Downloaded from bjo.bmj.com on April 24, 2013 - Published by group.bmj.

com

Review

Vernal keratoconjunctivitis: an update

Stefan De Smedt,1 Gerhild Wildner,2 Philippe Kestelyn3
1
Ophthalmology Department, ABSTRACT SYMPTOMS AND SIGNS
Kabgayi Hospital, Muhanga, Vernal keratoconjunctivitis (VKC) is a bilateral, usually Vernal keratoconjunctivitis is usually bilateral,
Rwanda
2
Section of Immunobiology,
seasonally recurrent, allergic inflammation of the although it can occasionally present unilaterally, at
Department of Ophthalmology, conjunctiva, characterised by limbal gelatinous least initially.3 15 Its predominant symptom is
Klinikum der Universität, hypertrophy and/or upper tarsal giant conjunctival intense ocular itching, followed by tearing, mucous
Munich, Germany papillae. Although rare in temperate regions, it stringy discharge, severe photophobia, blepharo-
3
Ophthalmology Department, represents an important cause of hospital referral in spasm and foreign body sensation.
Ghent University Hospital,
Ghent, Belgium many parts of Africa and Asia. Clinical and It can present as purely palpebral or purely
immunohistochemical studies suggest that IgE-dependent limbal disease, but a range of mixed appearances
Correspondence to (type I allergic) and IgE-independent (type IV allergic) exist.10 The hallmark sign of palpebral VKC is pap-
Dr Stefan De Smedt, mechanisms are involved in the immunopathogenesis of illary hyperplasia of the upper tarsal conjunctiva,
Leopoldstraat 36 2800
Mechelen, Belgium; VKC, in which various inflammatory cells, including ranging from papillae of 1 mm of diameter to
[email protected] different T cell subpopulations play an active role via a typical giant or cobble stone papillae (figure 1).10
cascade of chemical mediators. Endocrine, genetic, The dominating clinical sign in limbal VKC is
Received 23 April 2012 neurogenic, environmental and socioeconomic risk infiltration of the limbal subconjunctival tissues
Revised 19 July 2012
Accepted 1 September 2012
factors have been identified. However, its aetiology and forming nodules, sometimes accompanied by
Published Online First pathophysiology remain unclear. The clinical course of pannus of superficial neovascularisation of the per-
4 October 2012 this disease is usually benign and self-limiting, but a ipheral cornea, making the limbus to appear thick-
minority of patients will face very debilitating and sight ened and opaque (figure 2). They often are topped
threatening complications. Topical corticosteroids are by chalky white excrescences, known as Horner–
often used during flare-ups in combination with mast Trantas dots (figure 2).13 Increased spotty pigmen-
cell stabilizers as maintenance treatment for VKC. tation of the interpalpebral exposed conjunctiva is
However this management is unsatisfactory in controlling common among patients from Africa and Asia,
severe cases and avoiding recurrences. Non-steroidal especially among very young children, but whether
immune modulators such as ciclosporin A and tacrolimus this sign is correlated to the disease activity is con-
are promising alternatives, but tolerance to these agents troversial.8–10 12
needs to be improved and production costs reduced. In tropical regions corneal complications develop
The purpose of this review is to give an update on its in 7% to 50% of patients with VKC presenting to a
epidemiology, immunopathogenesis and management. hospital facility.1 3 9 10 16 During exacerbations of
palpebral VKC, punctate epithelial keratopathy may
develop, leading to macroerosion and sight threa-
EPIDEMIOLOGY tening shield ulcers (figure 3).13 17 Generally, a
Vernal keratoconjunctivitis (VKC) is a bilateral, shield ulcer is differentiated from an infective
chronic, external ocular inflammatory disorder, corneal ulcer by its transversely oval shape, and its
mainly affecting patients in their first or second location in the centre of the superior third of the
decade.1–3 Although it is a rare allergic disorder in cornea, but superinfection can occur. The base of a
temperate regions, in many parts of Africa, Latin shield ulcer can be transparent or translucent, and
America and Asia VKC represents an important can be filled with opaque white or yellow deposits,
cause for hospital attendance, ranging from 3% to eventually forming an elevated plaque.17
6% of patients of all ages, rising to 33% and 90% Limbal disease can induce stem cell deficiency, that
in children and adolescents.2 4–7 A population leads to compromised corneal surface, characterised
prevalence of 4% to 5% has been found among by corneal vascularisation, chronic stromal inflamma-
African children.3 8 In large European and Asian tion, persistent epithelial defects and ingrowth of con-
case series boys appear to be affected more than junctival epithelium onto the corneal surface.18 These
girls, but this sex distribution is not found uni- central extension of limbal vegetations may affect
formly in Africa, and becomes less obvious with vision (figure 4).6 9–13 Other corneal signs are sube-
age.1–4 8–11 Palpebral forms are more prevalent in pithelial scarring, sterile stromal melt, pseudogeron-
Europe and the Americas, whereas mixed and toxon and keratoconus.1 19 20
limbal forms are more seen in Asia and Africa Although some signs and symptoms of VKC may
respectively, with some geographic variation.1–3 6 8– be similar to other ocular allergic diseases, the pres-
14
In Europe and Asia VKC has a prominent sea- ence of limbal and/or giant tarsal papillae differentiate
sonal variation in disease expression, but flare-ups VKC from seasonal allergic conjunctivitis (SAC) or
during winter months can happen in a significant perennial allergic conjunctivitis.21 VKC and atopic
percentage of cases, leading to chronic, perennial keratoconjunctivitis (AKC) are more severe forms of
disease after a few years.1 11 14 In Africa, however, allergic eye disease. In contrast to VKC, AKC is more
To cite: De Smedt S,
Wildner G, Kestelyn P. Br J VKC is less seasonal and occasionally continues seen in older children and adults with an atopic
Ophthalmol 2013, 97, until adulthood, explaining the substantial number history such as facial atopic dermatitis and does not
9–14. of cases seen in clinics throughout the year.2 5 9 10 regress quickly after adolescence.22

