Atopic keratoconjunctivitis

Authors
Pedram Hamrah, MD
Reza Dana, MD, MPH, MSc
Section Editors
Bruce S Bochner, MD
Robert A Wood, MD
Deputy Editor
Elizabeth TePas, MD, MS
Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2013. | This topic last updated: Mei 23, 2012.
INTRODUCTION There are five main types of ocular allergy: seasonal allergic conjunctivitis (SAC),
perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis
(AKC), and giant papillary conjunctivitis (GPC). VKC and AKC are chronic, bilateral, and severe forms
of allergic inflammation affecting the ocular surface. These two relatively uncommon types of allergic
eye disease can cause severe damage to the ocular surface, leading to corneal scarring and vision
loss if not treated properly. Type I hypersensitivity reactions are important in these diseases, although
they are not the only pathophysiologic mechanism.

The term AKC is not ideal, as it is not specific and does not by itself differentiate AKC from other forms
of atopic eye disease. AKC in general refers to a "perennial" form of allergic conjunctivitis (AC) that
also has potential significant corneal involvement, where as VKC is the "seasonal" form (at least
initially) of AC that may affect the cornea. AKC is reviewed in this topic. VKC is discussed in detail
separately. (See "Vernal keratoconjunctivitis".)

GPC is an inflammatory disorder that represents a reaction to lid movement over a foreign substance,
such as contact lenses. 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. GPC and toxic conjunctivitis are discussed in detail separately. (See "Giant papillary
conjunctivitis" and "Toxic conjunctivitis".)

Seasonal and perennial allergic conjunctivitis, the most common forms of ocular allergy, are also
discussed separately. (See "Allergic conjunctivitis".)

EPIDEMIOLOGY AKC is a chronic allergic ocular disease that occurs most often in patients with a
history of atopic dermatitis [1,2]. The exact prevalence is unknown. However, 4.4 percent of 1079
patients with ocular allergy had AKC in one study [3]. Another study demonstrated that 77 percent of
patients with atopic dermatitis (AD) suffered from AKC [4], although a subsequent series noted lower
rates of AKC in patients with AD, in the range of 20 to 40 percent [5].

AKC primarily affects adults. Symptoms most commonly begin in the second and third decades, with
a peak incidence between 30 and 50 years of age. This is in contrast to VKC, in which the peak
incidence is between 7 and 12 years of age. However, onset of symptoms of AKC have been
described between 7 and 76 years of age. AKC has a male:female ratio of 2.4:1 [1]. Personal and
family histories are almost always positive for atopy (more commonly atopic dermatitis and asthma
than allergic rhinitis) [2].

PATHOGENESIS AKC consists of type IV (delayed-type) hypersensitivity reactions and some

involvement of type I hypersensitivity. There are increased numbers of mast cells, eosinophils, CD4+
T cells, monocytes, and fibroblasts in the conjunctiva compared with normal individuals
(see 'Histology' below) [6,7]. The strong upregulation of HLA-DR in the epithelium and substantia
propria shown by immunohistochemistry suggests a role in antigen presentation [8].
Elevated levels of IgE are observed in the tears and serum of AKC patients compared with normal
controls [6]. However, only about one-half of patients with AKC test positive to specific allergens.
Those that are sensitized to aeroallergens tend to be positive to multiple allergens. Tears contain
CD4+ T cells and B cells and increased levels of the cytokines IFN-gamma, TNF-alpha, IL-4, IL-5, and
IL-10 and the chemokine eotaxin compared with normal controls [7,9-11]. Patients with AKC may
show dysfunctional cell-mediated immunity, and occasionally have lower levels of circulating T cells
[12].

CLINICAL MANIFESTATIONS The most commonly reported symptom of AKC is intense itching,
which can occur perennially or only in certain seasons [1,6]. Tearing, clear mucus discharge, and
redness are also almost always present.

Other symptoms include:

Blurry vision

Burning

Photophobia

Foreign body sensation

PHYSICAL FINDINGS AKC can involve the eyelid, conjunctiva, and cornea [1,2,13]. There is a
wide range of severity, from mild isolated eyelid involvement to sight-threatening corneal involvement.
The severity can also be highly asymmetric even though involvement is typically bilateral.

Eyelid changes in AKC are usually quite striking (picture 1). Characteristic findings include:

Thickened eyelids

Intermittent swelling of the eyelids due to chronic inflammation

A profound 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, superciliary madarosis (loss of eyelashes), lateral canthal ulceration, and ptosis can
sometimes develop as well. Lid margins may show meibomianitis, keratinization, and punctal
ectropion (lacrimal puncta is everted). Blepharitis caused by staphylococcal bacteria is also common.
Eye rubbing is almost always reported.

