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Vernal 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: Apr 23, 2012.
INTRODUCTION There are five main types of ocular allergy: seasonal allergic conjunctivitis,
perennial allergic conjunctivitis, 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 (this occurs more commonly with AKC than VKC). Type I hypersensitivity
reactions are important in these diseases, although they are not the only pathophysiologic
mechanism. VKC is reviewed in this topic. AKC is discussed separately. (See "Atopic
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 is 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 VKC most commonly occurs in boys living in warm, dry subtropical climates,
such as the Mediterranean, the Middle East, central and west Africa, South America, and Asian
countries, such as Japan, Thailand, and India [1]. The limbal form of VKC is seen most often in dark-
skinned individuals from Africa and India. VKC is generally rare in cooler climates, such as Northern
Europe and the temperate areas of North America. However, the prevalence in these regions has
increased, probably due to immigration of individuals from susceptible populations [2].

Exacerbations are common in the spring (hence the name "vernal"), although reactivation often
occurs in the winter. Initially the exacerbations are seasonal, but perennial attacks increase after a few
years.

Males are more commonly affected than females. In one series, the male to female ratio was 3.2:1 in
patients <20 years of age, but was nearly equal in older patients [3]. Age at onset is generally before
10 years, with the earliest reported onset at five months of age [4], although VKC can infrequently
occur in adults. Patients usually "outgrow" the disease with the onset of puberty.

VKC is associated with other atopic manifestations in approximately one-half of patients [3,5]. The
most common concomitant atopic diseases are asthma and allergic rhinitis. Aeroallergen
sensitization, by skin prick testing or allergen-specific immunoassay, was reported in over 50 percent
of patients in one study [3]. A family history of atopy was also reported in about one-half of patients in
this same study. In another study, atopy was more common in patients with the palpebral, or tarsal
form of the disease, compared with the limbal form [6].
PATHOGENESIS The exact pathogenic mechanisms of VKC are not fully elucidated. Classic IgE-
mediated hypersensitivity and T helper cell type 2 (Th2)-mediated responses are thought to play a
major role [5,7-9], but other mechanisms may be involved, including IgG-mediated responses,
basophil hypersensitivity, and cellular delayed-typed hypersensitivity.

Evidence supporting an atopic origin for VKC includes the following:

Seasonal incidence

Increased number of eosinophils and mast cells in conjunctival specimens

High levels of IgE in serum and tears

Increased levels of mediators derived from mast cells and eosinophils, including histamine
and tryptase, in tears

Therapeutic response to mast cell stabilizers

Conjunctival accumulation of T helper type 2 (Th2) CD4+ cells may give rise to hyperreactivity against
substances that commonly contact the conjunctiva. Offending allergens include pollens, dust mites,
molds, and animal epithelium [6,10,11]. Nonspecific stimuli, such as wind, sunlight, and heat also
probably play a role [12,13].

Mast cells play a key role in the development of IgE-mediated reactions. In addition, they release
mediators that stimulate fibroblast activity and production of collagens I and III, resulting in the typical
formation of giant papillae in VKC [14]. Histamine, interleukins, and other inflammatory mediators are
found in elevated levels in the tears of VKC patients [15-17]. In addition, there is increased expression
of histamine receptors (H1, H2, and H4 receptors) in conjunctival tissue [18]. The necessary vascular
supply of the forming giant papillae is provided by capillary proliferation. Chronic conjunctival
inflammation in VKC is associated with increased staining of mediators that may stimulate vascular
proliferation [19].

CLINICAL MANIFESTATIONS Almost all patients with VKC note ocular pruritus [1,3].

Other symptoms of VKC include (in approximate order of frequency):

Photophobia

Thick mucus discharge

Tearing

Burning

Foreign body sensation

Pain

Blurred vision

VKC is named as such because severe symptoms most commonly occur in the spring (hence
"vernal"), at least in the first few years of the disease. In one series of 195 patients, symptoms began
in March/April in over three-quarters of patients and resolved in September in one-third [3]. However,
approximately two-thirds of patients noted the occurrence of severe episodes year-round and over
one-fifth had chronic symptoms since disease onset. An additional 12 percent of patients went on to
have chronic symptoms.