De Smedt S, et al. Br J Ophthalmol 2013;97:9–14. doi:10.1136/bjophthalmol-2011-301376 9

 Downloaded from bjo.bmj.com on April 24, 2013 - Published by group.bmj.com

Review

Figure 3 Corneal shield ulcer. This figure is only reproduced in colour

Figure 1 Giant papillary reaction of the tarsal conjunctiva causing a in the online version.
shield ulcer. This figure is only reproduced in colour in the online
version.
the limbal palisades and the tarsal conjunctiva produces
Apart from the traditional distinction between limbal, palpe- nodules, due to the firm attachments of the conjunctiva to
bral and mixed types of VKC, various other classification limbus and tarsus respectively. Giant papillae are characterised
systems, useful to appreciate the different degrees of severity of by squamous epithelial hyperplasia and dense fibrous tissue, har-
the disease and its corneal complications have been developed bouring the described population of inflammatory cells.25
over time.3 5 10 17 20 23 The average clinical presentation of Limbal VKC is histologically differentiated from the palpebral
VKC can differ significantly depending on geographic area and form by the enormous epithelial overgrowth with solid down-
genetic background, so that there is no consensus on the defin- ward extensions of epithelial plugs in the limbal tissue. It has
ition of severity of disease in literature. not yet been fully explained why in tropical regions changes in
vernal conjunctivitis tend to localise at the limbus rather than
HISTOPATHOLOGY in the tarsal palpebral conjunctiva, as in temperate climates.
Conjunctival biopsy specimens from patients with active VKC Nevertheless, there is a more prominent B lymphocyte cluster-
exhibit an intense influx of a variety of inflammatory cells, ing at the limbus in patients with VKC from tropical coun-
hyperplasia of the epithelium with numerous epithelial tries,16 and in dark skinned people the limbus is richer on mast
ingrowths, proliferation of new blood vessels and extensive cells and melanocytes.26
deposition of extracellular matrix components (ECM).
Substantia propria and epithelium are infiltrated by mast cells, DIAGNOSIS AND ASSOCIATION WITH OTHER ATOPIC
eosinophils, basophils, plasma cells, monocytes/macrophages, CONDITIONS
dendritic cells, CD4 T lymphocytes, fibroblasts and B lympho- Diagnosis is mainly based on the typical clinical VKC signs. So
cytes, organised as small lymphoid follicles.24 Inflammation of far only a few laboratory tests are used to confirm the disease.

Figure 2 In this case of limbal vernal keratoconjunctivitis, the limbus Figure 4 Central extension of limbal vegetations in limbal vernal
appears thickened and opaque and topped by Horner–Trantas dots. keratoconjunctivitis. This figure is only reproduced in colour in the
This figure is only reproduced in colour in the online version. online version.

