Interventions for Mooren’s ulcer (Review)

Alhassan MB, Rabiu M, Agbabiaka IO

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2011, Issue 6
http://www.thecochranelibrary.com

Interventions for Mooren’s ulcer (Review)

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 17
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Interventions for Mooren’s ulcer (Review) i

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Interventions for Mooren’s ulcer

Mahmoud B Alhassan1 , Mansur Rabiu2 , Idris O Agbabiaka3

1 Clinical Ophthalmology, The National Eye Centre, Kaduna, Nigeria. 2 Prevention of Blindness Union, Riyadh, Saudi Arabia. 3 National

Eye Centre, Kaduna, Nigeria

Contact address: Mahmoud B Alhassan, Clinical Ophthalmology, The National Eye Centre, Western Bye Pass, Nnamdi Azikiwe Way,
Kaduna, Kaduna State, PMP 2267, Nigeria. mbalhassan@yahoo.com.

Editorial group: Cochrane Eyes and Vision Group.

Publication status and date: New, published in Issue 6, 2011.
Review content assessed as up-to-date: 15 April 2011.

Citation: Alhassan MB, Rabiu M, Agbabiaka IO. Interventions for Mooren’s ulcer. Cochrane Database of Systematic Reviews 2011,
Issue 6. Art. No.: CD006131. DOI: 10.1002/14651858.CD006131.pub2.

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT
Background
Mooren’s ulcer is a chronic, painful peripheral ulcer of the cornea. Its cause is unknown but it can or will lead to loss of vision if
untreated. Severe pain is common in patients with Mooren’s ulcer and the eye(s) may be intensely reddened, inflamed and photophobic,
with tearing. The disease is rare in the northern hemisphere but more common in southern and central Africa, China and the Indian
subcontinent. There are a number of treatments used such as anti-inflammatory drugs (steroidal and non-steroidal), cytotoxic drugs
(topical and systemic), conjunctivectomy and cornea debridement (superficial keratectomy). There is no evidence to show which is the
most effective amongst these treatment modalities.
Objectives
The aim of this systematic review is to assess the effectiveness of the various interventions (medical and surgical) for Mooren’s ulcer.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group
Trials Register) (The Cochrane Library 2011, Issue 4), MEDLINE (January 1950 to April 2011), EMBASE (January 1980 to April
2011), Latin American and Caribbean Health Sciences Literature Database (LILACS), (January 1982 to April 2011), the metaRegister
of Controlled Trials (mRCT) (www.controlled-trials.com) and ClinicalTrials.gov (www.clinicaltrial.gov). There were no language or
date restrictions in the search for trials. The electronic databases were last searched on 16 April 2011.
Selection criteria
We planned to include randomised controlled trials (RCTs) or discuss any prospective non-RCTs in the absence of any RCTs. The
trials included would be of people of any age or gender diagnosed with Mooren’s ulcer and all interventions (medical and surgical)
would be considered.
Data collection and analysis
Two authors screened the search results independently; we found no studies that met our inclusion criteria.
Main results
As we found no studies that met our inclusion criteria, we highlighted important considerations for conducting RCTs in the future in
this area.
Interventions for Mooren’s ulcer (Review) 1
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Authors’ conclusions

We found no evidence in the form of RCTs to assess the treatment effect for the various interventions for Mooren’s ulcer. High quality
RCTs that compare medical or surgical interventions across different demographics are needed. Such studies should make use of various
outcome measures, (i.e. healed versus not healed, percentage of area healed, speed of healing etc.) as well as ensuring high quality
randomisation and data analysis, as highlighted in this review .

PLAIN LANGUAGE SUMMARY

Interventions for Mooren’s ulcer

Mooren’s ulcer is inflammation that occurs at the edge of the cornea (clear part of the front of the eye). Its cause is unknown. It is very
painful and can or will lead to loss of vision if untreated. It occurs worldwide and affects all age groups. It is diagnosed by excluding
other causes of ulcerations at the edge of the cornea such as chronic inflammation of the joints due to rheumatoid arthritis. Mooren’s
ulcer can be treated both medically and surgically. Medical treatment includes the use of drugs such as steroids and non-steroidal anti-
inflammatories. Surgical methods include resection of the conjunctiva (the thin clear tissue that covers the surface of the eye) from the
cornea, removal of dead cornea tissue and cornea transplant. We set out to determine the best available intervention for the treatment of
Mooren’s ulcer by looking for randomised controlled trials (RCTs) comparing one form of treatment to another; and treatment versus
no treatment. The electronic database searches did not find any RCTs on the treatment of Mooren’s ulcer. This review recommends
the need for well conducted RCTs for both medical and surgical interventions for Mooren’s ulcer. These trials should look at outcomes
such as number of participants that healed against those that did not, what percentage of area healed and the speed at which healing
took place.

