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CORNEAL ULCERS
Diagnosis and Management
Namrata Sharma
MD DNB MNAMS
Associate Professor of Ophthalmology
Cornea, Cataract and Refractive Surgery Services
Dr. Rajendra Prasad Centre for Ophthalmic Sciences
All India Institute of Medical Sciences, New Delhi
India
Rasik B Vajpayee
MS FRCSEd FRANZCO
Head, Corneal and Cataract Surgery
Centre for Eye Research Australia
Royal Victorian Eye and Ear Hospital
University of Melbourne
Australia
Forewords
Hugh R Taylor
Peter R Laibson
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This book has been published in good faith that the materials provided by authors is original. Every effort is made to ensure
accuracy of material, but the publisher, printer and authors will not be held responsible for any inadvertent error(s). In case of any
dispute, all legal matters are to be settled under Delhi jurisdiction only.
ISBN 978-81-8448-217-1
Typeset at JPBMP typesetting unit
Printed at Ajanta
Dedicated to
Peter R. Laibson MD
Professor of Ophthalmology
Thomas Jefferson University School of Medicine
Director Emeritus
Cornea Department
Wills Eye Institute
Philadelphia, Pennsylvania
Preface
Corneal ulcer is a major cause of blindness in the developing world. The condition requires early recognition and
prompt management to minimize the impact of disease process. There are many books available on the corneal
and external diseases and include details on various aspects of corneal ulcer. However, most of these books carry
enormous amount of information, some of which may not be required for the routine management of a case of
infectious keratitis. We felt that there is a need for a book on the specific aspect of corneal ulceration that carries
relevant, specific and practical information and can help general ophthalmologists in treating cases of corneal
ulceration effectively. Our book includes a chapter highlighting a practical approach on how to examine a case of
infectious keratitis and chapters on various types of keratitis. It also includes chapters on basic sciences relevant to
corneal ulcer and provides comprehensive information on various management issues including surgical options,
if required. We have tried to provide a precise format for our book and have written it in a user-friendly style. We
hope that this book will serve as a useful guide for the residents as well as the general ophthalmologists.
Namrata Sharma
Rasik B Vajpayee
Acknowledgements
We would like to acknowledge Dr Tushar Agarwal, Dr M Vanathi, Dr Tishu Saxena and Dr Gunjan Prakash for
their useful inputs. We would also like to thank Departments of Microbiology of All India Institute of Medical
Sciences and St. Vincent Hospital for the photographs. Our heart felt to heartfelt gratitude to Ms Meena Verma,
Ms Sudha, and Ms Lata for helping us with clinical photography.
Contents
5. Clinical Examination 35
6. Investigations 51
7. Bacterial Keratitis 65
8. Fungal Keratitis 77
9. Viral Keratitis 91
10. Protozoal Keratitis 107
Index 199
Anatomy and Physiology 1
Cornea is the principal refractive surface of the human believed that the tear film is actually a two-layered
eye and along with sclera forms the outermost coat of structure where under the lipid layer lies an aqueous–
the eyeball. It constitutes up to one-sixth of the entire mucin gel, in which the mucins have a decreasing
eyeball. The corneal epithelium is derived from the gradient of concentration from the epithelium to the
surface ectoderm and the mesoderm gives rise to surface.3 Tear film keeps the corneal surface moist and
Bowman’s layer, stroma, Descemet’s membrane and prevents the adherence of microbes. A deficient pre-
endothelium. The average diameters of the cornea vary corneal tear film may predispose to the occurrence of
from 11 to 12 mm horizontally and 9 to 11 mm vertically. corneal infection.
Cornea accounts for approximately 48 diopters of the
More than 98 percent of the volume of the tears is
power. The posterior surface of the cornea is more
water. The tear film has many essential substances such
spherical than the anterior surface and the central cornea
as electrolytes, glucose, immunoglobulins, lactoferrin,
is thinner (520 μm) than the peripheral cornea (650 μm
lysozyme, albumin and oxygen. It also has many
or more). The tear film covers the anterior corneal
surface and the posterior corneal surface is in contact biologically active substances such as histamines,
with the aqueous. interleukins, prostaglandins and growth factors.4 Some
of these factors modulate corneal epithelial migration,
PRE-CORNEAL TEAR FILM proliferation and differentiation.
The tear film forms an important defense mechanism
STRUCTURE OF CORNEA
against the microbial infection. It is 7 μm thick and has
a volume of 6.5 ± 0.3 μl.1 The tear film is made up of an Cornea essentially consists of 5 layers namely—epithe-
outer lipid layer (0.1 μm), middle aqueous layer (7 μm) lium, Bowman’s layer, stroma, Descemet’s membrane
and innermost mucin layer (0.02 to 0.05 μm).2 It is now and the endothelium (Figs 1.1 to 1.3).
BASEMENT MEMBRANE
The basal cells of corneal epithelium are attached by
Figure 1.3: Histologic section of cornea consisting of stromal layers, hemi-desmosomes to a basement membrane, which
Descemet’s membrane and endothelium
is located between the corneal epithelium and the
Bowman’s membrane and contains type IV and type
EPITHELIUM VII collagen and glycoproteins. The basement layer of
corneal epithelium has two parts: Lamina lucida
Corneal epithelium has a thickness of 50-90 μm and is
(superficial) and Lamina densa (deep).
comprised of five to seven layers of stratified, squamous
and non-keratinized cells (Fig. 1.2). It represents 10
percent of the total corneal thickness. BOWMAN’S LAYER
The cells of corneal epithelium can be classified in The Bowman’s layer is an acellular membrane like zone,
to three categories—the superficial squamous cells, 8 to 14 μm thick and has numerous pores for the pas-
middle wing cells and deeper basal cells.5 sage of corneal nerves into the epithelium. Ultrastruc-
turally it is made up of a fine meshwork of uniform
Superficial Squamous Cells collagen fibrils of type I and III.
Superficial or squamous cells form the outermost 1-2
layers of corneal epithelial cells. They are the oldest CORNEAL STROMA
epithelial cells and they disintegrate and shed into the The corneal stroma is approximately 500 μm thick and
tear film by the process of desquamation. These cells comprises 90 percent thickness of the cornea and is
have microscopic projections (microvilli, reticulations, located between the Bowman’s layer and Descemet’s
microplicae) and fibrillar glycocalyx on their which membrane (Fig. 1.2). It is composed of lamellae formed
interacts with the mucinous tear film. The epithelium from flattened bundles of collagen, stromal keratocytes
turns over approximately every 7 to 14 days.6 and ground substances like keratan sulphate. Collagen
The superficial cells are connected to each other by (type I is the major constituent, others are III and VI) is
desmosomes and junctional complexes. This complex the major structural component of corneal stroma. There
consists of tight junctions, which surround the entire are 200 to 250 bundles of collagen fibrils. Each bundle
cell, and resist the flow of fluid through the epithelial extends the width of the cornea and is 2 nm thick and 9
surface. to 260 nm wide. The collagen fibers are arranged in a
regular manner, parallel to the corneal surface. Such
Middle Wing Cells
arrangement and equal spacing of collagen fibers creates
The middle layer of the corneal epithelium consists of a lattice or three-dimensional diffraction grating, which
the wing cells, which have lateral, thin wing like is responsible for the ability of the cornea to scatter
extensions emanating from a more rounded cell body. 98 percent of the incoming light rays. The lamellae in
The adjacent cells are joined by desmosomal junctions the posterior part of the stroma have an orthogonal
and gap junctions. layering, i.e. the bundles are at right angles to each other.
4
Anatomy and Physiology 1
In the anterior one-third of the stroma, the lamellae have 2500 cells/mm 2. As cells decrease in number, they
a more oblique layering. become thinner and attenuated. Cornea loses it clarity
The primary glycosaminoglycans of the stroma are when the endothelial cell densities reach 400-700 cells/
keratin sulfate and chondroitin sulfate, which occur in mm2 below which corneal edema occurs.
the ratio 3:1. The lamellar stroma is secreted and Unlike corneal epithelium, endothelial cells cannot
maintained by stromal fibroblasts called the keratocytes, undergo mitosis after birth. The endothelial cells are
which occupy 3-5 percent of the stromal volume. They linked to each other by junctional complex structures
are responsible for the maintenance of stromal and presence of gap junctions but no desmosomes are
components and they synthesize collagen degradative present.
enzymes such as matrix metalloproteases (MMPs).5 The endothelial cells do not replicate in human
The MMPs are particularly important in the beings. The endothelial cells decrease in density with
pathogenesis of peripheral ulcerative keratitis as they increasing age, raised intraocular pressure, following
accumulate in the tears and trigger an autoimmune intraocular surgery and inflammation.
response involving the ocular tissue. Keratocytes The corneal endothelium plays a major role in
undergo cellular differentiation in response to injury maintaining stromal hydration (which is normally 78%)
converting into fibroblasts. Keratocytes usually lie through the Na-K-activated adenosine triphosphatase
between the lamellae being flat with long attenuated (ATPase) present in the basolateral borders of the cells.
processes extending from a central cell body in all
directions. Depletion of keratocytes is a characteristic INNERVATION OF THE CORNEA
feature of Acanthamoeba keratitis. The cornea is primarily supplied by the sensory nerves
derived from the ciliary nerves of the ophthalmic branch
DESCEMET’S MEMBRANE of the trigeminal nerve. The long ciliary nerves supply
the perilimbal nerve ring. Nerve fibers penetrate the
Descemet’s membrane is the basement membrane of the cornea in the deep peripheral stroma radially and then
corneal endothelium and is synthesized by the endothe- course anteriorly forming a terminal subepithelial
lium.7 At birth, the human Descemet’s membrane is plexus. The nerve fibers lose their myelination soon after
3 μm wide but in adulthood, the width increases to penetrating the clear cornea and enter the Bowman’s
12 μm (Fig. 1.3). There are two distinct regions—anterior, layer and terminate at the level of the wing cells. An
one-half to one-third, which is banded, and posterior autonomic sympathetic supply is also present in the
two-third, which is non-banded. cornea.
In certain types of bacterial keratitis and Mooren’s The physiologic role of corneal innervation is unclear.
ulceration, this membrane remains intact and protrudes Presence of corneal sensation is vital to the maintenance
as a descemetocele due to the intraocular pressure of the integrity of the cornea. In cases of herpes simplex,
following dissolution of overlying stroma.5 herpes zoster and diabetes, corneal sensations are
diminished and this may lead to persistent epithelial
ENDOTHELIUM defects or delayed epithelial wound healing.
7
1 Applied Basic Sciences
2 Pathogenesis of
Corneal Ulceration
Introduction
Corneal ulceration occurs due to the host cellular and
immunologic responses to the offending agent which
may be bacterial, viral, fungal or protozoal organism.
Sometimes it is sterile corneal ulceration, which may
occur due to systemic dermatologic or connective tissue
disease and chemical or thermal injuries.
The host cellular responses are mainly responsible
for corneal destruction in infections and sterile corneal
melting. In all cases, stromal melting is preceded by a
corneal epithelial defect. The ulceration occurs secon-
dary to the action of tissue collagenases. The polymor-
phonuclear cells (PMNs) are secreted in response to the
corneal insult, which secrete various lytic enzymes such
as collagenase, elastase and cathepsin causing destruc- Figure 2.1: Corneal ulcer
tion of the cornea.1 Simultaneously, reactive fibroblasts,
synthesize collagen and cause repair of the cornea.
Apart from the infective processes, the immunologic
mechanisms consequent to infection may also play a
role. For example, in herpes simplex interstitial keratitis
stromal cellular destruction occurs due to immunologic
mechanisms as a consequence of acquisition of herpes
antigens, thereby resulting in an influx of PMNs and
phagocytes, which cause tissue destruction.
For the reparative phase of corneal ulcer, the inter-
action between the keratocytes and blood vessels is
essential. Stromal vascularization inhibits the ulcerative
process as nutrients (such as ascorbate) and antiprotea-
ses are delivered by the vessels to the ulcerated area.2
Figures 2.4A to D: Healing corneal ulcer with end stage leukomatous corneal opacity
Figure 2.5: Descemetocele formation with perforation Figure 2.6: Perforated corneal ulcer with pseudocornea formation
10
Pathogenesis of Corneal Ulceration 1
Figure 2.7: Corneo-iridic scar Figure 2.8: Large corneal perforation and corneal melting
surrounded by a white cicatricial ring and under the suddenly, the suspensory ligament of the lens gives way,
influence of a raised intraocular pressure may eventually causing subluxation of the lens, anterior dislocation and
rupture. spontaneous expulsion of the lens and the vitreous through
the perforation (Figs 2.9A and B).
Perforation
Ectatic Cicatrix
Perforation of corneal ulcer occurs due to sudden
exertion by the patient such as coughing, sneezing, Due to the presence of anterior synechiae and plugging
straining or spasm of the orbicularis muscle. An increase of the iris, adherent leukoma is formed and this leads
in intraocular pressure occurs due to these maneuvers to secondary glaucoma. The cicatricial tissue is too weak
so that the weak floor of the ulcer gives way. When an to support this raised intraocular pressure and hence
ulcer perforates, the aqueous suddenly escapes and the the cicatrix becomes ectatic. An ectatic cicatrix into which
intraocular pressure falls to the atmospheric levels. the iris is incarcerated is called as the anterior staphyloma,
Subsequently, the lens iris diaphragm moves forward which may be partial or total. It is so called due to the
and adheres to the back of the cornea. Due to the lobulated appearance (Fig. 2.10).
decreased intraocular pressure, the pain is alleviated;
extension of the ulcer decreases and the process of scar Corneal Fistula
formation is initiated.
If the perforation is small, the iris is plugged to the If the perforation occurs near the pupillary margin, the
back of the cornea, adhesions from the iris get organized iris becomes adherent to the back of the cornea and the
and the scar tissue is formed which is called as aperture is filled with the fibrin and the exudates. As
“pseudocornea” (Fig. 2.6). The iris, which is plastered the anterior chamber reforms, the aperture is subjected
at the back of the cornea, allows anterior chamber to to repeated strain, so that a permanent opening forms
form and hence aqueous is secreted. which is called as the corneal fistula (Fig. 2.11).
If the perforation is large, the iris prolapses out of
the site of perforation; in cases of longstanding of iris Hemorrhage
prolapse, fibrin and exudates deposition occurs on the
surface, thinning of the iris stroma occurs and the black The sudden decrease in the intraocular pressure when
pigmentary epithelium becomes visible. Thus any perforation occurs dilates the intraocular blood vessels,
adherence of iris tissue to the back of cornea, which is which may rupture causing an intraocular hemorrhage.
subsequent to a perforated corneal ulcer, is called as a Rupture of retinal vessels may give rise to vitreous
corneo-iridic scar (Fig. 2.7). hemorrhage, choroidal, a subretinal or subchoroidal
In very large perforations, only a small rim of the hemorrhage. It may be so profuse that it may lead to
cornea remains and the total prolapse of the iris and expulsion of the intraocular components leading on to
the lens may occur (Fig. 2.8). If the perforation occurs expulsive hemorrhage. 11
1 Applied Basic Sciences
Figures 2.9A and B: Perforation causing spontaneous expulsion of lens and vitreous
Figure 2.10: Anterior staphyloma subsequent to perforated Figure 2.11: Corneal fistula
corneal ulcer
Endophthalmitis
The organisms, which are causing the ulceration of the
cornea, may gain access to the interior of the eye as a
result of perforation and cause purulent iridocyclitis,
endophthalmitis (Fig. 2.12) and even panophthalmitis.
References
1. Kenyon KR, Ghinelli E, Chaves HV. Morphology and
pathologic response in corneal and conjunctival disease.
In: Foster CS, Azar DT, Dohlman CH (Eds): Smolin and
Thoft’s Cornea. Lippincott Williams and Wilkins NY;
4th edition, 2005;4:103-40.
2. Kenyon KR. Inflammatory mechanisms in corneal
ulceration. Trans Am Ophthalmol Soc 1985;83:610-63.
3. Nordlund M, Pepose JS. Corneal Response to Infection.
In: Krachmer JH, Mannis MJ, Holland EJ (Eds): Cornea,
Figure 2.12: Corneal ulcer with endophthalmitis
2nd Edition Elseivier Co. NY. 2005;7:95-114.
12
Microbiology 1
3 Microbiology
Introduction Acanthamoeba
The various microorganisms which can cause infectious Primarily, Acanthamoeba is the protozoa, which can cause
keratitis can be classified into eukaryotic and prokaryotic keratitis. The pathogenic species of Acanthamoeba
organisms (Table 3.1). The eukaryotic organisms include include Acanthamoeba castellanii, Acanthamoeba polyphaga,
the relatively complex cells such as protozoa and the Acanthamoeba culbertsoni, Acanthamoeba palestinensis,
fungi and the prokaryotic organisms are more primitive Acanthamoeba astronyxis, Acanthamoeba hatchetti, Acan-
cells, which include the filamentous bacteria, true thamoeba rhysodes, Acanthamoeba divionesis, Acanthamoeba
bacteria, spirochaetes, mycoplasma and rickettsiae and equina, Acanthamoeba lugdunensis, and Acanthamoeba
chlamydiae. griffini.1
Acanthamoeba are ubiquitous organisms and have
Protozoa been isolated from soil, water (including natural and
Protozoa are unicellular organisms which exist in two treated water), air, and dust. They are free living, patho-
morphologic phases. Examples which cause ocular genic amoeba. Most persons are exposed to this
infections include the Acanthamoeba and the organism during their lifetime, as 50-100 percent of
Microsporidia. healthy people have serum antibodies directed against
Acanthamoeba.
TABLE 3.1 The life cycle consists of 2 stages: a trophozoite
Classification of microorganisms causing infectious (which is 14-45 microns in diameter) and a cyst (which
keratitis
has a double-layered wall with a diameter of 10-25
EUKARYOTES microns). The trophozoites are motile and usually have
Protozoa one nucleolus and huge cytoplasmic vacuoles and feeds
Sporozoa : Toxoplasma
on bacteria (Fig. 3.1). In unfavorable conditions the
Amoebae: Entamoeba, Naegleria, Acanthamoeba
Microsporidia trophozoites encyst.2 The cyst has a double wall, which
is made of cellulose (Fig. 3.2). The cyst is resistant to
Fungi
alterations in temperature, pH, osmolarity and anti-
Mould like: Aspergillus
Yeast like: Candida microbial agents.
Dimorphic : Histoplasma. Blastomyces, Coccidioides
True yeasts: Cryptococcus
Microsporidia
PROKARYOTES
Filamentous bacteria Microsporidia are eukaryotic, spore forming obligate
Actinomyces, Nocardia, Mycobacterium, Streptomyces intracellular parasites. Microsporidial keratitis occurs in
True Bacteria two forms keratoconjunctivitis is usually seen in
Gram-positive Bacilli and Cocci immunocompromized individuals or in contact lens
Gram-negative Bacilli and Cocci wearers, mostly by genus Encephalitozoon while Nosema
Spirochaetes and Microsporidium cause the stromal keratitis which is
Borrelia, Treponema, Leptospira
generally seen in the immunocompetent host.3 Most
Mycoplasma
infections are transmitted by feco-oral route but corneal
Rickettsiae and Chlamydia infections occur due to direct inoculation. These
13
1 Applied Basic Sciences
whether the hyphae are pigmented or non-pigmented phic fungi. These include Blastomyces, Coccidioides,
on the culture media. Filamentous septate fungi can thus Histoplasma and Sporothrix.
be broadly classified into:
i. Moniliaceae (light colored fungi like Fusarium and Moniliaceae
Aspergillus species)
ii. Dematiaceae (dark colored fungi such as Alternaria ASPERGILLUS
and Curvularia). This is a common contaminant in hospital air. Aspergillus
fumigatus is the most commonly isolated species, while
YEASTS Aspergillus flavus and Aspergillus niger may also cause
Yeasts are unicellular fungi, represented by Candida, and keratitis. The Aspergillus fungi are readily recognized
are characterized by an oval or round blastoconidium. by their morphology (Fig. 3.4). The conidospore with
Yeasts reproduce by budding and are characterized by its swollen terminal end is surrounded by a flask shaped
the presence of pseudohyphae (Fig. 3.3). The phase, sterigmata, each of which produces long chains of
which has pseudohyphae, is the most virulent phase. conidia that radiate from the terminal end (Fig. 3.5).
The cell walls of pseudohyphae have constrictions and Their hyphae are septate and branch dichotomously.6
are not parallel to each other unlike the hyphae. In infections progressing rapidly they are more uniform
Candida species especially Candida albicans commonly but in more indolent infections the hyphae may be
causes majority of the cases of keratitis. In culture they irregular in shape.
form smooth creamy white colonies resembling Colonies of A. fumigatus are at first white but as
staphylococci in the early phases of growth. The spores are produced they become velvet green due to
presence of budding yeasts in corneal scrapings is pigmentation of conidia. A. niger on the other hand,
diagnostic for Candida.5 This organism produces both turns completely black as they undergo sporulation.
true hyphae and pseudohyphae. Both yeast and hyphal FUSARIUM
forms can be seen in corneal scrapings. Candida colonies
are white to tan and opaque with smooth, round, flat Fusarium causes localized infection after trauma in
contour and pasty consistency. They have a distinctive otherwise healthy patients. Fusarium solani is the most
fruity odor, which aids in easy identification. common species. It has sickle shaped macroconidia and
clusters of fusiform microconidia (Fig. 3.6). Fusarium
colonies are white initially and later acquire a buff
DIMORPHIC FUNGI
coloration. A range of color pigments from yellow to
Some fungi appear as yeasts in vivo at 37 oC and molds red to purple is produced on the undersurface of the
in the environment at 25oC. They are called as dimor- colony (reverse pigmentation).7
15
1 Applied Basic Sciences
Figure 3.5: Aspergillus fumigatus (Courtesy: Dr N Nayak) Figure 3.6: Fusarium species (Courtesy: Dr N Nayak)
Figure 3.7: Curvularia species (Courtesy: Dr N Nayak) Figure 3.8: Alternaria species (Courtesy: Dr H Sheorey, Dept. of
Microbiology, St Vincent Hospital, Melbourne)
17
1 Applied Basic Sciences
2. Beta-hemolytic streptococci lyse red blood cells Mycobacterium chelonae and Mycobacterium fortuitum are
completely and a clear halo appears around a colony. responsible for keratitis after refractive surgery. On
An example of beta-hemolytic streptococci is Strepto- blood agar and chocolate agar plates, the colonies may
coccus pyogenes which when identified from cornea take a week to appear. Routine mycobacterial isolation
is pathogenic. medium such as Löwenstein-Jensen medium is more
3. Gamma-hemolytic or non-hemolytic streptococci definitive for isolation or organisms.
which have no hemolysis pattern around a colony. When mycobacteria are suspected to cause keratitis,
special acid-fast stains should be used to stain them as
Antibiotic Susceptibility they have a cell wall with high content of lipid which
They exhibit high resistance to polymyxin. They are resists Gram staining.
susceptible to cefazolin, bacitracin, chloramphenicol and
Antibiotic susceptibility: They are susceptible to clarithro-
sulphacetamide. The in vitro susceptibility of Streptococ-
mycin and amikacin.
cus species to fluoroquinolones is low.