10 De Smedt S, et al. Br J Ophthalmol 2013;97:9–14. doi:10.1136/bjophthalmol-2011-301376

 Downloaded from bjo.bmj.com on April 24, 2013 - Published by group.bmj.com

Review

The eosinophils usually found in conjunctival scrapings of involvement in the regulation of lymphocyte recruitment.53
patients with VKC support the diagnosis, but their absence does Furthermore, the conjunctival hyperplasia is modulated by
not exclude it.11 13 27 Total and specific immunoglobulin growth factors and conjunctival epithelial cells interact with acti-
E (IgE) determination in tears and serum and skin prick tests vated T cells via CD40 adhesion molecules in vitro.54 55
can provide additional evidence, but there is a high variability in Mononuclear cells and eosinophils affect fibroblast functions
IgE levels, and skin tests may not always be positive among via histamine, cytokines, integrin receptors and a range of
VKC cases, especially in Africa.8 11 13 Limbal and palpebral growth factors.56 As part of the remodelling of the conjunctiva
forms do not differ in IgE levels in serum or tears.13 in VKC, extensive deposition of ECM happens in the substantia
Recently, confocal microscopy has been used to quantify in a propria, including collagen types I, III, IV, V and VII, tenascin
non-invasive manner the morphological characteristics of the and laminin.57 58 Laminin and tenascin facilitate the transmigra-
conjunctiva and limbus in VKC.28 tion of inflammatory cells into the conjunctiva via their adhesive
A higher incidence of associated atopic conditions such as properties and induce matrix metalloproteinases (MMPs) such
asthma, rhinitis and eczema has been reported among patients as gelatinase B, that disrupt the integrity of the ECM, allowing
with VKC in up to 41.5% of cases, although this was not found invasion of inflammatory cells and contributing to tissue remod-
everywhere.1 3 11 29–31 Especially in Africa the majority of elling.58 59 MMP enzymes are inactivated by tissue inhibitors of
studies reported only a small percentage of patients with these MMPs (TIMP-1). Increased levels and activity of MMP and an
other atopic diseases.4 8–10 imbalance between MMPs and TIMP may be involved in the
pathogenesis of VKC.60
IMMUNOPATHOGENESIS
Many clinical and laboratory findings support the presence of a RISK FACTORS
type I (IgE-dependent) immediate hypersensitivity reaction in An endocrine risk factor has been suggested by the following
VKC.32–35 B lymphocytes from the lymphoid follicle of the con- clinical and immunohistochemical findings; (1) sexual disparity
junctiva locally produce IgE.36 Mast cell degranulation results in in VKC prevalence,8 11 (2) the role of sex hormones in other
the release of a range of mediators such as histamine, leading to immunological diseases,61 (3) overexpression of oestrogen and
the classical allergic reactions of vasodilatation, oedema, hyper- progesterone receptors by conjunctival eosinophils and altered
aemia, smooth muscle contraction and the recruitment of other neuroreceptor expression in conjunctival epithelium in VKC54
inflammatory cells. and (4) growth factors, neuropeptides such as substance P and
The important role of the eosinophil in the pathogenesis of prostaglandins detected in high amounts in serum and tears in
ocular allergy is suggested by the consistent presence of this cell VKC.14 62 63
type in conjunctival biopsy tissues affected by ocular allergy and The difference in prevalence of limbal and palpebral VKC
by eosinophilic cationic protein levels in tears.37 38 Activated observed in different races in the same study region and the
eosinophils elicit ocular surface inflammation by their soluble identification of disease susceptibility genes for ocular allergy
mediators and adhesion molecules and the inflammation can via linkage analysis support the important role of a genetic risk
even lead to corneal epithelial breakdown.39 factor.9 13 64
The fact that there is no strict requirement for allergen- Exposure to ultraviolet light, diesel fumes or smoking might
specific sensitisation to result in this eosinophilic response, and also influence signs and symptoms of allergic conjunctivitis.9 16
the conflicting results in the literature concerning the association Staphylococcal colonisation of the lid margins has also been sug-
between VKC and atopy suggest that IgE-independent mechan- gested to influence the VKC pathogenesis.65
isms are also involved.1 11 13 29–31 40 41 In this pathway it is pos- Although coexistent trachoma had been proposed to play a
tulated that antigen-presenting cells induce an influx of role via type IV hypersensitivity reaction on the intraepithelial
eosinophils from the blood vessels into the conjunctival tissue chlamydial inclusions in the conjunctival epithelium, no correl-
by chemokines.40 These chemokines can also activate mast cells ation was found between the prevalence of chlamydial infection
independently of IgE (‘pseudoallergic reaction’) and attract and the prevalence of VKC.1 3 10 66
T lymphocytes.42 The influence of helminth infestation on the pathogenesis is
There is also growing evidence for the involvement of a CD4 controversial. Some clinical studies reported a reduction in aller-
T helper 2 (Th2)-driven type IV (delayed or cell-mediated) gic conjunctivitis symptoms following antiparasitic treatment,
hypersensitivity reaction as well.3 29 43 44 In order to adhere to while laboratory studies observed a reduction in allergic con-
endothelial and antigen-presenting cells and become active, junctivitis parameters in Ascaris and Cholera toxin B treated
T lymphocytes need cell adhesion molecules, which are increas- mouse models.3 67–69 A nested population-based case control
ingly expressed in VKC. Once activated, these Th2 lymphocytes study in Rwandan primary schools did not find any association
play a role in recruitment and activation of mast cells and eosi- between VKC and current intestinal parasitic load, but identified
nophils,45–48 and in B cell switching to the production of IgE. higher economic status as a risk for VKC.8 This effect appears
No differences in the percentage of Th2 lymphocytes were not to act through differences in parasitic intestinal load.
found between patients with tarsal or limbal affection.46
Recently, it has been suggested that other T cells (CD4 Th1 cells TREATMENT
and CD8 T cells) may play a role as well.48–51 52 Topical medication
Apart from acting as simple physical barrier to the entrance Because the exact immunopathogenesis of VKC remains unknown,
of foreign invaders, ocular surface epithelium is actively the same topical antiallergic agents are used as for other forms of
involved in the initiation and continuation of the allergic inflam- allergic conjunctivitis.
matory process. The epithelium is stimulated by inflammatory Topical antihistamines, such as levocabastine and emedastine
molecules, such as histamine, to express intercellular adhesion alleviate ocular allergy quickly by binding to histamine receptors
molecules (ICAM-1) and to secrete inflammatory cytokines but are only effective in mild cases.45 70 Mast cell stabilisers
and chemokines. Chemokine receptor CXCR3 is abundantly such as cromolyn sodium, nedocromil sodium, lodoxamide and
expressed on T lymphocytes in VKC conjunctiva, suggesting its pemirolast interfere with the release of mast cell mediators by

De Smedt S, et al. Br J Ophthalmol 2013;97:9–14. doi:10.1136/bjophthalmol-2011-301376 11