BACKGROUND Risk factors

Description of the condition
Mooren’s ulcer is a chronic, painful, peripheral ulcerative keratitis
(PUK) (peripheral ulcer of the cornea). It is bilateral in approxi-
mately one-third of cases and the cause is unknown.
Epidemiology
The prevalence of Mooren’s ulcer and the blindness caused by it
worldwide is unknown. The disease is rare in the northern hemi-
sphere but more common in southern and central Africa, China
and the Indian subcontinent (Tuft 2003). It is more common in
males (1.3:1) than females (1.6:1) and very rare in children (Tuft
2003). In a three-year retrospective review in a hospital in Nigeria,
amongst 18 people (25 eyes) with Mooren’s ulcer, the age range
was 12 to 42 years (average 27.9 years) (Alhassan 1999).
The incidence varies from one case per year seen in specialist clinics
in Europe and North America, to between one in 350 and one in
2200 clinic visits in India and Nigeria (Zegans 1998). A large case
series from China (715 eyes treated in 36 years) put the incidence
at 0.03% of the study population (Chen 2000).
Interventions for Mooren’s ulcer (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Although the cause is unknown, it has been suggested that there
is a genetic as well as an environmental basis for the disease. The
likely environmental factors include antecedent history of acci-
dental trauma or surgery and exposure to viral and parasitic in-
fections. However, an increase in the rate of hepatitis C infection
has not been found in patients from India with Mooren’s ulcer
(Tuft 2003). An association with helminthiasis (intestinal worm
infestation) has also been noted, but the disease can develop in the
absence of helminthiasis. Even where helminthiasis is endemic,
Mooren’s ulcer is still rare (Tuft 2003). Human leukocyte antigens
(HLAs) can confer susceptibility to several autoimmune disorders
and in Asian and black African patients the presence of HLA-
DR17 or DQ2 (histocompatibility antigens) may confer suscep-
tibility to Mooren’s ulcer (Taylor 2000). Zhao 1993 also reported
increased expression of HLA DR in patients with the disease.
Presentation and diagnosis
Classification
2
There are various forms of classifications of the disease. A recent
and more often used classification groups Mooren’s ulcer into three
distinct types on the basis of clinical features, fluorescein angio-
graphic evidence of capillary closure or leakage and response to
treatment (Watson 1997).
1. Unilateral Mooren’s ulceration (UM) is a painful
progressive corneal ulceration in elderly patients and is associated
with non-perfusion of the superficial vascular plexus of the
anterior segment.
2. Bilateral aggressive Mooren’s ulceration (BAM) occurs in
young patients and progresses circumferentially then centrally in
the cornea. There is vascular leakage and new vessel formation
extending into the base of the ulcer.
3. Bilateral indolent Mooren’s ulceration (BIM) usually occurs
in middle-aged patients and presents with progressive peripheral
corneal guttering in both eyes, with little inflammatory response.
There is no change from normal vascular architecture except an
extension of new vessels into the ulcer.
Another common classification is based on laterality and age of
onset. The disease is grouped into two types.
• A unilateral type common amongst older age groups with
same sex distribution, and slow progression.
• A type that occurs mostly in Africa, as a bilateral rapidly
progressive disease, that is less responsive to treatment
(Wilhelmus 2001).
Clinical manifestation
Severe pain is common in Mooren’s ulcer and the eye(s) may be
intensely reddened, inflamed and photophobic, with tearing. The
disease is characterised by a crescent-shaped, peripheral corneal
ulcer, with an extensively undermined central edge that results
in the characteristic ’overhanging’ edge of the cornea (Bouchard
1998; Foster 1999; Kanski 2003; Wilhelmus 2001; Young 1982).
The ulcer typically progresses with an anterior stromal yellow-
white infiltrate 2 mm to 3 mm from the limbus at the advancing
margin of the ulcer, often in the interpalpebral zone (Kanski 2003;
Tuft 2003). An overlying linear epithelial defect then develops
often at the central margin. This is followed by progressive stromal
melting, which affects the deeper stroma first and subsequently
the anterior stroma. The ulcer progresses circumferentially and
centrally. A re-epithelialised, conjunctivalised, thinned cornea may
remain.
Chronic Mooren’s ulcer ultimately results in a central island of
hazy stromal tissue with severe peripheral thinning. Topogra-
phy demonstrates significant irregular astigmatism and peripheral
steepening. No scleral involvement occurs, although associated
conjunctival and episcleral inflammation may be seen. Visual loss
as a result of irregular corneal astigmatism and scarring is com-
mon.
Clinical grading
Interventions for Mooren’s ulcer (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Mooren’s ulcer can be graded as follows (Sharma 2005).
1. The extent of corneal thinning in one or more quadrants,
subdivided into a) mild - thinning affecting less than 25% of
corneal circumference; b) moderate - thinning affecting 25% to
50% of corneal circumference; and c) severe - thinning affecting
more than 50% of corneal circumference.
2. Impending corneal perforation.
3. Corneal perforation of more than 2 mm.
Diagnosis
Mooren’s ulcer is diagnosed by its typical clinical features as de-
scribed above (in ’Clinical manifestation’) and exclusion of any
systemic disease. This distinguishes it from other, more common
types of PUK associated with collagen vascular disease, which must
be excluded in order to diagnose Mooren’s ulcer.
Description of the intervention
Treatment options
Some investigators advocate ’the stepladder approach’ in the treat-
ment of aggressive Mooren’s ulcer. This includes medical (local
and systemic) and surgical therapy (Brown 1984).
Medical treatment
Local
It has been suggested that initial treatment should be with topical
corticosteroids, followed by limbal conjunctival resection if the
inflammation is not controlled. Topical cyclosporine 1% drops
have been used in some cases (Zhao 1993). In addition, bandage
contact lenses (to reduce discomfort and promote epithelial heal-
ing); tissue adhesive; subconjunctival heparin injections; artificial
tears and topical collagenase inhibitors, such as acetylcysteine (Mu-
comyst 10%) and L-cysteine 0.2 molar have been used. Lecinthi-
nated superoxide dismutase use has also been reported (Shimmura
2003).
Systemic
Immunosuppression with cyclophosphamide followed by azathio-
prine may be initiated if treatment with conjunctival resection fails,
and may be considered earlier in bilateral cases or in cases where
the disease is advanced at first examination, with extensive corneal