Enterococcus Bacillus
Enterococcus species are gram-positive ovoid cocci or Bacillus species are large, gram-positive rods but may
coccobacilli and are isolated or broth media with or sometimes be gram-variable. They are spore bearing,
without red blood supplementation. Enterococcus fecalis catalase positive, motile and grow aerobically or as
is the most common species isolated from the cornea facultative anaerobes. The most important corneal
which can cause corneal ulcer. pathogens are Bacillus cereus and Bacillus anthracis, which
appear as large, grainy, dry beta-hemolytic colony on
Diphtheroids agar media. Most organisms are opportunistic
Diphtheroids appear microscopically as gram-positive pathogens.
pleomorphic rods. They are aerobic non-spore formers. Antibiotic susceptibility: They are susceptible to aminogly-
The most common diphtheroid isolated from the cosides, fluoroquinolones and sulphacetamides.
compromised corneas include Corynebacterium and
Propionibacterium. They grow well on blood-supplemen- Nocardia
ted media, in a CO2 atmosphere but it may require 24
Nocardia species belong to the group of actinomycetes
to 48 hours extra for the colonies to appear. Enriched
and appear as gram-positive, branching, filamentous
thioglycollate, liquid broth is a good medium for the
bacteria. They are aerobic, non-motile, partially acid-fast
colonies to appear. Diphtheroids are known to occur as
and appear as white, tiny, dry colonies.
saprophytes, although in compromised conditions they
They are associated with infections after trauma,
may also cause infectious keratitis.
contact lens wear and following laser in situ kerato-
Corynebacterium diphtheriae and Listeria monocytogenes
mileusis (LASIK) surgery. The pathogenic species are
are corneal pathogens, which can breach the intact
Nocardia asteroids and Nocardia brasiliensis.
epithelium without prior trauma.
Antibiotic susceptibility: They are susceptible to sulpha-
Antibiotic susceptibility: They are susceptible to vanco-
cetamide, trimethoprim – sulfamethoxazole and
mycin, chloramphenicol, ofloxacin and partially to
amikacin.
cefazolin. Diphtheroids demonstrate a good in vitro
susceptibility to most antibiotics except to trimethoprim. GRAM-NEGATIVE BACTERIA
Gram-negative bacteria appear red because the lipid
Mycobacterium
layer is not removed by the decolorizing step. A blue
Mycobacteria are obligate parasites and opportunistic crystal violet complex cannot form in the cell wall and
pathogens. They are gram-positive bacteria which are safranin counter stains the bacteria (Fig. 3.10).
slightly curved or straight bacilli. They appear as The common gram-negative bacteria, which infect
“ghosts” or beaded gram-positive rods on Gram stain. cornea include Pseudomonas aeruginosa, Serratia marce-
18
Microbiology 1
Figure 3.10: Gram-negative bacilli Figure 3.11: Gram-negative diplobacilli (Moraxella) (Courtesy:
Dr H Sheorey, Dept. of Microbiology, St Vincent Hospital, Melbourne)
scens, Moraxella species and Haemophilus species. Antibiotic susceptibility: They are susceptible to fluoroqui-
Generally gram-negative infection occurs due to bacilli. nolones and aminoglycosides and have intermediate
Rarely, gram-negative cocci may cause infection such susceptibility to chloramphenicol, trimethoprim and
as in cases of Neisseria gonorrhoeae, Neisseria meningitides sulfasoxazole.
and Branhamella catarrhalis.
MORAXELLA
SERRATIA MARCESCENS
Stains and Culture Media
Serratia marcescens is an opportunistic pathogen, which
along with corneal epithelial breakdown due to trauma Various methods have been used to identify the
or contact lenses can lead to corneal ulceration. On Gram organisms from a case of infectious keratitis. These
stain they appear as coccobacilli and its colonies are include various stains to identify the morphology of the
reddish in color. They are a frequent contaminant of inciting organisms and culture media, which are used
contact lenses and contact lens solutions. to grow these organisms.
19
1 Applied Basic Sciences
STAINING METHODS
The stains used to routinely identify various organisms
include potassium hydroxide wet mount preparation,
Gram’s stain, Giemsa stain and special stains such as
Ziehl-Neelsen acid-fast stain, fluorochromatic stains and
modified Grocott-Gomori methenamine-silver nitrate
stain.
CULTURE MEDIA
Most bacteria appear on culture media with distinct
characteristics, which allows easy identification. The
features to be noted while studying the colonies on solid
media include the following: shape, size, elevation,
margins, surface, edges, color, structure and consistency.
There various culture media are used to identify the
Figure 3.14: Nutrient agar
bacteria include the following:
22
Microbiology 1
Chocolate agar is incubated with 10 percent carbon Mycobacteria are specifically isolated on Löwenstein-
dioxide to isolate facultative organisms. It is prepared Jensen media. Glycerol and egg mixture which are
by heat denaturation of blood to 56oC to provide human added to this media provide fatty acids and protein
and diphosphopyridine nucleotide for the growth of required for the metabolism of mycobacteria. The
organisms such as Haemophilus, Neisseria and Moraxella. coagulated egg albumin provides a solid medium for
inoculation purposes. It also contains malachite green
Thioglycolate broth as an inhibitor to microorganisms other than acid-fast
bacilli. Cultures should be read within 5-7 days after
This is a liquid media, which is incubated at 35°C for inoculation and once a week thereafter for up to 8 weeks.
and is used for the isolation of aerobic and anaerobic
bacteria. It contains a sulfhydryl compound which acts Thayer-Martin Medium
as an oxygen-reducing agent to facilitate recovery of
anaerobic bacteria. Thiol is a variation of thioglycollate This is a special, selective, chemically enriched chocolate
broth and contains special complexes and 0.1 percent agar, which is used to isolate Neisseria gonorrhoeae by
semisolid agar to prevent convection currents and suppressing the growth of other inhibitory fungi and
promote the growth of aerobic bacteria as well as bacteria.
obligate and facultatively anaerobic organisms.
Brain-heart Infusion (BHI) broth
Sabouraud agar Brain-heart infusion broth with neopeptone is incubated
This consists of Sabouraud glucose and peptone agar at room temperature and is used to enhance the isolation
of filamentous fungi and yeasts and less frequently
and is a non selective media for opportunistic fungi.
Bacillus species.
Yeast extract is used to improve the nutrition and an
antibiotic such as gentamicin is added to inhibit the
Robertson Cooked Meat Medium
bacterial contamination (Fig. 3.16). The medium should
not contain cycloheximide as this inhibits the growth of Robertson cooked meat medium provides a favorable
the saprophytic fungi. environment for the growth of anaerobes. The muscle
23
1 Applied Basic Sciences
3. Rauz S, Tuft S, Dart JK, Bonshek R, Luthert P, Curry A.
Ultrastructural examination of two cases of stromal
microsporidial keratitis. J Med Microbiol 2004;53:775-
81.
4. Joseph J, Murthy S, Garg P, Sharma S. Use of different
stains for microscopic evaluation of corneal scrapings
for diagnosis of microsporidial keratitis. J Clin Microbiol
2006;44:583-5.
5. Forster RK, Wirta MG, Solis M, Rebell G. Methenamine-
silver-stained corneal scrapings in keratomycosis. Am J
Ophthalmol 1976;82:261-5.
6. Kozlowski M, Stepien PP. Restriction enzyme analysis
of mitochondrial DNA of members of the genus
aspergillus as an aid in taxonomy. J Gen Microbiol
1982;128:471-6.
7. Nelson PD, Toussoun TA, Marasas WF. Fusarium
species: An illustrated manual for identification,
University Park: The Pennsylvannia State University
Press, 1983;3-48.
Figure 3.17: Robertson cooked meat medium 8. Sharma S, Silverberg M, Mehta P, Gopinathan U,
Agrawal V, Naduvilath TJ. Early diagnosis of mycotic
tissue is a source of amino acids and reducing keratitis: Predictive value of potassium hydroxide
preparation. Indian J Ophthalmol 1998;46:31-5.
substances, particularly glutathione, which permits the
9. Vajpayee RB, Angra SK, Sandramouli S, Honavar SG,
growth of strict anaerobes. Glucose, Hemin and Vitamin
Chhabra VK. Laboratory diagnosis of keratomycosis:
K1 is supplemented with yeast extract, to enhance the Comparative evaluation of direct microscopy and
growth of anaerobic microorganisms ( Fig. 3.17). Growth culture results. Ann Ophthalmol 1993;25:68-71.
is indicated by turbidity and, with some organisms, by 10. Jones DB. Initial therapy of suspected microbial corneal
the presence of gas bubbles in the medium. Disinte- ulcers. II. Specific antibiotic therapy based on corneal
gration and blackening of the meat particles indicates smears.Surv Ophthalmol 1979;24:97, 105-16.
proteolysis. 11. Marines HM, Osato MS, Font RL. The value of calcofluor
white in the diagnosis of mycotic and Acanthamoeba
infections of the eye and ocular adnexa. Ophthalmology
References
1987;94:23-6.
1. Bacon AS, Frazer DG, Dart JK, Matheson M, Ficker LA, 12. Gomez JT, Robinson NM, Osato MS, Wilhelmus KR.
Wright P. A review of 72 consecutive cases of Acantham- Comparison of acridine orange and Gram’s stains in
oeba keratitis, 1984-1992. Eye 1993;7:719-25. bacterial keratitis. Am J Ophthalmol 1988;106:735-7.
2. McCulley JP, Alizadeh H, Niederkorn JY. The diagnosis 13. Groden LR, Rodnite J, Brinser JH, Genvert GI. Acridine
and management of Acanthamoeba keratitis. CLAO J. orange and Gram’s stains in infectious keratitis. Cornea
2000;26:47-51. 1990;9:122-4.
24
Pharmacology 1
4 Pharmacology
Medical therapy forms the first line of treatment of in cases of scleral involvement, perforated corneas or
infectious keratitis. The drugs used to treat microbial impending perforations disease.
keratitis include antimicrobial agents, cycloplegics, anti-
glaucoma medications and adjuvants. ANTIBACTERIAL AGENTS
TABLE 4.1
Emperical therapy for bacterial keratitis
Gram’s stain Topical Subconjunctival Systemic
25
1 Applied Basic Sciences
which are resistant to aminoglycosides or fluoroquino- Macrolides
lones.2
Macrolides are bacteriostatic agents (e.g. erythromycin,
tetracycline) that can suppress the growth of susceptible
Tetracyclines
gram-positive cocci. These drugs cause inhibition of
Tetracyclines are broad-spectrum bacteriostatic bacterial protein synthesis by reversibly binding to the
antibiotics. Various forms of tetracycline are available, 50-S ribosomal unit thereby preventing elongation of
including chlortetracycline (topical), oxytetracycline, peptide chain in bacteria. Erythromycin acts both as a
doxycycline, minocycline, and tetracycline. They act by bactericidal and a bacteriostatic agent depending on the
inhibiting bacterial protein synthesis by binding to the concentration of the drug and is effective against gram
30-S ribosomes. -positive and some gram-negative organisms. S.
They are active against gram-positive organisms, pneumoniae and S. pyogenes are highly susceptible . It is
gram-negative bacteria, mycoplasma, chlamydia and one of the least toxic and best tolerated antibiotic agents.
amoeba. They are not effective against P. aeruginosa, However, its penetration into cornea is sub-optimal due
Bacteroides species, or group B streptococci. The various to lack of solubility and bioavailability.
microorganisms acquire a plasmid-mediated resistance Newer macrolides such as azithromycin and clari-
to tetracycline. thromycin have higher tissue concentrations and are
more effective against C. trachomatis, and non-tuber-
Glycopeptides culous mycobacteria where they are used topically.4
26
Pharmacology 1
chemical structures of the C8-methoxy fluoroquinolones
add protection from bacterial resistance in addition to
enhancement of bactericidal properties. The substitution
of the methoxy group at the eighth carbon on the basic
ring in both gatifloxacin and moxifloxacin reduces the
likelihood of ocular pathogens developing resistance to
these fluoroquinolones. The methoxy group allows
binding of the antibiotics to two bacterial enzymes -
DNA gyrase and topoisomerase IV. As a result, C8
methoxy fluoroquinolones require two simultaneous
mutations for development of resistance, the chance of
which are one in ten trillion . Previous generations of
fluoroquinolones required only a single mutation.
Moreover, a bulky side chain at the C7 position of these
antibiotics makes it the difficult for the antibiotics to
reach out of the bacterial cells. Figure 4.1: Ciprofloxacin deposit in a case of corneal transplantation
Spectrum of Activity
The fluoroquinolones have broad-spectrum of activity crystallize in the urine, especially in patients who are
and are more active against gram-negative bacteria than dehydrated. Interstitial nephritis has been reported after
gram-positive bacteria. They are active against enteric high doses of ciprofloxacin. Insomnia and restlessness
gram-negative rods, such as Haemophilus influenzae and have occurred in elderly patients taking fluoroquino-
Neisseria gonorrhoeae. The third generation fluoroquino- lones. Children should not be given quinolones because
lones are active against Staphylococcus aureus, Non- animal studies have shown crystal deposits in cartilage
coagulase Staphylococci, and Pseudomonas aeruginosa. and hence the topical fluoroquinolones are not
Ofloxacin and ciprofloxacin have a comparable spectrum recommended for children younger than 2 years.
of activity against gram-positive and gram-negative
organisms.5 PREPARATION OF FORTIFIED
The pathogens with respond less to fluroquinolones TOPICAL ANTIBIOTICS
include Streprotoccus Pneumoniae, S. Viridans MRSA,
anaerobes and non-aerugines Pseudomonas.6,7 (Adapted from Basic Clinical and Science Course 2000-
2001. American Academy of Opthalmology)
1. Cefazolin 50 mg/ml or ceftazidime 50 mg/mL
Side Effects
a. Add 9.2 mL of artificial tears to a vial of cefazolin,
The side effects of the fluoroquinolones may occur 1 g (powder for injection).
locally or they may be systemic. The topical adminis- b. Dissolve. Take 5 mL of this solution and add it to
5 ml of artificial tears.
tration of ciprofloxacin has been associated with crystal
c. Refrigerate and shake well before instillation.
deposits in the cornea. This occurs in approximately
2. Tobramycin 14 mg/mL or gentamicin 14 mg/mL
20 percent of patients treated with ciprofloxacin in cases
a. Withdraw 2 mL of tobramycin or gentamicin
of bacterial keratitis8 (Fig. 4.1). This crystallization has
injectable vial (40 mg/mL).
not been seen with norfloxacin or ofloxacin, presumably b. Add 2 mL to a tobramycin or gentamicin ophthal-
due to their high solubility. The advantage of crystalline mic solution (5 mL) to give a 14 mg/mL solution.
deposits is that it acts as a depot from which the drug is 3. Vancomycin 15 mg/mL, vancomycin 25 mg/mL or
released. However the disadvantage is that its presence vancomycin 50 mg/mL
retards epithelialisation. a. Add 33 mL of 0.9 percent sodium chloride for
The systemic side effects of fluoroquinolone include injection (no preservatives) or artificial tears to a
toxicity, fever, rash, and nausea which occurs in 500 mg vial of vancomycin to produce a solution
4 percent of patients. Occasionally patients have of 15 mg/mL. Add 20 mL of 0.9 percent sodium
elevation of levels of liver enzymes. The drugs can chloride for injection (no preservatives) or
27
1 Applied Basic Sciences
artificial tears to produce a solution of 25 mg/ dependent and may be altered by changes in the osmotic
mL. Add 10 mL of 0.9 percent sodium chloride environment.
for injection (no preservatives) or artificial tears
to produce a solution of 50 mg/mL. Nystatin
b. Refrigerate and shake well before instillation.
Nystatin was the first polyene antibiotic identified. It is
4. Amikacin
not used routinely because of its corneal toxicity and
Intravenous formulation can be used (80 mg/2 cc
poor ocular penetration .
ampules).
5. Trimethoprim/sulfamethoxazole
Natamycin
16 mg/mL and 80 mg/mL commercial preparation
can be used. Natamycin is a small semisynthetic tetraene and is
considered the least toxic, the least irritating, and the
Antifungal Agents most stable of all polyenes. It has broad spectrum of
CLASSIFICATION OF ANTIFUNGAL AGENTS activity, especially against Fusarium species.9 It has
low penetration in the presence of an intact epithelium.
1. Polyenes Surface debridement of the cornea increases its
i. Large polyenes penetration. Since natamycin is used as a suspension, it
Nystatin, amphotericin B can dry on the ocular surface forming white deposits
ii. Small polyenes on the cornea and adenexa. Natamycin can be toxic to
Natamycin the corneal and conjunctival epithelium, causing
2. Azoles hyperemia and epithelial defects.
i. Imidazoles
Miconazole, ketoconazole, clotrimazole Dosage
ii. Triazoles
Fluconazoles, itraconazoles It is available for topical use as a 5 percent suspension
3. Pyrimidines (Table 4.2). Topical therapy is given every hour for the
Flucytosines first 48 to 72 hours, and treatment is usually continued
on a tapering basis for 3 to 6 weeks depending on the
activity of the keratitis.
POLYENES
28
Pharmacology 1
and stored under refrigeration at 2-8°C to prevent TABLE 4.2
chemical degradation. Routes and dosage of antifungal agents
Antifungal agent Route Dosage
AZOLES
Amphotericin B Topical 0.15%
Imidazoles (freshly prepared)
Miconazole Triazoles
Miconazole is a phenethylimidazole that is extremely The triazoles were developed in order to increase the
stable in solution form. It has a broad spectrum of spectrum of activity and reduce the side effects of their
activity against Cryptococcus, Aspergillus, Curvularia, predecessors, the imidazoles.
Candida, and Trichophyton.13
Fluconazole
For topical use, a 1 percent solution in arachis oil or
a 10 mg/mL is used (Table 4.2). It is also available as a Fluconazole is now used mainly for the treatment of
2 percent dermatologic ointment. Candida keratitis. A topical 1 percent solution is
29
1 Applied Basic Sciences
available. 14 The 2 mg/L aqueous solution for TABLE 4.3
intravenous use can also be applied topically to provide Dosage and route of administration of antiviral agents
a higher concentration of the antifungal agent.
Idoxuridine Topical 0.1% solution and
Oral fluconazole can be given in a dose of 50 to 40 0.5% ointment
mg/day, with the usual adult dose being 200 mg/day. Vidarabine Topical ointment 3%
Systemic side effects of fluconazole include gastritis, Trifluridine Topical solution 10 mg/ml
headaches, rash, hepatotoxicity, Stevens-Johnson Acyclovir Topical ointment 3%
syndrome, and thrombocytopenia. Systemic 200-800 mg
(oral capsules)
Itraconazole Valacyclovir Systemic 1000 mg
32
Clinical Examination 2
5 Clinical Examination
35
2 Work Up of Corneal Ulcer
Figure 5.1: Corneal ulcer with yellow discharge Figure 5.2: Corneal ulcer with greenish discharge
Onset of Disease
The pattern of onset of microbial keratitis depends on
the nature of predisposing factor/s, virulence of the
offending organism and status of the ocular and
systemic immunity of the patient.
Cases of bacterial keratitis usually report with a
sudden onset and rapid progression of the corneal infec-
tion. This in fulminant cases may also cause a threat to
vision loss and potential corneal perforation. If a patient
presents with history of pain, photophobia, sudden
diminution of vision and discharge of 1-2 days duration
bacteria like Staphylococcus aureus (Fig. 5.3), Pseudomonas
aeruginosa and Pneumococcus species are likely
organisms responsible for the occurrence of corneal ulcer
Figure 5.3: Corneal ulcer due to Staphylococcus aureus (diffuse) However, certain bacteria like Moraxella, coagulase
negative Staphylococcus, Nocardia species and atypical
Mycobacteria cause corneal ulcers that present with
Central corneal ulcers, particularly those caused by
gradual onset and have an indolent course.
organisms like Pseudomonas species, Staphylococcus
Microbial keratitis caused by fungi and parasites like
aureus, and Fusarium species are invariably associated
Acanthamoeba, also have a chronic course. The course of
with significant loss of visual acuity. Other factors that
development of Acanthamoeba keratitis is variable. It may
can reduce visual acuity include the presence of an
emerge slowly over weeks or months or may rapidly
associated pupillary membrane, hypopyon, cataract,
worsen within several days after presumed inciting
glaucoma and endophthalmitis.
event. The course of infection is usually chronic and
The vision may not be severely reduced in cases
gradually progressive and may have some periods of
which have small, peripheral ulcers, such as those
caused by Herpes simplex and non-coagulase Staphylo- temporary remission.
coccus.
PREDISPOSING FACTORS
In Acanthamoeba keratitis, vision may not be
significantly reduced during the initial stages, when the Identification of a predisposing factor is an integral
corneal epithelium alone is involved. Later, as the component of history taking in a case of corneal ulcer
infection spreads deeper into the corneal stroma, visual and is essential for successful management of microbial
36 acuity is severely reduced. keratitis.
Clinical Examination 2
TABLE 5.1
Predisposing factors in case of corneal ulcer
• Ocular
Trauma
Contact lenses
Lid and adnexal infections
Ocular surface disease
Allergic eye disorders
Bullous keratopathy
Topical medications
Prior ocular surgery
• Systemic
Diabetes mellitus
Sjögren’s syndrome
Steven-Johnson syndrome
AIDS
Advanced malignancies
Connective tissue disorders Figure 5.4: Mycotic keratitis due to vegetative trauma
Alcoholics
Extremes of age
Measles malnutrition Corneal trauma caused by vegetative matter is
• Occupational known to predispose to occurrence of mycotic (Fig. 5.4)
Farmers and Acanthamoeba keratitis.4
Animal handlers
Gardeners
If there is history of human or animal bites along
with extensive necrosis of the tissue, anaerobic infections
Normally, corneal epithelium along with the tear film should be suspected.5
is a formidable barrier against the invasion of the
microbes. However, in certain situations this barrier is CONTACT LENS
compromised and organisms invade the corneal tissue The contact lens wear is one of the commonest predis-
and cause infection. posing factor for the occurrence of keratitis especially
Various risk factors may make the cornea susceptible in series from western literature.6 The type of contact
for developing microbial keratitis (Table 5.1). These risk lens use, the duration of use of contact lenses and the
factors may be ocular, systemic and occupational. In method of lens care hygiene and disinfection and
some cases more than one factor may be present or a frequency of lens replacement should be enquired.
co-existence of an ocular or systemic factor may be Proper contact lens hygiene decreases the chances of
present. microbial keratitis but infections have been reported to
occur even when the patients were compliant with an
Ocular Factors adequate lens care hygiene.6
The various ocular factors which may predispose to the It has been demonstrated that the risk of contact lens
occurrence of corneal ulcer include corneal trauma, induced keratitis is more with the extended wear soft
prolonged use of topical corticosteroids, use of contact contact lenses and overnight wear as compared to daily
lenses, precorneal tear film disorders, eyelid disease, and wear hard and soft contact lenses (Fig. 5.5).7,8 Infections
ocular surface disease.1 with organisms such as Pseudomonas species have also
been reported with orthokeratology.9
TRAUMA History of smoking coupled with contact lens wear
Corneal injuries cause a breach in the intact corneal is known to increase the risk of microbial keratitis as it
epithelial barrier which is the first line of defense against increases the amount of corneal hypoxia.8 The daily
the occurrence of infectious keratitis.2 Seemingly trivial disposable soft contact lenses in our experience have a
trauma with contaminated matter, foreign bodies, lower risk of infectious keratitis compared with other
makeup or contact lenses may also cause inoculation of lens wear regimens. However, reports have shown that
the organism.3 at least some risk remains.10,11
37
2 Work Up of Corneal Ulcer
mos, exophthalmos, proptosis, blepharitis and meibomi-
tis may predispose the occurrence of infectious keratitis.
