapy, as it should be monitored carefully and only used for brief periods of time. Long-term use of topical corticosteroids increases the risk of cataract formation, glaucoma, and serious eye infections (eg, herpes keratitis).
●For mild-to-moderate symptoms, we suggest one of several "soft" ester steroids, such as loteprednol 0.5 or 0.2%, prednisolone acetate 0.12%, fluorometholone ointment, and rimexolone 1%. We prefer loteprednol etabonate 0.5%, applied twice per day for two weeks. Greater than six weeks of use is associated with an increased risk of complications. The soft steroids undergo rapid inactivation upon penetration of the cornea and have decreased ocular penetration. They are therefore less likely to cause elevations of intraocular pressure.
●For severe symptoms, we use prednisolone acetate (1% suspension), eight times per day for approximately one week. This can be reduced to four times daily and then tapered slowly with close follow-up.
Data on the efficacy of topical corticosteroids in treating AKC are limited. In a double-blind trial of 38 patients with AKC, topical 2% sodium cromoglycate (a mast cell stabilizer without antihistamine properties) was applied every six hours in one eye and 1% medrysone in the contralateral eye for four weeks . Medrysone (discontinued in the United States) significantly improved itching, watering, photophobia, and hyperemia, whereas cromolyn had little effect.
Topical calcineurin inhibitors — Topical calcineurin inhibitors are also used for refractory symptoms. They have the advantage of not increasing intraocular pressure . However, they act more slowly than topical corticosteroids, and the availability of these agents often limits their use. Only one preparation (cyclosporine ophthalmic 0.05% solution) is commercially available in the United States. Preparations of cyclosporine (1 and 2% solutions) and tacrolimus (0.03% solution) can be compounded. Adverse effects include stinging and eyelid maceration. (See "Vernal keratoconjunctivitis", section on 'Calcineurin inhibitors'.)
●Trial data are limited. In one small, randomized trial, topical cyclosporine (2% four times daily) was more effective than placebo in reducing topical corticosteroid use and improving signs and symptoms in patients with AKC . We prefer this to the commercially available 0.05% cyclosporine solution, as lower concentrations of cyclosporine have shown mixed efficacy [24-27].
●Evidence for the efficacy of tacrolimus is limited to case series. In a series of 30 children and young adults with severe AKC refractory to topical corticosteroids, 0.1% tacrolimus suspension was effective over the course of one year in controlling symptoms and allowing for reduction in corticosteroid dose . Three cases of herpetic keratitis developed during treatment but were managed successfully with antiviral medications. In a smaller study of five patients with severe AKC, continuous therapy with topical tacrolimus led to significant improvement as well . Topical tacrolimus ointment has also been used to treat associated eyelid eczema .
Systemic immunosuppressive agents — Systemic immunosuppressive agents (eg, prednisone, cyclosporine, or tacrolimus) are sometimes used in severe cases in which topical corticosteroids are ineffective or are required for longer than six weeks. Three small case series found that long-term therapy with oral calcineurin inhibitors (cyclosporine, 3 to 5 mg/kg daily or tacrolimus, 0.03 to 0.08 mg/kg daily) was generally safe and resulted in complete remission in most patients with severe, refractory AKC [31,32]. Comanagement with an ophthalmologist, internist, allergist, dermatologist, and/or rheumatologist is recommended to maximize the outcome and minimize side effects in these difficult cases.
●Oral, nonsedating antihistamines, including fexofenadine, loratadine, desloratadine, cetirizine, and levocetirizine, have demonstrated efficacy in the treatment of allergic conjunctivitis, although no extensive studies have been performed specifically in patients with AKC. Activation of ocular H1 receptors via histamine is responsible for some AKC symptoms , suggesting that oral antihistamines may be helpful. We use oral antihistamines when topical treatment alone does not control itching sufficiently. (See "Vernal keratoconjunctivitis", section on 'Add-on initial therapy for moderate-to-severe disease'.)
●Allergen immunotherapy may be helpful for patients with AKC and environmental allergies, based on its efficacy in allergic conjunctivitis and in some patients with atopic dermatitis (AD) . Immunotherapy for AKC specifically has not be studied. Consultation with an allergist for allergy testing and administration of immunotherapy is required. Allergists can also guide measures to limit exposure to the allergens that are relevant to that patient. (See "Subcutaneous immunotherapy (SCIT) for allergic rhinoconjunctivitis and asthma: Indications and efficacy".)