PHYSICAL FINDINGS Bilateral eye involvement and presence of giant cobblestone-like papillae
on the upper tarsal conjunctiva (conjunctiva lining the upper eyelid) are nearly universal findings in
patients with VKC [1,3].

Other signs of VKC include (in approximate order of frequency):

Conjunctival and episcleral hyperemia

Superficial keratopathy

Sticky, nonpurulent mucus discharge

Horner-Trantas dots

Corneal shield ulcers

Ptosis

Blepharospasm

Examination of VKC patients may reveal a predominance of upper tarsal signs (palpebral VKC),
limbal signs (limbal VKC), or a combination thereof:

The tarsal or palpebral form involves the part of the conjunctiva that covers the inside of the
eyelid (tarsus). Upper tarsal papillae are discrete, enlarged (>1 mm), and give rise to a classic
"cobblestone" appearance with flattened tops (picture 1). Subepithelial fibrosis resulting from
papillae hypertrophy can cause increased eyelid thickening and ptosis. Thick, ropy, mucus
secretions are usually present and associated with tarsal papillae. Cytologic examination of
mucus secretions reveals a predominance of eosinophils. Physical findings are generally
confined to the cornea and conjunctiva, and rarely involve the skin or lid margins.

The limbal form involves the limbus of the eye, the thin border between the cornea and the
sclera. Gelatinous, confluent, yellow-gray infiltrates (Horner-Trantas dots) are pathognomonic
of the limbal form of the disease (picture 2). Punctate collections of epithelial cells,
eosinophils, and calcified corneal concretions may also be observed. Other corneal signs,
which may also be sight-threatening, include superficial peripheral neovascularization,
punctate corneal epitheliopathy, shield ulcers, subepithelial scarring, and plaque formation
secondary to accumulation of inflammatory debris. Shield ulcers are usually found in the
upper half of the visual axis (picture 3). After resolution, the ulcerated area leaves a ring like
scar. Vision loss in VKC is uncommon, but can occur due to corneal scarring,
neovascularization, and amblyopia.

HISTOLOGY Histologic analysis of ocular tissue reveals proliferative changes in the epithelium,
cellular infiltration of the substantia propria, and hyperplasia of connective tissue [3,14]. The
inflammatory infiltrate includes eosinophils, neutrophils, basophils, lymphocytes, plasma cells, mast
cells, and fibroblasts. Conjunctival scrapings of VKC patients show a predominance of eosinophils,
while basophils, neutrophils, and lymphocytes are rare. Increased numbers of mast cells, eosinophils,
and lymphocytes are seen in conjunctival biopsies.

DIAGNOSIS There are no established diagnostic criteria or laboratory tests for VKC. The diagnosis
of VKC is based upon the typical epidemiology and clinical features of VKC (eg, young boys living in
warm climates who present with ocular pruritus and giant papillae on the conjunctival lining of the
upper eyelid). A clinical grading system was proposed to aid in the diagnosis and management of
VKC [20,21]. (See 'Epidemiology' above and'Clinical manifestations' above and 'Physical
findings' above.)

Differential diagnosis The main disease to consider in the differential diagnosis is atopic
keratoconjunctivitis (AKC). However, in contrast to VKC, AKC is perennial from the outset, affects
predominantly the lower tarsus (eyelid), and commonly presents with vision-threatening corneal scars
and neovascularization.

TREATMENT Therapy for VKC is long-term and requires frequent follow-up. The management
approach includes both pharmacologic and nonpharmacologic therapies [22].

Topical antihistamines and mast cell stabilizers are 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. Additional
medications that may be effective in some patients include calcineurin inhibitors, nonsteroidal
antiinflammatory drugs, and oral antihistamines.

A proposed grading system may aid in choice of treatment [21]. A more severe baseline grade, a
younger age of onset, and a higher rate of recurrences of ocular inflammation were all associated with
a worse visual outcome in a series of 110 patients, suggesting more aggressive treatment may be
appropriate in these higher-risk patients [21].

Treatment of underlying conditions, such as blepharitis, is also necessary for successful management
of VKC. (See "Blepharitis".)