BULLOUS KERATOPATHY
Figure 5.5: Contact lens induced ulcer
Bullous keratopathy caused by corneal endothelial
Use of contaminated and non-sterile solutions such decompensation disturbs the barrier function of the
precorneal tear film and the corneal epithelium. The
as homemade saline solution or tap water may be used
corneal surface becomes irregular and corneal erosions
to rinse, store or lubricate contact lenses which is typical
and epithelial defects develop. All these factors facilitate
of contact lens induced keratitis due to Acanthamoeba.
the entry of microbes in the corneal tissues. The risk
Acanthamoeba keratitis may also occur due to conta-
factors for development of corneal infection in these
mination from swimming pool and muddy water
cases include prolonged bullous keratopathy time,
(Fig. 5.6). steroid use and use of bandage soft contact lens.
Ulcerative keratitis developed in 4.7 percent of patients
LID AND ADNEXAL INFECTIONS with bullous keratopathy in a study by Luchs et al.15
Ulcerative keratitis caused by Pneumococcus has a
known association with dacryocystitis.12 Likewise, TOPICAL MEDICATIONS
infection with Actinomyces occurs more commonly in Amongst the topical medications, the prolonged use of
cases of canaliculitis. Any abnormality in the lid such topical corticosteroids is known to predispose the
as trichiasis, coloboma, ectropion, entropion, lagophthal- occurrence of infectious keratitis (Fig. 5.8). Topical
Figure 5.6: Acanthamoeba keratitis Figure 5.7: Keratitis with ocular surface disorder
38
Clinical Examination 2
Figure 5.8: Microbial keratitis (Prolonged topical corticosteroid use) Figure 5.9: Microbial keratitis after traditional eye medicine (honey)
corticosteroids adversely affects the precorneal tear film The use of traditional eye medicines in developing
and local ocular immunity, and can cause bacterial and countries has also been known to predispose the
fungal keratitis.9 Also, corticosteroids prevent neutrophil occurrence of keratitis (Fig. 5.9).18
migration in response to chemotactic factors released
during microbial keratitis.9 Moreover, there is impaired PRIOR OCULAR SURGERY
opsonization when encapsulated bacteria cause Ocular surgeries like cataract surgery,19 pterygium
microbial keratitis. Corneal super-infection has been surgery, keratoplasty19-22 (Fig. 5.10) photorefractive
reported after indiscriminate use of corticosteroids in keratectomy23 and laser in situ keratomileusis (LASIK)
cases of Apollo conjunctivitis.16 may be complicated by the occurrence of microbial
Continued use of non-steroidal anti-inflammatory keratitis24 (Fig. 5.11). Infectious keratitis particularly with
agents,17 anesthetics, inappropriate use of antibiotics, Mycobacterium chelonei has been reported after LASIK
antiviral and anti-glaucoma medications such as timo- surgery both in sporadic as well as in epidemic forms.25
lol may also predispose the occurrence of infectious
Systemic Factors
corneal ulcer if used for a very long time. All these drugs
cause toxic changes in the corneal epithelium. Certain systemic diseases like diabetes mellitus (Fig.
5.12), acquired immunodeficiency syndromes, Sjögren’s
Figure 5.10: Microbial keratitis after keratoplasty Figure 5.11: Microbial keratitis after LASIK surgery
39
2 Work Up of Corneal Ulcer
Figure 5.12: Microbial keratitis in a case of diabetes mellitus Figure 5.13: Microbial keratitis in a case of rheumatoid arthritis
syndrome and Steven-Johnson syndrome may act as risk Other Systemic Factors
factors for the occurrence of microbial keratitis. Moraxella
Pseudomonas keratitis occurs more frequently in cases of
lacunata ulcers are usually associated with alcoholics,
burn patients, semicomatose or comatose patients,
diabetics and debilitated patients.27
patients with corneal exposure and patients on pro-
Diabetes Mellitus longed ventilator support. 9 In children, microbial
keratitis may occur in association with conditions such
The basement membrane and the hemidesmosome
as measles, diarrhea and malnutrition.28
attachments to the corneal epithelium are impaired in
the diabetes. Diabetics also have duplicated and
Occupational Factors
thickened basement membrane and its anchoring fibrils
to the stroma are weak. These changes in basement Some occupations may render a person susceptible to
membrane may cause persistent corneal epithelial developing microbial keratitis. Mycotic keratitis occurs
erosions predisposing it to the occurrence of infectious more commonly in persons involved in farming and
keratitis (Fig. 5.12). agriculture and outdoor laborers.9 They are prone to be
inflicted by minor vegetative or plant trauma while
Acquired Immunodeficiency Syndromes and handling farms. It also occurs more commonly in
Advanced Malignancies conjunction with the use of gardening tools (e.g. nylon–
An impaired immune status, as seen in acquired line lawn trimmers) without protective eyewear. Certain
immune deficiency syndromes and advanced malig- type of keratitis such as due to Listeria monocytogenes is
nancy render the patient susceptible to developing known to occurs in cases of animal handlers.8
microbial keratitis, especially by the unusual bacteria.26
These cases are prone to develop Candida keratitis. Clinical Examination and Signs
Further, the course of keratitis is more fulminant in these
cases. Examination of any patient of an ocular disease begins
with the general examination of patient. A close look is
made at the facial structures to look for the presence of
Connective Tissue Diseases
any lesion like blisters of herpes zoster or simplex,
Systemic diseases like rheumatoid arthritis may adver- presence of any facial palsy, abnormal blink rate and
sely affect the healing of the corneal ulcer (Fig. 5.13). excessive corneal and conjunctival exposure.
They may also predispose to corneal melting and The level of visual acuity and the size of the lesion
predispose to secondary infectious keratitis. are two important indicators of severity of a case of
40
Clinical Examination 2
infectious keratitis. A particular type of organism may lamp biomicroscopy should include an examination of
present with a characteristic type of clinical picture that the precorneal tear film, conjunctiva, cornea, anterior
may provide an important clue to etiological diagnosis. chamber, iris, lens and anterior vitreous.29
A patient of ulcerative keratitis should be examined as
follows: CONJUNCTIVA
Record of Visual Acuity The bulbar conjunctiva and the upper and lower tarsal
conjunctiva should be examined for the presence of any
It is usually possible to record only uncorrected visual lesion or diseases like vernal catarrh and atopic
acuity (UCVA) in an eye with ulcerative keratitis. A conjunctivitis. Conjunctival reaction is usually not speci-
Snellens’ chart may be used to record the visual acuity. fic but may occasionally help in diagnosis. An associated
UCVA should be recorded at the time of presentation severe conjunctivitis is present in gonococcal, pneumo-
and also at subsequent follow-up visits. Monitoring of coccal and Haemophilus infections usually with
the visual acuity is an important parameter to check the chemosis and sometimes with conjunctival pseudo-
severity and the progress of the ulcer. In young children membranes. Presence of chemosis or membranes should
an attempt should be made to record the visual acuity thus be recorded.
using Teller’s acuity cards. Bacterial infections may be characterized by the pre-
sence of papillae which are tufts of capillaries infiltrated
External Ocular Examination by inflammatory cells and separated by septa bound
down by tarsus and are suggestive of inflammation of
Eyelids and lacrimal sac area should be examined for
the conjunctiva. Prominent limbal vessels or circum-
any abnormality besides recording usual concomitant
ciliary flush is usually seen in bacterial keratitis.
presence of lid swelling and circumciliary congestion.
Presence of discharge may also be seen and a note
EYELIDS of its color and consistency should be made. A watery
discharge is generally seen with viral keratitis, whereas
Eyelids should be examined for the presence of any a mucoid or mucopurulent discharge is associated more
abnormality such as trichiasis, coloboma, entropion, lid often with bacterial keratitis. The color of the discharge
lag, ectropion, lagophthalmos, proptosis, exophthalmos may also help in clinching the final diagnosis, as a
and blepharitis. These conditions act as predisposing greenish purulent discharge is seen in cases of
factors and may require simultaneous management Pseudomonas keratitis (Figs 5.2 and 5.14).
along with that for infectious keratitis.
If there is a history of foreign body going in to the
PRECORNEAL TEAR FILM
eye, the eyelids should be everted and the fornices
should be examined. If required and possible a double In a case of active keratitis the precorneal tear film and
eversion of upper eyelid should be done to find and the meniscus typically consist of numerous cells and
remove the foreign bodies. debris unlike an inactive corneal ulcer. A breach in the
corneal epithelium is more characteristically seen in
LACRIMAL SAC cases of active keratitis unlike a non-infective infiltrate
A gross external examination of lacrimal sac area should where the overlying epithelium is intact. However, in
undertaken to rule out dacryocystitis. Pneumococcal cor- some cases of deep ulceration, the overlying epithelium
neal ulcers may be associated with lacrimal sac infec- may be completely intact.
tions. A sac pressure test or regurgitation test is performed One should also look for the presence of filaments
by pressing over the lacrimal sac area just medial to the in the precorneal tear film to rule out the presence of
medial canthus and observing regurgitation of discharge filamentary keratitis. Fluorescein dye may be used to
from the puncta. A positive regurgitation test indicates stain the filaments.
the presence of dacryocystitis.
CORNEA
Slit-lamp Biomicroscopy
The examination of the cornea includes the examination
A detailed slit-lamp biomicroscopic examination is of the corneal ulcer as well as the examination of the
mandatory to examine a case of infectious keratitis. Slit- surrounding cornea.
41
2 Work Up of Corneal Ulcer
Figure 5.14: Pseudomonas keratitis Figure 5.15: Slit-lamp biomicroscopy of corneal ulcer
Figure 5.16A: Giant papillary conjunctivitis in a case of vernal conjunctivitis Figure 5.16B: Shield corneal ulcer in same case in Figure 5.16A
42
Clinical Examination 2
Figure 5.17: Bacterial corneal ulcer due to Staphylococcus species Figure 5.18: Fungal corneal ulcer due to Candida (Feathery margins)
Figure 5.19A: Dendritic ulcer due to herpes simplex (Rose Bengal Figure 5.19B: Dendritic ulcer due to herpes simplex (Fluorescein
dye) staining)
Figure 5.20A: Active corneal ulcer with hazy margins Figure 5.20B: Healing corneal ulcer with distinct margins
TABLE 5.2
Grading of corneal ulcer
Feature Mild Moderate Severe
size of the lesion is an important parameter for monitor- Figure 5.21: Mooren’s corneal ulcer with over hanging margins
ing the success of the treatment modality.
A grading system of corneal ulcers may be used to
objectively study and monitor the progress of a case of is an indicator of evaluation the progress of any case of
infectious keratitis30 (Table 5.2). ulcerative keratitis.
The epithelial defects should be stained with fluore-
scein dye and the size should be measured with the help
EPITHELIAL DEFECT
of slit-lamp micrometer at all follow-up visits (Fig.
The size of the epithelial defect and the size of the infil- 5.22B). The staining of the lesion may be achieved either
tration should be measured separately in the two largest by putting a drop of the dye from the dropper or
meridians. They should be measured separately as their applying dye stained strips in the conjunctival sac. Most
sizes may not be similar. In some of the cases the corneal corneal specialists prefer to use fluorescein or rose bengal
epithelium may be intact over an infiltrated area in the strips to stain the lesion. These strips are more useful as
stroma such as in cases of non-infections corneal ulcers they are sterile as compared to the drop of the dye
or corneal abscesses. Also, the size of the epithelial defect solutions. Because of the fluorescence property of the
may be smaller or larger than the size of the infiltration fluorescein dye, the stained epithelial defect is examined
(Figs 5.22A and B). Change in the size of epithelial defect using the cobalt blue light of the slit-lamp. The minute
44
Clinical Examination 2
INFILTRATION
Figure 5.23: Multiple infiltrates
Infiltration is an intrinsic component of suppurative
infectious keratitis. The infiltrates may be single or
multiple and may be of varying sizes depending on the infiltrate depth and density and involvement of sclera.30
organism involved and the duration of the infection (Figs (Table 5.2).
5.22A and 5.23). The infiltrate should be measured in
the two largest dimensions and recorded on a schematic Corneal Sensations
cornea diagram. If there are multiple infiltrates as seen Corneal sensations should be assessed with the help of
in some fungal corneal ulcers, or cases of polymicrobial a cotton wisp or esthesiometer, if available. In cases of
keratitis31 each one of them is measured separately at herpetic keratitis the corneal sensations are markedly
all visits (Fig. 5.23). An estimated depth of the stromal decreased.
ulceration may be determined by comparing the
adjacent uninvolved corneal thickness. It should be
Special Characteristics
recorded at every follow-up visit.
The ulcers may be graded as mild, moderate or Some organisms produce lesions of particular shapes,
severe depending on the size of the ulcer, depth of ulcer, color or have some distinctive features. A mere clinical
45
2 Work Up of Corneal Ulcer
TABLE 5.3 localized lesions with distinct borders and minimal
Characteristics of various corneal ulcers surrounding edema. Some organisms like Pseudomonas
Dendritic keratitis—Herpes simplex, Herpes zoster produce ulcers in which the surrounding cornea
Radial neurokeratitis—Acanthamoeba becomes hazy and grossly edematous appearing like a
Amoeboid ulcer—Herpes simplex ground glass. Clearing of surrounding corneal edema
Black/brown discoloration—Demetacious fungal keratitis,
after the initiation of medical therapy is an early sign of
corneal ulcer in a tattooed corneal opacity resolution of the ulcer.
Yellow-greenish discharge—Pseudomonas
Corneal Vascularization
Satellite lesions—Fungus, Acanthamoeba
Ring shaped stromal infiltrates—Acanthamoeba, fungus
Superficial or deep corneal vascularization of varying
extent may be seen in cases of infectious keratitis. A
Disk shaped corneal edema—Herpes simplex
quadrant wise record of corneal vascularization should
Limbal peripheral lesions—Staphylococcus aureus, Herpes
simplex, immunological and connective tissue disorders,
be made. Presence of corneal vascularization suggests
Mooren’s ulcer the commencement of the healing of the corneal ulcer
Endothelial plaques—Fungus (Figs 5.24A to C).
Feathery hyphate edges—Fungus
CORNEAL THINNING/PERFORATION
Dry surface—Fungus
Crystalline infiltrates—Streptococcus viridans The ulcer should be closely monitored for the develop-
Overhanging margins—Mooren’s ulcer ment of corneal thinning, descemetocele and perforation.
In the presence of shallow anterior chamber and low
intraocular pressure a Seidel’s test should be performed
examination of such lesions may aid in establishing the in all cases.32
etiological diagnosis, although clinical observation
When the escape of aqueous is suspected, fluorescien
should not replace the laboratory investigation of direct
dye is applied directly to the site of the leakage. When
microscopy and culture of corneal scrapings.2
present, escaping aqueous dilutes the fluorescien to flow
The classical examples of such features are dendritic
down the surface of the eye. The application of concen-
keratitis, radial neurokeratitis, satellite lesions, hyphate
trated fluorescien results in a dark non-fluorescing
extensions, black/brown color of the lesion, etc. The
background against which the diluted and now brightly
lesions clinical characteristics and the possible etiological
fluorescing dye is highly visible, even in the presence
diagnosis are highlighted in Table 5.3.
of modest flow.
Occurrence of corneal perforation is an indication of
Surrounding Cornea
failure of medical therapy (Figs 5.25A and B). Severe
The cornea surrounding the lesion may be, clear or hazy corneal thinning and corneal perforation warrant
due to edema depending on the virulence of the orga- immediate surgical therapy in the form of application
nisms. Gram-positive cocci and Candida tend to cause of glue or a tectonic patch graft.
Figures 5.25A and B: Thining (A) progressing to perforation (B) in a case with corneal ulcer
ANTERIOR CHAMBER
The anterior chamber reaction may range from mild flare
and cells to severe hypopyon formation. A record of
hypopyon and its characteristics should be made using
a slit-lamp biomicroscopy (Fig. 5.26). The size of the
hypopyon should be measured using the slit-lamp
micrometer. Figure 5.26: Hypopyon corneal ulcer
Fixed immobile hypopyon is a feature of fungal
keratitis. In order to test for the mobility of the
form of synechiae. Presence of rubeosis iridis should also
hypopyon, following a slit lamp examination, the patient
be noted.
is asked to lie supine for 10 minutes and a slit-lamp
If the ulcer perforates uveal prolapse may occur and
evaluation is then done. In cases of the fixed hypopyon, this may later form a corneoiridic scar.
there is no change in position of the hypopyon as
demonstrated by the height of the hypopyon which is PUPIL AND LENS
similar. However, in cases of mobile hypopyon, the Any abnormality in the pupil size, its shape and location
position, i.e. the upper level or the height of the hypo- should be recorded using the slit-lamp biomicroscopy.
pyon decreases and there is actual movement (Figs 5.27A If visible, lens should be examined for the presence of
and B). cataract or any other abnormality.
Figures 5.27A and B: Hypopyon moves as the patient moves from erect (A) to supine position (B)
48
Clinical Examination 2
Varying Clinical Picture
Based on the presenting clinical history, antecedent risk
factors, predisposing ocular and systemic factors and
distinctive clinical signs, infectious keratitis may be easy
to diagnose. However, there may be following factors,
which may alter the typical clinical features of infectious
keratitis:
1. Previously partially treated corneal ulcers with
antibiotic therapy alone or combination antibiotic-
corticosteroid therapy may mask or blunt the
distinctive/classical features of corneal ulcer.
Withdrawal of the previous topical corticosteroids
may cause an initial resurgence of the stromal
inflammation and necrosis if they are withdrawn
Figure 5.28: Corneal ulcer with posterior segment involvement abruptly, and hence during the initial management
this can confuse the initial response to treatment.
in the management protocol, since this warrants the use 2. In cases of partially treated ulcers especially with
of systemic antimicrobial agents. Sclerokeratitis usually topical antibiotics, the normal conjunctival flora is
occurs in cases of immunologic disorders and suppressed and this leads to invasion with
Acanthamoeba keratitis. saprophytic bacteria so that the typical features of
infection are masked.
POSTERIOR SEGMENT 3. Additionally, the toxicity of certain topical drugs
such as aminoglycosides, anesthetics, idoxuridine
Usually, it is not possible to view the vitreous and retina
and amphotericin B may simulate corneal infection
in a case of corneal ulcer due to the presence of hazy
by causing epithelial and stromal ulceration and
cornea. However, if the ulcer is small and peripheral,
multiple focal suppurative inflammation.
slit-lamp biomicroscopy may be done to visualize the
anterior one-third of the vitreous. Additionally, an 4. Non-infectious keratitis may mimic suppurative
indirect ophthalmoscopy may be performed to check keratitis especially, if the inflammation is marked.
for the involvement of the posterior segment (Fig. 5.28). 5. The clinical features may be different in a patient
with previously compromised corneas. Individuals
INTRAOCULAR PRESSURE with neurotrophic or exposure keratopathy may
Digital tonometry in the experienced hands is the most develop ulceration, which may be indistinguishable
practical method of assessing intraocular pressure in from infectious keratitis.
cases of corneal ulcer in our experience. Secondary
glaucoma may be present in some cases and should be References
appropriately treated.
1. Ormerod LD, Hertzmark E, Gomez DS, et al. Epidemio-
Ultrasonography logy of microbial keratitis in southern California. A
multivariate analysis. Ophthalmology 1987;94:1322-33.
In cases where it is not possible to view the posterior 2. Ogawa GSH, Hyndiuk RA. In: Smolin G, Thoft RA (Eds):
segment, an ultrasonography A scan and B scan may The Cornea Scientific Foundations and Clinical Practice.
be undertaken to assess the posterior segment. A clear 3rd ed, Lippincott Williams and Wilkins Philadelphia.
posterior segment evaluation rules out the presence of Bacterial Keratitis and Conjunctivitis. Chapter 5, p125
3. Wilson SE, Bannan RA, McDonald MB, Kaufman HE.
vitritis/endophthalmitis. In cases of perforated corneal
Corneal trauma and infection caused by manipulation
ulcers, endophthalmitis, choroidal and retinal of the eyelashes after application of mascara. Cornea
detachment should be excluded. This helps to progno- 1990;9:181-2.
ticate the cases, especially if a therapeutic keratoplasty 4. Bharathi MJ, Ramakrishnan R, Vasu S, Meenakshi R,
is contemplated in these cases. Palaniappan R. Epidemiological characteristics and
49
2 Work Up of Corneal Ulcer
laboratory diagnosis of fungal keratitis. A three-year 19. Cosar CB, Cohen EJ, Rapuano CJ, Laibson PR. clear
study. Indian J Ophthalmol 2003;51:315-21. corneal wound infection after phacoemulsification. Arch
5. Zaidman GW, Coudron P, Piros J. Listeria monocyto- Ophthalmol 2001;119:1755-9.
genes keratitis. Am J Ophthalmol 1990;109:334-9. 20. Vajpayee RB, Boral SK, Dada T, Murthy GV, Pandey
6. Najjar DM, Aktan SG, Rapuano CJ, Laibson PR, Cohen RM, Satpathy G. Risk factors for graft infection in India:
EJ. Contact lens-related corneal ulcers in compliant a case-control study. Br J Ophthalmol 2002;86:261-5.
patients. Am J Ophthalmol 2004;137:170-2. 21. Vajpayee RB, Sharma N, Sinha R, Agarwal T, Singhvi
A. Infectious keratitis after keratoplasty. Surv Ophthal-
7. Poggio EC, Glynn RJ, Schein OD, Seddon JM, Shannon
mol 2007;52:1-12.
MJ, Scardino VA, et al. The incidence of ulcerative
22. Sharma N, Gupta V, Vanathi M, Agarwal T, Vajpayee
keratitis among users of daily-wear and extended-wear RB, Satpathy G. Microbial keratitis following lamellar
soft contact lenses. N Engl J Med 1989;321:779-83. keratoplasty. Cornea 2005;24:989-91.
8. Schein OD, Buehler PO, Stamler JF, Verdier DD, Katz J. 23. Donnenfeld ED, O’Brien TP, Solomon R, Perry HD,
The impact of overnight wear on the risk of contact lens- Speaker MG, Wittpenn J. Infectious keratitis after
associated ulcerative keratitis. Arch Ophthalmol photorefractive keratectomy Ophthalmology 2003;
1994;112:186-90. 110:743-7.
