Ebisike Philips Ifeanyichukwu (OD, MSc (Pharm), FAAO).
Introduction
Mooren
ulcer (MU) is characterized by painful peripheral corneal ulceration of unknown
etiology. The disease generally begins with intense limbal inflammation and swelling
in the episcleral and conjunctiva1. Mooren ulcer is a painful,
relentless, chronic ulcerative keratitis that begins peripherally and
progresses circumferentially and centrally. It was named by Mooren who first
clearly described this insidious corneal problem and defined it as a clinical
entity2.
Corneal
changes begin within 2-3 mm from the limbus, first appearing as grey swellings
that rapidly furrow, affecting the superficial one-third of the cornea and then
proceeding circumferentially and centrally over 4-12 months1,3. The
bed of the furrow becomes vascularized, with vessels advancing into the base of
the undermined edges of the ulcers1. These ulcers are often
described as crescent-shaped and can leave behind an opaque and edematous
central cornea. Alternatively, they can completely consume the corneal stroma,
replacing it with a thin fibrovascular membrane3.
Inflammation is not seen in the sclera adjacent to
the peripheral ulcers, nor does it affect the underlying Descemet’s membrane4.
Destruction of the cornea generally affects stromal tissue only, leaving behind
an intact endothelium and epithelium5. The central edges of the
ulcer can develop an overhanging edge with or without opacification, and neovascularization
of the cornea can occur, extending from the limbus into the ulcer bed3.
Neovascularization can occur up to the advancing edge of the ulcer but not
beyond it5.
Etiology
Although the etiology of Mooren’s ulcer is
unknown, there is evidence suggesting an autoimmune basis, and possibly genetic
and environmental factors contribute to the pathogenesis. Gottsch and
colleagues have suggested that this disorder can result from a host response to
calgranulin C, a normally hidden antigen expressed by keratinocytes in the
corneal stroma. This molecule has also been found in circulating
polymorphonuclear leukocytes6.
Risk Factors
Risk factors for Mooren's ulcer include
corneal surgery, previous trauma, and infection. Although corneal surgery is a
well-described risk factor, one study of 242 eyes affected by Mooren's ulcer in
South India described an interesting caveat. In this study, Srinivasan and
colleagues described 36 eyes that developed ulceration following extracapsular
cataract extraction through a superior limbal incision; however, only 31% of
these eyes developed ulceration at or contiguous to the site of the surgical
wound. Nevertheless, this ratio of superior corneal involvement of Mooren's
ulcer is still higher than expected when compared with 10% superior involvement
found in eyes with no history of ocular surgery.
Epidemiology
Mooren ulcer is a rare disease. The
incidence of MU in China was found to be 0.03%3. The disease is more
common in the southern hemisphere including Southern and Central Africa and
India, indicating a genetic and/or geographic predisposition5.
Although it is generally agreed upon that Mooren's ulcer is more common in men,
figures differ from one geographic population to the next in terms of age
distribution. Studies from South India and China have suggested that patients
tend to be affected between their sixth and eighth decades of life, with men
being affected more than women by a ratio between 1.6:1 to 5:13,7.
However,
this epidemiological picture may differ in African populations, as suggested by
a study in Nigeria where the disease mostly affected men in their 20s-30s8.
Another study from West Africa supported this epidemiologic finding, causing
the authors to postulate that there were two distinct populations of patients
with Mooren's ulcer9. The first population is older, more often
develops unilateral disease, and responds to treatment whereas the second
population is younger, tends to have bilateral disease which perforates more
often, and does not respond to treatment. Also, as reported by Fasina and his
associates in south-west Nigeria, that
Mooren’s ulcer remains an uncommon disease in Ibadan, and the demographics and
clinical presentation are similar to other parts of the West African sub-region10.
