CLINICAL SCIENCE

Outcome of Treatment of Mooren Ulcer

With Topical Cyclosporine A 2%
Radhika Tandon, MD, FRCOphth, FRCSEd, Bhavna Chawla, MS, Kamna Verma, MS,
Namrata Sharma, MD, and Jeewan S. Titiyal, MD
Purpose: To study the clinical outcome of treatment of Mooren
ulcer with topical cyclosporine A (CsA) 2% as an adjunct to standard
therapy.
Methods: Seventeen eyes of 15 patients with Mooren ulcer treated
with CsA 2% eyedrops were included. Five eyes had undergone
a full-thickness patch graft for perforation and were started on topical
CsA therapy after surgery. Topical CsA had been started in the other
12 eyes as an adjunct to standard medical therapy after treatment
failure. Clinical efcacy was evaluated on the basis of reduction in
lesion size, healing of the epithelial defect, visual recovery, and
recurrence rate.
Results: In 12 eyes to which topical CsA had been given as an
adjunct therapy, the ulcers had resolved completely with various
degrees of vascularization. The mean healing time including com-
plete epithelization was 34.4 6 13.1 days (range, 1456 days). Dur-
ing the follow-up period of 12 months, recurrence had been observed
in 1 patient. No recurrence of the ulcer was seen in the 5 eyes that
were started on topical CsA therapy after tectonic keratoplasty. A
signicant (P = 0.004) improvement was seen in the mean best-
corrected visual acuity from the pretreatment values at 12 months.
No adverse effects attributable to CsA were observed.
Conclusions: Topical 2% CsA therapy can be a safe and useful
adjunct to standard medical therapy in recalcitrant cases of Mooren
ulcer.
Key Words: Mooren ulcer, topical cyclosporine A 2%
(Cornea 2008;27:859861)
M
ooren ulcer is a peripheral ulcerative keratitis of
unknown etiology. The initial management of this
condition is with the use of topical corticosteroids.
1
However,
some cases may be unresponsive to topical steroids and can
progress relentlessly, threatening the visual axis and structural
integrity of the globe. Immunosuppression
1
has been shown to
be benecial in such cases when used as an adjunct to
conventional therapy. Few studies have reported the efcacy of
cyclosporine A (CsA), systemic
2,3
or topical,
47
as a treatment
modality for Mooren ulcer. In this study, we report our
experience with the use of topical CsA 2% prepared in
polyvinyl alcohol in Mooren ulcer refractory to treatment with
standard medical therapy.
MATERIALS AND METHODS
For this study, we retrospectively reviewed records of 15
consecutive patients with Mooren ulcer who presented to the
Cornea Service of Dr. Rajendra Prasad Center for Ophthalmic
Sciences, All India Institute of Medical Sciences, New Delhi,
India, between January 2001 and June 2004 and who had
already had a treatment failure with standard medical therapy
(intensive topical steroids, topical cycloplegics, prophylactic
antibiotics, and lubricants) administered for at least 2 weeks.
A detailed history including the duration of symptoms,
treatment already taken, and history suggestive of collagen
vascular disorders was recorded. A thorough ocular exami-
nation, which included recording of the best-corrected visual
acuity (BCVA) and a detailed slit-lamp biomicroscopy, was
undertaken. A physical examination was carried out to rule out
any systemic disease. Laboratory studies conducted included
a complete hemogram, Erythrocyte Sedimentation Rate, blood
urea, serum creatinine, antistreptolysin O, antinuclear anti-
body, and rheumatoid factor. In all cases, corneal scrapings
had been taken and sent for smear and culture with antibiotic
sensitivity testing. All other local and systemic causes that
could have led to peripheral corneal ulceration were ruled out
before a diagnosis of Mooren ulcer was established. Informed
consent was obtained before starting adjunctive therapy with
topical CsA.
Of 17 eyes, 12 had been managed medically and 5 had
needed surgical intervention for corneal perforation. Topical
CsA 2% had been extemporaneously prepared by reconstitut-
ing the intravenous formulation of CsA (Sandimmun; Novartis
Pharma, Switzerland) in 1.4% polyvinyl alcohol at the Ocular
Pharmacy of our center by using a standard protocol. Under
sterile conditions, CsA was diluted from the intravenous
preparation available as a 5% concentration (250 mg/5 mL) to
a 2% concentration by adding 7.5 mL of 1.4% polyvinyl
alcohol. The 2% CsA drops thus prepared were started 4 times
a day in the 12 eyes in addition to standard medical therapy
consisting of topical prednisolone acetate 1% two hourly,
Received for publication July 13, 2007; revision received February 14, 2008;
accepted February 17, 2008.
From the Cornea and Refractive Surgery Services, Dr. Rajendra Prasad Centre
for Ophthalmic Sciences, All India Institute of Medical Sciences, New
Delhi, India.
