1040-5488/14/9112-e301/0 VOL. 91, NO. 12, PP.

e301Ye304
OPTOMETRY AND VISION SCIENCE
Copyright * 2014 American Academy of Optometry

CLINICAL CASE

Severe Primary Ocular Surface Involvement

in Behcet Disease
Jun Zeng* and Baihua Chen

ABSTRACT
Purpose. Behcet disease (BD) is a chronic, relapsing inflammatory disorder of unknown etiology characterized by ob-
structive vasculitis. Ocular surface involvement is a less frequent anterior segment finding. We report a patient with BD
whose ocular presentation was severe surface involvement.
Case Report. A 26-year-old Chinese woman, who was diagnosed as having BD by a dermatologist because of oral and
genital ulceration and erythema nodosum in the upper extremities 1 month ago, presented with dry eye syndrome, corneal
ulceration, and conjunctival lesions. Both clinical and confocal microscope examination revealed bilateral severe in-
flammatory ocular surface disease. However, she did not have the common clinical ocular manifestations such as
iridocyclitis, vitritis, retinal perivasculitis, or retinitis for BD. In addition to oral methylprednisolone and thalidomide, topical
1% prednisolone acetate ophthalmic suspension, tacrolimus ophthalmic suspension, and artificial tears were used. We
observed for the first time histopathological changes of the eyelid in BD by confocal microscopy.
Conclusions. Ocular surface lesions should be noted as an uncommon but possible manifestation of BD. Such severe
ocular surface lesions without uveitis require a thorough medical history, dermatological examination, and serological
testing to arrive at a diagnosis of BD. Accordingly, routine examination of the ocular surface is recommended in patients
with BD, and BD should be included in a list of differential diagnoses for patients with ocular surface lesions.
(Optom Vis Sci 2014;91:e301Ye304)

Key Words: Behcet disease, ocular surface, dry eye

B
ehcet disease (BD) is a chronic, recurrent, multisystemic
inflammatory disorder of unknown etiology, characterized
by the presence of oral ulceration plus any two of the fol-
lowing: genital ulceration, typical defined ocular lesions, typical
defined skin lesions, or a positive pathergy test.1 Behcet disease is a
systemic vasculitis of small and large vessels affecting both veins
and arteries. The underlying pathology shows a nonspecific in-
flammatory process of blood vessels.2 It occurs more frequently
from eastern Asia to the Mediterranean basin, mainly between 18-
and 40-year-old men.3 HLA-B51 is the most strongly associated
known genetic factor to BD.4 Ocular manifestations are consid-
ered among the major criteria for the diagnosis of BD, occurring
in 50 to 70% of the patients with BD.5 Ocular impairment is
frequent and severe with a variety of ocular lesions reported in-
cluding anterior uveitis, cataract, glaucoma, posterior segment
involvement with vasculitis, vitritis, retinitis, panuveitis, retinal
*PhD
MD, PhD
Department of Ophthalmology, The Second Xiangya Hospital, Central South
University, Changsha, Hunan Province, China (both authors).
edema, cystoid macular degeneration, venous or arterial occlusion,
disc edema, and retinal detachment.3 Despite the wide range of
ocular involvement in BD, isolated ocular surface involvement in
BD has been described in only a few reports6Y13 and it is difficult
to diagnose for an eye care practitioner. We herein report a case of
BD with severe ocular surface involvement, occurring in a young
Chinese woman. We also observed the histopathological changes
of the eyelid in BD by Heidelberg confocal microscopy. Our
objective is to emphasize this rare condition and to discuss possible
mechanisms of ocular surface involvement.
CASE REPORT
A 26-year-old Chinese woman presented in October 11, 2012,
complaining of severe foreign body sensation, dryness, irritation,
and photophobia in both eyes for 1 month. Because of a history of
severe oral and genital ulceration and erythema nodosum in the
upper extremities during the past 1 month, she had been diag-
nosed as having BD based on the clinical findings by a derma-
tologist and had taken oral methylprednisolone 40 mg daily
and thalidomide 25 mg daily as directed by the dermatologist.