thinning (Foster 1985). Systemic immunosuppressive treatment
of the more aggressive bilateral disease has included the use of oral
corticosteroids, cyclosporine A, and methotrexate (Brown 1984).
The use of high-dose cyclosporine A has been reported (Foster
3
1985). Plasma exchange has also been tried. Systemic interferon
alfa-2b has been used in the treatment of patients positive for the
hepatitis C virus who have Mooren’s ulcer (Moazami 1995; Wilson
1994). Two case reports showed favourable responses to mono-
clonal antibodies campath- 1H and infliximab (Fontana 2007;
Van der Hoek 2003).
Surgical treatment
Surgical interventions include conjunctival resection, lamellar ker-
atoplasty, epikeratoplasty, delimiting keratotomy, conjunctival flap
and patch grafts of periosteum or fascia lata (Kinoshita 1991).
Some investigators advocate “removal of the presumed antigenic
corneal source (central lamellar keratectomy)” in an attempt to me-
diate a more rapid resolution of the inflammation (Brown 1984).
Although initial corneal surgery is usually contra-indicated, some
authors have reported good results with a primary lamellar kerato-
plasty combined with topical cyclosporine A. Using this regimen
Chen 2000 achieved a cure of 74% for the first procedure, and a
final cure rate of 95%.
How the intervention might work
The local and systemic immunosuppressives act by mitigating the
immune response to inciting antibodies while the surgical inter-
ventions like conjunctival resection act by preventing the delivery
of immune complexes to the cornea stroma.
Why it is important to do this review
The multiplicity of therapeutic strategies employed for Mooren’s
ulcer underscores the relative lack of knowledge about effective
treatment. The outcome of management is difficult to determine
because of the different treatments and different patient character-
istics. Thus, it is imperative to identify the most effective modal-
ity or modalities for the treatment of this condition, for different
patient characteristics, so that informed decisions can be made for
optimal management of the disease.
OBJECTIVES
The aim of this systematic review is to assess the effectiveness of the
various interventions (medical and surgical) for Mooren’s ulcer.
METHODS
Criteria for considering studies for this review
Interventions for Mooren’s ulcer (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Types of studies
Only RCTs were eligible for inclusion. However, as there were no
eligible RCTs, we presented a narrative summary of other forms
of prospective studies on the disease.
Types of participants
We planned to include people of any age and gender, clinically di-
agnosed with Mooren’s ulcer as a PUK, epithelial defect with over-
hanging edges. The diagnosis had to exclude other causes of PUK
such as collagen vascular diseases by laboratory examinations. We
had planned to exclude trials which enrolled people with a his-
tory of eye infections in the affected eye prior to the diagnosis of
Mooren’s ulcer, unless data for these participants could be sepa-
rated. We had planned to exclude trials that enrolled people with
other systematic diseases, unless data for these participants could
be separated.
Types of interventions
We considered the following comparisons.
1. Any single intervention for Mooren’s ulcer against no interven-
tion.
2. One form of intervention for Mooren’s ulcer against another.
3. A combination of interventions for Mooren’s ulcer against an-
other intervention or another combination of interventions.
Intervention refers to any type of measure either medical, surgical
or otherwise used for the treatment of the disease.
Types of outcome measures
Primary outcomes
1. Complete healing - present or not, after eight weeks of
follow-up.
Fluorescein staining or slit-lamp examination may be used to as-
certain healing. Complete healing is defined as non-progression of
the ulcer and filling of ulcer crater, with no fluorescein staining.
Secondary outcomes
1. Speed of healing as determined by a) the period (days or
weeks) taken to complete healing; and (b) the percentage/
proportion/length/area of the ulcer healed after a period (days or
months).
2. Number of ulcers that have reoccurred after healing.
3. Visual outcomes: level of visual acuity change before
treatment and after treatment. Any measure of visual acuity that
can be converted to a LogMAR chart.
Healed portions of the ulcer refers to parts of the ulcer crater with
no fluorescein staining and progressive filling of the crater.
4
Adverse effects (severe, minor)
1. Severe adverse effects of interventions - local effects or systemic
effects or both, defined as life threatening conditions.
2. Minor adverse effects of interventions - local effects or systemic
effects or both, defined as non-life threatening conditions.
Quality of life measures
We planned to examine any measure of quality of life used by the
trialists.
Economic data
We collected information about costs of treatments where avail-
able.
Follow-up
We planned to consider a minimum follow-up period of eight
weeks.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Central Register of Controlled Tri-
als (CENTRAL) 2011, Issue 4, part of The Cochrane Library.
www.thecochranelibrary.com (accessed 16 April 2011), MED-
LINE (January 1950 to April 2011), EMBASE (January 1980
to April 2011), Latin American and Caribbean Health Sciences
Literature Database (LILACS) (January 1982 to April 2011),
the metaRegister of Controlled Trials (mRCT) (www.controlled-
trials.com) and ClinicalTrials.gov (www.clinicaltrials.gov). There
were no date or language restrictions in the electronic searches
for trials. The electronic databases were last searched on 16 April
2011.
See: Appendices for details of search strategies for CENTRAL
(Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix
3), LILACS (Appendix 4), mRCT (Appendix 5) and ClinicalTri-
als.gov (Appendix 6).
Searching other resources
We planned to search the Science Citation Index to identify fur-
ther studies. We planned to search the reference lists of included
studies to find further trials. We specifically did not handsearch
journals or conference proceedings for this review. We planned to
contact companies and pharmaceutical firms that produce med-
ications used in Mooren’s ulcer treatment which includes, but is
not limited to immunosuppressive agents (e.g. cyclophosphamide,
azathioprine, methotrexate and topical and systemic steroids). We
planned to contact companies such as Alcon, GlaxoSmithKline,
Novartis, Pfizer, Troge, Baxter oncology and Duopharma for any
unpublished data they may have, or further information on any
company that may have information to give on this subject.
Interventions for Mooren’s ulcer (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Data collection and analysis