Chronic ocular surface inflammation can lead to vision loss (picture 2). Signs of chronic ocular surface
inflammation include:

Conjunctival chemosis

Conjunctival hyperemia

Tarsal papillary hypertrophy

The papillary hypertrophy in AKC is more prominent in the inferior fornix. This is in contrast to vernal
keratoconjunctivitis (VKC) and giant papillary conjunctivitis (GPC), in which papillary formation occurs
on the upper lids. 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.

Other issues that involve the cornea with AKC and can lead to significant vision loss include:

Corneal neovascularization

Dry eyes

Infectious and sterile ulcers

Other eye disorders that are associated with AKC include:

Corneal thinning disorders

Herpetic keratitis

Retinal detachment

Several forms of cataracts

The use of corticosteroids frequently causes worsening of cataracts in these patients. Long-term eye
rubbing may or may not contribute to the other eye disorders associated with AKC.

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 [6-8,14]. In addition, large numbers of mononuclear cells are present in the
substantia propria.

DIAGNOSIS There are no established diagnostic criteria or laboratory tests for AKC. The diagnosis
of AKC is based upon the typical epidemiology and clinical features of AKC (eg, adults with a history
of atopic dermatitis who present with ocular pruritus, eyelid dermatitis, and giant papillae on the
conjunctival lining of the lower tarsus and inferior fornix). A clinical grading system was proposed to
aid in the diagnosis and management of AKC [13]. (See 'Epidemiology' above and 'Clinical
manifestations' above and 'Physical findings' above.)

Differential diagnosis The main disease to consider in the differential diagnosis is vernal
keratoconjunctivitis (VKC). However, in contrast to AKC, VKC occurs in prepubertal boys from warm
climates, symptoms are most often seasonal initially, and the upper tarsus (eyelid) is predominantly
affected.

TREATMENT The approach to patients with AKC is multi-pronged and includes topical and
systemic medications, as well as nonpharmacologic therapies.

Nonpharmacologic measures include avoidance of nonspecific triggers/environmental irritants, eye

rubbing, and known allergens (in patients with IgE-mediated disease) and use of cold compresses
and artificial tears. Punctal plugs are also used to prevent eye dryness. (See "Vernal
keratoconjunctivitis", section on 'Nonpharmacologic measures' and "Dry eyes".)
Topical antihistamines and mast cell stabilizers are generally the first line pharmacologic therapies.
Treatment with topical corticosteroids is best undertaken by an ophthalmologist. Patients who do not
respond to these therapies may benefit from an allergy evaluation and possibly allergen
immunotherapy, although data on efficacy are lacking. Additional medications that may be effective in
some patients include topical and systemic calcineurin inhibitors. (See "Allergic conjunctivitis", section
on 'Stepwise approach to therapy'.)

Mast cell stabilizers and dual acting agents Topical mast cell stabilizers are typically used as
daily, long-term, prophylactic therapy. Patients with perennial symptoms are treated year round. The
use of 2 percent sodium cromolyn reduced itching, tearing, and photophobia in one double-blind,
crossover trial, but was ineffective in another [15,16]. Dual acting mast cell stabilizers/antihistamines
(eg, lodoxamide, olopatadine,azelastine, or ketotifen) may be helpful as well, although there are no
randomized trials or observational studies using these drugs in AKC. (See "Vernal
keratoconjunctivitis", section on 'Topical antihistamines and mast cell stabilizers'.)

Topical corticosteroids Referral to an ophthalmologist is highly recommended for patients who do

not respond to two or three weeks of consistent therapy with an antihistamine/mast cell stabilizer
agent, since pulse therapy with topical corticosteroids is typically the next step.

There are few data on the efficacy of topical corticosteroids in treating AKC. In a double-blind trial of
38 patients with AKC, topical 2 percent sodium cromoglycate was applied every six hours in one eye
and 1 percent medrysone in the contralateral eye for four weeks [16]. Medrysone significantly
improved itching, watering, photophobia, and hyperemia (improved by 76, 64, 81, and 73 percent,
respectively), whereas cromolyn had little effect (improved by 12, 4, 7, and 2 percent, respectively).
As with VKC, application of prednisolone acetate eight times per day for approximately one week is
generally used for severe exacerbations, and twice per day dosing for two weeks of a "soft" steroid,
such as medrysone is used in milder cases. "Soft" corticosteroids have a lower risk of raising
intraocular pressure. The use of topical corticosteroids should be transient and monitored carefully.
(See "Vernal keratoconjunctivitis", section on 'Topical corticosteroids'.)

Topical calcineurin inhibitors Topical calcineurin inhibitors are generally used as steroid-sparing
agents. Unlike corticosteroids, these medications do not increase intraocular pressure. In one small
randomized trial, topical therapy with cyclosporine 2 percent four times daily was more effective than
placebo in reducing topical corticosteroid use and improving signs and symptoms in patients with AKC
[17]. Lower concentrations of cyclosporine have shown mixed results [18-20]. In a case series,
continuous therapy with topical tacrolimus led to moderate to marked improvement in the signs of
AKC in patients with severe disease [21]. (See "Vernal keratoconjunctivitis", section on 'Calcineurin
inhibitors'.)