Pathophysiology
It has been postulated that Mooren’s ulcer may result from
an autoimmune etiology. Sensitization to calgranulin C, an antigen expressed by
corneal stromal keratinocytes, may occur after trauma or infection of the
cornea, causing the unveiling of this hidden corneal antigen5. The
unveiling of the hidden antigen may also occur naturally in predisposed people
with aging. It has been hypothesized that antigen-presenting cells at the
limbus can present the unveiled self-antigens via certain HLA class II
molecules to T-cells, priming them. Alternatively, antigen-presenting cells may
present a helminthic antigen that cross-reacts with calgranulin C (since
certain helminths express receptors that bind calgranulin C) resulting in a
similar reaction5. Later, upon injury of the cornea, humoral and
cellular responses result in Mooren's ulcer4,5
Martin and colleagues have suggested that infection,
trauma, or a systemic disease can expose corneal antigens and stimulate an
immune response in which complement is activated and neutrophils degranulate
and release collagenases. Collagenases then destroy the corneal stroma, further
perpetuating the process by exposing more altered corneal antigens. Eventually,
the entire cornea becomes consumed10. Evidence for a humoral immune
response comes from a study that found circulating IgG against corneal and
conjunctival epithelium in patients with Mooren's ulcer11. Studies
have also found antibodies and complements bound to the conjunctival epithelium
in addition to elevated serum IgA levels4.
Clinical
Classification of Mooren Ulcer
There are
various classifications of Mooren ulcer. One common classification divides the
disease into two types based on laterality (one or two eyes) and age of onset:
§ Limited (benign) type: This type of MU doesn’t cause much pain or
discomfort. It usually only happens in one eye (unilaterally). Only 25 percent
of cases of the benign type happen in both (bilaterally). It’s more common if you
are older.
§ Atypical (malignant) type: This type is more painful and can quickly cause the
cornea to break down if it’s not treated. It usually happens in both eyes. About
75 percent of cases of the malignant type happen in both eyes.
More recent classifications grouped Mooren
ulcer into three (3) types based upon their clinical presentation:
§ Unilateral Mooren's ulceration (UM). This is a painful and progressive corneal ulcer
typically seen in elderly patients.
§ Bilateral aggressive Mooren's ulceration (BAM). This type occurs in young patients. The ulcer progresses
circumferentially then centrally in the cornea.
§ Bilateral indolent Mooren's ulceration (BIM). This type usually occurs in middle-aged
patients. It presents with progressive peripheral corneal ulceration in both
eyes.
Diagnosis
The
diagnosis of Mooren's ulcer requires the absence of any ocular infection or
systemic rheumatological diseases known to cause peripheral corneal ulceration12.
Srinivasan and colleagues described three patterns of ulceration: partial
peripheral, complete peripheral, and total corneal ulceration (Figure A). In
complete peripheral ulceration, the disease process has completely encompassed
the corneal periphery, leaving behind a “central island of cornea” that is
often opacified (Figure B). In total corneal ulceration, the corneal stroma has
been completely replaced with a fibrovascular membrane (Figure C). Partial
peripheral ulceration can be sub-divided into nasal, temporal, superior, and
inferior ulceration, of which, temporal and nasal (the so-called intrapalpebral
cornea) involvement is more common12.
Key:
Figures; (A) Partial peripheral Mooren’s ulcer with a descemetocele within.
Conjunctival and episcleral injection is present along with deep vessels in the
base of the ulcer. A characteristic overhanging central ulcer margin is also
seen.
(B) Total peripheral Mooren’s ulcer with an
edematous, opacified central cornea.
(C)
Complete Mooren’s ulcer where a fibrovascular membrane has replaced the corneal
stroma. (Figure reproduced from Srinivasan, Zegans, Zelefsky, Kundu,
Lietman, Whitcher, and Cunningham. Adopted from the British Journal of
Ophthalmology.)
History and Physical Examination
Patients often experience severe pain,
photophobia, and tearing along with a red inflamed eye. About one third of
cases present bilaterally13. A slit-lamp examination may reveal a crescent-shaped
peripheral corneal ulcer with an undermined central edge. A linear epithelial
defect may develop at the central margin, followed by progressive stromal
melting. The ulcer progresses both circumferentially and centrally, resulting
in a re-epithelialized, conjunctivalised thinned cornea13. Consequently,
severe irregular astigmatism may result. Conjunctival and episcleral
inflammation may occur; however, the sclera is spared. Decreased visual acuity
can occur secondary to iritis, central corneal involvement, or irregular
astigmatism2.