9. Young AL, Leung AT, Cheng LL, Law RW, Wong AK, 24. Solomon R, Donnenfeld ED, Azar DT, Holland EJ,
Lam DS. Orthokeratology lens-related corneal ulcers in Palmon FR, Pflugfelder SC, et al. Infectious keratitis after
children: A case series. Ophthalmology 2004;111:590-5. laser in situ keratomileusis: Results of an ASCRS survey.
10. Sankaridurg PR, Sweeney DF, Holden BA, Naduvilath J Cataract Refract Surg 2003;29:2001-6.
T, Velala I, Gora R, et al. Comparison of adverse events 25. Karp CL, Tuli SS, Yoo SH, Vroman DT, Alfonso EC,
with daily disposable hydrogels and spectacle wear: Huang AH, et al. Infectious keratitis after LASIK.
Results from a 12-month prospective clinical trial. Ophthalmology 2003;110:503-10.
26. Aristimuno B, Nirankari VS, Hemady RK, Rodrigues
Ophthalmology 2003;110:2327-34.
MM. Spontaneous ulcerative keratitis in immunocom-
11. Su DH, Chan TK, Lim L. Infectious keratitis associated
promised patients. Am J Ophthalmol 1993;115:202-8.
with daily disposable contact lenses. Eye Contact Lens. 27. Garg P, Mathur U, Athmanathan S, Rao GN. Treatment
2003;29:185-6. outcome of Moraxella keratitis: Our experience with 18
12. Aasuri MK, Reddy MK, Sharma S, Rao GN. Co- cases—A retrospective review. Cornea 1999;18:176-81.
occurrence of pneumococcal keratitis and dacryocystitis. 28. Vajpayee RB, Ray M, Panda A, Sharma N, Taylor HR,
Cornea 1999;18:273-6. Murthy GV, et al. Risk factors for pediatric presumed
13. Vajpayee RB, Gupta SK, Bareja U, Kishore K. Ocular microbial keratitis: A case-control study. Cornea 1999;
atopy and mycotic keratitis. Ann Ophthalmol 1990; 18:565-9.
22:369-72. 29. Waring GO. Slit-lamp microscopy of the cornea. In:
14. Sridhar MS, Garg P, Das S, Vemuganti G, Gopinathan Leibowitz HM, Waring GO (Eds): Corneal disorders:
U, Rao GN. Infectious keratitis in climatic droplet kerato- Clinical diagnosis and management. 2nd edition, WB
pathy 2000;19:455-8. Saunders Co. Philadelphia 1998;2:34-81.
15. Luchs JI, Cohen EJ, Rapuano CJ, Laibson PR. Ulcerative 30. Harrison SM. Grading corneal ulcers. Ann Ophthalmol
keratitis in bullous keratopathy. Ophthalmology 1975;7:537-9, 541-2.
31. Miedziak AI, Miller MR, Rapuano CJ, Laibson PR,
1997;104:816-22.
Cohen EJ. Risk factors—microbial keratitis leading to
16. Vajpayee RB, Sharma N, Chand M, Tabin GC, Vajpayee
penetrating kertoplasty. Ophthalmology 1999;106:1166-
M, Anand JR. Corneal superinfection in acute hemor- 70.
rhagic conjunctivitis. Cornea 1998;17:614-7. 32. Romanchuck KG. Seidl’s test using 10% fluorescein. Can
17. Guidera AC, Luchs JI, Udell IJ. Keratitis, ulceration, and J Ophthalmol 1979;14:253-6.
perforation associated with topical nonsteroidal anti- 33. Waring GO, Laibson PR. A systematic method of draw-
inflammatory drugs. Ophthalmology 2001;108:936-44 ing corneal pathologic conditions. Arch Ophthalmol
18. Yorston D, Foster A. Traditional eye medicines and 1977;95:1540-2.
corneal ulceration in Tanzania. J Trop Med Hyg 1994; 34. Warmg GO. Slit beam ruler. Am J Ophthalmol 1976;
97:211-4. 82:802-3.
50
Investigations 2
6 Investigations
Ocular and systemic investigations including micro- antibody –absorption (FTA-ABS) in suspected cases of
biological investigations are an integral part of work- syphilis.
up of a case of infectious keratitis. These investigations
help in making accurate etiological diagnosis and Ocular Investigations
initiation of appropriate therapy.
The ocular investigations include the clinical investiga-
tions and the microbiological investigations.
Systemic Investigations
Systemic investigation should be done in cases of sterile Clinical Investigations
corneal ulcers.
Systemic investigations in cases of peripheral The clinical investigations include the estimation of the
ulcerative keratitis include laboratory tests, which intraocular pressure and posterior segment evaluation
should focus on the systemic diseases (Table 6.1). This by ultrasonography to rule out any evidence of
concomitant endophthalmitis.
include a hemogram in cases of immuno compromised
individuals and blood sugar examination in suspected
INTRAOCULAR PRESSURE
cases of diabetics.
A complete blood count including ESR, urine Tonopen can be used to measure intraocular pressure
analysis, blood urea, nitrogen and creatinine. IgM- in cases of non-perforated corneal ulcers. Digital
rheumatoid factor, which is positive in cases of estimation of the intraocular pressure may also be done
Rheumatoid arthritis, scleroderma, polyarteritis nodosa, to rule out secondary glaucoma. The intraocular pressure
Wegner’s granulomatosis, systemic lupus erythematosis, will be low in cases of perforated corneal ulcers.
sarcoidosis should also be sent for. Circulating
antibodies such as ANA (>90%), anti-DNA (70%) are ULTRASONOGRAPHY
positive in systemic lupus erythematosis. Angiotensin
Ultrasonography B scan should be done to evaluate the
converting enzyme (ACE) is elevated in sarcoidosis and
status of the posterior segment in cases of corneal ulcers
antineutrophil cytoplasmic antibodies (ANCA) are where endophthalmitis is suspected.
present in 96 percent cases of Wegner’s granulomatosis.
Hepatitis B surface antigen is sent for in suspected cases
of polyarteritis nodosa and fluorescent treponemal Microbiological Investigations
Laboratory procedures for the diagnosis of keratitis are
directed towards the detection of bacteria, fungi or
TABLE 6.1 parasites. A well-equipped dedicated ocular microbio-
Investigation in a case of peripheral ulcerative keratitis
logy laboratory staffed with trained technicians who are
1. Complete blood count specially oriented towards handling ocular specimens,
2. Urine analysis have a greater leverage over a general microbiology
3. Blood urea laboratory. The samples should be collected and a smear
4. Serum creatinine examination should be done. Further, the scrapings
5. Ig M Rheumatoid factor
should also be directly inoculated into the culture media
51
2 Work Up of Corneal Ulcer
and sensitivity of the organisms to the antibiotics should Figure 6.2: Fixation of smear by heating
be obtained.
COLLECTION OF SAMPLES of corneal ulcer and its examination is the main stay in
The samples should be collected at the initial presenta- the diagnosis and subsequent management (Fig. 6.1).
tion prior to the start of anti-microbial therapy. The
treatment can be initiated based on the results of smear Anesthesia
examination and, if required modified in accordance Corneal scraping is performed under topical anesthesia
with the culture and sensitivity results. preferably after instillation of two drops of 0.5 percent
Various types of samples may be collected to aid the proparacaine in the lower fornix of the affected eye.
diagnosis of corneal ulcer (Table 6.2). The most impor- Topical 0.5 percent proparacaine is least bactericidal as
tant sample for microbiological examination is the compared to other anesthetic agents such as tetracaine
corneal scraping1,2 (Fig. 6.2). The samples should also and xylocaine. 1,3 Proparacaine provides adequate
be obtained from the contact lenses, contact lens case anesthesia within one minute and does not cause intense
and contact lens solutions if the patient is a contact lens stinging on first installation.
wearer. If there is any lacrimal sac discharge, it should General anesthesia and sedation may be required in
also be sent for microbiological investigations. Although children, uncooperative adults or mentally impaired
it has also been recommended to obtain samples such patients.3, 4
as a conjunctival swab and an eyelid swab, it has not
proved to be of much help in our experience. Instruments
Corneal scraping is obtained using a Kimura’ s spatula
Corneal Scraping (Fig. 6.3). The other instruments for corneal scraping,
Corneal scraping is the most valuable specimen in cases are 26-gauge needle, Bard Parker blade #57 (Becton
TABLE 6.2
Samples for diagnosis of corneal ulcer
53
2 Work Up of Corneal Ulcer
Figure 6.4A: KOH wet mount preparation Figure 6.4B: Gram positive cocci
Figure 6.4C: Gram negative bacilli Figure 6.4D: Acid fast Mycobacteria
be performed in outpatient area and does not involve Overall, Gram’s stain is accurate in 61 percent of
too much of cost.10,11 cases of bacterial keratitis.4 If performed correctly,
Gram’s stain identifies the organism correctly in upto
Gram’s Staining 75 percent of the cases caused by a single organism and
Gram’s stain classifies the bacteria into two major groups in 37 percent cases of polymicrobial keratitis.12
based on the cell wall of the bacteria (Table 6.4). Gram-
positive bacteria retain the gentian violet-iodine complex Difficulties in Gram Staining
and appear blue-purple (Fig. 6.4B), whereas the Gram- Sometimes only small number of organisms is present
negative bacteria lose their gentian violet-iodine complex in the smear, which may be difficult to identify as these
with decolorization step and appear pink when are usually present in areas which contain necrotic
counterstained with safranin (Fig. 6.4C). A 5-minute epithelial cells and numerous large polymorphonuclear
Gram staining procedure as well as a 5-second Gram cells.
staining procedure is also available.12,13 We prefer to use Gram-negative organisms are more difficult to
the 5-minute Gram staining procedure (Table 6.3). identify than the Gram-positive organism due to their
54
Investigations 2
TABLE 6.3 Special Stains
Gram Stain Procedure
Giemsa Staining
• Fix smear by either of the following methods:
Place in methanol for 5-10 min and allow to air dry: The Giemsa stain is usually used to determine the type
preferred method of inflammatory cells present. We do not recommend
Pass the slide, through flame two or three times. Allow its use routinely. This stain differentiates bacteria from
cooling. fungi, and also identifies chlamydia inclusion bodies and
• Flood the slide with crystal violet stain. - Allow stain to cysts and trophozoites of Acanthamoeba species. It
remain on for 1 minute identifies the normal and inflammatory cells. With
• Rinse gently with tap water. Giemsa technique the bacteria appear dark blue in color.
• Flood slide with Gram’s iodine solution. Allow solution- The yeast cells and fungal hyphae absorb the stain and
to remain on for 1 minute. appear purple or blue while the cell walls and the
• Rinse gently with tap water. septations do not stain. The conventional Giemsa stain
• Decolorize with decolorizer solution until the color stops takes 60 minutes to perform, although a rapid 15-minute
running from the smear modification of the stain is also available.
• Rinse gently with tap water.
• Flood the slide with Safranin stain. Allow stain to remain Ziehl-Neelsen Acid-fast Stain
on for 30 seconds.
• Rinse gently with tap water. Special stains include the use of carbol-fuchsin or Ziehl-
Neelsen acid-fast stain for identification of suspected
• Allow to air dry.
Mycobacteria, Actinomyces or Nocardia. Mycobacteria are
acid fast (Fig. 6.4D), Nocardia stain variably, whereas
lighter color. Gram-negative organism may appear Actinomyces are non-acid fast.
gram-positive if decolorization is inadequate. The use of this stain is based on the resistance of the
Caution is also mandatory against various artifacts, mycobacterial species and certain strains of Nocardia to
which may accompany Gram’s stain such as stained decolorization by strong mineral acids after staining
deposits, carbon particles, talcum powder, sodium with basic carbol fuchsin. This resistance is due to the
chloride, crystals, melanin and granules. Precipitated presence of intact cell walls that contain specific lipid
gentian violet may mimic gram-positive cocci.13 If the unsaponifiable wax fraction.
Gram stain reagents are not used frequently, yeast may
grow in the solutions and periodic filtering helps to Calcofluor White
remove these particles.4
Calcofluor white binds to chitin and cellulose. Because
the cell walls of the yeast and filamentous fungi are
TABLE 6.4 composed of chitin and cellulose, these organisms stain
Gram stain morphology of organisms bright green with calcofluor white under epiflorescent
Type of stain Organism Color of the
microscope (Fig. 6.5).14 Blankophone stain, which is
visualized organism similar to calcofluor can also be used to identify fungal
hyphae (Fig. 6.6). The cysts of Acanthamoeba likewise also
Gram stain Bacteria Gram positive- have chitin and cellulose and also stain bright green.
purple
Gram negative-pink
The trophozoites of Acanthamoeba stain reddish –orange
in color.15
Acridine orange Bacteria Yellow–orange
Fungi Yellow-orange
Acanthamoeba Acridine Orange
Calcofluor white Fungi Bright green The acridine orange is a chemoflorescent dye, which
Acanthamoeba cysts Bright green stains fungi and bacteria yellow-orange against a green
Acanthamoeba Reddish orange
background when the pH is acidic and an epi-
trophozoites
Mycobacteria flourescent microscope is used to visualize these
Acid fast Mycobacteria
organisms. It identifies gram-positive and gram-negative
bacteria, yeast and hyphal forms of fungi and both the
55
2 Work Up of Corneal Ulcer
Figure 6.5: Fungal hyphae stained with calcofluor white (Courtesy: Figure 6.6: Fungal hyphae stained with blankophore (Courtesy:
Dr H Sheorey, Dept. of Microbiology, St Vincent hospital, Melbourne) Dr H Sheorey, Dept. of Microbiology, St Vincent hospital, Melbourne)
Routine
Soybean casein digest broth Saturation of swabs 35 oC
(trypticase soy broth)
Blood Agar plate Aerobic bacteria 35 oC
Facultative anaerobic bacteria
Fungi
Chocolate Agar plate Aerobic bacteria 35 oC
Facultative anaerobic bacteria
Neisseria
Haemophilus
Moraxella
Thioglycolate broth Aerobic bacteria 35 oC
Anaerobic bacteria
Sabouraud’s dextrose agar plate Fungi Room temperature
with antibiotic Nocardia
Brain Heart infusion broth plate Fungi Room temperature
with antibiotic Nocardia
Special
Cooked meat broth Anaerobic bacteria 35 oC
Schaedler agar Anaerobic bacteria 35oC
Thayer Martin Blood agar plate Neisseria 35oC
Brucella blood agar plate 35 oC
Lowenstein-Jensen media Myocobacteria species 35oC with 3 to 10% CO2
Middlebrook-Cohn agar MyocobacteriaNocardia 35oC with 3 to 10% CO2
the surface to produce a row of separate inoculation phytic fungi at room temperature (Fig. 6.7). The agar is
marks in a C shaped configuration.4 Fresh material derived from the seaweed and produces optimal surface
should be obtained for each row of C streaks (Fig. 6.7). moisture, and addition of 5 to 10 percent red blood cells
C streak method of inoculation differentiates valid provides nutrients and an index of hemolysis. Rabbit
growth from contamination as growth on the C streak and horse serum are preferred for supporting the growth
is considered significant whereas outside this is a of Haemophilus.
possible contamination.
Liquid thioglycolate broth is inoculated by trans- Chocolate Agar
ferring the material to cotton tipped applicator which Chocolate agar is prepared by the heat denaturation of
has been moistened with trypticase soy broth or calcium blood and provides hemin (X factor) and diphosphopyri-
alginate swab (Fig. 6.9). The swab is inserted to the dine nucleotide (V factor) essential for the growth of
bottom of the tube to enhance the growth of anaerobic Heamophilus. It should be incubated at 35°C with
organisms. 10 percent carbon dioxide. It also supports the growth
of Neisseria and Moraxella.
Blood Agar
Sabouraud’s Agar
Enriched media such as blood and chocolate agar help
to isolate the fastidious organisms. Blood agar is the Sabouraud’s agar consists of glucose and peptone agar.
standard medium for the isolation of aerobic bacteria at Yeast extract is added to improve nutritional characteri-
35oC and helps to support the growth of most sapro- stics and an antibiotic such as gentamicin or chloram-
57
2 Work Up of Corneal Ulcer
phenicol is added to inhibit bacterial contamination (Fig. tion of nutritional variant streptococci, which may be a
6.8). The Sabouraud’s agar should not contain any causative organism for infectious crystalline kerato-
additives such as cycloheximide as this inhibits pathy.19 The anaerobic media should not be exposed to
saprophytic fungi commonly responsible for ocular air and should be incubated in an anaerobic system such
infections. as anaerobic jar, anaerobic bag system or anaerobic
Following primary cultures the fungi are transferred chamber. In the GasPack Pouch system (Bacton
to the sporulating media for subculture of the species. Dickinson, Cockeysville) a packet that has sodium
Sabouraud’s agar plates are preferred to the slants borohydride, sodium bicarbonate and citric acid
because of the ease of inoculation, observation of colony generate hydrogen and carbon dioxide after water is
growth, transfer to secondary media and dilution of added in order to create an anaerobic environment.
inhibitory substances to the fungi.1
Brain Heart Infusion (BHI)
Thioglycolate Broth
Brain Heart Infusion (BHI) broth at room temperature
It promotes the growth of aerobic bacteria, as well as
enhances the growth of filamentous fungi and yeasts. It
obligate and facultatively anaerobic organisms.18
is especially relevant in ocular infections as the inoculum
Thioglycolate broth grows aerobic and anaerobic
material is small and it provides a more even exposure
bacteria at 35oC (Fig. 6.9). It consists of the basic nutrients
to the essential nutrients.
required to support the growth of aerobic bacteria and
also has sulf-hydryl compound that act as an oxygen-
Thayer-Martin Media
reducing agent to facilitate the recovery of the anaerobic
bacteria. It also supports a number of saprophytic fungi. This is an enriched chocolate media that suppresses the
The limitation of this media for the growth of growth of the inhibitory components and selectively
anaerobic organisms is its inability to restrict the growth allows the growth of the N. gonorrhoeae.
of the aerobic organisms.
Lowenstein Jensen Media
Pre-reduced Anaerobically Sterilized Media (PRAS)
In cases of suspected atypical microorganisms, the
This is an ideal medium for the isolation of the anaerobic cultures should also be sent on Lowenstein Jensen
bacteria. A PRAS brucella blood agar plate enriched with media. This medium allows the growth of Mycobacteria.
vitamin K and hemin allows the growth of the anaerobes It contains glycerol and egg mixture which provides
within 4 to 7 days. This is also recommended for isola- fatty acids and proteins (Fig. 6.10).
58
Investigations 2
Micro-Antimicrobial Removal Device (Micro-ARD) medium of an organism with positive smear results or
growth of same organism in liquid media.22 Jones criteria
In cases, which have been treated with anti-biotics pre-
for positive culture include: clinical signs of infection
viously, antimicrobial removal device can be used to
increase the yield of the positive cultures. The commer- plus isolation of bacteria (10 or more colonies) on one
cially available blood ARD is modified for smaller solid medium and one additional medium, or isolation
ophthalmological samples by transferring 2.5 ml aliquots of fungi (any detectable growth) on any two media or
of all components to test tubes. The ARD is composed one medium in the presence of a positive smear. 23
of sterile resins(amberlite XAD4 and C-249) which binds Although liquid media provide a highly sensitive
antibiotics suspended in sodium chloride. In a study by method for demonstrating a pathogen, a positive culture
Osato et al the use of micro-ARD increased the isolation from broth is less specific than a positive culture from
of organisms from 88 to 100 percent.20 solid media as it is difficult to quantify the broth cultures.
Anaerobic bacteria are suspected in following situations:
Duration of Isolation of Organism Pleomorphic, slender or fusiform morphology seen on
Gram stain of corneal smear or culture, growth in the
Most aerobic bacteria responsible for keratitis are seen
anaerobic zone of liquid medium or within the depth
on standard culture media within 48 hours. In some
of solid agar, production of gas on liquid media and
cases the pathogen may be recognized in 12 to 15 hours.
All plates should be examined daily with the help of failure to grow organism in aerobic media despite
dissecting microscope and liquid media should be organism detection in Gram stain.21
evaluated for the presence of turbidity. In cases of severe
keratitis the media should be evaluated after 12 to 18 Negative Cultures
hours of inoculation. Negative cultures may be present truly in cases of
Growth outside the C streak should be disregarded sterile/non-infectious ulcers or due to prior partial
as it implies contamination and circled with wax pencil. antibiotic treatment, inadequate sampling methods,
Indigneous organisms in the tear film may appear on improper selection of the media and incubation
the inoculation marks but may be distinguished on the conditions and false interpretation of the data.1 Negative
basis of their sparse growth and isolation of the same cultures have been reported in 44 percent of cases in a
organism from the ipsilateral lids or the conjunctiva, if series of 663 cases of microbial keratitis.22
these specimens have been taken.
When the culture results are negative, antibiotic
Aerobic cultures of the corneal specimens should be
treatment can be suspended temporarily for 24 hours
held for 7 days, anaerobic cultures for 7 to 14 days and
and rescraping is done following which repeat cultures
Mycobacterial and fungal cultures for 4 to 6 weeks before
are sent and examined.
being reported as no growth.
Mixed Organisms/Polymicrobial keratitis
Interpretation of Culture Results
Polymicrobial keratitis is a distinct clinical entity23. More
The interpretation of the culture results should be made than one organism in corneal cultures may be identified
with regard to the clinical situation, the adequacy of in 6 to 32 percent of cases depending on the laboratory
the sample and the possibility of contamination by techniques and the criteria for for positive or negative
organisms present on the skin, eyelids and conjunctiva. culture.22,23 The most frequent combination in mixed
microbial infections is an aerobic gram-positive coccus
Positive Culture
and a gram-negative rod. Rarely it may be a combination
Reported culture positive rates in presumed infectious of bacteria and fungi.1
keratitis varies from 40 to 73 percent.21,22 As soon as the growth is detected, an estimate of the
Criteria for a significant positive culture by some number of the colonies should be made, with a
investigators include the clinical signs of keratitis plus description of the colony morphology. Determination
one of the following: (i) growth of the organism in two of the antibiotic sensitivities is done. Minimal inhibitory
or more media (ii) confluent growth of a known ocular and bactericidal concentrations are usually available
pathogen in one solid medium or (iii) growth in one within a few days.
59
2 Work Up of Corneal Ulcer
ANTIMICROBIAL SUSCEPTIBILITY TESTING
The preferred methods for testing the susceptibility of
the antimicrobial agents are the standard disk diffusion
method and the micro-dilution techniques (Fig. 6.11).
The limitation of the ocular antimicrobial susceptibility
testing is that the results of agar disk diffusion tests relate
to the levels of drug in the serum rather than the concen-
tration of the antibiotics achieved in the ocular tissues
and fluids.
The quantitative minimal inhibitory concentration
(MIC) estimation by the broth microdilution methods
provide greater information about the ocular infections.
Once a MIC value of a particular antibiotic is found out
the bactericidal effect of the antibiotic may be titrated
by sub culturing the clear broth on the antibiotic free
Figure 6.11: Antimicrobial Susceptibility Testing
zone.
