Re-Keratoplasty in Corneal Ulcer

Dr.dr. Lukman Edwar Sp. M (K)

Ocular infection and immunology division, depertement of opthalmology, Faculty of Medicine,
Universitas Indonesia – Cipto Mangunkusumo Hospital

Corneal blindness is one of the major public-health problems; especially in

developing countries. Corneal transplantation surgery is the most successful tissue
transplantation procedure in humans. The first successful corneal transplantation
was performed by Eduard Zirm in 1905.
Keratoplasty is a full -thickness corneal transplant procedure, has long been
the only surgical method available for treatment of severe loss of corneal
transparancy. There're few techniques have been reported for keratoplasty:
Penetrating Keratoplasty (PK), Boston Keratoprosthesis, Deep Anterior Lamellar
Keratoplasty (DALK), Descement Stripping Automated Endothelial Keratoplasty
(DSAEK), Descemen's Membrane Endothelial Keratoplasty (DMEK).
Despite advances in ocular immunosuppressive, antibiotic and
antiglaucoma therapy, corneal trasplantation techniques, and postoperatives care,
failed graft remains a common clinical indication for penetrating keratoplasty PKP.
Repeat keratoplasty continues to be an important and increasingly common
indication for PKP. In most large eye care centers, repeat PKP is the second leading
indication for corneal transplantation, accounting for a mean of approximately 18%
(range, 6% to 41%) of the rejection rate was reported to be as high as 30% after 5
years of a successful keratoplasty. Ocular surface disease was the most frequent
associated risk factor for graft failure. Other risk factors included: endothelial graft
rejection, microbial keratitis, galucoma, and neovascularization. Corneal
neovascularization is an independent risk factor that can jeopardize the outcome of
a successfully performed keratoplasty by causing episodes of graft rejection.
In conclusion, despite the limitations in repeat keratoplasty, such as
suboptimal visual gain and decreased graft clarity rates, regrafting should be done
particularly in motivated and realistic patients whose quality of life is expected to
improve significanly after surgery, especially patients with corneal ulcer
previously; otherwise keratoprosthesis should be considered as an alternative
surgical treatment.

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Adjuvant Treatment for Corneal Ulcer

Dr. Getry Sukmawati Sp M (K)
Infection Immunology Subdivision, Ophtalmology Depertement Medical Faculty Andalas
University / M Djamil Hospital Padang West sumatera Indonesia

ABSTRACT
Introduction : Adjuvant Treatment : treatment that is given in addition to primary
(initial) treatment, is an addition designed to help reach the ultimate goal. The goal
in corneal ulcer cases is to improve visual acuity, anatomical (epithelial healing)
outcomes and to reduce complications. the treatment usually use for non healing /
refractory corneal ulcers depend on the facilitation and type of the ulcers, some
adjuvant treatment common use daily for corneal ulcer not wait until the term of
non healing corneal ulcer.
Purpose : To report some adjuvant treatment for corneal ulcer
Method : Theoretical and clinical appearance for corneal ulcer management
Result : Adjuvant treatment for corneal ulcer can divided in 4 groups
1. Medical Treatment: 1. Povidone Iodine (PVI), 2. topical coenzyme Q 10, 3.
collagenase inhibitor, 4. platelet-rich plasma, 5. topical corticosteroids, 6. other:
cycloplegic, anti glaucoma medicine , analgesics, and supplement. 2. Non Invasive
Treatment: 1. tissue adhesive: cayanoacrylate glue, fibrin glue, 2. hyperbaric
oxygen therapy, 3. corneal cross linking (CXL), 4. Cryotheraphy, 5. bandage
contact lense. 3. Surgical Treatment: 1. debridement/ remove necrotic tissue, 2.
conjunctival Flap, 3. anterior chamber parasentese , 4. amnion membran
transplantation, 5. Keratoplasty. 4. Radiotherapy.
Conclusion: the adjuvant treatment is not fixed , depends on facilitation , type of
corneal ulcer, patient and surgeon. devided on 4 groups and we can combine some
adjuvant treatment depends on indication, and clinical manifestation of ulcer, and
can reappearance if necessary.
Keywords: adjuvant hyperbaric, corneal cross Linking (CXL), cryotheapy,
keratoplasty