Differential Diagnosis
To diagnosed MU successfully, the
following must be ruled out;
Terrien’s marginal degeneration differs from Mooren’s ulceration
in that it is a painless, non-inflammatory disease, causing peripheral corneal
thinning without ulceration. Terrien’s marginal degeneration also usually
begins in the superior cornea (rather than the interpalpebral region) and
proceeds circumferentially but not centrally. A clear zone with superficial
vascularization remains between the limbus and the infiltrate4.
Pellucid marginal degeneration causes inferior corneal thinning
and causes irregular against-the-rule astigmatism but lacks the inflammation
and pain seen in Mooren's ulcer4. Senile furrow degeneration causes
thinning between the limbus and an arcus in elderly patients; however, no inflammation
or vascularization occurs4.
Rheumatoid arthritis can
cause peripheral corneal ulcers that start as gray, swollen areas within 2 mm
of the limbus1. Corneal thickness diminishes rapidly and may leave
behind a fragile descemetocele. Angiography can show venous non-perfusion and
disrupted limbal arcades with neovascularization reaching the base of the
gutter. Scleritis may be associated, whereas Mooren's ulcer spares the sclera.
Other findings in rheumatoid arthritis include keratoconjunctivitis sicca,
episcleritis, and sclerosing keratitis4.
Keratolysis is a
disease of central corneal stromal disintegration that is often seen in
patients with long-standing rheumatoid arthritis. First, the central cornea
swells and the epithelium begins to shed1. The disease process
spreads until the corneal stroma is fully resorbed and a fragile Descemet’s
membrane is left. This disease is generally painless.
Other collagen vascular diseases in
which peripheral ulcerative keratitis can occur include systemic lupus
erythematosus, systemic sclerosis, and relapsing polychondritis4.
Peripheral ulcerative keratitis has also been reported to occur in association
with inflammatory bowel disease, giant cell arteritis, staphylococcal marginal
keratitis, HSV, and acanthamoeba keratitis.
Management
§
The initial treatment of
Mooren’s ulcer consists of topical corticosteroids. Topical use of 1% or 2%
Cyclosporine and interferon alfa 2 a were also suggested for the treatment of
Mooren's ulcer13.
§
If corticosteroids do not
control the inflammation, limbal conjunctival excision can be performed.
§
Conjunctival Excision of a 3-4
mm ring of limbal conjunctiva at least 2 clock hours adjacent to a Mooren's
ulcer has been shown to be an effective treatment. Studies have shown that when
less than half of the limbus is involved, the cure rate after conjunctival
excision and corneal ulcer resection is performed is 51.3%. When more than half
of the limbus is involved, the cure rate after the procedure decreases to 36.8%2.
§
In a 1975 study where limbal
conjunctival excision was performed, 8 out of 10 eyes healed, and one developed
recurring ulcer which then healed upon re-treatment13. It was
hypothesized that the limbal conjunctiva may contain antibodies that react with
antigens in the corneal stroma in addition to enzymes that destroy the corneal
stroma -therefore, excision may interrupt the disease process.
§
Bilateral indolent Mooren’s
ulceration often resolves with dietary changes and treatment of any systemic
infection that may be present. It can also be treated with local steroids and
cyclosporine A1.
§
Bilateral aggressive Mooren’s
ulceration can also be treated with aggressive local and systemic
immunosuppression.
§
Surgical interventions can also
include lamellar keratoplasty, keratoepithelioplasty, delimiting keratotomy,
and conjunctival flap and patch grafts using periosteum or fascia lata13.
§
Resection of the corneal lesion
and adjacent conjunctiva combined with lamellar keratoplasty can achieve a
final healing rate of 89.6%. If topical 1% cyclosporine A is added, a 95% final
healing rate can be achieved2.