 Downloaded from bjo.bmj.com on April 24, 2013 - Published by group.bmj.com

Review

blocking calcium transport across the mast cell membrane system is based on disease severity, expressed in terms of
requiring prophylactic treatment or a loading period.71 symptom/sign intensity and frequency and the presence of
Although mast cell stabilisers are unanimously effective in corneal involvement. It may help clinicians and researchers to
studies in Europe and North America, results from the Middle reach agreement on which therapeutic option is appropriate for
East and Africa have not consistently shown a which disease activity.
benefit.3 9 16 31 71–73
Dual action agents such as olopatadine and ketotifen combine Oral medication
the best of both worlds by their immediate histamine receptor Montelukast (a leukotriene antagonist) and aspirin tablets have
antagonism, coupled with the long-term disease-modifying been reported as treatment options.97 98 Oral ciclosporin
effect of mast cell stabilisation.74 (3–5 mg/kg/day) has been successfully used in refractory severe
Non-steroidal anti-inflammatory drug (NSAID) topical agents VKC.99 The use of oral steroids and antihistamine is limited by
reduce ocular inflammatory signs by inhibiting cyclooxygenase their systemic side effects.3 20 97 98 100
and have a beneficial effect on the course of VKC reducing the
local steroid needs.20 75–77 Careful follow-up is needed, since
Periocular injections and surgery
corneal melting has been reported after instillation of several
Supratarsal injection of corticosteroids is very effective for tem-
types of topical NSAID.78 However, in severe VKC the above
porary suppression of severe inflammation associated with VKC,
mentioned agents often appear inadequate, making the use of
but it is difficult to administer to small children without sed-
corticosteroid drops inevitable. Topical corticosteroids are the
ation, and recurrence has been reported in the majority of
most effective treatment for moderate to severe forms of VKC
patients within 6 months.101
because of their broad and early interference with the inflamma-
A surgical approach has been tried in severe and complicated
tory cascade.3 20 79 Their use should be strictly limited and care-
cases. Early surgical scraping dramatically improve epithelial
fully monitored because of the known complications of
resurfacing in corneal shield ulcers.17 37 Corneal scars can be
long-term steroid use (glaucoma, cataract and secondary ocular
removed either surgically or by excimer laser phototherapeutic
infections).1 3 10 11 37 Loteprednol, a smart ester-corticosteroid
superficial keratectomy, and penetrating keratoplasty has a good
with an better safety profile has been effective in SAC, but its
clinical outcome for keratoconus in VKC.17 102
efficacy in VKC is unknown.80
Persistent corneal epithelial defects can be treated by amniotic
Ciclosporin A (CsA) is an established option for the manage-
membrane transplantation and limbal epithelial cell transplant-
ment of VKC. It is a calcineurin inhibitor that abolishes T cell
ation.103 104 A Boston keratoprosthesis has successfully been
proliferation via inhibition of CD4 T cell receptor signal trans-
implanted for severe blinding VKC.105
duction and down regulation of interleukin (IL)-2 receptor
Treatment of tarsal or limbal papillae in severe VKC by cryo-
expression.81 It also inhibits apoptosis, eosinophil and mast cell
therapy or laser have been reported, but may only have a transi-
activation and the release of IL-2, IL-1β and IL-5, which are
ent response and destruction of the limbus may exacerbate
important mediators of allergic inflammation.82 Double-masked
corneal stem cell failure.1 3 5 106
placebo-controlled studies performed in Europe and Asia report
a beneficial effect of topical CsA 2% in the treatment of VKC
with an aggregate reduction in scores for symptoms and signs PROGNOSIS
ranging from 45% to 55% after 2 weeks.83 84 In an open trial Generally VKC is a benign and self-limiting condition with
topical CsA 1% has been suggested to be the minimal effective spontaneous resolution after puberty without any further symp-
concentration in severe VKC.85 Studies on off-label use of toms or visual complication, but therapeutic action may be
topical CsA 0.05% (Restasis; Allergan, Irvine, California, USA) necessary beyond this age to control the course of the
have reported conflicting evidence on its beneficial effects in disease.5 10 11 In large hospital-based case series VKC has the
severe allergic conjunctivitis.86–88 In a double-masked, rando- potential to induce serious visual changes in 6% to 55% of
mised controlled clinical trial (RCT) no difference in efficacy patients depending on the regions of origin.1 9 11 37 107 This is
between CsA 2% and dexamethasone 0.1% was found in the due to corneal complications and unsupervised corticosteroid
treatment of limbal VKC in Africa, but CsA was less well toler- use.1 16 A chronic disease course has been found to increase the
ated.89 Using a lower dose, an Italian trial demonstrated an odds for complications and the development of keratoconus.1 6 11
inferior efficacy of CsA (0.1%) compared with dexamethasone Signs indicating deterioration were the size of cobble stones,
0.15%.90 Chronic use of topical CsA 0.05% has been shown to the presence of Trantas dots and the number of eosinophils on
be effective in preventing seasonal recurrences of VKC.90 conjunctival scrapings.3 11 37
Tacrolimus, another immunomodulator, has a similar mechan-
ism as CsA but is more potent.91 Case series and placebo- CONCLUSIONS
controlled RCT have shown a beneficial effect of tacrolimus VKC is a bilateral, allergic inflammation of the conjunctiva,
ointment (0.1% to 0.2%) and drops (0.005% and 0.1%) in affecting predominantly boys in warm climates. The distribution
severe VKC.92–94 However, it makes patients more susceptible of the main clinical hallmarks, upper tarsal giant conjunctival
for opportunistic infections and herpes simplex keratitis.94 papillae and gelatinous limbal hypertrophy, varies considerably
Although CsA and tacrolimus might be powerful alternatives with different climatic conditions and races. Clinical and
for corticosteroids in the management of VKC, a higher cost immunohistochemical studies suggest that IgE-dependent and
price limit their wide spread use in the developing world. IgE-independent mechanisms are both involved in its immuno-
Monoclonal antibodies directed against IgE antibody, adhe- pathogenesis, in which various inflammatory cells, including
sion molecules and chemokines receptors may interfere with the different T cell subpopulations play an active role. Although
immunopathogenesis of VKC and represent new therapeutic endocrine, genetic, neurogenic, environmental and socio-
modalities.24 95 96 economic factors have been identified, its aetiology remains
Recently, an algorithm approach to the management of VKC unknown. Despite new insights in the mechanisms of ocular
has been proposed in palpebral VKC.21 This clinical grading allergy, topical steroidal and non-steroidal immune modulators