Selection of studies
Two authors (MA and IA) independently assessed all titles and
abstracts. We retrieved full-text copies of all possibly or definitely
relevant articles. Two authors (MA and IA) independently assessed
the articles to determine whether they met the inclusion criteria.
As we did not find any trials, we did not collect any data.
Future updates of this review
For future updates, we will continue to follow the method set out
above for screening the search results from the electronic databases
and will complete the following processes for any trials that meet
our inclusion criteria.
We will contact the authors of articles with inadequate information
for further details of their studies. If we do not receive a response
within a given time, we will send reminders and may contact co-
authors. We will resolve disagreements in the included articles by
consulting the third author (MR).
Data extraction and management
Two authors will independently extract data from all included
studies. The third author will settle any differences between the
two authors. We will extract the following Information from the
included studies.
• Methods: method of allocation of participants; masking
(participant, provider, outcome); exclusions after randomisation;
losses to follow-up; compliance; unusual study design such as
randomisation by persons but analysis by eyes.
• Participants: country where participants enrolled;
participant’s racial/ethnic background; number randomised; age;
sex; main inclusion and exclusion criteria.
• Interventions: treatment; comparison intervention
(control); duration of intervention.
• Outcomes: primary and secondary outcomes as reported.
We will contact the authors of studies with missing data to ask for
more information.
We will group together similar outcomes (units of measurements)
for analysis.
Assessment of risk of bias in included studies
Two authors will independently assess the methodological quality
of studies for inclusion in the review. We will use the criteria
for assessing risk of bias, as stated in The Cochrane Handbook for
Systematic Reviews of Interventions (Higgins 2011), for each of the
following domains. Each parameter will be graded as: low risk,
high risk or unclear risk of bias.
• Random sequence generation (selection bias).
5
 • Allocation concealment (selection bias).
• Blinding of participants and personnel (performance bias).
• Blinding of outcome assessment (detection bias).
• Incomplete outcome data (attrition bias).
• Selective reporting (reporting bias).
• Other biases.
Measures of treatment effect
We will calculate and pool risk ratios (RRs) and their 95% con-
fidence intervals (CIs) for dichotomous data (such as healed/not
healed). For continuous data we will calculate mean differences
(MDs) and their 95% CIs for each included study and pool the
data to derive the mean difference (MD). If the scales vary, we
will calculate and pool the standardised mean difference (SMD).
If possible, we will calculate a hazard ratio (HR) and 95% CI for
time-to-event data.
Unit of analysis issues
If the unit of analysis differs from the unit of randomisation (for
example analysis by eyes but randomisation done per individual)
then we will ensure that the correct denominator is used for anal-
ysis, or else we will adjust for the non-independence between the
two eyes.
Dealing with missing data
We plan to contact primary authors for missing data. If we do not
get a response from the primary author, we will address missing
data by using replacement values (assuming that the data were
missed at random and that the missing values signify poor out-
comes). We will perform sensitivity analysis using various assump-
tions.
Assessment of heterogeneity
We will assess statistical heterogeneity using a P value of less
than 0.10 to determine significant heterogeneity (Chi2 test). We
will use a random-effects model and subgroup analysis to address
significant heterogeneity.
Assessment of reporting biases
We plan to assess for reporting bias if at least 10 papers are included
in the review. We also plan to include unpublished studies. We have
not restricted the electronic database searches by language (see ’
Search methods for identification of studies’). We will also examine
the funnel plot for asymmetry by visual inspection. For continuous
data we will use linear regression of the intervention effect estimate
on their standard error to test for funnel plot asymmetry. For
dichotomous data we will use linear regression of the log odds
Interventions for Mooren’s ulcer (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ratio (OR) on its standard error by the inverse of the variance of
the log OR.
Data synthesis
If meta-analysis is deemed appropriate we will combine studies
using a fixed-effect model where there are three or less studies, or
a random-effects model where there are more than three studies.
If meta-analysis is not possible, we will report included studies
in a narrative synthesis. We will group the studies according to
study design and intervention with consideration of variation in
recruited participants, outcome measures and methodological va-
lidity. If possible, we will present RRs, HRs or WMDs and 95%
CIs in graphical format, without statistical pooling of data.
Subgroup analysis and investigation of heterogeneity
If data permit, and included studies are sufficiently similar, we will
perform exploratory subgroup analyses according to the following
variables that may affect the prognosis of the disease.
• Severity of disease at presentation, using the clinical grading
mentioned above or any other used by the trialists.
• Racial disposition of participants.
• Whether the participants have unilateral or bilateral
Mooren’s ulcer.
• Age of participants at diagnosis (child - age 15 years and
below; adult - older than 15 years).
Sensitivity analysis
If data permit, we will perform sensitivity analyses to explore the
impact of the study design and methodological quality on the
summary estimate. We will repeat the analysis excluding unpub-
lished studies and studies that have assumed that eyes within an
individual are independent.
RESULTS
Description of studies
See: Characteristics of excluded studies.
The electronic searches yielded a total of 1312 titles and abstracts
(Figure 1). After deduplication the Trials Search Co-ordinator
scanned 1019 records and discarded 351 records as they were not
relevant to the scope of the review. We screened the title and ab-
stracts of the remaining 668 references. We rejected a further 649
abstracts as not eligible for inclusion in the review. We obtained
and screened full-text copies of 19 references, however none of
these were reports of RCTs.
6
 Figure 1. Results from searching for studies for inclusion in the review.