Minimal Bactericidal concentration (MBC) is the
concentration of the antibiotic, which reduces the growth
of the bacterial strain by 99.9 percent. The minimum The advantages of PCR include greater speed than
antibacterial concentration (MAC) is the inhibitory effect culture methods (up to 4 hours) and the ability to ana-
of the antibacterial agent, which is observed in 5.5 hours lyze specimens far from where they are collected. The
in which 90 percent of the bacterial population is cost of PCR to diagnose infections generally exceeds that
inhibited.4 The post antibiotic effect (PAE) is the result of conventional culture methods, a factor that currently
observed after the bacterial population is exposed to limits its widespread use.24 16S rDNA typing has been
antibiotics for approximately one hour followed by used as a rapid alternative to culture for identifying
removal of the antibiotic either after enzymatic treatment pathogens in patients with bacterial keratitis, 25 whereas
or dilution and then subculturing to see the amount of 18S ribosome gene is used to detect fungal keratitis.24
bacterial population that remains.4
CONFOCAL MICROSCOPY
SEROLOGICAL INVESTIGATIONS
It is particularly useful when relatively large infecting
A variety of DNA probe assays are available for the
organisms (15 microns) are present, as are seen in Acan-
confirmation of the results of the culture and for direct
thamoeba , filamentous fungal, microsporidial, and, possi-
detection of the organisms. The expensive molecular
microbiologic tests however, should not replace the time- bly, Lyme Borrelia keratitis.25,26 Confocal microscopy can
tested culture and staining techniques, the efficacy of clearly demonstrate both the cyst and often the tropho-
which have a proven track record. Such serological test zoite forms of acanthamoeba in suspected keratitis. It
may be divided into three categories4: also shows the enlarged corneal nerves accompanying
i. Target amplification systems such as polymerase radial neurokeratitis and the characteristic honeycomb-
chain reaction (PCR), cell sustaining sequence repli- pattern intrastromal microcavities seen during the late
cation (3 SR) or strand displacement amplification stages of the disease.25
(SDA) Retina Tomograph II—Rostock Cornea Module
ii. Probe amplification systems which includes ligase (HRTII-RCM) has also demonstrated the presence of
chain reaction (LCR) fungi. Filamentous fungi-infected patients’ corneas
iii. Signal amplification in which the signal generated reveal numerous high-contrast lines 200–300 μm in
from each probe is increased by using compound length and 3–5 μm in width, with branches at 90° angles
probes or branched chain technology (in cases of Fusarium) or 45o at angle (Aspergillus
These techniques detect whether DNA and RNA species).26
from a particular organism is present but do not detect Candida albicans—infected patient’s cornea reveal
the viability of the organism. numerous high-contrast elongated particles measuring
60
Investigations 2
References
1. Herbert E Kaufman, Bruce A Barron, Marguerite B
McDonald, Stephen C Kaufman. The Cornea, Second
Edition. Boston, Massachusetts, Butterworth-
Heinemann, 1999.
2. Jones BR. Principles in the management of oculomycosis.
XXXI Edward Jackson memorial lecture. Am J
Ophthalmol 1975;79:719-51.
3. Huang AJW, Wichiensui P, Yang MC. Bacterial keratitis:
In: Krachmer JH, Mannis MJ, Holland EJ (Eds): Cornea
Fundamentals, Diagnosis and Management, 2nd edition
2005;1:1005-34.
4. Vajpayee RB, Ray M, Panda A, Sharma N, Taylor HR,
Murthy GV, et al. Risk factors for pediatric presumed
microbial keratitis: A case-control study. Cornea 1999;
18:565-9.
Figure 6.12: Corneal biopsy with dermatologic trephine 5. Sridhar MS, Sharma S, Gopinathan U, Rao GN. Anterior
chamber tap: diagnostic and therapeutic indications in
the management of ocular infections. Cornea 2002;21:
10–40 μm in length and 5–10 μm in width in the anterior 718-22.
stroma resembling Candida pseudo-filaments. 6. Allen HF. Current status of prevention, diagnosis, and
management of bacterial corneal ulcers. Ann Ophthal-
mol 1971;3:235-46.
CORNEAL BIOPSY 7. Benson WH, Lanier JD. Comparison of techniques for
culturing corneal ulcers. Ophthalmology 1992;99:800-4.
Sometimes repeated smear examinations and cultures 8. Jacob P, Gopinathan U, Sharma S, Rao GN. Calcium
of corneal scrapings done by standard method do not alginate swab versus Bard Parker blade in the diagnosis
demonstrate presence of any microorganisms. This may of microbial keratitis. Cornea 1995;14:360-4.
be true for certain cases of deep mycotic keratitis and 9. Forster RK, Wirta MG, Solis M, Rebell G. Methenamine-
silver-stained corneal scrapings in keratomycosis. Am J
intrastromal abscesses.27 A vertical or oblique incision
Ophthalmol 1976;82:261-5.
can allow sampling using a sterile needle or a mini- 10. Vajpayee RB, Angra SK, Sandramouli S, Honavar SG,
spatula. Alternatively, a deep lamellar excision may be Chhabra VK. Laboratory diagnosis of keratomycosis:
undertaken to reach a focal abscess. comparative evaluation of direct microscopy and culture
In such cases, a diagnostic superficial keratectomy results. Ann Ophthalmol 1993;25:68-71.
or corneal biopsy may be necessary to obtain microbe- 11. Gopinathan U, Garg P, Fernandes M, Sharma S,
Athmanathan S, Rao GN. The epidemiological features
infested tissue to make an accurate microbiological
and laboratory results of fungal keratitis: a 10-year
diagnosis. Corneal biopsy is superior to scraping for review at a referral eye care center in South India. Cornea
isolating fungus from a case of mycotic keratitis. The 2002;21:555-9.
procedure is performed under topical anesthesia under 12. Jones DB. Initial therapy of suspected microbial corneal
an operating microscope. A dermatologic 2-3 mm ulcers. II. Specific antibiotic therapy based on corneal
trephine or a small Elliot microtrephine is advanced in smears. Surv Ophthalmol 1979;24:97, 105-16.
13. Popescu A, Doyle RJ. The Gram stain after more than a
to the anterior corneal stroma, to incorporate both the
century. Biotech Histochem 1996;71:145-51.
infected and the clinically normal 1 mm rim. Care is 14. Sutphin JE, Robinson NM, Wilhelmus KR, Osato MS.
taken to avoid the visual axis as far as possible. A Improved detection of oculomycoses using induced
crescent blade or Bard Parker knife is then used to fluorescence with cellufluor. Ophthalmology 1986;
undermine the tissue, which may then be cut with a 93:416-7.
surgical blade or a microscissors and the tissue is excised 15. Marines HM, Osato MS, Font RL. The value of calcofluor
(Fig. 6.12).28 The biopsy tissue is excised with a fine tooth white in the diagnosis of mycotic and Acanthamoeba
infections of the eye and ocular adnexa. Ophthalmology
forceps taking care not to crush the tissue. The specimen
1987;94:23-6.
thus obtained should be divided in to pieces and 16. Gomez JT, Robinson NM, Osato MS, Wilhelmus KR.
subjected to smear examination, cultures and histo- Comparison of acridine orange and Gram stains in
pathological examination. bacterial keratitis. Am J Ophthalmol 1988;106:735-7.
61
2 Work Up of Corneal Ulcer
17. Groden LR, Rodnite J, Brinser JH, Genvert GI. Acridine 23. Jones DB. Polymicrobial keratitis. Trans Am Ophthalmol
orange and Gram stains in infectious keratitis. Cornea Soc 1981;79:153-67.
1990;9:122-4. 24. Gaudio PA, Gopinathan U, Sangwan V, Hughes TE.
18. Jones DB, Robinson NM. Anaerobic ocular infections. Polymerase chain reaction based detection of fungi in
Trans Am Acad Ophthalmol Otolaryngol 1977;83:309- infected corneas. Br J Ophthalmol 2002;86:755-60.
31. 25. Parmar DN, Awwad ST, Petroll WM, et al. Tandem
19. Ormerod LD, Ruoff KL, Meisler DM, Wasson PJ, Kintner scanning confocal corneal microscopy in the diagnosis
JC, Dunn SP, et al. Infectious crystalline keratopathy. of suspected acanthamoeba keratitis. Ophthalmology
Role of nutritionally variant streptococci and other 2006;113:538-47.
bacterial factors. Ophthalmology 1991;98:159-69. 26. Brasnu E, Bourcier T, Dupas B, Degorge S, Rodallec T,
20. Osato MS, et al. Clinical applications of Antimicrobial Laroche L, et al. In vivo confocal microscopy in fungal
removal device in ocular infectious diseases. Ophthal- keratitis. Br J Ophthalmol 2006.
mology (Suppl) 1983;90:103. 27. Knox CM, Cevellos V, Dean D. 16S ribosomal DNA
21. Asbell P, Stenson S. Ulcerative keratitis. Survey of typing for identification of pathogens in patients with
30 years’ laboratory experience. Arch Ophthalmol. bacterial keratitis. J Clin Microbiol 1998;36:3492-6.
1982;100:77-80. 28. Alexandrakis G, Haimovici R, Miller D, Alfonso EC.
22. Liesegang TJ, Forster RK. Spectrum of microbial keratitis Corneal biopsy in the management of progressive micro-
in South Florida. Am J Ophthalmol 1980;90:38-47. bial keratitis. Am J Ophthalmol 2000;129:571-6.
62
Bacterial Keratitis 3
7 Bacterial Keratitis
Bacteria are the most important cause of infectious only a small number of these bacteria cause keratitis.
keratitis. Prompt recognition, expedient evaluation and There are various pre-disposing factors, which may
rapid initiation of antibiotic therapy are of vital precipitate bacterial keratitis which include the
importance. Most cases respond to medical therapy and following:
yield gratifying results. With an advanced infection,
devastating complications such as corneal thinning, CORNEAL TRAUMA
corneal perforation scleral extension and consequently,
endophthalmitis may occur. Corneal trauma causing a breach in the intact epithelium
There are no pathognomic clinical signs that confirm along with concurrent inoculation of organisms can
a definite bacterial etiology. However, based on occur from vegetable matter, industrial foreign bodies,
distinctive corneal signs such as the status of the contact lenses, cosmetic application and administration
epithelium, type of stromal inflammation and the site of ocular medications causing bacterial keratitis1-3
of the inflammation, a possible suspicion of the bacterial (Fig. 7.1).
etiology may be reached which is confirmed on the
laboratory examination. EYELID DISEASE
Ocular adnexal disorders such as blepharitis, dacryo-
Risk Factors cystitis, ectropion with exposure, entropion (Fig. 7.2)
with trichiasis or lagophthalmos (Fig. 7.3) lead to
The eye is continuously exposed to a large number of disturbed precorneal tear film that can predispose to
bacteria, which form a part of ocular flora. However, bacterial keratitis.
Figure 7.1: Keratitis in a case of repaired corneal perforation Figure 7.2: Keratitis in a case of entropion
65
3 Types of Microbial Keratitis
OCULAR SURFACE DISORDER risk for bacterial corneal ulcers, but when they develop
bacterial keratitis it takes a more fulminant course and
Ocular surface disorders such as dry eye, Stevens
ulcers are most often caused by Pseudomonas.5
Johnson syndrome and ocular burns can cause chronic
corneal decompensation may predispose the eye to
bacterial keratitis. Ocular surface disorders causes the CONTACT LENS USE
disturbance of the tear film dynamics and leads to The contact lens keratitis may occur due to the contact
persistent epithelial defects (Fig. 7.4) which are lens per se, which compromises the corneal health as it
secondarily infected and cause stromal ulceration.1 causes corneal hypoxia (Fig. 7.5). Contact lenses cause
hypoxia and increased corneal temperature.5-8 Extended
TEAR FILM DYSFUNCTION soft contact lens wearers are at 10 to 15 times increased
risk for bacterial keratitis as compared to daily lens
Tear film dysfunction which predispose to bacterial
wearers.7 Aphakic contact lens wearers have 6 to 9 times
keratitis include dry eye due to aqueous layer insuffi-
ciency, mucin layer abnormality due to goblet cell loss/
dysfunction, lipid layer instability or lacrimal drainage
obstruction.
69
3 Types of Microbial Keratitis
Figure 7.6: Ulcer due to Staphylococcus with intrastromal abscess Figure 7.7: Corneal ulcer due to Pneumococcus
Figures 7.8A and B: (A) Pseudomonas keratitis (B) Pseudomonas keratitis with corneal melting
and concentrically to involve whole width and depth of Other Gram-negative Rods
cornea.
Other gram-negative bacilli include Klebsiella,
A characteristic feature of Pseudomonas ulcer is
Escherichia coli and Proteus, which most commonly cause
diffuse epithelial graying which characteristically occurs
indolent ulcerations in previously compromised corneas
away from the main site of epithelial and stromal
with milder anterior chamber reaction.
infiltration. A ring ulcer is often seen at 48 to 96 hours
with an untreated infection. The progressive untreated
Moraxella Ulcers
ulcer is associated with melting of the cornea (Figs 7.8A
and B), and with greenish-yellow mucopurulent The ulcer caused due to Moraxella is typically indolent
discharge which is adherent to the ulcer. This leads to with only mild to moderate anterior chamber reaction.
descmetocele formation and eventual perforation within It is usually oval and located in the inferior part of the
2 to 5 days of onset of infection. cornea.19 It tends to remain localized as it spreads into
70
Bacterial Keratitis 3
the deep stroma. Some ulcers may have prolonged,
moderately severe stromal and anterior chamber
reactions with endothelial decompensation despite
proper treatment.
Anaerobes
Anaerobic infections usually follow corneal injuries with
contaminated soil.21
Clostridium species are suggested by the presence of gas
bubbles, which are visualized in the anterior chamber
in the corneal stroma or under the epithelium.
Listeria monocytogenes causes ulcerative keratitis in
animal handlers.1 Propionibacterium acnes and Pepto-
streptococcus are rare anaerobes. Actinomyces infections
are associated with canaliculitis.1
Nocardia species inhabit the soil and cause indolent
ulceration and are introduced into the eye following
trauma.24 These ulcers simulate fungal corneal ulcers Figure 7.9: Blood agar at room temperature (A) and at 37 degree
and occasionally have elevated, hyphate edges and often centigrade (B), Chocolate agar (C), Sabouraud’s agar (D)
produce satellite lesions and cracked-windshield
appearance of the cornea. Sabrouraoud agar plate or blood agar plate at room
Mycobacterium fortuitum inhabits the soil and cause temperature (Fig. 7.9) for fungi and chopped meat
indolent ulcers, which progress slowly over weeks.22,23 glucose broth or Thioglycolate medium with hemin and
The bed of the ulcer has cracked windshield appearance vitamin K for anaerobes.
with minimal changes in the surrounding cornea or the In case of contact lens keratitis, contact lens, case and
anterior chamber. solution should also be sent for microbiologic
examination.24
Microbiologic Work Up However, sometimes the Gram stain may fail to
reveal the offending organisms, in that case, it is
A provisional diagnosis can be reached after the clinical inadvisable to delay treatment while awaiting the results
work up of a case which is confirmed on microbiology. of culture. The empirical treatment with the broad-
Traditionally, the treatment regimen should be spectrum antibiotic drops should thus be started while
started only after smears and cultures have been taken. waiting for the culture reports.
Corneal scraping from the ulcer area is obtained and is
sent for microbiologic work up which includes direct
Treatment
microscopy and culture.
The smears include the Gram’s smear, Giemsa Ideally a patient of bacterial keratitis should be
staining, KOH wet mount preparation and Grocott- hospitalized especially if the compliance of the patient
Gomori methenamine-silver staining, especially if fungal is in doubt or it is a more severe form of disease. Reliable
infection is suspected. Acid-fast stains are necessary patients with mild or moderate ulcers may be treated
when M. fortuitum, Actinomyces sp. or Nocardia sp. are as outpatients with careful follow-up. In general the
suspected as in cases of indolent corneal ulceration. most rapidly destructive microbial keratitis is bacterial
The material obtained should also be inoculated and should be treated as bacterial corneal ulcer until a
directly on the culture media, rather than placed on definitive diagnosis is made.
carrier or transport media, since specimen obtained Until the results of the definitive cultures are
usually contain very few organisms. The specimens are available, Gram’s stain is a quick and helpful tool for
C streaked on Blood agar plate, Chocolate agar, initiating a rational antibiotic therapy. If done properly,
71
3 Types of Microbial Keratitis
Gram’s stain may identify pathogen in upto 75 percent TABLE 7.2
of the cases caused by single organism and 37 percent Preparation of fortified topical antibiotics*
of the cases caused by mixed organisms.1 We do routine
1. Cefazolin 50 mg/ml or ceftazidime 50 mg/mL
Gram’s staining and KOH wet mount preparation in all a. Add 9.2 mL of artificial tears to a vial of cefazolin,
cases of suspected microbial non-herpetic keratitis. 1 g (powder for injection).
The initial management of cases of bacterial keratitis b. Dissolve. Take 5 mL of this solution and add it to
includes the use of medical therapy. However, in cases 5 ml of artificial tears.
of corneal perforation surgical modalities may be c. Refrigerate and shake well before instillation.
resorted to. 2. Tobramycin 14 mg/mL or gentamicin 14 mg/mL
a. Withdraw 2 mL of tobramycin or gentamicin injectable
vial (40 mg/mL).
MEDICAL THERAPY b. Add 2 mL to a tobramycin or gentamicin ophthalmic
solution (5 mL) to give a 14 mg/mL solution.
The frequent administration of the broad-spectrum
3. Vancomycin 15 mg/mL, vancomycin 25 mg/mL or
antibiotic topical drops is the mainstay of the treatment. vancomycin 50 mg/mL
Additional supportive therapy includes the use of topical a. Add 33 mL of 0.9 percent sodium chloride for injection
cycloplegic agents, antiglaucoma medications and use (no preservatives) or artificial tears to a 500 mg vial
of lubricants. of vancomycin to produce a solution of 15 mg/mL.
Add 20 mL of 0.9 percent sodium chloride for injection
Choice of Antibiotics (no preservatives) or artificial tears to produce a
solution of 25 mg/mL. Add 10 mL of 0.9 percent
The treatment with topical antibiotics is initiated with sodium chloride for injection (no preservatives) or
either a combination fortified therapy or monotherapy. artificial tears to produce a solution of 50 mg/mL.
b. Refrigerate and shake well before instillation.
Types of Antibiotic Therapy 4. Amikacin
Intravenous formulation can be used (80 mg/2 cc
In cases where no treatment has been given earlier it is ampules).
mandatory to take corneal scrapings and send them for 5. Trimethoprim/Sulfamethoxazole 16 mg/ml and 80 mg/
culture examination. ml commercial preparation used.
In case where topical antibiotics were given before *(Adapted from Basic Clinical and Science Course 2000-2001,
one can suspend the topical medications for 12 to Section 8, External Disease and Cornea. American Academy
24 hours before obtaining the specimen for corneal of Ophthalmology
scraping.
Combination Therapy hourly dosage. Some people prefer to use 10% cefazolin
We prefer to use the combination therapy in cases of sodium instead of 5% cefazolin sodium in the
bacterial keratitis. A combination therapy consists of a combination therapy. The cephalosporin provides
cephalosporin, which acts against the gram-positive coverage against gram-positive cocci and some of the
cocci and some of the gram-negative rods and an gram-negative rods while the aminoglycoside are covers
most of gram-negative bacilli.24,25
aminoglycoside which acts against the gram negative
Following clinical response the frequency of the
organisms.25 Alternatively one of newer generation
antibiotics is reduced 4 hourly after 72 hours and is
fluoroquinolones may also be combined with fortified
subsequently tapered over the next few days.
cefazolin. The newer generation fluoroquinolones cover
some gram-positive organisms and most of the
Monotherapy
significant gram-negative rods including many
Pseudomonas species.25 Ciprofloxacin 0.3 percent, ofloxacin 0.3 percent,
Combined fortified 5 percent cefazolin sodium and Gatifloxacin 0.3 percent or moxifloxacin 0.5 percent can
1.3 percent tobramycin sulphate are given in hourly be given as monotherapy and is effective against most
dosage for the initial 48 hours (Table 7.2).26 Following corneal pathogens.27 Additionally they are also effective
an initial response to this therapy, the frequency of the against most strains of aminoglycoside resistant
drugs is tapered and the topical drugs are given two Pseudomonas, methicillin resistant Staphylococcus and
72
Bacterial Keratitis 3
exquisitely potent against Neisseria keratitis.27 They are but are best avoided as they may cause increased
well-tolerated and more convenient to use. chances of corneal melting.
Monotherapy is advocated in cases of small corneal
ulcers not involving the visual axis. Topical Corticosteroids
The patients are followed up daily and detailed
Topical corticosteroids are started 48 hours after the
drawings and measurements are taken to monitor the
organism have been identified on the culture along with
progress of the therapy.
the topical antibiotics.23 This is done after the fungal
This includes the resolution of the parameters which
organisms as causative agents have been ruled out.
include the lid edema, conjunctival congestion, the ulcer
size in mm and the depth, the size of the infiltration, Alone with the combination therapy it may decrease
corneal epithelial edema and the size of the hypopyon the amount of inflammation and reduces chances of
(if any) (Fig. 7.10). corneal scaring. Topical corticosteroids should not be
Due to emergence of methicillin resistant Staphylo- used in cases of corneal thinning for impending
coccus aureus (MRSA), vancomycin should not be used perforation.
routinely but should be reserved for very severe or MODIFICATION OF THERAPY
recalcitrant infections.
The results of microbial culture an the antimicrobial
susceptibility testing data may suggest a modification
ADJUNCTIVE THERAPY
from the intial therapeutic plan. If the patient is
Topical cycloplegics should be administered along with responding clinically to the original therapeutic plan,
the antimicrobial therapy. This relieves the ciliary spasm, no modification in antibiotic drugs is instituted.
alleviates pain and prevents the formation of synechiae. However, if the patients is not responding to the therapy
Homatropine eye drops 1 percent is used in three to or there is worsening of the clinical features , the
four times daily. antibiotic drugs may be changed according to the culture
Significant inflammation may cause a rise in sensitivity reports.
intraocular pressure and hence in such cases anti- If microbial culture fails to grow an organism,
glaucoma medications may be added. These include the topical medications are stopped for 24 hours before a
use of topical beta blockers such as 0.5 percent timolol re-scrape is done and cultures are sent again.
maleate or systemic carbonic anhydrase inhibitors such
as Acetazolamide in more severe cases. SPECIFIC DRUGS
The precise role of non-steroidal anti-inflammatory Specific drugs may be used when the keratitis occurs
agents has not been studied in cases of bacterial keratitis due to specific agents. For Nocardia keratitis combination
73
3 Types of Microbial Keratitis
trimethoprim (16 mg/ml) and sulfametoxazole ( 80 mg/ When culture results are negative but infection is still
ml) is the treatment of choice.28 Alternatively, sulfona- suspected, and the progression of the disease is such
mides, tetracyclines, erythromycin or amikacin may be that antibiotic treatment can be suspended temporarily,
used. it is wise to discontinue antibiotics and obtain specimens
In cases of acid fast-stained positive corneal scrapings for re-culture. Antibiotics may then be re-instituted on
topical amikacin 10 to 20 mg/ml one drop every hour an empirical basis if there is clinical deterioration until
is indicated.22,23 Systemic amikacin may be used in cases an organism is identified to allow for more specific
of corneal perforation or scleral involvement. More treatment.
recently, the fluroquinolones have found to be effective
against mycobacteria and can be used as a first line of SURGICAL THERAPY
treatment.