12 De Smedt S, et al. Br J Ophthalmol 2013;97:9–14. doi:10.1136/bjophthalmol-2011-301376

 Downloaded from bjo.bmj.com on April 24, 2013 - Published by group.bmj.com

Review

remain the standard treatment but are often unsatisfactory in 27 Bonini S, Lambiase A, Sgrulletta R, et al. Allergic chronic inflammation of the
controlling severe cases and avoiding regular flare-ups. ocular surface in vernal keratoconjunctivitis. Curr Opin Allergy Clin Immunol
2003;3:381–87.
Contributors SDS and PK substantially contributed to conception and design and 28 Le Q, Hong J, Zhu W, et al. In vivo laser scanning confocal microscopy of vernal
interpretation of data; drafting the article or revising it critically for important intellectual keratoconjunctivitis. Clinical and Experimental Ophthalmology 2011;39:53–60.
content; and approved the final version to be published. GW contributed to the design, 29 Frankland A, Easty D. Vernal keratoconjunctivitis- an atopic disease. Trans Ophthal
revision and approval of the immunopathogenesis section of the paper. Soc UK 1971;91:479–82.
30 Neumann E, Gutmann M, Blumankrantz N, et al. A review of four hundred cases
Competing interests None. of vernal keratoconjunctivitis. Am J Ophthalmol 1959;47:166–72.
Provenance and peer review Not commissioned; externally peer reviewed. 31 El Hennawi M. Clinical trial with 2% sodium cromoglycate in vernal
keratoconjunctivitis. Br J Ophthalmol 1980;64:483–86.
32 Ballow M, Mendelson L. Specific immunoglobulin E antibodies in tear secretions of
patients with vernal conjunctivitis. J Allergy Clin Immunol 1980;66:112–18.
33 Allansmith M, Hann G, Simon M. Tissue tear and serum IgE concentrations in
REFERENCES vernal conjunctivitis. Am J Ophthalmol 1976;81:506–11.
1 Khan MD, Kundi N, Saeed N, et al. A study of 530 cases of vernal conjunctivitis 34 Aalders-Deenstra V, Kok P, Bruynzeel P. Measurement of total IgE antibody levels
from the North West Frontier Province of Pakistan. Pak J Ophthalmol in lacrimal fluid of patients suffering from atopic and non-atopic eye disorders.
1986;2:111–14. Evidence for local IgE production in atopic eye disorders? Br J Ophthalmol
2 Chenge B, Makumyamviri AM, Kaimbo wa Kaimbo D. La limbo-conjonctivite 1985;69:380–84.
endemique des tropiques à Lubumbashi, Republique Démocratique du Congo. Bull 35 Samra Z, Zavaro A, Barishak Y, et al. Vernal keratoconjunctivitis: the significance
Soc belge Ophtalmol 2003;290:9–16. of immuneglobuline E levels in tears and serum. Int Archs Allergy Appl Immunol
3 Resnikoff S, Cornand G, Filliard G, et al. Limbal vernal conjunctivitis in the tropics. 1984;74:158–64.
Rev Int Trachome 1988;3–4:53–71. 36 Abu El-Asrar A, Fatani RA, Missotten L, et al. Expression of CD23/CD21 and
4 McMoli T, Assonganyi T. Limbal vernal kerato-conjunctivitis in Yaounde, CD40/CD40 ligand in vernal keratoconjunctivitis. Eye 2001;15:217–24.
Cameroon. A clinico-immunology study. Rev Int Trach Pathol Ocul Trop Subtrop 37 Tabbara KF. Ocular complications of vernal keratoconjunctivitis. Can J Ophthalmol
Sante Publique 1991;68:157–70. 1999;34:88–92.
5 Diallo J-S. La limbo-conjonctivite endémique des tropiques. Rev Int Trachome 38 Leonardi A, Borhesan F, Faggian D, et al. Eosinophil cationic protein in tears of
1976;3–4:71–9. normal subjects and patients affected by vernal keratoconjunctivitis. Allergy
6 Dantas PEC, Alves MR, Nishiwaki-Dantas MC. Topographic corneal changes in 1995;50:610–13.
patients with vernal keratoconjunctivitis. Arq Bras Oftalmol 2005;68:593–98. 39 Trocme SD, Leiferman KM, George T, et al. Neutrophil and eosinophil participation
7 Uchio E, Kimura R, Migita H, et al. Demographic aspects of allergic ocular in atopic and vernal keratoconjunctivitis. Curr Eye Res 2003;26:319–25.
diseases and evaluation of new criteria for clinical assessment of ocular allergy. 40 Pucci N, Novembre E, Lombardi E, et al. Atopy and serum eosinophil cationic
Graefes Arch Clin Exp Ophthalmol 2008:291–96. protein in 110 white children with vernal keratoconjunctivitis: differences between
8 De Smedt S, Nkurikiye J, Fonteyne Y, et al. Vernal keratoconjunctivitis in school tarsal and limbal forms. Clin Exp Allergy 2003;33:325–30.
children in Rwanda and its association with socio-economic status: a 41 Allansmith M. Vernal conjunctivitis. In: Duane TD, ed. Clinical Ophthalmology. vol
population-based survey. Am J Trop Med Hyg 2011;85:711–17. 4. Chap 9. New York: Harper and Row, 1980.
9 Dahan E, Appel R. Vernal keratoconjunctivitis in the black child and its response 42 Abu El-Asrar A, Struyf S, Al-Kharashi S, et al. Expression of T lymphocyte
to therapy. Br J Ophthalmol 1983;67:688–92. chemoattractants and activation markers in vernal keratoconjunctivitis. Br J
10 Sandford-Smith J. Vernal eye disease in Northern Nigeria. Trop Geogr Med Ophthalmol 2002;86:1175–80.
