Perilimbal

conjunctival
pigmentation in
Chinese patients
with vernal
keratoconjunctivitis
FOJ Luk
1,2
, VWY Wong
1,2
, SK Rao
1
and DSC Lam
1
Abstract
Purpose To document the disease spectrum
and evaluate the presence of perilimbal
conjunctival pigmentation in Chinese patients
with vernal keratoconjunctivitis (VKC).
Method A casecontrol study was conducted
between November 2004 and July 2005.
Patients aged 18 or younger with VKC and
age-matched children attending our eye clinic
for refractive or orthoptic problems were
recruited and compared. Detailed slit-lamp
examination was performed noting in
particular the presence of perilimbal
conjunctival pigmentation, the severity of
papillary reaction, and corneal complications
of VKC.
Results A total of 19 patients and 23 controls
were evaluated. The presence of bilateral large
tarsal or limbal papillae and epithelial defect
were signicantly associated with symptoms
severity (Fishers exact test, P0.015 and
P0.035 respectively). All VKC patients were
found to have perilimbal conjunctival
pigmentation in at least one eye. There was a
signicant correlation in the colour and
density of pigments between the two eyes
(Spermans r 0.93, Po0.001). None of the
controls was found to have such perilimbal
conjunctival pigmentation (Fishers exact test,
Po0.001).
Conclusion The presence of perilimbal
conjunctival pigmentation appears to be a
consistent clinical nding in Chinese patients
with VKC and may be a useful diagnostic sign
for patients with subtle signs or symptoms.
Eye (2008) 22, 10111014; doi:10.1038/sj.eye.6702816;
published online 27 April 2007
Keywords: conjunctival pigment; vernal
keratoconjunctivitis; Chinese
Introduction
Vernal keratoconjunctivitis (VKC) is a bilateral
chronic ocular allergic disorder affecting mainly
children and young adults, more commonly in
persons of Asian and African origin.
1
Some of
the patients have associated atopy or a family
history of atopy. The disease may occur on a
seasonal or perennial basis. Patients with VKC
typically present with ocular itchiness, tearing,
photophobia, foreign body sensation,
hyperaemia, and mucous discharge. Papillary
changes can be seen on the palpebral conjunctiva
as well as the limbus. The hallmark feature of
VKC is the presence of giant cobblestone-like
papillae on the upper tarsal conjunctiva.
2
In
severe cases, associated corneal changes such as
supercial punctate keratitis, corneal erosion,
epithelial defect, plaque formation and ulcers
may also be present.
3
In mild or atypical
cases of VKC, however, clinical features may
overlap with other ocular allergies such as
seasonal and perennial allergic conjunctivitis
and giant papillary conjunctivitis, leading to
misdiagnosis of the disease, although the
latter is often associated with contact lens wear
or other foreign body response. Recently, a new
clinical sign of VKC was reported in Indian
patients suffering from this disease and was
described as ne, golden brown spotty
pigmentations mostly located in the perilimbal
bulbar conjunctiva.
4
A casecontrol study of
Indian patients suffering from VKC showed
that the perilimbal pigmentation was a consistent
nding in VKC patients and this sign was
sensitive and specic.
5
The aim of this study
was to document the presence or absence of
perilimbal conjunctival pigmentation in Chinese
patients and to examine the relationship
between these pigments and the severity and
chronicity of the disease.
Received: 9 October 2006
Accepted in revised form:
7 March 2007
Published online: 27 April
2007
Financial interest: nil
Financial support: nil
Presentation: poster
presentation in Hong Kong
Ophthalmological
Symposium, Hong Kong,
2005
1
Department of
Ophthalmology & Visual
Science, The Chinese
University of Hong Kong,
Hong Kong SAR, Peoples
Republic of China
2
Hospital Authority
Ophthalmic Service, Hong
Kong Eye Hospital,
Kowloon, Hong Kong SAR,
Peoples Republic of China
Correspondence:
VWY Wong,
Hong Kong Eye Hospital,
147K Argyle Street,
Hong Kong, Peoples
Republic of China
Tel: 852 2762 3000;
Fax: 852 2768 7058.
E-mail: drvwong@
hotmail.com
Eye (2008) 22, 10111014
& 2008 Nature Publishing Group All rights reserved 0950-222X/08 $30.00
www.nature.com/eye
C
L
I
N
I
C
A
L
S
T
U
D
Y
Methods
A non-interventional casecontrol study was carried out
in Hong Kong Eye Hospital between November 2004 and
July 2005. VKC was diagnosed clinically in patients
presenting with symptoms of allergic conjunctivitis
together with cobblestone-like papillae on the tarsal
conjunctiva or limbus. Consecutive patients aged
18 years or younger attending the cornea and external
eye clinic with VKC were recruited into the study after
obtaining informed consent from their parents.
Age-matched children attending our general
ophthalmology clinic for refractive and orthoptic
problems were recruited as controls. The study was
performed in accordance to the declaration of Helsinki.