Nonpharmacologic measures Several nonpharmacologic measures include:

Avoidance of nonspecific triggers, such as wind, heat, salt water, and sunlight whenever
possible

Avoidance of eye rubbing, as it leads to a mechanical mast-cell degranulation, as well as


exacerbation of the allergic process

Avoidance of known allergens in patients with IgE-mediated disease (this can be challenging,
as patients with VKC can react to multiple allergens)

Artificial tears, especially in patients who develop tear film insufficiency due to the anti-
cholinergic effect of systemic antihistamines

Cold compresses

Topical antihistamines and mast cell stabilizers Topical dual acting mast cell stabilizers and
antihistamines are typically chosen as first line therapy and should be used on a daily basis
throughout the affected season. Alternatives are a combination of a separate topical mast cell
stabilizer and a topical antihistamine or a mast cell stabilizer alone. However, the dual agents were
more effective than mast cell stabilizers alone in studies using a conjunctival allergen challenge model
[23-28]. Topical antihistamines alone are minimally effective for VKC and are not used as
monotherapy.

These agents have two main actions:

As mast cell stabilizers, they inhibit mast cell degranulation, which is the first step is the
allergic cascade. They also inhibit leukocyte activity and dampen mediator release from mast
cells, basophils, eosinophils, and neutrophils.

As antihistamines, they competitively and reversibly block histamine receptors in the


conjunctiva and eyelids, thus blocking the actions of the primary mast cell-derived mediator
[29]. This also helps reduce the late phase of the allergic response.

Dual acting agents include olopatadine, azelastine HCl, epinastine, pemirolast potassium,
andketotifen fumarate. These drugs have been studied extensively in seasonal and perennial allergic
conjunctivitis [30-32]. However, there are only a few nonrandomized studies on use of these drugs,
specifically olopatadine and ketotifen, in patients with VKC [28,33].

In one observational study, topical olopatadine hydrochloride 0.1 percent significantly decreased most
signs and symptoms of VKC, including itching, tearing, burning, mucus discharge, conjunctival
hyperemia, and corneal involvement after two months of therapy [28]. However, photophobia and
limbal papillae did not improve significantly. In another observational study, patients treated
with ketotifen had greater improvement in itching, tearing, conjunctival hyperemia, mucus discharge,
and photophobia after three weeks of therapy than patients treated with olopatadine [33].

Ketotifen fumarate is available in a generic formulation and is over-the-counter in the United States.
Common side effects of these medications include stinging upon instillation and headache. The dual
acting agents alone may be sufficient to treat mild acute symptoms. However, addition of a topical
corticosteroid is generally required to gain control in patients with moderate to severe acute
symptoms. (See "Allergic conjunctivitis", section on 'Stepwise approach to therapy'.)

Topical mast cell stabilizers include cromolyn sodium [34], nedocromil sodium [35,36],
and lodoxamide [37,38]. Mast cell stabilizers have repeatedly been shown to be effective in patients
with VKC [34-38]. In particular, efficacy of topical cromolyn was demonstrated in several small
randomized trials [39]. In one of these trials, 4 percent cromolyn sodium demonstrated significant
improvement in conjunctival and limbal injection, limbal edema, tearing, and symptoms summary
score compared with placebo [34]. In this study, cromolyn was more effective in patients with
evidence of IgE-mediated disease. Subsequent studies demonstrated that lodoxamide was more
efficacious than cromolyn sodium [37,38]. The onset of action of these drugs is 5 to 14 days after
initiation of therapy. Thus, these drugs are NOT useful for acute symptoms. In addition, dosing of mast
cell stabilizers is four times daily, compared to twice daily for most agents with combined actions.
These features may limit patient compliance.

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 topical corticosteroids are typically the next line of therapy.

Observational studies and one randomized trial have shown that topical corticosteroids are effective in
treating VKC [3,35,40]. In the randomized trial, a two week course of fluorometholone 0.1 percent was
more effective thannedocromil 2 percent in decreasing signs and symptoms of VKC, including
papillary hypertrophy, Horner-Trantas dots, mucus discharge, conjunctival hyperemia, and tearing
[35].
Corticosteroids suppress the late phase reaction in both experimental and clinical settings. These
drugs, in part, limit the inflammatory cascade by inhibiting phospholipase A2. Consequently, they
reduce the formation of lipid-derived mediators from arachidonic acid, which prevents leukocyte
migration, hydrolytic enzyme release, fibroblast growth, and changes in vascular permeability.