Interventions for Mooren’s ulcer (Review) 7

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Included studies
We did not find any RCTs that met our inclusion criteria.
Excluded studies
We excluded 19 studies as they were not RCTs. See the ’
Characteristics of excluded studies’ table for details.
Risk of bias in included studies
We did not assess any studies for risk of bias as no RCTs were
included.
Effects of interventions
As we did not include any trials, we could not measure the effects
of the interventions.
DISCUSSION
The electronic searches did not find any prospective RCTs that
met our inclusion criteria. We did not find any prospective non-
randomised studies comparing various interventions for Mooren’s
ulcer. We found either case reports or retrospective case series stud-
ies which we have discussed in the ’Characteristics of excluded
studies’ table.
The available evidence of treatment effects for Mooren’s ulcer
are level 4 (intervention case series) (Wormald 2004) (case se-
ries: Brown 1975; Chen 2000; Hill 1987; Karegelopolous 2004;
Sharma 2005) and level 5 (intervention case reports: Chen 2004;
Erdem 2007; Tiev 2002).
In a traditional literature review, Chow 1996 discussed exten-
sively the various treatment modalities available for Mooren’s ul-
cer. These include topical steroids, conjunctival resections, ker-
atoepithelioplasty, systemic immunosuppression with cyclophos-
phamide, methotrexate and azathioprine and topical immunosup-
pression with cyclosporine A.
Other surgical procedures that have been tried in the treatment
of Mooren’s ulcer included superficial lamellar keratoplasty, con-
junctival flaps, penetrating keratoplasty and periosteal grafts.
Zegans 1998 has summarised the various strategies into four as
follows: local immunosuppression, systemic immunosuppression,
removal of local stimulatory antigens and removal of distant stim-
ulatory antigens.
Interventions for Mooren’s ulcer (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A combination of these strategies has been used in many of the
studies cited above. Chen 2000 used a combination of conjuncti-
val excision, lamellar keratoplasty and topical 1% cyclosporine A
with some success. This is the largest case series reported.
Sharma 2005 used a step ladder approach, selecting the type of
intervention for each case of Mooren’s ulcer. The classification is
based on the degree of cornea thinning at time of commencement
of treatment.
Definition of success also seems to vary in the literature. Some
studies used ‘healed’(Brown 1975; Chen 2000; Erdem 2007; Tiev
2003; Zhao 1993) while others used ’visual acuity’ (Chen 2004;
Hill 1987). Failure was defined as progression of corneal melting
leading to perforation and loss of the eye.
Any RCT design for the measurement of treatment effect for
Mooren’s ulcer needs to take into consideration the above factors
i.e. combination of modalities, step ladder approach and clear def-
initions of outcome measures such as visual acuity, healing, cornea
thinning/perforation, time to healing and adverse events. Case
definition has to be clearly stated including how the other causes
of PUK were ruled out. All interventions compared should be well
defined. We suggest any RCT on interventions for Mooren’s ulcer
should consider the following points.
Participants’ selection
Selection of participants must ensure that the mechanism for ex-
clusion of PUK from systemic conditions is followed. The panel
of tests to be carried out will include the following: antinuclear
antibody (ANA); antiphospholipid antibodies; rheumatoid factor
(Rh); erythrocyte sedimentation rate (ESR); serum antibodies to
hookworm; C-reactive protein (CRP); and stool microscopy for
hookworm (Van der Gaag 1983; Zelefsky 2007). Adequate con-
cealment of allocation must also be insured. The Wilhelmus 2001
classification of Mooren’s ulcer is suggested in any planned RCT.
Assessment
Masking of participants and the care giver should be effected in
trials involving use of drugs.
Adequate masking of the assessors needs to be made for all in-
terventions. This may easily be effected by assessing quality pho-
tographs of the ulcer instead of the patient.
The following intervention combinations can be used in an RCT
on Mooren’s ulcer treatment: topical immunosuppressives (topical
steroids, topical cyclosporine and topical cyclophosphamide); sys-
temic immunosuppressives (steroids, cyclosporine and cyclophos-
phamide); and conjunctivectomy with superficial keratectomy.
8
Outcome measures
Types of outcome measures that should be considered include:
1. Primary outcomes (fluorescein staining and/or slit-lamp exam-
ination may be used to ascertain healing).
• Complete healing present or not present.