Treatment of eyelid dermatitis — Treatment of AKC also involves therapy for eyelid dermatitis. Topical calcineurin inhibitors, such as topical tacrolimus (1%) and pimecrolimus (1%) ointments, are preferred because they have fewer long-term side effects [34-37]. In a randomized, crossover trial, there was a nonsignificant trend toward superior benefit of topical tacrolimus in reducing signs and symptoms of eyelid eczema compared with the topical corticosteroid clobetasone in patients with AKC . Ocular signs and symptoms also improved with topical tacrolimus therapy restricted to the eyelids in several case series [35,36]. Once the symptoms have improved, the frequency of application can be reduced to the lowest dose that maintains symptom control.
Low-potency topical corticosteroid ointments, such as fluorometholone or loteprednol, are also options for refractory symptoms. These may be applied to the eyelids two to four times per day for several weeks to treat inflamed periocular skin. However, patients should be warned that prolonged use of corticosteroids on the skin can lead to dermal thinning. Additionally, these patients should be monitored by an ophthalmologist for ocular side effects because of the permeability of corticosteroids through the skin.
PROGNOSIS — With therapies, most patient's symptoms can be adequately controlled, and vision impairment or loss is rare.
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: Allergic eye disease".)
SUMMARY AND RECOMMENDATIONS
●Atopic keratoconjunctivitis (AKC) is a chronic and aggressive form of ocular allergy that occurs most often in adults with a history of atopic dermatitis (AD). If not treated properly, AKC can damage the ocular surface, leading to corneal scarring, keratoconus due to persistent eye rubbing, and vision loss. (See 'Introduction' above and 'Epidemiology' above.)
●AKC is characterized by intense ocular itching, which can occur perennially or only in certain seasons. Most patients rub their eyes incessantly. Tearing, clear mucus discharge, and redness are also almost always present. Other symptoms include blurry vision, burning, photophobia, and foreign body sensation. (See 'Symptoms and signs' above.)
●AKC involves the eyelid, conjunctiva, and cornea. The eyelids may thicken, swell intermittently, and acquire a scaly and indurated appearance, with flaking dermatitis and a reddened base (picture 1). Ocular findings include conjunctival chemosis and hyperemia. (See 'Physical findings' above.)
●AKC should be suspected in a patient with a history of AD who presents with ocular itching and eyelid dermatitis. Referral to an ophthalmologist should be pursued in all patients with suspected AKC, regardless of severity. The diagnosis is based upon typical epidemiology and clinical features. Routine laboratory tests are not helpful, and there are no established diagnostic criteria. (See 'Evaluation and diagnosis' above.)
●The approach to patients with AKC includes basic eye care, topical medications, and systemic medications, if needed. We suggest a topical, dual-acting antihistamine/mast cell stabilizer as first-line therapy (Grade 2C). Specific medications include olopatadine (Patanol, Pataday, Pazeo [brand names]), alcaftadine (Lastacaft [brand name]), bepotastine (Bepreve [brand name]), azelastine hydrochloride (Optivar [brand name]), epinastine (Elestat [brand name]), ketotifen fumarate (generic, Ketotifen [brand name]), and emedastine (Emadine [brand name]). Treatments beyond first-line therapies (eg, topical corticosteroids and calcineurin inhibitors and systemic immunosuppressive agents) should be initiated only in consultation with an ophthalmologist. (See 'Treatment' above.)
●For patients with AKC who fail to respond to two to three weeks of a mast cell stabilizer or dual-acting antihistamine/mast cell stabilizer, we suggest a brief course of topical corticosteroids (Grade 2C). This should only be administered under the guidance of an ophthalmologist. (See 'Topical corticosteroids' above.)
●We suggest using topical cyclosporine (2%, compounded) as a steroid-sparing agent in patients with resistant or moderate-to-severe disease who require frequent or prolonged courses of topical corticosteroids (Grade 2C). As with topical corticosteroids, cyclosporine should only be administered under the guidance of an ophthalmologist. (See 'Topical calcineurin inhibitors' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