The surgical modalities to treat bacterial corneal ulcer
include the use of cyanoacrylate glue, patch grafts and
Subconjunctival Route
therapeutic keratoplasty.
Subconjunctival antibiotics can produce high corneal
drug levels. The injections are painful and anxiety TISSUE ADHESIVES
provoking. We do not advocate the use of subconjuncti-
val antibiotics as these injections may result in Cyanoacrylate glue to treat small perforations (less than
subconjunctival hemorrhage, and if repeated, may lead 3 mm), progressive stromal keratolysis and thinned
to subconjunctival fibrosis. descemetoceles (Figs 7.11A and B). The tissue adhesive
is known to have anti-bacterial activity. However, since
it is toxic to the corneal endothelium , it should be used
SYSTEMIC THERAPY with caution. It restores the integrity of the cornea, till
Systemic antibiotics are started along with the topical the antimicrobial therapy can reduce the ulceration size.
antibiotics in cases of severe keratitis with scleral The edges and the bed of the site of the perforation is
melting, impending perforation, frank perforations dried completely before application of the glue following
which a therapeutic bandage contact lens is placed.
which have a propensity for intraocular spread and also
when the infection occurs in children due to H. influenza
and P. aeruginosa.25 PATCH GRAFTS
Patch grafts of upto 5 mm diameter may be used to
SIGNS OF HEALING debulk the cornea and to remove the clinically visible
margin of the infected area (Fig. 7.12). It is preferable to
The signs of healing of bacterial keratitis or response to encompass 1 mm of the normal cornea in the trephinated
therapy include the following: The signs and symptoms area.
decrease and visual acuity continues to improve. The
stromal infiltrates consolidate and the anterior chamber
THERAPEUTIC KERATOPLASTY
reaction decreases. Epithelialization is complete and
necrotic stroma is replaced by scar tissue laid down by If there are large areas of perforation or necrotic tissue,
fibroblasts. Vascularisation occurs and following a therapeutic keratoplasty is indicated. Pre-operatively,
complete healing the vessels regress completely but maximal antibiotic therapy to eradicate infection and to
sometimes leave “ghost vessels” which are visible reduce inflammation is recommended. It is preferable
through indirect illumination. to encompass one mm of the normal cornea in the
trephinated area (Figs 7.13A and B). Further, the corneal
button obtained should be sent for microbiological
SIGNS OF PROGRESSION/NON-RESPONSE
culture and histopahological examination. Post
Signs of progression include increase in the size of the operatively, systemic antibiotic therapy should also be
infiltrate, epithelial defect, height of hypopyon, corneal given along with the topical antimicrobial agents and
thinning and eventually perforation. topical corticosteroids.
74
Bacterial Keratitis 3
Figure 7.11A: Impending perforation (Courtesy: Medical Photographic Figure 7.11B: Glue applied (Courtesy: Medical Photographic Imaging
Imaging Centre, Royal Victorian Eye and Ear Hospital, Melbourne) Centre, Royal Victorian Eye and Ear Hospital, Melbourne)
Figures 7.13A and B: Perforated corneal ulcer (A) therapeutic keratoplasty done (B)
75
3 Types of Microbial Keratitis
References 14. Luchs JI, Cohen EJ, Rapuano CJ, Laibson PR. Ulcerative
keratitis in bullous keratopathy. Ophthalmology 1997;
1. Terrence PO Brien. Bacterial keratitis. In: Smolin G, Thoft 104:816-22.
RA, Foster C, Azar D, Dohlman C (Eds): The Cornea 15. Vajpayee RB, Gupta SK, Bareja U, Kishore K. Ocular
Scientific Foundations and Clinical Practice, 4th edition, atopy and mycotic keratitis. Ann Ophthalmol 1990;
Lippincott Williams and Wilkins Philadelphia 235-88. 22:369-72.
2. Wilson SE, Bannan RA, McDonald MB, Kaufman HE. 16. Mah-Sadorra JH, Yavuz SG, Najjar DM, Laibson PR,
Corneal trauma and infection caused by manipulation Rapuano CJ, Cohen EJ. Trends in contact lens-related
of the eyelashes after application of mascara. Cornea corneal ulcers. Cornea 2005;24:51-8.
1990;9:181-2. 17. Asbell P, Stenson S. Ulcerative keratitis. Survey of 30
3. Upadhyay MP, Rai NC, Brandt F, Shrestha RB. Corneal years’ laboratory experience. Arch Ophthalmol 1982;
ulcers in Nepal. Graefes Arch Clin Exp Ophthalmol 100:77-80.
1982;219:55-9.
18. Choudhuri KK, Sharma S, Garg P, Rao GN. Clinical and
4. Ormerod LD, Hertzmark E, Gomez DS, Stabiner RG, microbiological profile of Bacillus keratitis. Cornea 2000;
Schanzlin DJ, Smith RE. Epidemiology of microbial
19:301-6.
keratitis in southern California. A multivariate analysis.
19. Das S, Constantinou M, Daniell M, Taylor HR. Moraxella
Ophthalmology 1987;94:1322-33.
keratitis: predisposing factors and clinical review of 95
5. Hemady RK. Microbial keratitis in patients infected with
cases. Br J Ophthalmol 2006;90:1236-8.
the human immunodeficiency virus. Ophthalmology
20. Bharathi MJ, Ramakrishnan R, Vasu S, Meenakshi
1995;102:1026-30.
Chirayath A, Palaniappan R. Nocardia asteroides
6. Najjar DM, Aktan SG, Rapuano CJ, Laibson PR, Cohen
keratitis in South India. Indian J Med Microbiol 2003;
EJ. Contact lens-related corneal ulcers in compliant
21:31-6.
patients. Am J Ophthalmol 2004;137:170-2.
21. Brook I. Ocular infections due to anaerobic bacteria. Int
7. Poggio EC, Abelson M. Complications and symptoms
Ophthalmol 2001;24:269-77.
in disposable extended wear lenses compared with
22. Donnenfeld ED, Kim T, Holland EJ, Azar DT, Palmon
conventional soft daily wear and soft extended wear FR, Rubenstein JB, et al. American Society of Cataract
lenses. CLAO J 1993;19:31-9. and Refractive Surgery Cornea Clinical Committee.
8. Glynn RJ, Schein OD, Seddon JM, Poggio EC, ASCRS White Paper: Management of infectious keratitis
Goodfellow JR, Scardino VA, et al. The incidence of following laser in situ keratomileusis. J Cataract Refract
ulcerative keratitis among aphakic contact lens wearers Surg 2005;31:2008-11.
in New England. Arch Ophthalmol 1991;109:104-7. 23. Karp CL, Tuli SS, Yoo SH, Vroman DT, Alfonso EC,
9. Liesegang TJ, Forster RK. Spectrum of microbial keratitis Huang AH, et al. Infectious keratitis after LASIK.
in South Florida. Am J Ophthalmol 1980;90:38-47. Ophthalmology 2003;110:503-10.
10. Lam DS, Houang E, Fan DS, Lyon D, Seal D, Wong E. 24. Das S, Sheorey H, Taylor HR, Vajapyee RB. Association
Hong Kong Microbial Keratitis Study Group. Incidence between cultures and contact lens and corneal scraping
and risk factors for microbial keratitis in Hong Kong: in contact lens related microbial keratitis. Arch
comparison with Europe and North America. Eye Ophthalmol 2007;125:1182-5.
2002;16:608-18. 25. Huang AJW, Wichiensin P, Yang MC. Bacterial keratitis.
11. Leck AK, Thomas PA, Hagan M, Kaliamurthy J, Chapter 81. In: Krachmer JH, Mannis MH, Holland EJ
Ackuaku E, John M, et al. Aetiology of suppurative (Eds): Cornea: Fundamentals, Diagnosis and Manage-
corneal ulcers in Ghana and south India, and epidemio- ment, NY, 2005;1005-33.
logy of fungal keratitis. Br J Ophthalmol 2002;86:1211- 26. Ofloxacin monotherapy for the primary treatment of
5. microbial keratitis: a double-masked, randomized,
12. Bharathi MJ, Ramakrishnan R, Meenakshi R, controlled trial with conventional dual therapy. The
Padmavathy S, Shivakumar C, Srinivasan M. Microbial Ofloxacin Study Group. Ophthalmology 1997;104:1902-
keratitis in South India: influence of risk factors, climate, 9.
and geographical variation. Ophthalmic Epidemiol 2007; 27. Contstantinou M, Daniell M, Snibson GR, Vu HT, Taylor
14:61-9. HR. Clinical efficacy of moxifloxacin in the treatment of
13. Srinivasan M, Gonzales CA, George C, Cevallos V, bacterial keratitis randomized clinical trial.
Mascarenhas JM, Asokan B, et al. Epidemiology and Ophthalmology 2007;114:1622-9.
aetiological diagnosis of corneal ulceration in Madurai, 28. Sridhar MS, Sharma S, Garg P, Rao GN. Treatment and
south India. Br J Ophthalmol 1997;81:965-71. outcome of nocardia keratitis. Cornea 2001;20:458-62.
76
Fungal Keratitis 3
8 Fungal Keratitis
Fungal keratitis is one of the most difficult forms of more recent series, Fusarium oxysporum is more common
microbial keratitis for the ophthalmologist to diagnose organism (37%) as compared to Fusarium solani (24%).1,7
and treat successfully.1,2 It is more common in the Fungal keratitis is a major blinding eye disease in
developing countries as compared to the developed Asia. One of the studies from south India has reported
countries. Problems encountered in cases of fungal that 44 percent of all corneal ulcers were due to fungi,8
keratitis include establishing the correct clinical diag- whereas its prevalence has been reported to be 17 per-
nosis and obtaining confirmation of the fungal orga- cent in Nepal,9 36 percent in Bangladesh,10 37.6 percent
nisms on laboratory diagnosis. Problems related to in Ghana as opposed to 35 percent in Florida.11 In India,
therapy include suboptimal penetration of the anti- the most common isolated organism was Aspergillus sp.
fungal drugs, difficulty in preparation and availability (27 to 64%) followed by Fusarium sp. (6 to 32%) and
of the anti-fungal medications. Penicillium sp. (2 to 29%).3,8 Fungal keratitis is usually
The treatment of fungal keratitis is quite challenging. seen in the rural areas and warm climates.
Generally, prolonged and intensive topical, intracameral
and systemic anti-fungal therapy is required to eradicate AGE DISTRIBUTION
the fungal infections, and surgical intervention in the
Approximately, 65 percent of the patients are in the age
form of penetrating keratoplasty, vasculoplasty or group 21 to 50 years, although it has been reported in
cryotherapy may be undertaken when the medical extremes of age also.2
therapy fails.
SEX DISTRIBUTION
Epidemiology
In general, fungal keratitis does not have any gender
INCIDENCE predilection, although it has been reported to occur more
commonly in males than females in the ratio varying
The incidence of fungal keratitis is low (6 to 20%) as
from 1.5:1 to 4.5:1.2
compared to bacterial keratitis in various studies of
microbial keratitis especially in the developed countries.2 SEASONAL VARIATION
However, the incidence of fungal keratitis may be
A higher preponderance of these cases occurs during
greater in developing countries where it has been repor-
monsoons and early winter because of the high humidity
ted in almost half of the cases of microbial keratitis.3
found during these months.12 A higher incidence has
GEOGRAPHICAL DISTRIBUTION also been reported during harvest seasons, springs, and
early winter, probably because of a larger number of
Worldwide Aspergillus species is the most common vegetative injuries during these seasons.
fungus responsible for fungal keratitis.4 In northern
United States, Candida species and Aspergillus species is
Risk Factors
the most common cause of fungal keratitis whereas in
southern United States Fusarium species is the most Various risk factors, which have been incriminated in
common organism.4-6 Fusarium solani was the most the causation of fungal keratitis, may be ocular or related
frequently isolated organism earlier, whereas in the to the systemic status of the patient.
77
3 Types of Microbial Keratitis
TABLE 8.1
Risk factors for the development of fungal keratitis
OCULAR FACTORS
Trauma
Chronic corneal inflammation
Herpes simplex
Herpes zoster
Vernal allergic conjunctivitis
Ocular surface problems
Dry eye
Bullous keratopathy
Exposure Keratopathy
Contact lens wear
Drugs
Corticosteroids
Anesthetics
Corneal surgery
Penetrating Keratoplasty Figure 8.1: Fungal keratitis after vegetative trauma
Refractive surgery
SYSTEMIC FACTORS
tivitis and neurotrophic ulcers secondary to varicella
Diabetes mellitus
HIV positive patients
zoster or herpes simplex viruses ocular surface disorders,
Leprosy dry eye, Steven Johnson syndrome and bullous kerato-
pathy. It may also occur in cases of ocular atopy.17
Figure 8.2: Fungal keratitis after using traditional eye medicine Figure 8.3: Fungal keratitis after Keratoplasty
SYSTEMIC FACTORS
Some systemic diseases associated with immunosup-
pression may increase the risk for the development of
fungal keratitis. These include diseases such as diabetes
mellitus, patients with chronically debilitated diseases
who are hospitalized in the intensive care units, HIV
positive patients and cases of leprosy (Table 8.1).29, 30 Figure 8.4: Fungal keratitis (due to Alternaria) after LASIK surgery
79
3 Types of Microbial Keratitis
TABLE 8.2 TABLE 8.3
Fungi causing human keratitis Clinical features of fungal keratitis
I. FILAMENTOUS Symptoms
Figure 8.5: Raised margins and creamy exudates in fungal keratitis Figure 8.6: Irregular feathery margins and dry texture in fungal keratitis
Figure 8.7: Endothelial plaque with perforation Figure 8.8: Keratitis due to Curvularia species
often filled with soft, creamy and raised exudates (Fig. upon the etiological agent. 31 The most common
8.5). The fungal ulcers have characteristic findings, manifestations of culture-proven mycotic keratitis are
which include elevated areas, hyphate (branching) reported to be a gray or dirty-white surface, anterior-
ulcers, irregular feathery margins, a dry rough texture chamber cellular reaction, irregular feathery margins,
(Fig. 8.6), and satellite lesions. Feathery borders or elevated borders, dry rough texture, satellite lesions,
hyphate edges are seen in 70 percent of the patients and Descemet’s folds, hypopyon, ring infiltrate, endothelial
satellite lesions are seen in 10 percent of the patients.29,30 plaque, and keratitic precipitates .
Hypopyon is generally fixed and may be present in 45
to 66 percent of the cases.12 An immune ring, endothelial Dematiacious Fungi
plaque and a posterior corneal abscess may be present The appearance of macroscopic brown pigmentation in
rarely3 (Fig. 8.7). fungal keratitis may be due to the presence of a dematia-
ceous fungus (Curvularia lunata)32,33 (Fig. 8.8). The
SPECIFIC FEATURES
pigmentation has been related to the alteration in the
Each case of fungal keratitis may exhibit these basic melanin metabolism and when present indicates a more
features but may differ in the clinical course depending superficial infection, low virulence of the organism and 81
3 Types of Microbial Keratitis
Figure 8.9: Fungal keratitis due to Fusarium Figure 8.10: Fungal keratitis due to Candida
less inflammatory reaction. In some cases of dematia- rayon swab, or a sponge-type material. The organisms
ceous keratitis where absence of pigmentation is correla- may be deeper in the tissues and may not be accessible
ted with a masking by a more intense inflammatory to a more superficial scraping. Corneal scraping not only
reaction.33 The presence of an intact epithelium with a provides diagnostic clues but also may be therapeutic
deep stromal infiltrate may also be found in fungal as it also aids in the initial debridement and debulking
keratitis. of the organisms. Further, it also breaches the epithe-
lium, which may provide a barrier to the penetration of
Fusarium the anti-fungal agents.
Cultures should also be sent from topically applied
Fusarium solani keratitis has a more severe course so that medications, cosmetics, contact lenses and their storage
deep extension and perforation may occur in few weeks and cleaning solutions, wherever indicated. In case of
(Fig. 8.9). Aspergillus species on the other hand, causes a deeper lesions in fungal keratitis, a surface is passed
less severe and not so rapidly progressive keratitis, through the lesion and may be sent for culture
which is amenable to therapy (Fig. 8.6). examination.
Apart from this anterior chamber tap and corneal
Yeast
biopsy may be done especially in cases of deep keratitis
A “collar button” configuration is typical of the keratitis and endothelial plaques.
caused by yeasts, which is often associated with a small Laboratory diagnosis of fungal keratitis primarily
ulceration and an expanding discreet stromal infiltrate includes direct microscopy, fungal cultures and newer
(Fig. 8.10). The stromal keratitis caused by C. albicans diagnostic modalities such as polymerase chain reaction
and related fungi resembles bacterial keratitis, with an (PCR) and confocal microscopy.
overlying epithelial defect, a more discrete infiltrate, and
slow progression. Such ulcers frequently occur in eyes DIRECT MICROSCOPY
with preexisting corneal disease and in areas of exposure
typically at the junction of the superior two-thirds and Direct microscopy uses KOH wet mount preparation
inferior one-third of the cornea. and smears, which are stained by Gram and Giemsa
stain.
Laboratory Diagnosis KOH Wet Mount Preparation
Corneal ulcer scrapings from the ulcer edge and the base In our experience, 10 percent KOH wet mount is simple,
form the mainstay of the diagnosis of a case of fungal cheap, rapid and easy to interpret and is particularly
keratitis. Corneal scraping with a spatula or a surgical useful in tropical countries. KOH smear has a sensitivity
blade is preferred to the use a calcium alginate, dacron/ of 72.2 to 91 percent.34,35
82
Fungal Keratitis 3
Gram’s Stain
Gram stain is equally sensitive in detecting fungal
organisms. Gram stain identifies fungal species in 31.6
to 98 percent.34,35
Giemsa Stain
Giemsa stain identifies fungal elements in 27 to 85
percent of the cases.34,35
Grocott’s Methenamine-silver Stain Figure 8.11: Culture media showing growth of various fungi
anti-glaucoma medications in cases where the A new azole antifungal agent, Voriconazole, is
intraocular pressure is high on digital tonometry. The derived from Fluconazole and exhibits a wider spectrum
eye should be examined twice daily preferably under of activity against Candida, Aspergillus and Fusarium. It
the slit lamp. Once the infiltrate started resolving, the exerts its effect from inhibition of cytochrome P450-
frequency of topical natamycin is reduced to 2-hourly dependant 14 alpha sterol demethylase, an enzyme
until the completion of resolution (Figs 8.12A and B). involved in the ergosterol biosynthetic pathway.44 The
The natamycin should be continued for 2 weeks after minimal inhibitory concentration of voriconazole
the resolution of infection in all cases. (0.5 μg/ml) is less as compared to other imidazoles.45
If worsening of the keratitis is observed on topical Topical voriconazole 1% has to be prepared in
natamycin, topical amphotericin B 0.15 percent with or pharmacy as it is not commercially available and is given
without fluconazole 2 percent may be added as a second in recalcitrant fungal keratitis if there is not response to
agent. In cases of proven Candida sp., amphotericin B topical natamycin and amphotericine B therapy.
0.15 percent or fluconazole 0.3 percent is the first drugs Echinocandins have also been used for systemic
of choice. mycoses.47 These agents target the synthetic cell wall
Amphotericin B has to be prepared extempora- enzyme complex beta-1, 3-D glucon synthase. The
neously. It is available as a systemic preparation. In order antifungal spectrum is however limited to Candida and
to prepare the topical form, the compound has to be Aspergillus species.48
diluted with dextrose or distilled water to obtain a
concentration of 0.15 percent. It is not effective against
Response to Therapy
Fusarium species.
The efficacy of Econazole 1 percent against filamen- Since fungal keratitis responds slowly over a period of
tous fungi has been found to be equivalent to natamycin weeks, clinical signs of improvement should be noted
5 percent.41 Clotrimazole is available in 1 percent topical which include the following: diminution of pain,
drops and ointment form and has been used in the decrease in size in size of infiltrate, disappearance of
treatment of fungal keratitis.42 The imidazoles (ketoco- satellite lesions, rounding out of the feathery margins
nazole and miconazole) are used systemically for the of the ulcer and hyperplastic masses, or fibrous sheets.
treatment of keratomycosis because of their relatively
reduced systemic toxicity. Fluconazole is a fungistatic
Duration of Treatment
bitriazole which is used topically and systemically in
the treatment of Candida and Aspergillus keratitis. It does In general the duration of treatment is longer than that
not show encouraging results against Aspergillus species for cases of bacterial keratitis. The clinician must
and Fusarium species.43 determine the length of treatment for each individual
85
3 Types of Microbial Keratitis
based on clinical response. The duration of the treatment Topical Corticosteroids
for topical treatment has not been firmly established
Topical corticosteroid in the treatment of fungal keratitis
clinically or experimentally and varies from 30 to 39
should not be used.56 The topical corticosteroids worsen
days.16. Problems that can rise from prolonged treatment
the disease when given alone and adversely influence
are due to toxicity. The inflammatory response from this
the efficacy of natamycin, flucytosine and miconazole
toxicity can be confused with persistent infection. If
when given in combination.
toxicity is suspected and if adequate treatment has been
given for at least 4 to 6 weeks, treatment should be
Intracameral Therapy
discontinued and the patient carefully observed for
evidence of recurrence. Intracameral amphotericin B may be a useful modality
in the treatment of severe keratomycosis not responding
Drug Interactions to topical natamycin.53 It ensures adequate drug delivery
into the anterior chamber and may be especially useful
Several topical anti-fungal medications act synergi-
to avoid surgical intervention in the acute stage of the
stically against a particular fungal organism.49,50 In
disease (Figs 8.13A and B).
clinical series more than one concurrent topical anti-
The procedure should be performed under strict
fungal has been needed 5 percent of the time.16 Synergi-
aseptic conditions. If the infection involves the anterior
stic drugs include a combination of amphotericin B and
capsule of the lens, care should be taken to avoid injury
flucytosine, (for Candida keratitis) and a combination of
to the lens. Patients with deep keratomycosis unrespon-
natamycin and ketoconazole (for Aspergillus keratitis).
sive to conventional medical treatment are candidates
Likewise, experimental models have demonstrated the
for intracameral injections of 5 μg to 7.5 μg amphotericin
potential antagonism between anti-fungals such as
amphotericin B and the imidazoles. B in 0.1 mL 5 percent dextrose.53-55 Injections can be
repeated in case of inadequate response.
Drug Resistance
Intrastromal Therapy
Resistance to anti-fungal agents is rare and generally
occurs when they are used for systemic mycoses. A recent modality advocated for non healing fungal
Competition for volume in the pre corneal tear film and corneal ulcers is the use of intracorneal Amphotericin B
washout may be of more concern when using two injection in 5-7.5 μg dosage, given in the vicinity of the
topical anti-fungals. stromal site of fungal growth.56 This would raise the local
concentration of the antifungal agent enough to be
Systemic Antifungal Agents effective in the eradication of the deep corneal infection.