Presented in part as a poster at the ESCRS Congress, London, UK, September
2006.
Reprints: Radhika Tandon, Cornea and Refractive Surgery Service, RP Centre
for Ophthalmic Sciences, All India Institute of Medical Sciences, New
Delhi 110029, India (e-mail: radhika_tan@yahoo.com).
Copyright 2008 by Lippincott Williams & Wilkins
Cornea

Volume 27, Number 8, September 2008 859
topical 2% homatropine hydrobromide 3 times a day, 0.3%
ooxacin eyedrops 4 times a day, and lubricants.
Five of 17 eyes presented with a perforation at the initial
visit, for which full-thickness patch grafting had been per-
formed. Postoperatively, these cases also received CsA 2%
topically 4 times a day in addition to standard medical therapy.
No other surgical measures were undertaken.
All patients were followed up on days 1, 7, and 14 and
thereafter at regular intervals for at least 1 year. In all cases,
topical CsAwas continued for at least 612 months depending
on the clinical response. The frequency of topical prednisolone
acetate had been gradually decreased once healing had taken
place and then tapered off over a few weeks. Prophylactic
antibiotics eyedrops were continued for 4 weeks. At each
follow-up visit, the BCVA was recorded, and slit-lamp biomi-
croscopy was performed to evaluate the healing of the epithelial
defect, reduction in lesion size (clock hour involvement), and
recurrence rate. Any adverse events were also noted.
RESULTS
A total of 15 cases (17 eyes) were included in this case
series. There were 12 men and 3 women (4:1), and the mean
age was 50 6 13.3 years (range, 3072 years). Six patients
were bilaterally affected. Of these, the fellow eye was phthis-
ical because of previous occurrences of Mooren ulcer in 4
cases. Five eyes had various degrees of corneal perforation at
the time of presentation. The mean BCVA at the time of
presentation was 0.095 6 0.12 (range, 0.0010.33).
Complete healing with vascularization was observed in
the 12 eyes treated with topical CsA therapy alone (Fig. 1).
The mean healing time including complete epithelialization
was 34.4 6 13.1 days (range, 1456 days). In 1 eye, Mooren
ulcer recurred 2 months after cessation of topical CsA therapy.
In 5 eyes that were treated with topical CsA therapy after
undergoing a corneal grafting surgery for perforation, the
grafts were well accepted, and no recurrence of the ulcer was
seen at the end of 1-year follow-up in any of these eyes.
The mean BCVA at 12-month follow-up was 0.33 6
0.27 (range, 0.0010.67). A signicant (P = 0.004) improve-
ment was seen in the mean BCVA from the pretreatment
values at 12 months. No adverse effects of CsA were noted
during the follow-up. The drug was well tolerated, and none of
the patients had to stop taking the preparation because of any
local complications such as irritation.
DISCUSSION
A possibility of an autoimmune mechanism has been
postulated in the pathogenesis of Mooren ulcer with cell-
mediated and humoral antibodies directed against target
molecules in the corneal stroma.
8
Hence, immunosuppression
was found to be benecial in cases refractory to conventional
management. CsA may have a benecial effect by causing
suppression of helper T cells and stimulating the depressed
population of suppressor T cells in Mooren ulcer.
2,3
Systemic
CsA was found to have a signicant positive effect on the
outcome of Mooren ulcer in cases unresponsive to standard
medical and surgical therapy.
2,3
Topical CsA has the advantage
that it obviates the potential serious adverse effects of systemic
immunosuppression.
Thus far, there are only 2 case series in literature, both
from China, describing the efcacy of topical CsA in Mooren
ulcer. In the rst case series by Zhao and Jin,
4
of 18 eyes with
severe progressive Mooren ulcer, 11 eyes were effectively
treated with topical CsA 0.5%. They concluded that efcacy of
topical CsA may be attributable to its effect of local depression
of ocular immunopathologic reactions,
4,5
although systemic
action cannot be ruled out. In this study, a concentration of
0.5% topical CsA (prepared by diluting 50 mg/mL Sandim-
mun with 0.9% sodium chloride sterile solution) was used,
which resulted in a cure rate of 61.1% (11 of 18 eyes). We used
a concentration of 2% topical CsA and found that the ulcers
healed in all 12 (100%) eyes and was completely cured in 11
eyes (91.7%), with a recurrence in only 1 eye after cessation of
topical CsA. Moreover, in our series, in an additional 5 eyes,
topical CsA 2% was also useful as an adjunctive therapy in
preventing recurrence of Mooren ulcer after tectonic kerato-
plasty. A higher concentration of CsA 2% may contribute to
a better healing rate than that observed in the study by Zhao
and Jin.