§
Cryotherapy to the conjunctiva
surrounding ulcers may temporarily halt the progression of the disease, but healing
may not occur until the conjunctiva is excised13. Other potential
local therapies include bandage contact lenses, tissue adhesive,
subconjunctival heparin, and artificial tears and collagenase inhibitors.
Complications
In addition to iritis being occasionally
associated with Mooren’s ulceration, complications can include glaucoma,
cataracts, and corneal perforation. Complicated cataracts can occur in 2.3%.
The rate of perforation has varied in different studies in various geographical
locations. Perforation occurs most often in the limbal cornea, followed by the
peripheral and then central cornea2.
CASE REPORT
A 52 years old airport taxi man reported
to the clinic with complain of severe pain in the left eye, associated with
tearing, throbbing and pulling sensations. He also complained of
fronto-temporal headache and sensitive to light. On inquiring, he said it
started about ten days ago with itching, sandy sensation, gradual progressive
pain, burning sensation with blurring vision and discomfort. According to him,
he suddenly woke up with a swallowed and gummed eye. With further inquiry, he confirmed
that he had a blunt trauma on the left eye some months ago (he claimed he
applied some medication and all the associated trauma symptoms resolved). He is
not hypertensive, diabetic and not aware of any systemic disease at the moment.
The Entering Visual Acuity (EVA) was OD: 6/12 and OS:
LP. The anterior examination with slit lamp bimicroscopy with fluorescein
stain showed a hyperaemic conjunctiva with concentric injections. A well
stained concentric ulcer was seen at the center of the cornea with the based emanating
or fanning towards the limbal areas of the cornea and anterior chamber appeared
cloudy.
He was diagnosed with active corneal ulcer
(Mooren ulcer suspected) and was placed on Moxifloxacin (4 hourly), Nepafenac, fluconazole
eyedrops and Tobramycin ointment. He was also advised to return back to the
clinic after one week.
N/B: Fluconazole
eyedrop was added as my clinic protocol of managing any form of corneal ulcer
on first day presentation with no confirmation of the causative isolate. Once
after collection of corneal swabs for laboratory work-up, combined therapy of
antibiotic, antifungal and antiviral if possible or when necessary, should
commence immediately.
q Highlight: He was placed on:
Gutt: Moxifloxacin gt 4hr X
3/52
Gutt: Nepafenac gt
q.i.d X 3/52
Gutt: Flucomid gt q.i.d X
3/52
Oct: Tobramycin b.d.s X
3/52
FOLLOW-UP
#1
The patient reported back to the clinic
after two weeks and four days with excuses of not being around and had taken a
passenger to another state and was caught up with some security issues and
circumstances. He reported that there was still pain, pulling sensations
especially when he bends down, redness and reduced vision. Though he said there
was quite improvement with the previous medication, especially in reducing the
pain, excessive tearing and discharge within the first one week of applying the
medications before leaving town on a trip.
His EVA was OD: 6/12 and OS: HM, slit lamp examination also revealed mild hyperaemic
conjunctiva, round marked projection and thinning of the central portion of the
cornea with leukoma. Also, the Descemet membrane of the cornea folds at the
base of the ulceration with a central clear area within the area of thinning,
the iris was not prolapsed and the anterior chamber appeared slightly deep. The
Seidel test was negative indicating there was no perforation.
He was diagnosed of Mooren corneal ulcer
with descemetocele and was asked to continue with moxifloxacin eyedrop and
tobramycin ointment in addition of dexamethasone and timolol eyedrops, oral
prednisolone 10mg twice daily. However, a bandage contact lens was placed on
the eye to reduce the rubbing friction of the eyelid. He was asked to return
back in one week for more evaluation and review.
N/B: Seidel test; This
test is used to reveal leaks from the cornea, sclera, or conjunctiva following
injury or surgery. It is named after the German ophthalmologist Erich Seidel
(1882-1948).