Introduction :
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Adjuvant Treatment : treatment that is given in addition to primary (initial)

treatment, is an addition designed to help reach the ultimate goal. The goal in
corneal ulcer cases is to improve visual acuity, anatomical (epithelial healing)
outcomes and to reduce complications. The treatment usually use for non
healing/refractory corneal ulcers depend on the facilitation and type of the ulcers,
some adjuvant treatment common use daily for corneal ulcer not wait until the term
of non healing corneal ulcer. Corneal wound healing is a complex process involving
various factors such as tear film, limbal stem cells, epithelial cells, keratocytes,
inflammatory cells, extracellular matrix components, growth factors and general
systemic conditions. some adjunctive therapies have been done to investigations the
non healing corneal ulcer problems.

Methods
A. Medical Treatment
1. Povidone Iodine (PVI)
Broad-spectrum micro biocidal effect against bacteria, virus, parasites
and fungi. Solution 1%, 5%, is strong oxidizing agent that inhibits cell
growth and destabilize membrane integrity of host cells and can use every
day for spooling/cleaning the ulcer. Single application of 5% PVI drop did
not reduce bacterial load, must be continue spooling every day or about two
days. The poor effect is deep penetration into the deep corneal stromal , and
more than 5% PVI, is corneal toxic.

2. Topical Coenzyme Q10 (Ubiquinol)

CoQ10 eye drop. CoQ10 is might contribute by preserving
mitochondria bioenergetics for anti apoptotic, anti-inflammatorty, anti-
oxidant effects, and restoring teh sub basal plexus cornea, can be considered
for promoting the corneal healing. Usually dose: twice- four time daily for
one week and decrease in one month.

3. Collagenase Inhibitors
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Collagen is the major structural corneal protein, and degraded during

ulceration by some factors. the collagenase inhibitors is calcium dependent
enzyme, cystein, sodium and calsium ethylendiaminetetraacetic acid
(NaEDTA, CaNa EDTA) and probably inhibit collagenase by removing the
essential calcium. The inhibitions effect should be short lived, usually used
in maceration corneal ulcer.
Ca EDTA (0.2 M) is much less toxic than EDTA given as eye drops
every walking hour (more frequent application), in 2-3 weeks is a
reasonable choice to improve collagenase inhibitions and poor epithelial
penetration. Acetylcystein(1.2 M) more effective and superior stability than
cytein. No toxicity using in eye drops in several weeks, Cystein (0.2M)
injected cause persistent stromal haze in rabbit.

4. Platelet-Rich Plasma
Human serum contains collagenase inhibitors, the clinical impression
that autologous serum can sometimes arrest ulceration, because contain
human α1 antitrypsin (α1-at) and human α2 -microglobin (α2-m) to prevent
ulceration. PRP rich in growth factors, neurotrophin, neuropeptides, nerve
growth factor (NGF) substance P (SP), and thymosin beta-4, platelet-
derived growth factors (PDGF), TGF,VEGF,EGF, insulin - like growth
factors IGF, α2-macroglobin (α2-m) directly injected into the stromal
cornea can prevent ulceration compare to topical use.

5. Topical Corticosteroids
Role of topical corticosteroids eye drops for bacterial corneal ulcers is
controversial, and are not recommended in any case of fungal; if steroids
are used it should be with great caution and close observation. Topical
chorticosteroids are known to inhibit neutrophil chemo taxis and believe to
reduce collagenase and cytokine burden that leads first to ulceration, and
then to inhibit neovascularization and scaring.
Delayed epithelial healing and neutrophil inhibition may exacerbate the
infection, particularly if the inadequate antibiotics. Pseudomonas corneal
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ulcer, improving after 5 days of fortified antibbiotics therapy but

dramatically worsened after 2 days of steroid use. (cases) topical steroid
may be unfortunately in fungal or acanthamoeba infections which are
thought to be exacerbate. all organisms are more prevalent with contact lens
use. stop topical steroid if the infaction worsens after initial improvement,
because reduce inflammation but may be stimulate collagenase enzyme.