A detailed history was obtained from the patients
noting in particular the age of onset of the disease,
seasonal variation of the symptoms, personal and family
history of atopy and other concomitant ocular or
systemic diseases. Patients were asked to document the
presence of symptoms including hyperaemia, itchiness,
tearing, photophobia, and mucous discharge and to
grade the severity of the condition on a three-point scale
(1Fmild, 2Fmoderate, 3Fsevere).
The extent and size of papillary changes on the
palpebral and bulbar conjunctiva were graded using
slit-lamp on a four-point scale based on the grading
system by Bonini et al (0Fno papillary reaction; 1Ffew
papillae o0.2 mm over the tarsal conjunctiva or around
the limbus; 2Fpapillae of 0.31 mm over the tarsal
conjunctiva or at the limbus; 3Fpapillae of 13 mm all
over the tarsal conjunctiva or for 3601 around the limbus;
4Fpapillae 43 mm in the tarsal conjunctiva or a
gelatinous appearance at the limbus covering the
peripheral cornea).
6
Corneal complications such as
epithelial changes, peripheral vascularisation, plaques,
and ulcers were recorded. The presence of the perilimbal
conjunctival pigmentation was documented using
slit-lamp photography and the colour, location and
extent of the pigmentation were recorded.
All data were entered into a statistical software for
analysis (SPSS v11.5, SPSS Inc., Chicago, USA). The
association between patients symptoms and clinical
signs was analysed using the w
2
test and Fishers exact
test. Correlation analysis was performed on the
characteristics of the perilimbal conjunctival
pigmentation between the two eyes using
non-parametric Spearman rank-sum test. A P value
of p0.05 was considered statistically signicant.
Results
Nineteen children with VKC and 23 age-matched
controls were recruited in the study. The mean age for
VKC patients and the controls was 11.2 and 10.7 years
respectively (two-tailed t-test, P0.59). For the VKC
group, 17 (89.5%) were boys and the mean age of disease
onset was 7.5 years (range, 415 years).
Patients with VKC reported symptoms of itchiness
(nine patients, 47.4%), mucous discharge (six patients,
31.6%), hyperaemia (ve patients, 26.3%), and tearing
(ve patients, 26.3%). Fifteen (78.9%) patients graded
their overall symptoms as mild, four (21.1%) as moderate
and none as severe at the time of the study. The papillae
were present in the upper lid only in 28 (73.7%) eyes and
10 (26.3%) eyes had involvement of both the upper and
lower lids. In 16 (42.1%) eyes, the papillae were larger
than 1 mm. There were limbal papillae in nine (23.7%)
eyes, mainly found in the inter-palpebral area. Seven
(18.4%) eyes had corneal epitheliopathy, two (5.3%) eyes
developed corneal ulcer and three (7.9%) eyes had cornea
plaque. None of these symptoms or clinical signs was
present in the controls. The presence of bilateral large
tarsal (grade 4) or limbal (grade 3) papillae and corneal
epithelial defects were signicantly associated with
symptoms severity (Fishers exact test, P0.015 and
P0.035 respectively).
All 19 VKC patients had perilimbal conjunctival
pigmentation in at least one eye with bilateral
involvement in 16 (84.2%) patients. The pigments
appeared as multiple, scattered, discrete, dot-like
deposits with colour varying from faint to dark brown
and were most frequently found in the interpalpebral
conjunctiva (68.6%), followed by inferior bulbar
conjunctiva (42.9%), superior bulbar conjunctiva (5.7%)
and circumferential (2.9%) (Figure 1). There was a
signicant correlation in the colour density of pigments
between the two eyes (Spermans r 0.93, Po0.001). The
density of the pigments however did not correlate with
age, disease severity or the chronicity of disease.
Conjunctival pigmentation was not observed in any of
the control patients (Fishers exact test, Po0.001).
Discussion
The pathophysiology of VKC has not been completely
claried to-date but is believed to involve more than one
form of immune mechanisms. VKC has been considered
as a type I IgE-mediated immune response and this was
supported by the personal or family history of atopy, and
the laboratory evidence of elevated IgE titres in patients
serum and tears.
7
However, in a case series of 195
patients with VKC, Bonini et al
6
found a positive
response to skin and radioallergosorbent tests in only
half of the patients. This suggested that the pathogenesis
is probably multifactorial with additional involvement of
Th2 lymphocytes, mast cells and eosinophils.
8
Other
neural factors such as substance P and nerve growth
Perilimbal conjunctival pigment in VKC
FOJ Luk et al
1012
Eye
factors may also play a role.
9,10
With abundant
melanocytes and mast cells around the limbus and
complex immune mechanisms involved in VKC, we
postulate that the perilimbal conjunctival pigments
observed in our patients may be a by-product of these
complex interactions and pathways. Growth factors
or interleukins may stimulate the melanocytes in
producing such pigments around the limbus. These
pigments are more commonly found in the
interpalpebral and inferior area of the bulbar conjunctiva
around the limbus but not in the tarsal conjunctiva.