- Explain
the procedure to the patient
- Clean
off the slit lamp and position the patient
- Gently
apply a topical anesthetic eye drop
- Using
a cotton tipped applicator, carefully dry the area of the suspected leak
- Carefully
apply a moistened fluorescein strip to the area of the suspected leak,
"painting" on the dye. Alternatively, the dye can be applied to
the superior conjunctiva, allowing the dye to flow down over the cornea
- Visualize
the injured site under a cobalt blue light source and evaluate for a green
flow (positive Seidel test)
- Estimate
the rate and volume of fluid exiting the wound
Figure 1 showed a section of the slit lamp
biomicroscopic examination during one of the follow-up visits.
FOLLOW-UP
#2
The patient came back to the clinic with the
report of much improvement, he admitted that the pain has subsided including
discharge and tearing. His EVA was OD: 6/12 and OS: CF and slit lamp
examination with and without contact lens, showed a well improved cornea
compare with his last visit. Though there was a mild conjunctiva injection, the
corneal thinning also looked well control especially with the help of the
contact lens. The anterior chamber looked mildly cloudy with the iris been more
quiet compare to his visit.
He was counselled and asked to continue
with all his medication and oral prednisolone 10mg was tapered form twice to
once daily and was asked to return back to the clinic after two weeks.
FOLLOW-UP #3
The patient came back to the clinic after two
weeks with report of much improvement in most of his previous complains such as
pain, pulling /throbbing sensation, photophobia, tearing and discharge. He only
complained of mild itching occasionally and sandy sensations.
His EVA was OD: 6/12+1 and OS: 3/60, slit lamp examination revealed quieter
and clearer conjunctiva, peripheral part of the cornea (ie., 1 - 3mm) appeared
quiet and clear with concentric less dense leukoma and some fibrovascular
tissues on the central portion of the cornea. The corneal thinning has reduced,
iris appeared quiet and non-reactive, anterior chamber was less dense/cloudy,
though there were slight flares seen in the anterior chamber.
He was also counselled and asked to
discontinue with dexamethasone, tobramycin ointment and the contact lens, while
he continued nepafenac, timolol, moxifloxacin, hypotears and the systemic
prednisolone was also tapered from 10mg to 5mg once daily. The patient was
referred for possible Cryotherapy in order to reduce the excessive
fibrovascular tissues on the cornea.
Figure
2 showed the appearance and condition of the eye before procedure.
CONCLUSION
As at the time of this case report, arrangement
was made for the Cryotherapy procedure as I do get an update from the referred
center. The patient is doing well with the same visual acuity. However, this
also has updated the literature on the prevalence of Mooren corneal ulcer in
our locality and also indicated that early presentation and appropriate diagnosis
is the major factor in management of Mooren cornea ulcer, especially in
preservation of the cornea form begin opacified or perforated.
REFERENCE
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1997. 11 (Pt 3): p. 349-56.
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3. Chen, J., et al., Mooren's ulcer in China: a study of clinical
characteristics and treatment. Br J Ophthalmol, 2000. 84(11): p. 1244-9.
4. Taylor, C.J., et al., HLA and Mooren's ulceration. Br J Ophthalmol,
2000. 84(1): p. 72-5.
5.
Gottsch, J.D., et al., Cytokine-induced calgranulin C expression
in keratocytes. Clin Immunol, 1999. 91(1): p. 34-40.
6.
Zelefsky, J.R., et al., Hookworm infestation as a risk factor for
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literature review. Ophthalmic Surg, 1987. 18(8): p. 564-9.
11. Schaap, O.L., T.E. Feltkamp, and A.C. Breebaart, Circulating
antibodies to corneal tissue in a patient suffering from Mooren's ulcer (ulcus
rodens corneae). Clin Exp Immunol, 1969. 5(4): p. 365-70.
12. Srinivasan, M., et al., Clinical
characteristics of Mooren's ulcer in South India. Br J Ophthalmol, 2007. 91(5):
p. 570-5.
13. Alhassan, M.B., M. Rabiu, and I.O.
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