Optometry and Vision Science, Vol. 91, No. 12, December 2014

Copyright American Academy of Optometry. Unauthorized reproduction of this article is prohibited.

e302 Ocular Surface Involvement in Behcet DiseaseVZeng et al.

She denied any other recent illness or vaccinations and did not
wear contact lenses before. The patient did not have diabetes or
hypertension. On ophthalmic examination, best-corrected vi-
sual acuity (BCVA) was 20/60 in the right eye and 20/40 in the
left eye. Intraocular pressure measured by a Goldmann to-
nometer was 16 mm Hg in each eye. Examination revealed
conjunctival vasodilation, mucosa keratosis of the palpebral
margin, conjunctival scarring, symblepharon, trichiasis, and
canalicular atresia in both eyes (Fig. 1A to E). Some granulation-
like tissue proliferation was also noted in the upper palpebral
margins of both eyes (Fig. 1A, B). There was scattered punctate
fluorescein staining in both corneas and a 1-mm round ulcer lesion
near the center of cornea with mild infiltration by fluorescein
staining in the right eye (Fig. 1D, E). The pupils were equal and
round, with a brisk reaction to light and no relative afferent
pupillary defect. No inflammation was found in the aqueous,
vitreous, or fundus. Fluorescein angiography showed no retinal
vascular inflammation. We had taken some samples with moist
swabs from the lower fornix of both eyes to incubate and did not
find pathogenic microorganisms. The Schirmer I test without
anesthetic was 2.5 mm OD and 3 mm OS. Heidelberg confocal
microscopy showed palpebral conjunctiva infiltration with a
large number of mature Langerhans cells of characteristic den-
dritic form and meibomian gland infiltration with a large
number of inflammation cells in both eyes. The granulation-like
tissue on the conjunctiva appeared as amorphous structures under
Heidelberg confocal microscopy (Fig. 1F to H). The results of
autoimmune screening including rheumatoid factor (G10.1 IU/ml;
reference range, 0 to 15 IU/ml), antinuclear antibody, antineu-
trophil cytoplasmic antibodies, extractable nuclear antigen, and
antimitochondrial antibody were negative. After administration
of topical prednisolone and artificial tear eye drops four times
daily for 3 months, symptoms subsided and there was no fluo-
rescein staining in both corneas. The corneal ulceration was healed
with a corneal macula resulting in a BCVA of 20/50 in the right eye
and 20/30 in the left eye. Concurrently, the erythema nodosum and
oral and genital ulceration improved. The dosage of drugs was
reduced under the supervision of the eye care practitioner and the
dermatologist. About 2 months later, all of the above symptoms
relapsed and the dry eye symptoms worsened with a BCVA of
20/100 in the right eye and 20/40 in the left eye. The Schirmer I
test without anesthetic was 1 mm OD and 2 mm OS. In addition
to oral methylprednisolone 50 mg daily and thalidomide 25 mg
daily, topical tacrolimus and prednisolone ophthalmic suspension
and artificial tears were again used for 2 months with relief of most
of the symptoms. The dry eye symptoms persisted and the ocular
surface lesions were recalcitrant to therapy.
DISCUSSION
Behcet disease, a vasculitic disorder affecting many organs, is
characterized by three primary components: iridocyclitis (histor-
ically with hypopyon), aphthous lesions in the mouth, and ul-
ceration of the genitalia. Erythema nodosum, arthropathy, and
thrombophlebitis often accompany these manifestations. In BD,
there is no relevant biological test for diagnosis. It depends on
the clinical presentation of BD; however, sarcoidosis, multiple
sclerosis, Crohn disease, Takayasu arteritis, polychondritis, or
antiphospholipid syndrome needs to be considered in the dif-
ferential.3 International criteria of classification have been defined
with a sensitivity of 85% and a specificity of 96%.1 Although there
are many factors that can cause dry eye, in this case, the primary
considerations were Steven-Johnson syndrome and cicatricial
pemphigoid. Steven-Johnson syndrome is usually induced by drugs
and it will not relapse if it healed. Cicatricial pemphigoid can be
distinguished from BD by laboratory test results. The results of
autoimmune screen in our case were useful for differential diag-
noses. The etiology and pathogenesis of BD are not well under-
stood, although immunologic mechanisms have been suspected
to be pathologically important because of the vasculitic nature of
BD and its cellular characteristics. A variety of ocular manifestations