1979;31:321–28. 43 Bacon A, Tuft S, Metz D. The origin of keratopathy in chronic allergic eye disease:
11 Bonini S, Bonini S, Lambiase A, et al. Vernal keratoconjunctivitis revisited. A case a histopathological study. Eye 1993;7:21–5.
series of 195 patients with long-term followup. Ophthalmology 44 Bonini S, Bonini S. IgE and non-IgE mechanisms in ocular allergy. Ann Allergy
2000;107:1157–63. 1993;71:296–99.
12 Rao SK, Meenakshi S, Srinivasan B, et al. Perilimbal Bulbar Conjunctival 45 Ono SJ, Abelson MB. Allergic conjunctivitis: update on pathophysiology and
Pigmentation in Vernal Conjunctivitis Prospective Evaluation of a New Clinical Sign prospects for future treatment. J Allergy Clin Immunol 2005;115:118–22.
in an Indian Population. Cornea 2004;23:356–59. 46 Leonardi A, DeFranchis G, Zancanaro F, et al. Identification of local Th2 and Th0
13 Tuft SJ, Dart JKG, Kemeny M. Limbal vernal keratoconjunctivitis: clinical lymphocytes in vernal conjunctivitis by cytokine flow cytometry. Invest Ophthalmol
characteristics and immunoglobulin E expression compared with palpebral vernal. Vis Sci 1999;40:3036–40.
Eye 1989;3:420–27. 47 Abu El-Asrar AM, al-Kharashi S, al-Mansouri S, et al. Langerhans’ cells in vernal
14 Pucci N, Novembre E, Lombardi E, et al. Long Eyelashes in a Case Series of 93 keratoconjunctivitis express the costimulatory molecule B7–2 (CD86), but not B7–
Children With Vernal Keratoconjunctivitis. Pediatrics 2005;115:86–91. 1 (CD80). Eye 2001;15:648–54.
15 Awwad ST, Najjar DM, Aouad A, et al. Vernal keratoconjunctivitis presenting 48 Leonardi A, Fregona IA, Plebani M, et al. Th1- and Th2-type cytokines in chronic
unilaterally. J Pediatr Ophthalmol Strabismus 2006;43:179–80. ocular allergy. Graefes Arch Clin Exp Ophthalmol 2006;244:1240–45.
16 Tuft SJ, Cree IA, Woods M, et al. Limbal vernal keratoconjunctivitis in the tropics. 49 Sumi T, Fukushima A, Fukuda K, et al. Thymus-derived CD4+ CD25+ T cells
Ophthalmology 1998;105:1489–93. suppress the development of murine allergic conjunctivitis. Int Arch Allergy
17 Cameron JA. Shield ulcers and plaques of the cornea in vernal keratoconjunctivitis. Immunol 2007;143:276–81.
Ophthalmology 1995;102:985–93. 50 Sgrulletta R, Bonini S, Lambiase A, et al. Allergy and infections: long-term
18 Sangwan VS, Jain V, Vemuganti GK, et al. Vernal keratoconjunctivitis with limbal improvement of vernal keratoconjunctivitis following viral conjunctivitis. Eur J
stem cell deficiency. Cornea 2011;30:491–96. Ophthalmol 2006;16:470–3.
19 Totan Y, Hepsen IF, Cekiç O, et al. Incidence of keratoconus in subjects with 51 Stern ME, Siemasko KF, Niederkorn JY. The Th1/Th2 paradigma in ocular allergy.
vernal keratoconjunctivitis: a videokeratographic study. Ophthalmology Curr Opin Allergy Clin Immunol 2005;5:446–50.
2001;108:824–27. 52 Fukushima A, Yamaguchi T, Fukuda K, et al. CD8+ T cells play disparate roles in
20 Buckley RJ. Vernal keratopathy and its management. Trans Ophthalmic Soc UK the induction and the effector phases of murine experimental allergic
1981;101:234–38. conjunctivitis. Microbiol Immunol 2006;50:719–28.
21 Bonini S, Sacchetti M, Mantelli F, et al. Clinical grading of vernal 53 Abu El-Asrar AM, Struyf S, Van Damme J, et al. Role of chemokines in vernal
keratoconjunctivitis. Curr Opin Allergy Clin Immunol 2007;7:436–41. keratoconjunctivitis. Int Ophthalmol Clin 2003;43:33–9.
22 Tuft SJ, Kemeny M, Dart J, et al. Clinical features of atopic keratoconjunctivitis. 54 Calonge M, Enriquez de Salamanca A. The role of the conjunctival epithelium in
Ophthalmology 1991;98:150–58. ocular allergy. Curr Opin Allergy Clin Immunol 2005;5:441–45.
23 Akpek EK, Hasiripi H, Christen WG, et al. A randomised trial of low-dose, topical 55 Abu El-Asrar AM, Al-Mansouri S, Tabbara KF, et al. Immunopathogenesis of
mitomycine-C in the treatment of severe vernal keratoconjunctivitis. Ophthalmology conjunctival remodelling in vernal keratoconjunctivitis. Eye 2006:71–9.
2000;107:263–69. 56 Abu El-Asrar AM, Al-Mansouri S, Tabbara KF, et al. Immunopathogenesis of
24 Abu El-Asrar A, Geboes K, Al-Kharashi S, et al. Adhesion molecules in vernal conjunctival remodelling in vernal keratoconjunctivitis. Eye 2006;20:71–9.
keratoconjunctivitis. Br J Ophthalmol 1997;81:1099–106. 57 Abu El-Asrar AM, Geboes K, Al-Kharashi S, et al. An immunohistochemical
25 Takakusaki I. Fine structure of the human palpebral conjunctiva with special study of collagens in trachoma and vernal keratoconjunctivitis. Eye
reference to the pathological changes in vernal conjunctivitis. Arch Histol Jap 1998;12:1001–06.
1969;30:247–82. 58 Abu El-Asrar A, Meersschaert A, Al-Kharashi S, et al. Immunohistochemical
26 Soukiasian S, Rice B, Foster C. The T cell receptor in normal and inflamed human evaluation of conjunctival remodelling in vernal keratoconjunctivitis. Eye
conjunctiva. Invest Ophthalmol Vis Sci 1992;33:453–59. 2003;17:767–71.