Treatment with a systemic anti-fungal agent is recom- This approach proves effective, with total elimination
mended in cases of very large ulcers, severe deep of the infection (Figs 8.14A and B). The intrastromal
keratitis, scleritis and endophthalmitis. Systemic anti- injection can be repeated after a period of 48 to 72 hours.
fungals also may be used as prophylactic treatment after Although further experience is required, intrastromal
penetrating keratoplasty for fungal keratitis. corneal injections of Amphotericin B may offer a good
The drugs, which have been used systemically, choice for recalcitrant cases of fungal keratitis.
include ketoconazole (oral), miconazole (intravenous)51
itraconazole (orally 200 mg/day) and fluconazole (orally SURGICAL THERAPY
200 mg/day).52 More recently oval voriconazole 200 mg
Debridement
bd has shown good results in recalcitrant fungal
keratitis.46 Daily debridement with a spatula or blade is the simplest
The most frequently used oral anti-fungal is form of surgical intervention and is usually performed
ketoconazole, which is given in the dose of 600 mg per at the slit lamp under topical anesthesia. Debridement
day. It is mandatory to assess liver function tests every is performed every 24 to 48 hours and works by
2 weeks after starting ketoconazole. Systemic therapy is debulking organisms and necrotic material and by
given for a period of 6 to 8 weeks. enhancing the penetration of the topical antifungal.
86
Fungal Keratitis 3
Figures 8.15A and B: Non-resolving fungal keratitis (Alternaria) on maximal anti-fungal medications (A) in which therapeutic keratoplasty (B)
was done
bites should be used to avoid cheese wiring of the suture infection. Postoperatively, systemic ketoconazole or
if the edge of the recipient becomes involved with a fluconazole may be used in addition to topical anti-
persistent organism. Irrigation of the anterior segment fungal agents. If the pathology laboratory reports that
should be performed to eliminate any organisms. As no organisms were seen at the edge of the corneal
far as possible the lens should be left untouched to specimen, anti-fungals could be stopped after 2 weeks
prevent the spread of infection in the posterior segment. and the patient followed carefully for recurrences. A
However, if affected the intraocular structures including report from the microbiology laboratory regarding
the iris, lens, and vitreous may be excised. The specimens growth of organisms from the corneal or intraocular
removed should be submitted to both the mcirobiology tissues should indicate the need for more prolonged
and pathology laboratories for culture and fixed section topical and systemic anti-fungal therapy, possibly for 6
examination. If involvement of intraocular structures or to 8 weeks.
endophthalmitis is suspected, an antifungal agent At the time of keratoplasty, if the infection has been
should be injected which includes amphotericin B (5 μg/ controlled clinically, topical corticosteroids may be used.
0.1 ml) or miconazole (25 μg/0.1 ml). If it is not known whether the infection is controlled,
It is mandatory to submit surgical specimens from corticosteroids should be avoided during the early
cases of microbial ketatitis for histopathologic exami- postoperative period. 13 Although the main goal of
nation especially if the microbiologic diagnosis is not penetrating keratoplasty in fungal keratitis is to
known. Histopathologic examination of corneal buttons eliminate the infecting organism, a secondary goal is
can reveal the presence of fungal elements in 75 percent the maintenance of a clear corneal transplant for optical
patients.57 It has been shown that 59 percent of corneas reasons (Figs 8.15A and B). Even if graft failure or
infected by fungi are still culture-positive at the time of rejection occurs, the patient can undergo a second optical
keratoplasty, with 90 percent of eyes exhibiting hyphal keratoplasty once the rejection is controlled. The effects
elements on pathologic examination.58,59 Fungal hyphae of other immunosuppressive medications such as
usually lie parallel to the corneal surface and lamellae. cyclosporin A and its effect on fungal growth has not
A vertical or perpendicular arrangement of fungal been well documented clinically.
hyphae in the corneal stroma has been associated with
increased virulence and in patients on topical cortico-
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North India. Cornea 2005;24:8-15. review at a referral eye care centre in South India. Cornea
14. Kremer I, Goldenfeld M, Shmueli D. Fungal keratitis 2002;21:555-9.
associated with contact lens wear after penetrating 32. Garg P, Vemuganti GK, Chatterjee S, Gopinathan U, Rao
keratoplasty. Ann Ophthalmol 1991;23:342-5. GN. Pigmented plaque presentation of demataticious
15. Cruz OA, Sabir SM, Capo H, Alfonso EC. Microbial fungal keratitis. A clinico-pathologic correlation. Cornea
keratitis in childhood, Ophthalmology 1993;100:192-6. 2004;23:571-6.
16. Wilson LA, Ajello L. Agents of oculomycosis: fungal 33. Berger ST, Katsev DA, Mondino BJ, Pettit TH. Macro-
infections of eye. In: Collier L, Balows A, Sussman (Eds): scopic pigmentation in dematiaceous fungal keratitis.
Topley and Wilson’s Microbiology and microbial Cornea 1991;10:272-6.
infections, 9th edition, Medical Mycology Arnold: 34. Vajpayee RB, Angra SK, Sandramouli S, Honavar SG,
London, 1998;4:525-67. Chhabra VK. Laboratory diagnosis of keratomycosis:
17. Vajpayee RB, Gupta SK, Bareja U, Kishore K. Ocular comparative evaluation of direct microscopy and culture
atopy and mycotic keratitis. Ann Ophthalmol 1990;22: results. Ann Ophthalmol 1993;25:68-71.
369-72. 35. Garg P, Gopinathan U, Choudhary K, et al. Keratomyco-
18. Wilhelmus KR, et al. Fungal keratitis in contact lens sis: clinical and microbiologic experience with
wearers. Am J Ophthalmol 1998;106:708-14. dematiaceous fungi. Ophthalmology 2000;107:574-80.
89
3 Types of Microbial Keratitis
36. Srinivasan M. Fungal keratitis. Curr Opin Ophthalmol keratitis caused by Candida albicans in a rabbit model.
2004;15:321-7. Antimicrob Agents Chemother 2005;49:1359-63.
37. Forster RK, Wirta MC, Solis M, Rebell G. Methenamine- 49. Stern GA, Okumoto M, Smolin G. Combined ampho-
silver-stained corneal scrapings in keratomycosis. Am J tericin B and rifampin treatment of experimental
Ophthalmol 1976;82:261-5. Candida albicans keratitis. Arch Ophthalmo 1979;l 97:
38. Gaudio PA, Gopinathan U, Sangwan V, et al. Polyme- 721-2.
rase chain reaction based detection of fungi in infected 50. Beggs WH. Mechanisms of synergistic interactions
corneas. Br J Ophthalmol 2002;86:755-60. between amphotericin B and flucytosin. J Antimicrob
39. Florakis GJ, Moazami G, Schubert H, et al. Scanning slit Chemother 1986;17:402-4.
confocal microscopy of fungal keratitis. Arch Ophthal- 51. Fitzsimons R, Peters AL. Miconazole and ketoconazole
mol 1997;115:1461-3. as a satisfactory first-line treatment for keratomycosis.
Am J Ophthalmol 1986;101:605-8.
40. Avunduk AM, Beuerman RW, Varnell ED, et al.
52. Rao SK, Madhavan HN, Rao G, et al. Fluconazole in
Confocal microscopy of Aspergillus fumigatus keratitis.
filamentary fungal keratitis. Cornea 1997;16:700.
Br J Ophthalmol 2003;87:409-10.
53. Sridhar MS, Sharma S, Gopinathan U, Rao GN. Anterior
41. Prajna NV, John RK, Nirmalan PK, et al. A randomized
chamber tap: diagnostic and therapeutic indications in
clinical trial comparing 2% econazole and 5% natamycin
the management of ocular infections. Cornea 2002;
for the treatment of fungal keratitis. Br J Ophthalmol 21:718-22.
2003;87:1235-7. 54. Kuriakose T, Kothari M, Paul P, Jacob P, Thomas R.
42. Mselle J. Use of topical clotrimazole in the treatment of Intracameral amphotericin B injection in the manage-
human keratomycosis. Ophthalmologica 2001;215:357- ment of deep keratomycosis. Cornea 2002;21:653-6.
60. 55. Kaushik R, Ram J, Brar GS, Jain AK, Chakraborti A,
43. Rao SK, Madhavan HN, Rao G, et al. Fluconazole in Gupta A. Intracameral amphotericin B: initial experience
filamentary fungal keratitis. Cornea 1997;16:700. in severe keratomycosis. Cornea 2001;20:715-9.
44. Jeu L, Piacenti FJ, Lyakhovetskiy, et al. Fung HB; 56. Garcia-Valenzuela E, Song CD. Intracorneal injection of
Voriconazole. Clin Ther 2003;25:1321-81. amphotericin B for recurrent fungal keratitis and
45. Shah KB, Wu TG, Wilhelmus KR, et al. Activity of endophthalmitis. Arch Ophthalmol 2005;123:1721-3.
voriconazole against corneal isolates of Scedosporium 57. Portnoy SL, Insler MS, Kaufman HE. Surgical
apiospermum. Cornea 2003;22:33-6. management of corneal ulceration and perforation. Surv
46. Jhanji V, Sharma N, Mannan R, Titiyal JS, Vajpayee RB. Ophthalmol 1989;34:47-58.
Management of tunnel fungal infection with 58. Cristol SM, Alfonso EC, Guildford JH, Roussel TJ,
voriconazole. J Cataract Refract Surg 2007;33:915-7. Culbertson WW. Results of large penetrating kerato-
47. Denning DW. Echinocandin anti-fungal drugs. Lancet plasty in microbial keratitis. Cornea 1996;15:571-6.
2003;4:362;1142-51. 59. Killingsworth DW, Stern GA, Driebe WT, Knapp A,
48. Goldblum D, Frueh BE, Sarra GM, Katsoulis K, Zimmerli Dragon DM. Results of therapeutic penetrating
S. Topical Caspofungin for the treatment of fungal keratoplasty. Ophthalmology 1993;100:534-41.
90
Viral Keratitis 3
9 Viral Keratitis
Viral keratitis is the commonest cause of keratitis in the HSV keratitis patients are also more prone to
developed world. The virus can infect individual layers infection with HIV virus and such patients are associated
of the cornea or in more severe form it may involve all with increased rates of recurrences.1
the layers of cornea. The various viral infections that Over 90 percent of the patients maintain a visual
can affect the cornea can be broadly grouped under the acuity of 20/20 and about 20-25 percent develop stromal
following categories herpes simplex keratitis, varicella keratitis. In half of the patients there may be history of
zoster induced keratitis and the adenoviral keratitis. orofacial lesions. Ocular HSV is at least 6 times more
prevalent after keratoplasty.
Herpes Simplex Virus
Pathophysiology
The herpes simplex virus is a DNA virus, which belongs
to the Herpesviridae family of viruses. The virus specific INFECTION
antigens differentiate HSV into two types that is the
herpes simplex virus type-1(HSV-1) and the herpes Herpes simplex virus is a large and complex enveloped
simplex virus type-2. virus measuring 150-200 nm. It has a double stranded
DNA core, which is surrounded by a protein capsid that
is made up of 162 subunits called capsomer. The capsid
Epidemiology
is surrounded by the tegument, membrane of the
Herpes simplex keratitis is the most common infective infected cell that has been altered by virus-induced
cause of blindness in many developed countries. The proteins.
ocular disease affecting the cornea may be classified into Humans are the only natural reservoirs of herpes.
primary or recurrent. The sources of infection are by direct contact with
The incidence of all episodes of of herpes simplex infected lesions, by salivary droplets or fomites from
keratitis was repaired as 20.7 cases/100,000 population children and adults with active disease and also of
and the prevalence of ocular HSV disease in the asymptomatic virus shedding carriers. A patient can also
community was calculated at 149 per 100,000 population acquire the infection iatrogenically by physician’s
in one study. The incidence of new episodes of HSV unwashed hands or by contaminated Schiotz or
was reported to be 8.4/100,000/year.1 applanation tonometer head.
The disease may occur bilaterally in 11.9 percent It is estimated that > 90 percent of population have
patients and is more common in atopes and immuno- had a type 1 HSV infection during their lifetime, usually
suppressed.2 during childhood or early adolescence.
The recurrences are generally caused by the same The most common type of herpes simplex virus is
strain of virus as the initial infection. Recurrences gene- HSV-1which causes cold sore or fever blister in the
rally occur in 20 percent patients by 2 years, 40 percent mouth, face and upper body and may affect the eye.
by 5 years and 67 percent by 7 years.1 Generally the HSV-2 causes genital herpes, a sexually transmitted
recurrence of the same type of ocular disease occurs that disease. Ocular herpes is caused primarily by HSV-1 and
is the patients with epithelial keratitis have an epithelial occasionally by HSV type-2 virus.
recurrence and that of stromal keratitis have stromal Primary HSV-1 infection occurs usually in the muco-
recurrence.2 cutaneous distribution of the trigeminal nerve. After the
91
3 Types of Microbial Keratitis
primary infection, the virus spreads from the infected devastating disease depend on the stage or trimester
epithelial cells to nearby sensory nerve endings and is when HSV is contracted. Of all the neonatal HSV, 4
transported along the nerve axon to the cell body located percent is acquired during intrauterine life, 86 percent
in the trigeminal ganglion. The virus genome enters the infection occurs at the time of birth and remaining 10
nucleus of a neuron, where it persists indefinitely in a percent occurs in the postnatal period.3 Congenital HSV
latent state. The primary infection of any of the 3 infection is characterized by the triad of skin vesicles,
branches (i.e. ophthalmic, maxillary, mandibular) of eye disease and microencephaly.
cranial nerve V can lead to latent infection of nerve cells
in the trigeminal ganglion. Inter-neuronal spread of HSV NEONATAL HSV KERATITIS
within the ganglion causes ocular disease even in cases
which have not had primary ocular HSV infection. Neonatal HSV infection usually presents as a bilateral
Infection is spread by direct contact of infectious disease at 2 days to 2 weeks of age.3 HSV keratitis in a
secretions with epidermis or mucous membrane. HSV- neonate is invariably associated with conjunctivitis.
2 may rarely infect the eye by means of direct contact Keratitis may manifest as diffuse microdendritis,
with infectious genital secretions and occasionally is serpiginous epithelial defects or a punctate keratitis. The
transmitted to neonates as they pass through the birth diagnosis of ocular HSV must be considered in any
canal of a mother with genital HSV-2 infection.3 infant with nonpurulent conjunctivitis or keratitis. Treat-
Recurrent HSV infection traditionally has been ment of neonatal ocular herpetic disease comprises of
thought of as reactivation of virus in the sensory gang- topical antivirals (1% Trifluridine ophthalmic solution
lion, which migrates down the nerve axon to produce a or 3% acyclovir ophthalmic ointment) in addition to
lytic infection in ocular tissue.4 The virus may be present systemic Acyclovir (2 g/day IV every 8 hourly for 14
in a latent phase within the corneal tissue, acting as a days).6
potential source of recurrent disease and also responsible
for the donor-derived HSV in transplanted corneas.5 PRIMARY OCULAR HERPES
The triggering agents for reactivation of an acute
attack of herpes includes fever, hormonal changes, Primary ocular HSV is an acute HSV infection of the
ultraviolet exposure, psychological stress, ocular trauma, non-immune host. It occurs after 6 months of age
immunocompromised and trigeminal nerve manipula- following decline in maternal antibodies. Most primary
tion. The excimer laser ablation may also trigger a infections occur between 1-5 years of age and are
reactivation of herpetic keratitis. subclinical. Only 6 percent of those infected actually
develop clinical manifestations, which typically affect
IMMUNE MECHANISMS the perioral area rather than the eye.6 Clinically overt
The cell mediated and the humoral immunity are disease begins 3-9 days after exposure and usually
activated which limit the spread of infection and are causes more symptoms than the recurrent disease. It
also responsible for the sequel to the pathologic process. manifests as intense occasionally hemorrhagic, vesi-
Stromal inflammation and endothelitis occur as a cular, periocular dermatitis or blepharitis, follicular
consequence of replicating virus or altered antigenicity conjunctivitis that may be pseudomembranous or
of the stromal cells causing immune mediated geographic ulceration or both, corneal ulceration, iritis
destruction. Secretion of glycoproteins is responsible for and non-suppurative periocular lymphadenopathy.
stromal inflammation which occurs in a greater quantity The primary infection is self-limited with complete
in stromal inflammation as compared to cases in which recovery and disappearance of virus from initial site of
epithelial involvement occurs alone. infection in immunocompetent individuals. The site of
primary infection determines the pathway of the viral
Clinical Features spread and the site of viral latency. The most common
site of primary HSV infection in the facial area is that
CONGENITAL OCULAR HERPES
served by maxillary division of trigeminal nerve. This
HSV-1 and HSV-2 can be acquired in utero, by trans- results in latency in the trigeminal ganglion. Herpes
placental or ascending infection, by exposure to genital simplex virus can also establish latent infection in other
lesions during delivery, or postnatally from relatives or neurons of the sensory and autonomic ganglia that
attendants.3 The clinical manifestations of this rare, but supply the affected area. It occurs within 3 weeks of
92
Viral Keratitis 3
primary infection whether clinically overt or asympto- TABLE 9.1
matic. This latency is life long and the virus can be Pathogenesis of herpetic keratitis
reactivated by number of trigger mechanisms. The Clinical presentation Pathogenesis
trigeminal ganglion is the most common site for HSV-1
latency. The superior cervical, vagus, sacral and Epithelial involvement
autonomic ganglia are other sites of latent virus. Apart Infectious epithelial keratitis Live virus in epithelium
from the sensory and autonomic ganglia, there are Immune response in stroma
evidences which suggest that cornea can also serve as a Neurotrophic keratopathy Impaired corneal nerves
Damaged basement membrane
non-neuronal site of latency and as a source of future of epithelium
infectious virus during reactivation.5 Drug toxicity
Stromal involvement
RECURRENT OCULAR HERPES
Immune stromal keratitis Antigen antibody complex
The recurrence rate of ocular herpes has been reviewed mediated
by Liesegang and is reported to be 36 percent at 5 years Necrotizing stromal keratitis Direct viral invasion
and 63 percent at 20 years after primary episode.1 After Endothelium involvement
a second episode, 70-80 percent of patients have Endothelitis Immune reaction involving
recurrence with in 10 years.1 Recurrent herpes simplex endothelium
can present as blepharitis, conjunctivitis, epithelial
keratitis, stromal keratitis, uveitis, trabeculitis and even Dendritic Keratitis
chorioretinitis.6 The plaques of swollen infected epithelial cells enlarge
Although the mechanism of viral reactivation is not to form branching dendrites. The epithelium in the
completely understood a variety of trigger factors are center sloughs to form dendritic ulcers. Dendritic ulcers
recognized which include fever, ultraviolet light, cold may be single or multiple (Fig. 9.1) and have linear
wind systemic illness, surgery, menstruation, minor local branches with terminal bulbs (Fig. 9.2). The edges of
trauma, immunosuppression from either endogenous the ulcers are raised and contain replicating virus. These
disease or iatrogenic drug management of disease and ulcers are usually central or paracentral. The area of
laser photokeratectomy.7 dendritic ulceration is typically anesthetic whereas the
surrounding cornea may retain normal sensation. These
MANIFESTATIONS OF KERATITIS ulcers stain with fluorescein along the length of the
HSV keratitis is predominantly a unilateral disease and lesion whereas the rose bengal stains the devitalized cells
bilateral herpetic keratitis occurs only in 3 percent of and is typically taken up by the swollen epithelial cells
patients with ocular HSV infection.7 Bilateral disease is at the ulcers border.
more common in cases of atopy and in younger patients.
HSV keratitis can manifest as one of the following
(Table 9.1):
• Infectious epithelial keratitis
• Neurotrophic epithelial keratitis
• Herpetic stromal keratitis
• Endothelitis.
Punctate Keratitis
Figure 9.1: Dendritic keratitis due to herpes simplex virus (Courtesy:
These lesions begin as punctate or stellate whitish Medical Photographic Imaging Centre. Royal Victorian Eye and Ear
opaque plaques of swollen epithelial cells. Hospital, Melbourne)
93
3 Types of Microbial Keratitis
Figure 9.2: Linear dendrite stained with fluorescein stain Figure 9.3: Amoeboid ulcer stained with rose bengal dye
Figure 9.4: Herpetic marginal keratitis Figure 9.5: Diffuse herpetic limbitis
Figure 9.9: Double immune ring of Wessely Figure 9.10: Sectoral stromal neovascularization
Diffuse Endothelitis
It is a rare presentation of ocular herpes simplex keratitis.
Patients characteristically have scattered KPs over the
entire cornea with overlying diffuse stromal edema and
associated iritis (Fig. 9.15). It is an immune reaction
targeted against the corneal endothelium. Aggressive
treatment with topical corticosteroids lead to complete
resolution of inflammation and edema.
Figure 9.13: Herpetic endothelitis (diffuse)
Linear Endothelitis
reaction) to herpes simplex viral antigen mediated by T It clinically appears as a line of KPs on corneal
lymphocytes. Endothelitis may present as disciform endothelium that progresses centrally from the limbus.
keratitis, diffuse endothelitis and linear endothelitis It is accompanied by peripheral stromal and epithelial
depending on the location of the KPs and the presence edema between the KPs and limbus.
of overlying edema (Fig. 9.13).