FIGURE 1.
A, B, Granulation-like tissue proliferation and scar on the right and left conjunctiva. C, Symblepharon and canalicular atresia on lateral nasal conjunctiva
(OS). D, E, Corneal ulceration and scattered punctate uorescein staining in the right eye. F, Inammatory cell inltration and meibomian gland on
Heidelberg confocal microscopy. G, A large amount of Langerhans cells presented in the palpebral conjunctiva under Heidelberg confocal microscopy.
H, Granulation-like tissue proliferation on the palpebral conjunctiva appeared as an acellular structure under Heidelberg confocal microscopy.

Optometry and Vision Science, Vol. 91, No. 12, December 2014

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have been found including anterior uveitis, cataract, glaucoma,
posterior segment involvement with vasculitis, vitritis, retini-
tis, panuveitis, retinal edema, cystoid macular degeneration,
venous or arterial occlusion, disc edema, and retinal detach-
ment.3 However, the presentation of ocular surface disease without
intraocular inflammation is rare. This case presented an unusual
severe ocular surface involvement in BD whose manifestations
were severe dry eye syndrome, symblepharon, granulation-like
tissue proliferation in the conjunctiva, and corneal ulceration,
all without coincident intraocular inflammation. Involvement of
the conjunctiva is not without explanation as it is a mucous
membrane like oral and genital mucosa. Therefore, changes in
conjunctiva would be expected to parallel the findings in the
other mucosa. Matsuo et al.6 and Tugal-Tutkun et al.14 found
intraepithelial neutrophil infiltration, lymphocytes, and plasma
cell infiltration around the vessels beneath the conjunctival ep-
ithelium by biopsy in BD. Matsuo et al.6 identified small lym-
phocytes as both T cells and B cells by immune-histochemical
staining, supporting the role of involvement of T cells in BD. In
this case, we observed a large number of mature Langerhans cells
of characteristic dendritic form and other inflammatory cells
infiltrated in the palpebral conjunctiva by Heidelberg confocal
microscopy consistent with the report of Matsuo et al.6 Mature
Langerhans cells of characteristic dendritic form found in pal-
pebral conjunctiva by Heidelberg confocal microscopy may be
associated with inflammation.15 We observed palpebral con-
junctiva infiltrated with a large number of mature Langerhans
cells of characteristic dendritic form, as well as meibomian gland
and corneal ulceration infiltrated with a great many inflamma-
tory cells in both eyes. The findings indicated the presence of
inflammation in the process of ocular surface lesions in BD. The
results of confocal microscopy suggest that it is an optional tool
to observe the histopathological changes of the eyelid in BD. In
addition to inflammation, the ocular surface damage in BD may
be related to the abnormity of conjunctival vessels.16,17 A video-
capillaroscopic study to assess the conjunctival microvascular
condition in BD has revealed significant changes in arterio/
venous diameter with an involvement of both the number and
the whole vessel structure.17 Flammer et al.18 reported that va-
sospasm plays a role in BD etiology, which causes ischemic
consequences. The vasospasm of conjunctival vessels may be the
main reason for necrosis of conjunctival goblet and epithelial
cells, and it may also be related to meibomian gland atrophy in
the region, which leads to irreversible loss of function and xe-
rophthalmia. Gunduz et al.19 found Schirmer I and BUT to be
significantly lower in BD patients than in the control group;
however, there was no significant difference in conjunctival
surface epithelial morphology in the two groups, consistent with
reported results. The ocular surface is known to play a major role
in the stabilization of the tear film. This stabilization is ensured
primarily by the mucin secreted by goblet cells. A decrease in
goblet cells and changes in conjunctival surface epithelial cells
disturb the stability of the ocular tear film.20 In our case, the
continuous dry eye syndrome may be associated with the damage
of conjunctiva. Corneal ulceration was also reported as an ocular
lesion in BD, the incidence of which was as high as 16%.10 In our
patient, there was a corneal ulceration in the right eye with mild
infiltration, predominantly with inflammatory cells revealed by
Optometry and Vision Science, Vol. 91, No. 12, December 2014
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Ocular Surface Involvement in Behcet DiseaseVZeng et al. e303