De Smedt S, et al. Br J Ophthalmol 2013;97:9–14. doi:10.1136/bjophthalmol-2011-301376 13

 Downloaded from bjo.bmj.com on April 24, 2013 - Published by group.bmj.com

Review

59 Abu El-Asrar AM, Van Aelst I, Al-Mansouri S, et al. Gelatinase B in vernal 84 Kiliç A, Gürler B. Topical 2% cyclosporine A in preservative-free artificial tears
keratoconjunctivitis. Arch Ophthalmol 2001;119:1505–11. for the treatment of vernal keratoconjunctivitis. Can J Ophthalmol
60 Leonardi A, Brun P, Abatangelo G, et al. Tear Levels and Activity of Matrix 2006;41:693–98.
Metalloproteinase (MMP)-1 and MMP-9 in Vernal Keratoconjunctivitis. Invest 85 Spadavecchia L, Fanelli P, Tesse R, et al. Efficacy of 1.25% and 1% topical
Ophthalmol Vis Sci 2003:3052–58. cyclosporine in the treatment of severe vernal keratoconjunctivitis in childhood.
61 Seamon V, Vellala K, Zylberberg C, et al. Sex hormone regulation of tear lipocalin Pediatr Allergy Immunol 2006;17:527–32.
in the rabbit lacrimal gland. Exp Eye Res 2008;87:184–90. 86 Ozcan AA, Ersoz TR, Dulger E. Management of severe allergic conjunctivitis with
62 Fujishima H, Takeyama M, Takeuchi T, et al. Elevated levels of substance P in tears topical cyclosporine 0.05% eye drops. Cornea 2007;26:1035–38.
of patients with allergic conjunctivitis and vernal keratoconjunctivitis. Clin Exp 87 Akpek EK, Dart JK, Watson S, et al. A Randomized Trial of Topical Cyclosporin
Allergy 1997;27:372–78. 0.05% in Topical Steroid–Resistant Atopic Keratoconjunctivitis. Ophthalmology
63 Sacchetti M, Micera A, Lambiase A, et al. Tear levels of neuropeptides increase 2004;111:476–82.
after specific allergen challenge in allergic conjunctivitis. Mol Vis 2011;17:47–52. 88 Daniell M, Constantinou M, Vu HT, et al. Randomised controlled trial of topical
64 Ono S, Nakamura T, Ohbayashi M, et al. Expression profiling: opportunities and ciclosporin A in steroid dependent allergic conjunctivitis. Br J Ophthalmol
pitfalls and impact on the study and management of allergic diseases. J Allergy 2006;90:461–64.
Clin Immunol 2003;112:1050–56. 89 De Smedt S, Nkurikiye J, Fonteyne Y, et al. Topical ciclosporin in the treatment of
65 Tuft SJ, Ramakrishnan M, Seal DV, et al. Role of staphylococcus aureus in chronic vernal keratoconjunctivitis in Rwanda, Central Africa: a prospective, randomised,
allergic conjunctivitis. Ophthalmology 1992;99:180–84. double-masked, controlled clinical trial. Br J Ophthalmol 2012;96:323–28.
66 Friedlaender MH, Cameron J. Vernal keratoconjunctivitis and trachoma. Int 90 Lambiase A, Leonardi A, Sacchetti M, et al. Topical cyclosporine prevents seasonal
Ophthalmol 1988;12:47–51. recurrences of vernal keratoconjunctivitis in a randomized, double-masked,
67 McConchie BW, Norris HH, Bundoc VG, et al. Ascaris suum-derived products controlled 2-year study. J Allergy Clin Immunol 2011;128:896–97.
suppress mucosal allergic inflammation in an interleukin-10-independent manner 91 Vichyanond P, Tantimongkolsuk C, Dumrongkigchaiporn P, et al. Vernal
via interference with dendritic cell function. Infect Immun 2006;74:6632–41. keratoconjunctivitis: result of a novel therapy with 0.1% topical ophthalmic
68 Schopf L, Luccioli S, Bundoc V, et al. Differential modulation of allergic eye disease FK-506 ointment. J Allergy Clin Immunol 2004;113:355–58.
by chronic and acute ascaris infection. Invest Ophthalmol Vis Sci 92 Tam P, Young A, Cheng L, et al. Topical tacrolimus 0.03% monotherapy for vernal
2005;46:2772–80. keratoconjunctivitis- case series. Br J Ophthalmol 2010;94:1405–6.
69 Saito K, Shoji J, Inada N, et al. Immunosuppressive effect of cholera toxin B on 93 Kheirkhah A, Zavareh M, Farzbod F, et al. Topical 0.005% tacrolimus eye drop for
allergic conjunctivitis model in the guinea pig. Jpn J Ophthalmol 2000;44:189–90. refractory vernal keratoconjunctivitis. Eye 2011;25:872–80.
70 Bielory L, Ghafoor S. Histamine receptors and the conjunctiva. Curr Opin Allergy 94 Ohashi Y, Ebihara N, Fujishima H, et al. A randomized, placebo-controlled clinical
Clin Immunol 2005;5:437–40. trial of tacrolimus ophthalmic suspension 0.1% in severe allergic conjunctivitis.
71 Easty D, Rice N, Jones B. Disodium cromoglycate (Intal) in the treatment of J Ocul Pharmacol Ther 2010;26:165–74.
vernal-kerato-conjunctivitis. Trans Ophthal Soc UK 1971;91:491–99. 95 Sánchez J, Cardona R. Omalizumab. An option in vernal keratoconjunctivitis?
72 Sayegh F, Samerra E, Khateeb M. Clinical trial of topical DSG in vernal Allergol et Immunopathol 2011, in press.
keratoconjunctivitis. Ophthalmologica 1978;177:208–13. 96 Abu El-Asrar AM, Struyf S, Al-Mosallam AA, et al. Expression of chemokine
73 Foster SC. Evaluation of topical cromolyn sodium in the treatment of vernal receptors in vernal keratoconjunctivitis. Br J Ophthalmol 2001;85:1357–61.