6. Other Medicine
 Cycloplegic
 Anti glaucoma medication
 Analgesics
 Supplements

B. Non Invasive Treatment:

1. Tissue Adhesives
 Cyanoacrylate Glue
Cyanoacrylates are esters of cyanoacrylic acid as a tissue
adhesive in the closure of impending corneal perforations, to avoid or
to postpone keratoplasty. Inhibition of PMN cells so inhibits epithelial
collagenase and can have affects special to Gram-positive bacteria
(bacteriostatic and bactericidal). It is certainly helpful for mechanical
closure and stabilization of corneal perforations from infectious and non
infectious etiologies, including corneal melting from immune
mechanisms. High toxicity and strong foreign body response.
 Fibrin Glue
Fibrin glue, used for skin graft by Tidrick et al in 1944 and Katzin
in 1946 used for corneal grafts in rabbit. That contains two mayor
components fibrinogen and trombin, two coagulating factors, aprotinin
(fibrinoliysis inhibitor) and calcium chloride, the setting time of
mixture is usually dependent on the thrombin concentrations. (fast in
30 s and slow setting mixture sets within 1-2 min.)
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Used in plugging corneal ulcer induced perforations, can be acute

or chronic perforations, success rate perforation closure was 85,7% for
acute and 60% for chronic perforations. Fibrin glue has been prepared
from blood, there is latent risk of viral transmission, low adhesion
strenght, include astigmatic scarring, tissue necrosis, cytotoxicity and
high cost. Despite the risk, the advantages shown to cause minimal
inflammation, moist environment it significant comfort post operative
compared with sutures, and antibacterial.

2. Hyperbaric Oxygen Therapy

 Hyperbaric Oxygen Therapy (pure oxygen)
It was started for 90 minutes daily for 3 days, at 2.0 atmosphere
absolute pressure (2 ATA) breathing 100% oxygen in a monoplace
chamber. The oxygen delivers both systemic and directly to the cornea,
given the cornea most oxygen supply via direct diffusion from the
atmosphere. The optimal dose of oxygen is unknown, the limited dose
3 ATA have syetemic toxicity.
 Intermittent Therapy also limit oxygen toxicity
HBO therapy can improves limbal ischemia, accelerate
epithelialization, increases corneal transparency, decrease corneal
vascularization in the acute phase of ocular chemical or thermal burns.
Perhaps this effect occur to improvement of orneal ulcer.
Side effects: narrowing of the visual field, trancient uni lateral
visual loose, eye lid twitching, retinal toxicity, vascular changes caused
by hyperoxia, can be multiple sclerosis, reversible myopia. to avoid
severe IOL rise, HBO therapy is contraindicated in patients with
therapeutic intraocular gas. other important complication is nuclear
cataract.

3. Corneal Collagen Cross Linking (CXL)

 CXL Procedures (Dresden Procol)
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Patients under aseptic, use topical anesthesia. The cornea was

soaked with 0.1% riboflavin drops every 2 minutes, over the next 30
minutes cornea was exposed to ultraviolet-A radiationof 370 nm with
3mw / cm3 with continued instillation of riboflavin drops.
 CXL Equipment
The possibility of CXL for corneal ulcer after CXL:
 Increase corneal hardness which enhanced the anti enzymatic
activity of protease and collagenase.
 Changed of corneal structure , the target site of collagenese acting
is detroyed and anti-enzyme reaction is increase.
 Reduce the infiltration of inflammatory cells in corneal tissue.
 Activity of pathogens more inactivated
 UVA anti-microbial effect
 Corneal repair, more fibroblast were found between corneal
collagen fibers
 Decrease pain and vascularization.