In the second case series by Chen et al,
7
a healing rate of
95.6% was reported in 114 eyes with Mooren ulcer in which
topical CsA 1% prepared in olive oil was used as an adjunct to
surgery, which involved extensive excision of the ulcer,
episclera, and adjacent conjunctiva combined with a lamellar
keratoplasty (LKP). The authors suggested that LKP surgery
removes antigenic targets of the cornea, prevents immunologic
reactions, reconstructs the anatomic structure, prevents it from
perforating, and improves vision. They concluded that LKP
surgery combined with topical CsA 1% is an effective
treatment of Mooren ulcer. In our case series, no surgical
FIGURE 1. Mooren ulcer (slit-lamp
microscopic photograph) and vascu-
larized scar after treatment (slit-lamp
microscopic photograph).
860 q 2008 Lippincott Williams & Wilkins
Tandon et al Cornea

Volume 27, Number 8, September 2008
procedure was performed in the 12 eyes treated by medical
management alone in which complete reepithelialization
occurred after administration of topical CsA 2%. Therefore,
we can attribute the healing of ulcers to the use of topical CsA
2% in addition to topical steroids.
One of the problems of topical preparations of CsA 2%
has been the vehicle in which it is delivered, the irritation
induced often overcoming the positive effects of the drug.
Although topical CsA 2% has not been previously reported for
the treatment of Mooren ulcers, in studies on the efcacy of
topical CsA 2% in other conditions such as vernal kerato-
conjunctivitis
912
and steroid-dependent atopic keratoconjunc-
tivitis,
13
castor
10
or maize oil
13
has been used as a vehicle. In 1
such study,
13
reported side effects of topical CsA included
blurring of vision, intense stinging, tearing, increased dis-
charge, redness, and pufness of the lids. In another study,
10
a mild and transient burning sensation was noticed on
administration of topical CsA. In the study by Chen et al,
7
topical CsA 1% was prepared in olive oil, and there are no
details on adverse effects observed, if any, with this
formulation. We described delivery of topical CsA 2% in
polyvinyl alcohol, which is easy to prepare and does not cause
any adverse effects. To our knowledge, this formulation has
not been described in the treatment of Mooren ulcer. A study
in which topical CsA 2% was prepared in preservative-free
articial tears and was used for the treatment of vernal
keratoconjunctivitis
12
also found the drug to be well tolerated.
There are a few studies in the literature on the levels of
CsA in the cornea, aqueous humor, and serum after topical
administration.
9,1416
A study on corneal penetration of topical
CsA 0.5% has shown that CsAwas able to achieve high levels
in the corneal epithelium, followed by endothelium and stroma
after topical administration. Another study
15
compared the
anterior chamber levels of CsA 2% after topical versus sys-
temic administration and concluded that CsA penetrates into
the anterior chamber after topical application, but these levels
are much lower than those attained after systemic CsA therapy.
Doan et al
16
studied the efcacy of topical CsA 2% in children
with phlyctenular keratoconjunctivitis. The patients were mon-
itored for adverse effects, and CsA levels in the blood were
evaluated every 3 months. They found that none of the patients
had detectable CsA blood levels and concluded that long-term
topical CsA 2% therapy is safe and effective in severe steroid-
dependent childhood phlyctenular keratoconjunctivitis.
In our study, we found that complete healing with
vascularization was achieved in all 12 eyes where topical CsA
2% was administered as an adjunct therapy. No recurrence of
the ulcer was seen in the 5 eyes that were started on topical
CsA 2% after a patch graft. There were no local or systemic
side effects attributable to the therapy. Our study has
a limitation that it is not a controlled trial but a small series
of patients, and as such, it lacks the denitive ndings that
a controlled trial would confer. Undoubtedly, a randomized
controlled trial would help to further characterize the specic
benets of this therapy. However, if we take into account that
the disease under discussion is relatively rare, a controlled trial
would be difcult to organize, and faced with the apparent
effectiveness of CSA, it would be unreasonable to withhold the
drug if clinically indicated.
Topical CsA 2% is efcacious, is easy to prepare, and is
well tolerated and may be worth trying in ulcers refractory to
steroids before embarking on a surgical procedure. Topical
CsA A 2% is safe and effective and can be used as an adjunct
to standard therapy in severe progressive cases of Mooren
ulcer refractory to conventional treatment.
ACKNOWLEDGMENTS
The authors thank Prof. Rasik B. Vajpayee, Head,
Cornea and Refractive Surgery Service, Dr. Rajendra Prasad
Centre for Ophthalmic Sciences, All India Institute of Medical
Sciences, presently at Centre for Eye Research Australia,
University of Melbourne, Melbourne, Australia. The authors
also thank the Department of Ocular Pharmacology, Dr.
Rajendra Prasad Centre for Ophthalmic Sciences, All India
Institute of Medical Sciences, for help in the preparation of
topical cyclosporine 2%.
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Volume 27, Number 8, September 2008 Treatment of Mooren Ulcer With Topical CsA 2%