confocal microscopy. The incidence of corneal ulceration ap-
pears rather high,10 but the reason remains unknown.
In our report, ocular surface damage developed in accordance
with the exacerbation of systemic symptoms of BD such as oral
and genital ulcerations and erythema nodosum. Our findings
indicated that ocular surface damage may develop as a clinical
manifestation of BD. In addition to conjunctival lesions, corneal
ulceration with infiltration was noted associated with ocular
surface damage. From our findings, ocular surface damage may
present as an isolated finding in BD without other retinal or in-
traocular inflammation. The present diagnostic criteria for BD
requires the presence of at least three of four signs such as oral and
genital ulcerations or skin and ocular lesions, with an emphasis on
oral ulcerations. The ocular lesions specified in the criteria do not
include ocular surface damage; however, to better diagnose BD,
the dissociation of ocular surface damage without intraocular
inflammation in this patient suggests that ocular surface damage
may be recognized as one additional sign of ocular lesions in BD.
The primary goals of treatment in BD are symptom control,
early suppression of inflammation, and prevention of end-organ
damage. Currently, the most commonly used agents are corticoste-
roids, cytotoxic drugs, colchicine, cyclosporine-A, and tacrolimus.
A trial showed that depot corticosteroids were useful only for er-
ythema nodosum lesions among women but not in men, whereas
there was no effect on genital ulcers, oral ulcerations, folliculitis, or
arthritis.21 Colchicine (1 to 2 mg/d) was effective only for genital
ulcers, erythema nodosum, and arthritis among women, but only
for arthritis among men.22 Thalidomide was effective for sig-
nificantly reducing the mean number of oral and genital ulcers
and follicular lesions.23 Because of well-known adverse effects of
polyneuropathy, teratogenesis, and sedation, thalidomide should
be used for a short period and adverse effects should be closely
monitored. Azathioprine significantly decreased the attacks of
hypopyon uveitis and the development of new eye disease among
patients without eye involvement and preserved visual acuity.24
Topical steroids provide high ocular surface drug concentrations
and promote lymphocyte apoptosis and suppress cell-mediated
inflammation.25 Ocular surface damage showed a positive re-
sponse to topical corticosteroids.11,12 Cyclosporine-A decreases
the severity and frequency of ocular attacks and improves visual
acuity. It also has a beneficial effect on mucocutaneous lesions.26
Topical cyclosporine 0.05% or 1% compounded preparation may
be used for treatment of dry eye syndrome associated with various
causes. The mechanism of action of this therapeutic agent is
through inhibition of T-cell activation and down-regulation of in-
flammatory cytokines in the conjunctiva and lacrimal gland.27,28
The reduction in anterior-segment inflammation is thought to allow
enhanced tear production.29 Topical cyclosporine also increases
goblet cell density and decreases epithelial cell apoptosis.30 Although
the mechanism of tacrolimus is similar to that of cyclosporine-A
(calcineurin inhibitor), the potency in vitro has been shown to be
significantly greater, exhibiting similar effects at 100 times lower
concentrations.31 In this case, in addition to tacrolimus, oral
methylprednisolone, topical prednisolone, and artificial tear eye
drops managed ocular damage at the early stage. Over the long term,
however, the ocular surface could not be significantly improved.
In conclusion, ocular surface disease may be an uncommon but
possible manifestation of BD. Therefore, routine examination of
e304 Ocular Surface Involvement in Behcet DiseaseVZeng et al.
the ocular surface is recommended in patients with BD, and BD
should be included in a list of differential diagnoses for patients
with ocular surface damage. In this context, eye care professionals
should look for systemic signs of BD in patients presenting with
ocular surface damage. The confocal microscope may be an optional
tool to observe the histopathological changes of the eyelid in BD.
ACKNOWLEDGMENTS
The authors declare no conflict of interest.
Received January 8, 2014; accepted September 1, 2014.
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Baihua Chen
Department of Ophthalmology
The Second Xiangya Hospital
Central South University
139 Renming Middle Rd
Changsha Hunan Province 410011
China
e-mail: chenbh2006@163.com