Whether environmental or racial factors have a role in
the distribution of the pigments remain to be solved.
Immunopathological studies of specimens of these
conjunctival pigments from VKC patients may provide
additional information.
In our study all 19 VKC patients had perilimbal
conjunctival pigmentation in at least one eye with
bilateral involvement in 84.2% patients. The pigments
appeared as multiple, scattered, discrete, dot-like
deposits with colour varying from faint to dark-brown.
The differential diagnoses of these pigments in children
include severe vitamin A deciency and chemical injury.
However, these diagnoses can be easily distinguished
from vernal conjunctivitis. Children with severe vitamin
A deciency may have Bitot spots as well as conjunctival
pigments. In cases of chemical injury, there would be a
history of trauma and other signs of chemical burn in the
lids or the cornea.
Diagnosis of VKC is generally based on the signs and
symptoms of the disease. In cases where the diagnosis is
difcult, histopathological analysis of conjunctival
scraping to demonstrate the presence of inltrating
eosinophils may be helpful.
11
However, this is an
invasive procedure and may be difcult to perform in
very young uncooperative children. In this study, we
have demonstrated that perilimbal conjunctival
pigmentation is a consistent clinical sign in patients
with VKC in our population. This sign may help to
conrm the diagnosis of mild or early VKC cases
when palpebral and limbal changes are not very
characteristic.
The presence of perilimbal conjunctival pigmentations
have been reported in Indian patients with VKC and they
were found to occur in all grades of VKC.
5
These
perilimbal conjunctival pigmentations were present even
when the disease was in remission.
5
Our results echoed
with the previous publication in the Indian population in
that despite a signicant correlation in the colour density
of pigments between the two eyes, there was no
relationship between the density of the pigments with
age, severity or the chronicity of disease.
A limitation of our study is the small sample size and
cross-sectional design. Further prospective studies with
long-term follow-up of a larger population and different
racial groups including Caucasians are warranted. It is
possible that the presence of this sign may depend on the
extent of pigmentation in the eyes as there is no literature
on the description of such pigmentation in Caucasian
patients.
In conclusion, the presence of perilimbal conjunctival
pigmentation appears to be a consistent clinical nding
in Chinese patients with VKC. The nding is similar to
previous report in Indian patients but has not been
reported in Caucasian patients. The presence of
perilimbal pigments may be a useful diagnostic sign in
VKC patients with early or mild disease when signs and
symptoms are subtle.
Figure 1 Perilimbal conjunctival pigmentation in a VKC patient.
Perilimbal conjunctival pigment in VKC
FOJ Luk et al
1013
Eye
References
1 Bielory L. Allergic and immunologic disorders of the eye.
Part II: ocular allergy. J Allergy Clin Immunol 2000; 106:
10191032.
2 Leonardi A, Abatangelo G, Cortivo R, Secchi AG. Collagen
types I and III in giant papillae of vernal
keratoconjunctivitis. Br J Ophthalmol 1995; 79: 482485.
3 Tanaka M, Dogru M, Takano Y, Miyake-Kashima M,
Asano-Kato N, Fukagawa K et al. The relation of
conjunctival and corneal ndings in severe ocular
allergies. Cornea 2004; 23: 464467.
4 Rao SK, Padmanabhan P. Perilimbal conjunctival
pigmentation in vernal keratoconjunctivitis: a new sign.
Cornea 2002; 21: 432.
5 Rao SK, Meenakshi S, Srinivasan B, Baluswamy S.
Perilimbal bulbar conjunctival pigmentation in vernal
conjunctivitis: a prospective evaluation of a new
clinical sign in an Indian population. Cornea 2004; 23:
356359.
6 Bonini S, Bonini S, Lambiase A, Marchi S, Pasqualetti P,
Zuccaro O et al. Vernal keratoconjunctivitis revisited. A case
series of 195 patents with long-term followup.
Ophthalmology 2000; 107: 11571163.
7 Allansmith MR, Hahn GS, Simon MA. Tissue, tear and
serum IgE concentrations in vernal conjunctivitis. Am J
Ophthalmol 1976; 81: 506511.
8 Bonini S, Bonini S. IgE and non-IgE mechanisms in ocular
allergy. Ann Allergy 1993; 71: 296299.
9 Fujishima H, Takeyama M, Takeuchi T, Saito I, Tsubota K.
Elevated levels of substance P in tears of patients with
allergic conjunctivitis and vernal keratoconjunctivitis. Clin
Exp Allergy 1997; 27: 372378.
10 Lambiase A, Bonini S, Bonini S, Micera A, Magrini L,
Bracci-Laudiero L. Increased plasma levels of nerve growth
factor in vernal keratoconjunctivitis and relationship to
conjunctival mast cells. Invest Ophthalmol Vis Sci 1995; 36:
21272132.
11 Bonini S, Coassin M, Aronni S, Lambiase A. Vernal
keratoconjunctivitis. Eye 2004; 18: 345351.
Perilimbal conjunctival pigment in VKC
FOJ Luk et al
1014
Eye