More than just dry eyes.
Evan Warner, MD
History
A 16-year-old female was referred to The University of Wisconsin ophthalmology department for
evaluation of dry eyes. She described both eyes as dry, scratchy, and painful; with itching and mucoid
discharge. She reported that her vision was intermittently blurry in both eyes. These symptoms had
been present for approximately 24 months, with minimal fluctuation in severity.
At the time of
presentation, she was using preservative-free artificial tears every two hours and a polyethylene glycolbased gel lubricant at night, each in both eyes.
Her medical history was significant for longstanding eczema, for which she used a triamcinolone
acetonide 0.1% topical cream. She denied frequent rhinorrhea, sneezing, asthma, or other systemic
allergy symptoms. She had no other history of ocular problems and no family history of eye disease.
Over the past two years, she had followed regularly with a local optometrist, who diagnosed her
with keratoconjunctivitis sicca and started her on multiple topical lubrication regimens. Silicone punctal
plugs had been placed in both lower lids without improvement in symptoms, and the patient had them
removed after three months due to epiphora. She felt her current regimen of lubrication was helpful,
but did not resolve her symptoms. Four months before presentation, she had been placed on a three
week course of loteprednol 0.5% ophthalmic solution, which improved her symptoms during treatment,
but control was quickly lost after discontinuing the drops.
Examination
At the time of her referral, ocular examination showed a best-corrected visual acuity of 20/20 in the
right eye and 20/25 in the left eye. Pupils, motility, and IOP were unremarkable. Anterior segment
examination revealed bilateral madarosis of the upper and lower lids, mild erythema of all four lid
margins, and 3+ meibomian gland dysfunction (MGD). There was 2+ bulbar conjunctival injection and
2+ papillae on the tarsal conjunctiva of both eyes. Fluorescein exam demonstrated 3-4+ confluent
punctate epithelial erosions across the entire corneal surface bilaterally, and a tear break-up time of six
seconds in each eye. The right eye had five small, cellular aggregates (Horner-Trantas dots) at the
superior limbus. Dilated fundoscopic examination was unremarkable bilaterally.
Discussion and diagnosis
Although this patient’s primary symptomatic complaints, prominent MGD with tear film instability,
and diffuse superficial punctate keratitis can call be seen in typical dry eye patients, her age, history of
eczema, and prominent pruritus with mucoid discharge all point to an allergic etiology.
The spectrum of chronic allergic eye disease encompasses seasonal allergic conjunctivitis (SAC) and
perennial allergic conjunctivitis (PAC), as well as the corneal-involving conditions vernal
keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC). While there is crossover between all
these entities, this patient’s severe corneal involvement, year-round symptoms, and history of atopy
was deemed most consistent with AKC.
AKC was first described by Hogan in 1952.1 It is best-defined as a chronic, non-seasonal, bilateral
allergic ocular disease that involves the cornea, and occurs in association with other atopic disease
including atopic dermatitis, asthma, or allergic rhinitis. Common symptoms include pruritis, tearing,
mucoid discharge, pain, and blurry vision.
Eyelids may exhibit periorbital eczema, lid edema,
lichenification, blepharitis/MGD, madarosis, and cicitricial changes. Conjunctiva may become injected
or chemotic, and typically develops a tarsal micropapillary reaction with mucoid discharge. HornerTrantas dots, aggregates of eosinophils and degenerated epithelial cells, may be seen near the limbus.
The corneal findings range from superficial keratopathy to pannus, scarring, shield ulcers, and thinning
or perforation. There is a high rate of subcapsular cataract, particularly anteriorly.
Onset of AKC is typically between the teens and fifth decade of life, with chronic symptoms over
many years, and often spontaneous resolution late in life. It has a prevalence of 1-8% in the adult
population. 2 The frequency in atopic dermatitis patients, which is roughly 11% of the U.S. population, 3
is reported most often between 20-40%2, but as high as 77%4.
Pathogenesis of AKC is poorly understood and is thought to involve type I and type IV
hypersensitivity reactions. Histologically, there are increased mast cells, eosinophils, and a high CD4/CD8
T-cell ratio in conjunctiva of AKC patients. 5 Their tears have elevated IgE, IFN-γ, and TNF-α; and low
levels of secretory IgA compared to normal controls. 6-8 Importantly, atopic diseases share an impairment
of innate, cell-mediated immunity, which leads to increased susceptibility to skin and eye infection with
Staphylococcus and the herpes simplex virus.9
Management of AKC can be complicated by secondary bacterial infections, HSV keratitis, and
treatment-related complications such as steroid-induced glaucoma and cataract. For mild cases,
lubrication, oral antihistamines, and topical mast cell stabilizer/antihistamine combinations can provide
relief, along with standard treatment for associated MGD. Topical steroids are successful at quieting
exacerbations, but symptoms tend to recur quickly after taper. Especially in this young patient, longterm use of topical steroids carries significant risks, making them a poor choice for chronic management.