4. Cryotherapy
Cryotherapy produces a stimulus causes a sudden decrease local tissue
temperature and metabolism, which results bacterial death and may activate
an immune response. cell death is not only dependent on the level of
cooling, also the rate of warming, the osmotic environment, duration of time
held at low temperature, and the growth phase of the organism have all been
shown to be critically important in determining cell survival after freezing.
For experimental, -790 for six seconds applied directly in infected
cornea, 99.9% reduction in bacteria, and endothelial death by six hours,
stromal death by ten hours, use probes cooled with CO or a fluorinated
refrigerant (Freon).
Cryotherapy (Ø 4mm) to central corneal, cause corneal thickness
increased and returned to normal after 10-12 days, cause by abnormality of
the intercellular junctions, and descement membrane was recovered by
endothelium after 3 days. Temperature of - 80oC for 2-3 seconds, by
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cryotherapy and CXL are limited in killing acanthamoebatrophazoites, cyst

or bacteria, and did not stimulate myofibroblastic transformation of
keratocyte. Temperature of - 50oC for 7-8 seconds using CO2 dry freezer,
can dramatically improve the fungal corneal ulcer (Candida albicans) with
few side effects.

5. Bandages Contact Lens (BCL)

Therapeutic BCL helps to: maintain ocular tissue integrity, to pain
relieve, mechanical protection of ocular surface, promotion of epithelial
healing. Usually use for recurrent erosion syndrome, bullous keratophaty,
corneal transplantation, immediately after LASEK, phototherapeutic
keratectomy, simple perforating corneal injuries.
Large-diameter BCL (scleral contact lenses) has also been reported as
a use treatment option in the management of refractory vernal ulcers,
corneal neurotropic ulcers. Scleral lenses favoring constant lubrication, to
prevent the absence of corneal-eyelid contact, adequate oxygenation, to
promote corneal healing.
BCL complications secondary corneal ulcers cause non sterile
techniques and topical antibiotics.

C. Surgical Treatment
1. Debridement / Removal of Necrotic Tissue
Removal necrotic or maceration of corneal tissue with sterile cotton
is used full for corneal scraping, decrease microorganism colony, to easy
passage eye drops, to decrease conjunctivalization, to promote corneal,
epithelialization, to relieve corneal pain. remove secrete and waste product
and washing with povidone iodine 3% solution, and sterile water. Serious
complications: corneal perforation, bleeding and when suspect foreign body
in ulcer.

2. Conjunctival Flaps
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Conjunctival flaps are used in cases with indolent progression and

corneal thinning. (gandersen). A conjunctival flaps brings in superficial blood
vessels to promote healing, preventing corneal perforation and can control
pain. the flap can not be used for active suppurative ulcer or with wide
perforation because the leak will continue under the flap. It is diffucultto
control the microorganism, especially anaerobe, which potentially increase
under the flap.
Specific procedures of the flaps depends of the patients, it can be total
flap or pedicle flap, or tongue-shaped partial flap, before corneal transplant
for improvement visual acuity. No serious complication after flap. The
complications are buttonhole formation, cyst, conjunctivalization, corneal
opacification, corneal vascularization.

3. Anterior Chamber Paracentesis

To evacuate the anterior chamber exudates and for diagnostic and
cultural purposes. operating time depends on the surgeon, it's not fixed.
Surgery is performed in the operating room, with all aseptic procedures under
anesthesia and with an operating microscope. The anterior chamber is
inserted from the temporal side with a measuring needle 22, because the
exudate cannot be removed, enters without a scalpel 11 and uses forceps.
wash all the exudates and anterior chambers, and inject intracameral
amphotericin B (5 micrograms) and ceftriaxone 2-2.25 mg / 0.1 cc.
Procedures and complications must be explained to the patient because
if the infection involves the anterior lens capsule it might cause cataract
development. Other complications are: hyphema, corneal abscess (rare),
superficial anterior chamber. The anterior chamber paracentesis procedure
usually performed for deep fungal keratitis is an uncommon procedure for
diagnosing microbial keratitis