keratoconjunctivitis. Ophthalmology 1988;95:194–201. 97 Lambiase A, Bonini S, Rasi G, et al. Montelukast, a leukotriene receptor
74 Yanni J, Stephens D, Miller S, et al. The in vitro and in vivo ocular pharmacology antagonist, in vernal keratoconjunctivitis associated with asthma. Arch Ophthalmol
of olopatadine (AL-4943A), an effective anti-allergic/antihistaminic agent. J Ocul 2003;121:615–20.
Pharmacol Ther 1996;12:389–400. 98 Abelson M, Butrus S, Weston J. Aspirin therapy in vernal keratoconjunctivitis. Am J
75 Duzman E, Warman A, Warman R. Efficacy and safety of topical oxymetazoline in Ophthalmol 1983;95:502–5.
treating allergic and environmental conjunctivitis. Ann Ophtalmol 1986;1:28–31. 99 Gokhale N, Samant R, Sharma V. Oral cyclosporine therapy for refractory severe
76 Sugar J, Nysberg M, Bernstein J, et al. Imipramine inhibition of ragweed allergic vernal keratoconjunctivitis. Indian J Ophthalmol 2012;60:220–3.
conjunctivitis. Invest Ophthalmol Vis Sci 1984;25:217–18. 100 Meyer E, Kraus E, Zonis S. Efficacy of antiprostaglandin therapy in vernal
77 Syrbopoulos S, Gilbert D, Easty D. Double- blind comparison of a steroid keratoconjunctivitis. Br J Ophthalmol 1987;71:497–99.
( prednisolone) and non-steroid (tolmetine) in vernal keratoconjunctivitis. Cornea 101 Singh S, Pal V, Dhull CS. Supratarsal injection of corticosteroids in the treatment of
1986;5:35–9. refractory vernal keratoconjunctivitis. Indian J Ophthalmol 2001;49:241–45.
78 Asai T, Nakagami T, Mochizuki M, et al. Three cases of corneal melting after 102 Egrilmez S, Sahin S, Yagci A. The effect of vernal keratoconjunctivitis on clinical
instillation of a new nonsteroidal anti-inflammatory drug. Cornea outcomes of penetrating keratoplasty for keratoconus. Can J Ophthalmol
2006;25:224–27. 2004;39:772–77.
79 Bielory BP, Perez VL, Bielory L. Treatment of seasonal allergic conjunctivitis with 103 Sangwan VS, Murthy SI, Vemuganti GK, et al. Cultivated corneal epithelial
ophthalmic corticosteroids: in search of the perfect ocular corticosteroids in the transplantation for severe ocular surface disease in vernal keratoconjunctivitis.
treatment of allergic conjunctivitis. Curr Opin Allergy Clin Immunol Cornea 2005;24:426–30.
2010;10:469–77. 104 Rouher N, Pilon F, Dalens H, et al. Implantation of preserved human amniotic
80 Dell S, Lowry G, Northcutt J, et al. A randomized, double-masked, membrane for the treatment of shield ulcers and persistent corneal epithelial
placebo-controlled parallel study of 0.2% loteprednol etabonate in patients with defects in chronic allergic keratoconjunctivitis. J Fr Ophtalmol 2004;27:1091–97.
seasonal allergic conjunctivitis. J Allergy Clin Immunol 1998;102:251–55. 105 Basu S, Taneja M, Sangwan VS. Boston type 1 keratoprosthesis for severe
81 Nussenblat R, Palestine A. Cyclosporine: immunology, pharmacology and blinding vernal keratoconjunctivitis and Mooren’s ulcer. Int Ophthalmol
therapeutic uses. Surv Ophthalmol 1986;31:159–69. 2011;31:219–22.
82 Whitcup SM, Chan C-C, Luyo DA, et al. Topical cyclosporine inhibits mast 106 Tanaka M, Dogru M, Takano Y, et al. Quantitative evaluation of the early changes
cell-mediated conjunctivitis. Invest Ophthalmol Vis Sci 1996;37:2686–93. in ocular surface inflammation following MMC-aided papillary resection in severe
83 Pucci N, Novembre E, Cianferoni A, et al. Efficacy and safety of cyclosporine allergic patients with corneal complications. Cornea 2006;25:281–85.
eyedrops in vernal keratoconjunctivitis. Ann Allergy Asthma Immunol 107 BenEzra D, Pe’er J, Brodsky M, et al. Cyclosporine eyedrops for the treatment of
2002;89:298–303. severe vernal keratoconjunctivitis. Am J Ophthalmol 1986;101:278–82.

14 De Smedt S, et al. Br J Ophthalmol 2013;97:9–14. doi:10.1136/bjophthalmol-2011-301376

 Downloaded from bjo.bmj.com on April 24, 2013 - Published by group.bmj.com

Vernal keratoconjunctivitis: an update

Stefan De Smedt, Gerhild Wildner and Philippe Kestelyn

Br J Ophthalmol 2013 97: 9-14 originally published online October 4,

2012
doi: 10.1136/bjophthalmol-2011-301376

Updated information and services can be found at:

http://bjo.bmj.com/content/97/1/9.full.html

These include:
References This article cites 102 articles, 17 of which can be accessed free at:
http://bjo.bmj.com/content/97/1/9.full.html#ref-list-1

Email alerting Receive free email alerts when new articles cite this article. Sign up in
service the box at the top right corner of the online article.

Topic Articles on similar topics can be found in the following collections

Collections
Conjunctiva (185 articles)
Cornea (416 articles)
Ocular surface (496 articles)
Epidemiology (810 articles)

Notes

To request permissions go to:

http://group.bmj.com/group/rights-licensing/permissions

To order reprints go to:

http://journals.bmj.com/cgi/reprintform

To subscribe to BMJ go to:

http://group.bmj.com/subscribe/