The most common and successful steroid-sparing agents for chronic control of AKC are the
calcineurin inhibitors cyclosporine and tacrolimus, which block expression of IL-2 and inhibit the T-cell
response. Topical cyclosporine 2% has been shown effective compared to steroid treatment,10 while
lower concentrations have given mixed or poor results.11-13 Topical tacrolimus as 0.03% ointment to the
lid margins and 0.02% ophthalmic solution have repeatedly demonstrated substantial improvement in
previously steroid-requiring AKC patients,14-18 with no effect on IOP.19 This patient was placed on
tacrolimus 0.02% ophthalmic suspension BID. By two months out, her symptoms had resolved and she
was using artificial tears an average of only twice daily. Exam revealed white and quiet conjunctiva, and
only trace inferior punctate staining of the cornea.
Conclusion
This case demonstrates the importance of proper evaluation, diagnosis, and management of
patients with suspected atopic keratoconjunctivitis. While AKC can present with a wide spectrum of
symptoms, it is a common condition that is important to consider early, as proper treatment can achieve
sustained symptomatic control, prevent vision-threatening corneal complications, and minimize
treatment side effects.
References
1. Hogan MJ. Atopic keratoconjunctivitis. Trans Am Ophthalmol Soc 1952; 50:265–281.
2. Bielory B, Bielory L. Atopic dermatitis and keratoconjunctivitis. Immunol Allergy Clin North Am
2010; 30:323.
3. Shaw TE, Currie GP, Koudelka CW, Simpson EL. Eczema prevalence in the United States: data
from the 2003 National Survey of Children's Health. J Invest Dermatol 2011; 131:67.
4. Moscovici BK, Cesar AS, Nishiwaki-Dantas MC, et al. [Atopic keratoconjunctivitis in patients of
the pediatric dermatology ambulatory in a reference center]. Arq Bras Ophtalmol 2009; 72:805.
5. Montan PG, van Hage-Hamsten M. Eosinophil cationic protein in tears in allergic conjunctivitis.
Br J Ophthalmol 1996; 80:556–560.
6. Leonardi A, Curnow SJ, Zhan H, Calder VL. Multiple cytokines in human tear specimens in
seasonal and chronic allergic eye disease and in conjuncttival fibroblast cultures. Clin Exp Allergy 2006;
36:777.
7. Metz DP, Hingorani M, Calder VL, et al. T-cell cytokines in chronic allergic eye disease. J Allergy
Clin Immunol 1997; 100:817.
8. Leonardi A, De Dominicis C, Motterle L. Immunopathogenesis of ocular allergy: a schematic
approach to different clinical entities. Curr Opin Allergy Clin Immunol 2007; 7:429.
9. Tuft SJ, Kemeny DM, Dart JK, Buckley RJ. Clinical features of atopic keratoconjunctivitis.
Ophthalmology 1991; 98:150.
10. Hingorani M, Moodaley L, Calder VL, et al. A randomized, placebo-controlled trial of topical
cyclosporin A in steroid-dependent atopic keratoconjunctivitis. Ophthalmology 1998; 105:1715.
11. Akpek EK, Dart JK, Watson S, et al. A randomized trial of topical cyclosporin 0.05% in topical
steroid-resistant atopic keratoconjunctivitis. Ophthalmology 2004; 111:476.
12. Daniell M, Constantinou M, Vu HT, Taylor HR. Randomised controlled trial of topical ciclosporin
A in steroid dependent allergic conjunctivitis. Br J Ophthalmol 2006; 90:461.
13. Ebihara N, Ohashi Y, Uchio E, et al. A large prospective observational study of novel
cyclosporine 0.1% aqueous ophthalmic solution in the treatment of severe allergic conjunctivitis. J Ocul
Pharmacol Ther 2009; 25:365. 13.
14. Rikkers S, Hollard G, Drayton G, et al. Topical tacrolimus treatment of atopic eyelid disease. Am
J Ophthalmol 2003;135:297–302.
15. Nivenius E, van der Ploeg I, Jung K, et al. Tacrolimus ointment vs steroid ointment for eyelid
dermatitis in patients with atopic keratoconjunctivitis. Eye (Lond) 2007; 21:968.
16. Zribi H, Descamps V, Hoang-Xuan T, et al. Dramatic improvement of atopic keratoconjunctivitis
after topical treatment with tacrolimus ointment restricted to the eyelids. J Eur Acad Dermatol
Venereol 2009; 23:489.
17. Miyazaki D, Tominaga T, Kakimaru-Hasegawa A, et al. Therapeutic effects of tacrolimus
ointment for refractory ocular surface inflammatory diseases. Ophthalmology 2008; 115:988.
18. Remitz A, Reitamo S. Long-term safety of tacrolimus ointment in atopic dermatitis. Expert Opin
Drug Saf 2009; 8:501–506.
19. Remitz A, Virtanen HM, Reitamo S, Kari O. Tacrolimus ointment in atopic
blepharoconjunctivitis does not seem to elevate intraocular pressure. ActaOphthalmol 2010.