• Percentage/proportion of ulcer healed.
• Rate (proportion/length/area of defect healed per unit
time).
2. Secondary outcomes
• Pain assessments using 0 to 100 score, visual analogue score
or any form of pain measurement.
• Visual outcomes using the visual acuity chart.
• Analgesia use; use of topical cycloplegics.
• Other symptoms e.g. photophobia.
• Quality of life measures.
• Daily living activities assessments.
• Insomnia assessments.
Adverse effects
1. Severe adverse effects of interventions - local effects or systemic
effects or both, defined as life threatening conditions.
2. Minor adverse effects of interventions - local effects or systemic
effects or both, defined as non-life threatening conditions.
Economic data
Information about costs of treatments.
REFERENCES
References to studies excluded from this review
Brown 1975 {published data only}
Brown SI. Mooren’s ulcer treatment by conjunctival
excision. British Journal of Ophthalmology 1975;59(11):
675–82.
Chen 2000 {published data only}
Chen J, Xie H, Wang Z, Yang B, Liu Z, Chen L, et
al.Mooren’s ulcer in China: a study of clinical characteristics
and treatment. British Journal of Ophthalmology 2000;84
(11):1244–9.
Chen 2004 {published data only}
Chen KH, Hsu WM, Liang CK. Relapsing Mooren’s
ulcer after amniotic membrane transplant combined with
conjunctival autograft. Ophthalmology 2004;111(4):792–5.
Chow 1996 {published data only}
Chow CY, Foster CS. Mooren’s ulcer. International
Ophthalmology Clinics 1996;36(1):1–13.
Interventions for Mooren’s ulcer (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
AUTHORS’ CONCLUSIONS
Implications for practice
There are no RCTs available to measure the effectiveness of the
various modalities for the treatment of Mooren’s ulcer. For now
the routine practice of selective treatment or step ladder approach,
judged clinically to be most appropriate for the patient character-
istics, will have to continue.
Implications for research
Mooren’s ulcer is potentially a blinding condition. High-qual-
ity RCTs are needed comparing the various treatment modalities
(medical or surgical) for the treatment of Mooren’s ulcer among
the different demographic status of patients. Such studies should
make use of various outcome measures such as (healed versus not
healed, percentage of area healed, speed of healing etc.) as well
as ensuring high quality randomisation and data analysis as high-
lighted in this review.
ACKNOWLEDGEMENTS
The Cochrane Eyes and Vision Group (CEVG) created and ran
the search strategies. We thank Catey Bunce, Steve Tuft, Swaroop
Vedula and Kirk Wilhelmus for their comments on the protocol
and/or review. We thank Anupa Shah, Managing Editor for the
CEVG for her help throughout the review process.
Erdem 2007 {published data only}
Erdem U, Kerimoglu H, Gundogan FC, Dagli S. Treatment
of Mooren’s ulcer with topical administration of interferon
alfa 2a. Ophthalmology 2007;114(3):446–9.
Fontana 2007 {published data only}
Fontana L, Parente G, Neri P, Reta M, Tassinari G.
Favourable response to infliximab in a case of bilateral
Mooren’s ulcer. Clinical & Experimental Ophthalmology
2007;35(9):871–3.
Hill 1987 {published data only}
Hill JC, Potter P. Treatment of Mooren’s ulcer with
cyclosporin A: a report of three cases. British Journal of
Ophthalmology 1987;71(1):11–5.
Kalogeropulous 2004 {published data only}
Kalogeropulous CD, Malamou-Mitsi VD, Aspiotis MB,
Psilas KG. Bilateral Mooren’s ulcer in six patients: diagnosis,
surgery and histopathology. International Ophthalmology
2004;25(1):1–8.
Mavrakanas 2007 {published data only}
Mavrakanas NA, Kiel R, Dosso AA. Autologous serum
9
 application in the treatment of Mooren’s ulcer. Klinische
Monatsblatter fur Augenheilkunde 2007;224(4):300–2.
Miyazaki 2008 {published data only}
Miyazaki D, Tominaga T, Kakimaru-Hasegawa A, Nagata
Y, Hasegawa J, Inoue Y. Therapeutic effects of tacrolimus
ointment for refractory ocular surface inflammatory
diseases. Ophthalmology 2008;115(6):988–92.
Sangwan 1997 {published data only}
Sangwan VS, Zafirakis P, Foster CS. Current concepts
in management of Mooren’s ulcer. Indian Journal of
Ophthalmology 1997;45(1):7–17.
Sharma 2005 {published data only}
Sharma A, Vishawanath KB, Mohan K. Critical analysis
of management options in Mooren’s ulcer. All India
Ophthalmological Society. Jan 2005.
Shimmura 2003 {published data only}
Shimmura S, Igarashi R, Yaguchi H, Ohashi Y, Shimazaki
J, Tsubota K. Lecithin-bound superoxide dismutase in the
treatment of noninfectious corneal ulcers. American Journal
of Ophthalmology 2003;135(5):613–9.
Spelsberg 2007 {published data only}
Spelsberg H, Sundmacher R. Amniotic membrane
transplantation and high dose systemic cyclosporin A
(Sandimmun optoral) for Mooren’s ulcer. Klinische