Treatment of eyelid dermatitis Treatment of AKC also includes therapy for eyelid dermatitis.
Topical application of a low-potency corticosteroid to the eyelids two to four times per day for several
weeks may be required to suppress the allergic process in the 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.

An alternative to topical corticosteroids for treatment of eyelid dermatitis is topical calcineurin

inhibitors [22-24]. 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 a
topical corticosteroid, clobetasone, in patients with AKC [22]. Ocular signs and symptoms also
improved with topical tacrolimus therapy restricted to the eyelids in several case series [23,24].

Systemic immunosuppressive agents AKC, unlike the milder forms of allergic eye disease, is a
chronic and aggressive form of ocular surface inflammation associated with sight-threatening fibrosis.
Thus, systemic immunosuppressive therapy (eg, prednisone, cyclosporine, or tacrolimus) is
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 systemic calcineurin
inhibitors (cyclosporine 3 to 5 mg/kg 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 [25,26]. Co-management
with an ophthalmologist, internist, allergist, dermatologist, and/or rheumatologist is recommended to
maximize the outcome and minimize side effects in these difficult cases.

Other therapies

Oral nonsedating antihistamines are effective in the treatment of allergic conjunctivitis,

although no studies have been performed in patients with AKC. Activation of ocular H1
receptors via histamine is responsible for some AKC symptoms [2], suggesting that oral
antihistamines may be effective in these patients. (See"Vernal keratoconjunctivitis", section
on 'Oral antihistamines'.)

Plasmapheresis was effective in two patients with AKC who had failed to respond to topical
and oral corticosteroids and topical cromolyn [27].

Consultation with an allergist for allergy testing and consideration of allergen immunotherapy
is appropriate for patients with AKC. Allergy testing helps identify the offending allergen in
about one-half of patients [6] and helps guide measures to limit exposure. Adequate control of
environmental triggers is one of the most effective management tools for AKC. There is
evidence that allergen immunotherapy improves symptoms of ocular allergy [28]. However,
there are no reports demonstrating this specifically for AKC. (See "Vernal
keratoconjunctivitis", section on 'Nonpharmacologic measures' and "Subcutaneous
immunotherapy for allergic disease: Indications and efficacy", section on 'Allergic rhinitis and
conjunctivitis'.)

SUMMARY AND RECOMMENDATIONS

Atopic keratoconjunctivitis (AKC), unlike the milder forms of allergic eye disease, is a chronic
and aggressive form of ocular surface inflammation associated with sight-threatening fibrosis.
(See'Introduction' above.)

AKC primarily affects adults, with a peak incidence between 30 and 50 years of age. Patients
commonly have a history of atopic dermatitis. (See 'Epidemiology' above.)

The most frequently reported symptom of AKC is intense itching, which can occur perennially
or only in certain seasons. (See 'Clinical manifestations' above.)

AKC can involve the eyelid, conjunctiva, and cornea. The severity can be highly asymmetric,
even though involvement is typically bilateral. Eyelids are usually thickened and swell
intermittently. There is a profound scaly and indurated appearance to the periocular skin, with
flaking dermatitis and a reddened base. Ocular findings include conjunctival chemosis and
hyperemia, and tarsal papillary hypertrophy in the inferior fornix. (See 'Physical
findings' above.)

There are no established diagnostic criteria or laboratory tests for AKC. The diagnosis of AKC
is based upon the typical epidemiology and clinical features of AKC. (See 'Diagnosis' above.)
 The approach to patients with AKC includes topical and systemic medications, as well as
nonpharmacologic therapies. Treatments other than 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 and "Vernal
keratoconjunctivitis", section on 'Nonpharmacologic measures'.)

We recommend a topical mast cell stabilizer as first line therapy (Grade 2C). Alternatives are
a dual acting mast cell stabilizer and antihistamine or a combination of a separate topical
mast cell stabilizer and a topical antihistamine. (See" Topical antihistamines and mast cell
stabilizers" above).

We recommend a short-term, high-dose pulse regimen of topical corticosteroids in patients

with AKC who fail to respond to two to three weeks of a mast cell stabilizer or dual acting
antihistamine/mast cell stabilizer (Grade 2C). (See 'Topical corticosteroids' above.)

We recommend using topical cyclosporine 2 percent as a corticosteroid-sparing agent in

patients with moderate to severe disease who require frequent or prolonged courses of
topical corticosteroids (Grade 2C). (See 'Topical calcineurin inhibitors' above.)

We suggest treating eyelid dermatitis with topical tacrolimus, rather than topical
corticosteroids (Grade 2B). (See 'Treatment of eyelid dermatitis' above.)

We suggest systemic immunosuppressive therapy with cyclosporine or tacrolimus in severe

cases in which topical corticosteroids are ineffective or are required for longer than six weeks
(Grade 2C). (See'Systemic immunosuppressive agents' above.)

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