Close follow-up with an ophthalmologist is required, due to vision threatening side effects of topical
glucocorticoids, such as glaucoma, cataracts, and secondary infections. Patients should know that
blindness is a risk of unsupervised topical corticosteroid therapy. Prednisolone acetate 1 percent
and dexamethasone 0.1 percent have the greatest risk of raising intraocular pressure (IOP) among all
topical corticosteroids. By comparison, "soft" steroids are a group of topical corticosteroids that have a
greatly reduced risk of causing increased IOP, because they undergo rapid inactivation upon
penetration of the cornea. Topical "soft" corticosteroids include prednisolone acetate 0.12
percent, fluorometholone, medrysone, loteprednol etabonate 0.5 or 0.2 percent, and rimexolone 1
percent.

A short-term, high-dose pulse regimen of topical corticosteroids is often necessary in patients with
VKC who fail to respond to two to three weeks of a dual acting antihistamine/mast cell stabilizer,
particularly those with significant seasonal exacerbations. In severe cases, prednisolone acetate 1
percent eight times daily for one week leads to significant symptom relief, and thereafter should be
tapered rapidly once control is gained [41]. In less severe cases, pulse therapy with topical "soft"
steroids on a two to four times per day basis for approximately two weeks is effective in gaining
control of the allergic response so that mast cell stabilizers, antihistamines, and artificial tears have a
greater chance to work [35,40]. Use of topical "soft" corticosteroids for greater than six weeks is
associated with a significantly increased risk of complications.

Allergy referral for immunotherapy Patients should be referred to an allergy specialist for
consideration of allergen immunotherapy if control is not obtained with topical corticosteroids after two
to three weeks of therapy. (See "Subcutaneous immunotherapy for allergic disease: Indications and
efficacy".)

Calcineurin inhibitors The calcineurin inhibitors that are most commonly used in ocular allergy
include topical cyclosporine and tacrolimus and systemic cyclosporine. An important advantage of the
calcineurin inhibitors is that they do not cause the same side effects typically seen with
corticosteroids, such as an increase in intraocular pressure. Thus, these agents may be used long-
term.

Cyclosporine diminishes the effect of interleukin (IL)-2 on T cells, and leads to decreased expansion
of clonal T helper cells. It may also inhibit mast cell proliferation and survival. Cyclosporine reduces
collagen production and induces apoptosis of conjunctival fibroblasts from VKC
patients. Tacrolimus has similar mechanisms of action [42,43].

Topical cyclosporine 2 percent emulsion improved signs and symptoms of VKC in several randomized
trials [44,45] and observational studies [46-49]. Both randomized trials demonstrated a significant
improvement in symptoms (eg, itching, tearing, mucus discharge) and signs (papillary hypertrophy,
conjunctival hyperemia, Horner-Trantas dots) compared with placebo [44,45]. However, several
patients in one of the trials required a brief course of topical corticosteroids during the four month
study period [45].

In a small randomized trial, topical cyclosporine 0.05 percent was more effective than
topical ketotifen fumarate 0.025 percent in preventing seasonal flare ups in patients with inactive
disease at the start of therapy (seasonal recurrences occurred in 10 of 31 on cyclosporine versus 18
of 33 on ketotifen eye drops) [50]. However, previous observational studies of cyclosporine 0.05
percent have demonstrated variable results [51,52]. A 1 percent solution was effective in one
observational study [53].
Some investigators have advocated for more concentrated use of topical cyclosporine. Specifically,
topical cyclosporine 2 percent may provide excellent therapy in severe cases of VKC, and can be
used as a corticosteroid-sparing agent. However, topical cyclosporine is generally not chosen over
topical corticosteroids for acute exacerbations because of its much slower onset of action. In one
study, topical cyclosporine 0.1 percent was less effective than topical dexamethasone 0.15 percent for
acute flare ups, with less improvement in symptoms and signs and a greater number of patients
requiring rescue therapy with dexamethasone [50].

Topical cyclosporine is recommended rather than topical corticosteroids if the corneal epithelium is
compromised, particularly in the presence of shield ulcers. Dosing is four times per day initially,
followed by gradual tapering when the disease is quiet. The authors prefer the 2 percent
concentration. Long-term use of topical cyclosporine is considered safe, unlike chronic use of topical
corticosteroids, and only minimal amounts can be traced systemically. Efficacy of topical tacrolimus in
patients with VKC was demonstrated in small observational studies [42,43].