Monatsblatter fur Augenheilkunde 2007;224(2):135–9.
Tandon 2008 {published data only}
Tandon R, Chawla B, Verma K, Sharma N, Titiyal JS.
Treatment of Mooren’s ulcer with cyclosporin a 2%. Cornea
2008;27(8):859–61.
Tiev 2003 {published data only}
Tiev KP, Borderie VM, Briant M, Ziani M, Morvant
C, Baret M, et al.Severe Mooren’s ulcer: efficacy of
monthly cyclophosphamide intravenous pulse treatment
[Ulceres de Mooren severes: efficacite du traitement par
cyclophosphamide en bolus intraveineux mensuels]. La
Revue de Medecine Interne 2003;24(2):118–22.
Van der Hoek 2003 {published data only}
∗
Van der Hoek J, Azuare-Blanco A, Greiner K, Forrester JV.
Mooren’s ulcer resolved with campath-1H. British Journal of
Opthalmology 2003;87(7):924–5.
Xie 2003 {published data only}
Xie H, Chen J, Wang Z, Yang B, Gong X, Feng C, et
al.Microsurgical treatment of bilateral Mooren’s ulcer.
Microsurgery 2003;23(1):27–31.
Zegans 1998 {published data only}
Zegans ME, Srinivasan M. Mooren’s ulcer. International
Opthalmology Clinics 1998;38(4):81–8.
Zhao 1993 {published data only}
Zhao JC, Jin XY. Immunological analysis and treatment of
Mooren’s ulcer with cyclosporin A applied topically. Cornea
1993;12(6):481–8.
Additional references
Interventions for Mooren’s ulcer (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Alhassan 1999
Alhassan MB. Mooren’s ulcer: clinical types and treatment
outcome. Ophthalmological Society of Nigeria Annual
Conference; Abuja, Nigeria. 1999.
Bouchard 1998
Bouchard CS. Mooren’s Ulcer. In: Yannoff M, Duker JS
editor(s). Ophthalmology. St Louis: Mosby, 1998.
Brown 1984
Brown SI, Mondino BJ. Therapy of Mooren’s ulcer.
American Journal of Ophthalmology 1984;98(1):1–6.
Foster 1985
Foster CS. Systemic immunosuppressive therapy for
progressive bilateral Mooren’s ulcer. Ophthalmology 1985;
92(10):1436–9.
Foster 1999
Foster CS. Immunologic disorders of the conjunctiva,
cornea and sclera. In: Albert DM, Jakobiec FA editor(s).
Principles and Practice of Ophthalmology. 2nd Edition.
Philadelphia: WB Saunders, 1999:803–28.
Glanville 2006
Glanville JM, Lefebvre C, Miles JN, Camosso-Stefinovic J.
How to identify randomized controlled trials in MEDLINE:
ten years on. Journal of the Medical Library Association 2006;
94(2):130–6.
Higgins 2011
Higgins JPT, Green S (editors). Cochrane Handbook
for Systematic Reviews of Interventions Version 5.1.0
[updated March 2011]. The Cochrane Collaboration,
2011. Available from www.cochrane-handbook.org.
Kanski 2003
Kanski JJ. Clinical Ophthalmology: A Systematic Approach.
5th Edition. Philadelphia: Butterworth-Heinemann, 2003:
117–9.
Kinoshita 1991
Kinoshita S, Ohashi Y, Ohji M, Manabe R. Long-
term results of keratoepithelioplasty in Mooren’s ulcer.
Ophthalmology 1991;98(4):438–45.
Moazami 1995
Moazami G, Auran JD, Florakis GJ, Wilson SE, Srinivasan
DB. Interferon treatment of Mooren’s ulcers associated with
hepatitis C. American Journal of Ophthalmology 1995;119
(3):365–6.
Taylor 2000
Taylor CJ, Smith SI, Morgan CH, Stephenson SF, Key T,
Srinivasan M, et al.HLA and Mooren’s ulceration. British
Journal of Ophthalmology 2000;84(1):72–5.
Tuft 2003
Tuft S. Mooren’s Ulcer. In: Johnson GJ, Minassian DC,
Weale RA, West SK editor(s). Epidemiology of Eye Disease.
London: Arnold, 2003:209–11.
Van der Gaag 1983
Van der Gaag R, Abdillahi H, Stilma JS, Vetter JCM.
Circulating antibodies against cornea epithelium and
10
 hookworm in patients with Mooren’s ulcer in Sierra Leone.
British Journal of Ophthalmology 1983;67(9):623–8.
Watson 1997
Watson PG. Management of Mooren’s ulceration. Eye
1997;11(3):349–56.
Wilhelmus 2001
Wilhelmus KR, Huang AJ, Hwang DG, Parrish CM,
Sutphin JE, Whitsett JC. External disease and cornea. In:
Liesegang TJ, Deutsch TA, Grand MG editor(s). Basic and
Clinical Science Course for Ophthalmologists Section 8. San
Francisco, CA: American Academy of Ophthalmology,
2001:217–8.
Wilson 1994
Wilson SE, Lee WM, Murakami C, Weng J, Moninger GA.
Mooren-type hepatitis C virus-associated corneal ulceration.
Interventions for Mooren’s ulcer (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Ophthalmology 1994;101(4):736–45.
Wormald 2004
Wormald R. Bridging the gap to evidence based eye care.
Community Eye Health Journal 2004;17(51):40–1.
Young 1982
Young RG, Watson PG. Light and electron microscopy of
corneal melting syndrome (Mooren’s ulcer). British Journal
of Ophthalmology 1982;66(6):341–56.
Zelefsky 2007
Zelefsky JR, Srinivasan M, Kundu A, Lietman T, Whitcher
JP, Cunningham ET Jr. Hookworm infestation as a risk
factor for Mooren’s ulcer in South India. Ophthamology
2007;114(3):450–3.
∗
Indicates the major publication for the study
11
CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Brown 1975 Not a randomised controlled trial, case report