4. Amnion Membrane Transplantation

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Amnion from human placenta has anti-inflammatory, anti-fibrosis, anti

angiogenesis, antibacterial properties. it also promotes reepithelization by
reinforcing basal epithelial cell adhesion, induction of epithelial migration
promotion of both differentiation and proliferation of conjunctiva and limbal
epithelial progenitor cells (include transient amplifying cell). prevention of
epithelial apoptosis, reduction of keratocytes apoptosis, and anticollagenase.
Reduce pain associated with the epithelial defect AM contains growth
factors as transforming growth factors (TGFα, TGFβ1, β2, β3), human
chorionic growth factor, nerve growth factors, epidermal growth factor
(EGF), β fibroblast growth factors which promote epithelial differentiation,
and prevent apoptosis, and reduce sicatrixial.
AM also contains collagen type IV, V, VII. in addition to laminin and
fibronectin. collagen type V helps the epithelial cell to anchor to the corneal
stroma, laminin aid in the adhesion of epithelial cells to the stroma.
Fibronectin is to facilitate epithelial cell migration, adhesion and cellular
differentiation.
HAM is not a substituting layer but rather a substrate upon which cells
can migrate, regenerate, forming new and healthy tissues, and reduce cicatrix
and neovascularization. it used as a biologic patch, bandage to treated, cornea
and conjunctiva inflammation.
The multilayered AMT has more success and the corneal defects heal
faster compared with the use of only single layer of Amnion Membrane

5. Keratoplasty
Penetrating Kkeratoplasty (PK) has been the gold standard for
rehabilitating cornea transparency cause by infaction, degeneration, or
dystrophy. PK has much problems: astigmatism related to multiple sutures,
endothelial rejection, and poor log term graft survival. PK is usually used for
impending or for perforation corneal ulcer.
 Intraoperative risk: poor graft centration, suprachordial hemorrhage,
infection, damage to surounding ocular structures can occur.
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 Postoperative risk: transplant wound dehiscence, infection, graft

rejection, graft failure, disease reccurence and severe astigmatism

D. Radiotherapy
1. Radiation treatment for Non-Neoplastic Disease:
 The relieve symptoms, particularly pain
 To promote healing, by resololution of inflammatory process,
absorption hemorrhages, to epithelialization ulcerated surface,
organization and removal of granulation tissue
 To affect blood vessels: to reduce blood vascular engorgement
and congestion by inflammation, to obliterate or reduce in size
newly vessels invading the cornea
 To reduce intra-ocular tension
 To restore function of the cornea
2. The used Radiotherapy in Ophtalmology: Inflammatory Processes:
 Pyogenic: Blepharitis
 Granulomatous: Tuberculosis, Sarcoidosis
 Allergic: Vernal Catharr, Phlyctenic Kerato-Conjunctivitis
 Viruses: Superficial Punctate keratitis, Post Herpetic Pain,
Dendritic Ulcer, Diform Keratitis. Trachoma
 Unknown Etiology: Rosacea Keratitis, Marginal Ulcerative
Keratitis.
3. Miscellaneous
 Corneal lesions: Ulcers (including Mooren’s), Opacities
following infection or trauma. Dystrophies and degenerations
(including Pterygium). Traumatic lesions and recurrent erosions.
 Epithelial Downgrowths
 Vascular Anormalities: Corneal Vascularization (particularly
after grafting), Eale’s Disease. Retinal Hemorrhage. Venous
Thrombosis
 Raised intra-ocular Tension , Secondary Glaucoma
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Conclusion
Adjuvant Treatment are treatment that is given in addition to primary
(initial) treatment, is an addition designed to help reach the ultimate goal. The goal
in corneal ulcer cases is to improve visual acuity, anatomical (epithelial healing)
outcomes and to reduce complications. The adjuvant treatment is not fixedp,
depends on facilitation , type of corneal ulcer, patient and surgeon. devided on 4
groups and we can combine some adjuvant treatment depends on indication, and
clinical manifestation of ulcer, and can reappearance if necessary.