In the authors' clinical experience, systemic cyclosporine can be helpful in controlling severe cases of
allergic ocular disease and thereby reducing the need for long-term corticosteroid use. However, no
randomized trial has been performed evaluating the utility of systemic cyclosporine in the treatment of
ocular allergy. If administered, dosing is 2.5 to 5 mg/kg per day. The patient must be closely monitored
for any adverse effect including kidney dysfunction, bone marrow suppression, hypertension, tremor,
hirsutism, and gingival hyperplasia.

Additional agents

Nonsteroidal antiinflammatory drugs NSAIDs block the action of cyclooxygenase and thus
inhibit the conversion of arachidonic acid to prostaglandins and thromboxanes. Topical NSAID
preparations includeketorolac [54,55], bromfenac [56], diclofenac [57], flurbiprofen [58],
and indomethacin [59]. Ketorolac was shown to be more effective in treating symptoms of VKC than
placebo in one small randomized trial [54], and had greater efficacy in treating symptoms, but not
signs of VKC, than cyclosporine 0.5 percent by day seven in another randomized trial [55].
Flurbiprofen demonstrated lower efficacy compared with topicalbetamethasone [58]. Indomethacin
treatment showed mixed results for VKC [59]. Overall, these agents have minimal to no role in
treatment of VKC.

Oral antihistamines 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
in patients with VKC [60]. These agents have a slower onset of action compared to topical agents,
although this is not relevant if they are taken prophylactically. Oral antihistamines may be useful as
add-on therapy in patients with moderate to severe disease. Maximizing the dose of nonsedating
antihistamine will often improve efficacy. (See "Allergic conjunctivitis".)

Oral antihistamine use may be associated with drying of mucosal membranes and decreased tear
production in some patients, especially those with concomitant dry eye. This side effect can usually be
countered with the liberal application of artificial tears. Cetirizine causes sedation in a subset of
patients, despite its categorization as nonsedating.

Treatment of corneal shield ulcers Corneal shield ulcers are a vision-threatening complication of
VKC. Sterile corneal ulcers are treated by debridement of inflammatory debris and the use of wide-
spectrum antibiotics, such as moxifloxacin or gatifloxacin four times per day [61-64]. Patching,
bandage contact lenses, and temporary tarsorrhaphy (upper and lower eyelids are partially sewn
together) may be required to help the epithelial defects heal. Infectious ulcers should be referred
promptly to the appropriate specialist due to the high likelihood of vision loss and the complexity of
treatment.
SUMMARY AND RECOMMENDATIONS

Vernal keratoconjunctivitis (VKC) is a chronic, bilateral, and severe form of allergic


inflammation affecting the ocular surface. This relatively uncommon type of allergic eye
disease can cause severe damage to the ocular surface, leading to corneal scarring and
vision loss if not treated properly. (See 'Introduction' above.)

VKC most commonly occurs in boys living in warm, dry subtropical climates.
(See 'Epidemiology' above.)

The most common manifestations of VKC are ocular pruritus and giant cobblestone-like
papillae on the upper tarsal conjunctiva. (See 'Clinical manifestations' above and 'Physical
findings' above.)

The diagnosis of VKC is based upon the typical clinical features. (See 'Diagnosis' above.)

The management approach includes both pharmacologic and nonpharmacologic therapies.


Medications include mast cell stabilizers, dual acting topical antihistamines and mast cell
stabilizers, topical corticosteroids, calcineurin inhibitors, nonsteroidal antiinflammatory drugs,
and oral antihistamines. (See'Treatment' above.)

Efficacy of some of the topical mast cell stabilizers, dual acting mast cell stabilizers and
antihistamines, and calcineurin inhibitors for treatment of VKC has been demonstrated in
randomized trials. (See'Treatment' above.)

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

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


with VKC who fail to respond to two to three weeks of a dual acting antihistamine/mast cell
stabilizer (Grade 1B). (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 1B). (See 'Calcineurin inhibitors' above.)

We suggest adding an oral antihistamine in patients with moderate to severe disease (Grade
2C).

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