Chen 2000 Not a randomised controlled trial, retrospective case series

Chen 2004 Not a randomised controlled trial, case report

Chow 1996 Not a randomised controlled trial, conventional literature review

Erdem 2007 Not a randomised controlled trial, case report

Fontana 2007 Not a randomised controlled trial, case report

Hill 1987 Not a randomised controlled trial, case report

Kalogeropulous 2004 Not a randomised controlled trial, case report

Mavrakanas 2007 Single case report

Miyazaki 2008 Case report

Sangwan 1997 Not a randomised controlled trial, literature review

Sharma 2005 Not a randomised controlled trial, case report

Shimmura 2003 Case reports

Spelsberg 2007 Not a randomised controlled trial, retrospective case report of three patients

Tandon 2008 Retrospective case series

Tiev 2003 Not a randomised controlled trial, case report

Van der Hoek 2003 A case report

Xie 2003 Not a randomised controlled trial, retrospective case series

Zegans 1998 Literature review

Interventions for Mooren’s ulcer (Review) 12

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

Zhao 1993 Not a randomised controlled trial, case report

Interventions for Mooren’s ulcer (Review) 13

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DATA AND ANALYSES
This review has no analyses.

APPENDICES

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor Corneal Ulcer
#2 mooren*
#3 (ulcer* or peripheral) near/3 (keratitis)
#4 (cornea* or marginal*) near/3 (ulcer*)
#5 ulcus rodens
#6 (#1 OR #2 OR #3 OR #4 OR #5)

Appendix 2. MEDLINE search strategy

1 randomized controlled trial.pt.
2 (randomized or randomised).ab,ti.
3 placebo.ab,ti.
4 dt.fs.
5 randomly.ab,ti.
6 trial.ab,ti.
7 groups.ab,ti.
8 or/1-7
9 exp animals/
10 exp humans/ )
11 9 not (9 and 10)
12 8 not 11
13 exp corneal ulcer/
14 mooren$.tw.
15 ((ulcer$ or peripheral) adj3 keratitis).tw.
16 ((cornea$ or marginal$) adj3 ulcer$).tw.
17 ulcus rodens.tw.
18 or/13-17
19 12 and 18
The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville (Glanville 2006).

Interventions for Mooren’s ulcer (Review) 14

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Appendix 3. EMBASE search strategy
1 exp randomized controlled trial/
2 exp randomisation/
3 exp double blind procedure/
4 exp single blind procedure/
5 random$.tw.
6 or/1-5
7 (animal or animal experiment).sh.
8 human.sh.
9 7 and 8
10 7 not 9
11 6 not 10
12 exp clinical trial/
13 (clin$ adj3 trial$).tw.
14 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
15 exp placebo/
16 placebo$.tw.
17 random$.tw.
18 exp experimental design/
19 exp crossover procedure/
20 exp control group/
21 exp latin square design/
22 or/12-21
23 22 not 10
24 23 not 11
25 exp comparative study/
26 exp evaluation/
27 exp prospective study/
28 (control$ or prospectiv$ or volunteer$).tw.
29 or/25-28
30 29 not 10
31 30 not (11 or 23)
32 11 or 24 or 31
33 exp corneal ulcer/
34 mooren$.tw.
35 ((ulcer$ or peripheral) adj3 keratitis).tw.
36 ((cornea$ or marginal$) adj3 ulcer$).tw.
37 ulcus rodens.tw.
38 or/33-37
39 32 and 38

Appendix 4. LILACS search strategy

keratitis or mooren$ or cornea$ or marginal and ulcer$ or peripheral

Interventions for Mooren’s ulcer (Review) 15

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Appendix 5. metaRegister of Controlled Trials search strategy
keratitis or mooren

Appendix 6. ClinicalTrials.gov search strategy

Keratitis OR Mooren

HISTORY
Protocol first published: Issue 3, 2006
Review first published: Issue 6, 2011

Date Event Description

9 October 2008 Amended Converted to new review format.

CONTRIBUTIONS OF AUTHORS
Conceiving the review: MR
Designing the review: MR, MA, IA
Co-ordinating the review: MR, MA, IA
Undertaking manual searches: IA
Screening search results: MR, MA
Organising retrieval of papers: MR
Screening retrieved papers against inclusion criteria: MR, MA
Appraising quality of papers: MR, MA, IA
Abstracting data from papers: MR, IA
Writing to authors of papers for additional information: MR
Obtaining and screening data on unpublished studies: IA, MR
Data management for the review: MR
Entering data into RevMan: MR, MA
Analysis of data: MA
Interpretation of data: MR
Writing the review: MR, MA, IA

Interventions for Mooren’s ulcer (Review) 16

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DECLARATIONS OF INTEREST
None known.

DIFFERENCES BETWEEN PROTOCOL AND REVIEW

The review ended with a discussion of the published case series or case reports on Mooren’s ulcer treatment.

NOTES
None

INDEX TERMS
Medical Subject Headings (MeSH)
Corneal Ulcer [∗ therapy]

MeSH check words

Humans

Interventions for Mooren’s ulcer (Review) 17

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.