HERPES SIMPLEX TRABECULITIS
Disciform Keratitis
Herpetic peripheral corneal involvement may extend to
The patient usually presents with symptoms of watering, trabecular meshwork and cause trabeculitis and
photophobia, discomfort and blurred vision. It is the secondary glaucoma.
most common form of endothelitis in which disk shaped
area of stromal edema overlying few KPs occurs with-
HERPES SIMPLEX IRIDOCYCLITIS
out any corneal infiltration or vascularization. The area
of involvement may be diffuse and central or eccentric. Herpes simplex keratitis may present as recurrent non-
Disciform keratitis can occur without previous occur- granulomatous anterior uveitis. The patient complains
rence of herpetic corneal epithelial disease. Disciform of pain, photophobia and ciliary flush. Iritis in a patient
Vidarabine (Ara-A) Topical 3% ointment Five times a day Inhibits viral DNA polymerase
Trifluridine Topical 1% solution 2 hourly while awake Inhibits viral thymidylate synthase
Acyclovir Topical, Oral 3% ointment Five times a day Activated by viral thymidine kinase
200,400 mg tablets to inhibit DNA polymerase
Valacyclovir Oral 1000 mg Three times a day Activated by viral thymidine kinase
to inhibit DNA polymerase
Dendritic keratitis Infection by live herpes 3% topical acyclovir ointment None Heals without significant
simplex virus (5 times/day) or 1% trifluridine corneal scarring
solution (2 hourly)
Epithelial debridement ±
Amoeboid/ Infection by live 3% topical acyclovir ointment None Heals without significant
geographical ulcer herpes simplex virus (5 times/day) or 1% trifluridine corneal scarring
solution (2 hourly)
Epithelial debridement ±
May add topical antibiotic
drops prophylactically
Neurotrophic keratitis Noninfectious, Lubricants, BCL, patching, Collagenase Low dose topical
↓ corneal sensitivity tarsorrhaphy, amniotic inhibitors like corticosteroids and
membrane tetracycline topical antiviral if
stromal edema and
inflammation present
Immune mediated Immune reaction to Topical antivirals and None Very gradual tapering of
stromal keratitis herpes virus antigen topical corticosteroids topical therapy
Necrotizing stromal Active viral replication Topical corticosteroids Gradual tapering off
keratitis in corneal stroma (1% prednisolone acetate topical therapy
suspension, 4 times a day)
with 3% topical acyclovir
ointment (5 times/day) or
1% Trifluridine solution
(9 times/day) ± mydriatic –
cycloplegic drug (2%
Homatropine hydrobromide
or 1% cyclopentolate
hydrochloride)
Endothelitis/ Immune reaction to Topical corticosteroids (1% Gradual tapering off
Disciform keratitis viral antigen Prednisolone acetate ophthalmic topical therapy
suspension, 4 times a day) with
3% topical acyclovir ointment
(5 times/day) or 1% trifluridine
± mydriatic – cycloplegic drug
(2% homatropine hydrobromide
or 1% cyclopentolate hydrochloride)
solution (2 hourly)
Figures 9.16A to C: (A) Neurotrophic keratitis (B) Amniotic membrane transplantation (C) Healing of neurotrophic keratitis
Figure 9.17: Herpetic dendrite in a graft stained with florescein dye Figure 9.18: Geographic ulcer in a graft stained with Rose Bengal
(Courtesy: Medical Photographic Imaging Centre, Royal Victorian Eye dye (Courtesy: Medical Photographic Imaging Centre, Royal Victorian
and Ear Hospital, Melbourne) Eye and Ear Hospital, Melbourne)
PREVENTION
103
3 Types of Microbial Keratitis
TABLE 9.6 Ophthalmic varicella zoster infection is accompanied
Differentiation between dendrites of herpes simplex by keratouveitis that varies in severity according to
and zoster immune status of the patient. The manifestations of
Feature HSV VZV ophthalmic varicella zoster infection are benign in
children as compared to adults who have severe and
Overall Fine, lacy Thick ropy
sometimes blinding disease. Corneal complications in
Epithelium Linear defect with Elevated, painted-on ophthalmic zoster are associated with skin eruption in
bared stroma, appearance
areas supplied by branches of the nasociliary nerve.
surrounded by
edematous Differences between dendrites of HSV and HZV
epithelial cells infections (Table 9.6).
Staining Base stains with Minimal fluororescein
fluorescein staining TREATMENT OF OPHTHALMIC VARICELLA ZOSTER
Diseased border
epithelial cells stain • Intravenous and oral acyclovir has been used
with rose bengal successfully for treatment of herpes zoster ophthal-
Terminal bulbs Frequent None micus. This treatment regime is particularly
important in immunocompromised patients. The
appropriate timing of the therapy is vital. Therapy
After acute infection the VZV travels down the
needs to be started within 72 hours after appearance
peripheral axons to cells in the dorsal root ganglion
of the rash. The use of oral acyclovir in a dosage of
where it remains in the latent phase.
800 mg five times daily for 10-14 days has been
The herpes zoster occurs due to reactivation of the
recommended. Although varicella zoster virus
VZV within the dorsal root ganglion and virions travel
keratopathy is an uncommon indication for
to skin or mucous membrane or skin along the axonal
penetrating keratoplasty, effective visual rehabili-
transport.
tation can be achieved in these patients. Careful
postoperative management, frequent lubrication, and
EPIDEMIOLOGY lateral tarsorrhaphies to protect the corneal surface
The annual incidence of herpes zoster is 1.5/1000 to 3.0/ are major factors in the successful outcome of these
1000 cases. The incidence is more in patients more than cases.25
75 years of age. There is no predilection for gender, race,
ADENOVIRAL INFECTIONS
or seasonal variation.
Herpes zoster has a greater preponderance in cases It is causative agent for epidemic keratoconjunctivitis
with altered cell mediated immunity, those taking which is predominantly caused by the serotypes 8, 19,
immunosuppressive agents, organ transplant recipients, and 37. The infection is highly contagious, with
syphilis, tuberculosis, and those having HIV. It is also approximately 10 percent transmission in household
precipitated by physical or emotional stress. contacts via hands and fomites. Transmission has also
The varicella zoster keratitis occurs in two forms: been associated with instrumentation, industrial trauma
• Primary (varicella) [shipyard workers (i.e. shipyard eye)], contaminated
• Recurrent (herpes zoster). ophthalmic solutions, and the hands of health care
The ocular manifestations are uncommon in varicella workers. Corneal trauma facilitates infection. After an
but common in ophthalmic zoster. The various ocular 8 days incubation period, an insidious onset of unilateral
manifestations in ophthalmic VZV include: red eye occurs, which spreads to involve both eyes.
• Eye lesions which are manifested as pocks on lids Patients have photophobia, tearing, and pain (indicating
and lid margins. corneal involvement). Children may have fever and
• Keratitis occurs rarely in cases of VZV. lymphadenopathy. Malaise and headache are reported.
• Epithelial keratitis with or without pseudodendrites Inflammation may persist for weeks, and residual
occurs more rarely. scarring and visual impairment may occur. The
• Disciform keratitis with uveitis of varying duration associated findings in epidemic keratoconjunctivitis are:
can occur. • Severe follicular keratoconjunctivitis.
104
Viral Keratitis 3
Figure 9.20: Subepithelial infiltration in adenoviral keratoconjuncti- Figure 9.21: Healed adenoviral keratoconjunctivitis (nummular
vitis opacities)
• Palpebral edema. naphazoline) and steroids (vexol, flarex, pred forte) two
• Preauricular lymphadenopathy is not common but to four times daily. Recently, cidofovir an antiviral drug
is a pathognomonic finding with adenovirus used intravenously to treat cytomegalovirus retinitis
infection. appears to be effective in adenoviral keratoconjunctivitis.
• Hemorrhagic conjunctivitis may develop. The topical form creates a faulty viral DNA structure.
In stage I corneal epithelial vesicle like elevations Twice daily instillation is recommended.27
are present which are 25 to 30 microns and barely
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for herpes simplex keratitis. Arch Ophthalmol 1999;117:
445-9. keratopathy. Cornea 2000;19:135-9.
17. Barney NP, Foster CS. A prospective randomized trial 26. Koidl C, Bozic M, Mossbock G, Muhlbauer G, Berg J,
of oral acyclovir after penetrating keratoplasty for herpes Stocher M, et al. Rapid diagnosis of adenoviral kerato-
simplex keratitis. Cornea 1994;13:232-6. conjunctivitis by a fully automated molecular assay.
18. Uchoa UB, Rezende RA, Carrasco MA, Rapuano CJ, Ophthalmology 2005;112:1521-8.
Laibson PR, Cohen EJ. Long-term acyclovir use to 27. Hillenkamp J, Reinhard T, Ross RS, Bohringer D,
prevent recurrent ocular herpes simplex virus infection. Cartsburg O, Roggendorf M, et al. Topical treatment of
Arch Ophthalmol 2003;121:1702-4. acute adenoviral keratoconjunctivitis with 0.2% cidofovir
19. Wilhelmus KR, et al. Herpetic eye disease study, a and 1% cyclosporine: A controlled clinical pilot study.
controlled trial of topical corticosteroids for herpes Arch Ophthalmol 2001;119:1487-91.
106
Protozoal Keratitis 3
10 Protozoal Keratitis
Acanthamoeba Keratitis
It was first described in the early 1970s, and a dramatic
increase in cases of Acanthamoeba keratitis has been
observed in the early to mid-1980s.
ETIOLOGY
The pathogenic species of Acanthamoeba include
Acanthamoeba castellanii, Acanthamoeba polyphaga, Figure 10.1: Acanthamoeba cysts (Blankophore stain) (Courtesy:
Acanthamoeba culbertsoni, Acanthamoeba palestinensis, Dr H Sheorey, Dept. of Microbiology, St Vincent Hospital, Melbourne)
Acanthamoeba astronyxis, Acanthamoeba hatchetti,
Acanthamoeba rhysodes, Acanthamoeba divionesis, The disease is generally unilateral; however bilateral
Acanthamoeba quna, Acanthamoeba lugdunensis, and cases have also been reported. There is no sex
Acanthamoeba griffini. predilection.
The life cycle of Acanthamoeba consists of 2 stages:
an active stage that is the trophozoite (which is 14-40
RISK FACTORS
microns in diameter) stage and a cyst stage (which has
a double-layered wall with a diameter of 12-16 microns) There are various risk factors which predispose to
which is the dormant phase (Fig. 10.1). Acanthamoeba keratitis (Table 10.1).3-5 The majority of the
cases occur in contact lens wearers.5 However, in the
EPIDEMIOLOGY Indian subcontinent it has also been reported in non-
contact lens wearers.6 Apart from this there may be other
The incidence of Acanthamoeba keratitis varies depending risk factors which are associated apart from this in the
on the geographic region and the type of contact lens
use. In the UK, Europe and Hong Kong, the rate of
incidence of Acanthamoeba keratitis was estimated to be Table 10.1
0.33 per 10 000 in hydrogel contact lens wearers per Risk factors for Acanthamoeba keratitis
year.1 In the recent years an increased incidence of new • Contact lens wearers
cases of Acanthamoeba has been noted from USA.2 The • Contaminated water/solutions especially home made
incidence of Acanthamoeba keratitis associated with use solutions
of rigid contact lenses is 9.5 times lower than for soft • Corneal trauma
lens wearers.1 • Orthokeratology
107
3 Types of Microbial Keratitis
Indian subcontinent including patients who have Table 10.2
undergone orthokeratology. Clinical features of acanthamoeba keratitis
Symptoms—waxing and waning course
Contact Lens Wear • Severe pain/foreign body sensation
Classically, it occurs in immunocompetent, healthy, • Redness
• Watering, mucus discharge
young individuals and the most important factor in these
• Decreased vision
cases is contact lens wear which occurs in 80 to 86 • Photophobia
percent of these cases.3-5 No type of contact lens has been
Signs—corneal
excluded from an association with Acanthamoeba
• Corneal epithelial abnormalities
keratitis. Out of the 75 percent of the patients who are • Epithelial haze
contact lens wearers, 40 percent were soft contact lens • Elevated lines
wearers, 22 percent were rigid gas permeable wearers • Microcysts
and 38 percent were either extended wear contact lens • Pseudodendrites
wearers or other types of contact lenses.7 • Punctate epithelial erosions
The safest form of contact lens wear remains daily • Stromal infiltrates
• Radial keratoneuritis (Along nerves of anterior stroma)
disposable lenses as very few cases of Acanthamoeba • Ring shaped stromal infiltrate
keratitis have been reported in patients using daily • Stromal thinning and furrowing
disposable lenses.2 • Satellite lesions
The first generation of silicone hydrogel contact • Stromal ulceration and perforation (rare)
lenses which used balafilcon A material showed Signs—others
increased chances of adherence of trophozoites8 as • Lid edema, pseudoptosis
compared to the second generation silicone hydrogel • Conjunctival injection, chemosis
contact lenses which use galyfilcon A.9 • Iritis, hypopyon
It is to be noted that most commercially available • Dacryoadenitis
• Reactive Ischemic Retinitis
contact lens-disinfection solutions are ineffective against
• Secondary Glaucoma
Acanthamoeba.10 • Cataract
• Severe anterior and posterior scleritis
Non-Contact Lens Wearer
In India Acanthamoeba keratitis has also been reported
in cases of non-contact lens wearers6 and the major risk (Table 10.2). One of the most important symptoms of
factor for Acanthamoeba keratitis in these cases was Acanthamoeba keratitis is severe pain especially in the
corneal trauma. early phase of the infection.
Classically Acanthamoeba keratitis follows a
Orthokeratology protracted waxing and waning course. The phase of
remission reflects the presence of dormant cysts,
Orthokeratology, that is the use of contact lens wear to
whereas the progression of keratitis is due to the
shape the cornea has also been associated with
emergence of replicating trophozoites from the cysts.
Acanthamoeba keratitis the incidence of which was
found to be as high as 30 percent out of all pathogens.11
SIGNS
Other Risk Factors
Acanthamoeba infection classically involves the cornea.
Other risk factors associated with Acanthamoeba keratitis However, in some cases lids, anterior chamber and sclera
include use of contaminated water or solutions including may also show signs of inflammation (Table 10.2).
the home made solution to disinfect contact lenses,
swimiming with contact lenses on and corneal trauma.
CORNEAL INVOLVEMENT
SYMPTOMS Early corneal signs included epithelial stippling with
The major clinical symptoms are severe or moderate microcystic edema; coarse, opaque streaks; fine epithelial
pain, decreased vision, redness, irritation, foreign body and subepithelial curvilinear opacities; and dendritiform
sensation, photophobia, mucous discharge and tearing epithelial lesions (Fig. 10.2).
108
Protozoal Keratitis 3
Figure 10.2: Subepithelial opacities in early Acanthamoeba keratitis Figure 10.3: Radial keratoneuritis: florescein stain along the radial
(Courtesy: Medical Photographic Imaging Centre, Royal Victorian Eye nerves (Courtesy: Medical Photographic Imaging Centre, Royal
and Ear Hospital, Melbourne) Victorian Eye and Ear Hospital, Melbourne)
Figure 10.4: Stromal thining in Acanthamoeba keratitis Figure 10.5: Acanthamoeba keratitis: stromal lysis and perforation
109
3 Types of Microbial Keratitis
Lids and Conjunctiva Involvement
Other associated clinical signs include lid abnormalities,
lid edema, reactive pseudoptosis and associated iritis.
Conjunctival injection and chemosis are almost always
present.
110
Protozoal Keratitis 3
stromal infiltrates and endothelial plaques. Severe pain,
annular infiltrates and radial keratoneuritis are
frequently absent in cases of fungal keratitis.
Laboratory Diagnosis
Acanthamoeba keratitis should be diagnosed as early as
possible, because therapy is most effective when initiated
early and requires prolonged treatment.
CORNEAL SCRAPING
Corneal scraping should be taken from the area of
abnormal epithelium and ulceration. It may fail to reveal
the presence of Acanthamoeba in early cases, when
epithelium is intact or in cases in which superficial
Figure 10.7: Gram stain sclerosing Acanthamoeba cysts (Courtesy:
cornea is unaffected. Dr H Sheorey, Dept. of Microbiology, St. Vincent Hospital, Melbourne)
WET SMEAR
Fresh wet mount specimens can also be used. The use cysts for an experienced ophthalmic pathologist;
of a spray fixture to avoid trophozoite disruption by air followed by periodic acid Schiff staining.19 The latter
drying has been recommended. two stains should be used routinely when screening for
Acanthamoeba in corneal tissue, whereas Gomori
STAINING methenamine silver should be done whenever there is
appreciable inflammation in tissue structures, because
Trophozoites and cysts can be identified in the corneal
the amoeba can sometimes resemble inflammatory cells
scrapings or smears by staining with hematoxylin and
(macrophages), and hematoxylin and eosin would then
eosin, Gram (Fig. 10.7), Giemsa-Wright, Calcofluor,
not be adequate to make the distinction.20
methylene blue, congo red, Janus green, Lugol solution,
The trophozoite is characterized by a large single
acridine orange or wheatly trichrome stains. Light
nucleus and spindle like pseudopodia. It is easier to
microscopy of cysts and motile trophozoites is facilitated
recognize the cysts, which are double walled, with the
using Nomarski optics. The staining characters with
inner wall having a variety of polygonal shapes.
various stains are described in Table 10.3.
Calcofluor white is a relatively simple and reliable
A study performed on corneal histopathologic
method for detection of Acanthamoeba, even in cases in
specimens showed that hematoxylin and eosin is
which Gram and Giemsa fail to reveal organisms.
adequate to highlight the Acanthamoeba trophozoites and
Calcofluor white is a fabric brightener and has an affinity
for chitin and cellulose, which are components of cell
walls of Acanthamoeba cysts and fungi but not
Table 10.3
Staining characteristics of Acanthamoeba trophozoites
Acanthamoeba trophozoites.
and cysts A solution containing 0.1 percent cell calcofluor white
and 0.1 percent Evans blue counter stain is applied to
Type of stain Staining of Staining of cyst
trophozoite
the specimen for 5 minutes. The specimen is than
examined under fluorescence microscope. Acanthamoeba
Giemsa-Wright Purple Purple cysts appear as apple green structures 10-25 μm in
Wheatly trichrome Green diameter. Trophozoites are considerably more difficult
Karyosome Red Green to detect with this method because they do not absorb
Calcofluor white Red-Brown Apple-Green calcofluor white. However, Evans blue counter stain
(counter stained with shows the trophozoites as red brown, irregularly shaped
Evan’s blue)
structures 15 to 20 μm in length.
111
3 Types of Microbial Keratitis
Fluorescein–conjugated lectins such as Concavalin A fragment of the contact lens may be placed directly
A and wheat gram agglutinin stain both trophozoites on the non-nutrient agar with an E.coli overlay. If
and cyst. Under fluorescent microscopy, the cyst walls Acanthamoeba are present, its trophozoites will migrate
stain green and the trophozoites stain red. In addition, onto the culture plate.
the more specialized technique of indirect fluorescent For wet mount preparation contact lens solution is
antibody staining is thought to be more sensitive and best centrifuged at 250 revolutions per minute and the
specific. sediment is transferred to a slide and covered with a
cover slip. The slide should be kept in a covered Petri
CULTURE MEDIA dish and can be examined using phase microscopy.
Alternatively, large volumes of contact lens solutions
The scraped material should be directly inoculated on a can be filtered through a 5μm polycarbonate membrane
confluent lawn of Escherichia coli (monoaxonic culture) filter, which is than placed upside down on the culture
plated on non-nutrient agar. The laboratories have plate.
recommended a temperature of 35°C, possibly with a
second plate at 30°C or even 25°C. The culture plates POLYMERASE CHAIN REACTION
should be sealed with adhesive tape to prevent
Polymerase chain reaction testing may be applied on
evaporation and loss of Acanthamoeba organisms from
epithelial scrapings to improve the yield, but it is still
drying.
experimental, appears to be highly strain-specific, and
Organisms such as Escherichia coli, Aerobacter
requires the use of numerous screening probes
aerogenes, Enterobacter species, Klebsiella pneumoniae or
Xanthomonas maltophilia are used as a source of
CORNEAL BIOPSY
nutrition for Acanthamoeba on nutrient agar medium.
Acanthamoeba trophozoites track through the lawn of the A corneal biopsy should be considered if the epithelium
bacteria. The bacteria do not fill in these paths as there is intact but the stromal lesion is active. It is particularly
is absence of nutrition for bacteria in the non-nutrient valuable in cases in which the infiltrate is deep in the
agar. The path depicts the ingestion of bacteria by cornea. A 1.5 to 2.0 mm corneal trephine may be used
trophozoites; the bacteria are unable to reproduce fast to obtain biopsy specimen from an area of infiltration
enough to fill in the defect in the nutrient poor medium. peripheral to the visual axis.
Large numbers of trophozoites are usually seen by 3 Non-nutrient agar plates can be used to culture the
days of incubation but may appear as early as 1 day. organisms in biopsy specimens. Other staining
At least one serial transfer should be done to confirm procedures such as hematoxylin and eosin, periodic acid
the amoebic isolation, as both macrophages and poly- Schiff, methenamine silver, calcofluor white, or
morphonuclear leukocytes can produce “pseudotrials” fluorescein labeled antibodies against Acanthamoeba can
on primary isolation. Macrophages and polymorpho- be used to stain organisms in biopsy specimens.
nuclear cells become non viable rapidly, and on serial Moreover, electron microscopy techniques can be
transfer do not form trails. applied to identify the parasite in the corneal tissues.
The cultures may require more than 9 days to By contrast, corneal biopsy is performed masked and
recover the organism and should be maintained for more is limited by its anterior location and yield. It is believed
than 2 weeks. The success rate of culturing Acantham- that Acanthamoeba trophozoites and cysts are found in
oeba from corneal scrapings is 44-74 percent.20 the anterior stroma initially and move deeper into the
stroma with prolonged infection. Topical drugs will act
Method for Examining Contact Lens on the more superficially positioned amoebas, whereas
the deeper organisms, particularly in large confluent
An excised fragment of the contact lens is placed on a
abscesses, are not susceptible to eradication by
microscope slide with a cover slip and examined
antiamoeba medications.
unstained or after staining with 0.1 percent Calcofluor
White. Evans blue counter stain should not be used as
CONFOCAL MICROSCOPY
it stains the contact lens intensely. The anterior and
posterior surfaces of the lens are examined with X200 Confocal microscopy has been used in the diagnosis and
to X400 magnification for the presence of Acanthamoeba. management of Acanthamoeba keratitis because of the
112
Protozoal Keratitis 3
ability to detect the organism in the cornea in vivo.21 TREATMENT
This technique can also be used to monitor patients who
The treatment of Acanthamoeba keratitis is difficult, as
have been treated for Acanthamoeba keratitis. It can also
the cystic form is highly resistant and may persist for
be used to assess if any cysts or trophozoites are present
years.
prior to transplantation surgery. One major advantage
The drugs which have been found to be effective
of this method is that it is essentially non-invasive,
against Acanthamoeba include propamidine 0.1 percent
although it requires a cooperative patient and a skilled
(Brolene), neomycin 1 percent and cationic antiseptic
operator. In addition, it seems quite likely that this
agents such as chlorhexidine (0.02%) and polyhexa-
method is more sensitive in identifying Acanthamoeba
methylene biguanide (PHMB, 0.02%).21,22 However,
organisms in early infections, which should improve
most of these medications are not commercially avail-
outcomes in these cases. In more advanced cases, it also
able and must be obtained through compounding
aids in differentiating epithelial drug toxicity from
pharmacies.
persistent disease. Using the confocal microscope, one
Most clinicians advocate a combination therapy and
can visualize high-contrast, real-time images of coronal
treatment with PHMB or chlorhexidine which is
corneal sections at magnifications of x 240-380 on a video
generally given in combination with a diamidine, either
monitor.
propamidine (Brolene) or hexamidine (Desmodine).
The cystic form of Acanthamoeba is more distinct and
appears as a double-walled, hexagonal, hyperreflective COMBINATION THERAPY
structure that is 10-25 microns in diameter (Fig. 10.5).
The trophozoite form is more difficult to discern, as it Therapy is effective if definitive treatment starts within
appears similar to normal corneal keratocyte nuclei: an one month of onset. Combination therapy consists of
ovoid, S-shaped, structure within the corneal stroma.20 use of two or three medications simultaneously. This
Other ovoid objects may be observed during confocal includes use of topical PHMB (0.02%) or chlorhexidine
microscopy of patients with Acanthamoeba keratitis and (0.02% or 0.04%) without propamidine 0.1 percent. They
may represent inflammatory cells, trophozoites and should be given every hour around the clock for the
altered keratocytes. Confocal microscopy also helps to initial 72 to 96 hours ,2 hourly for 2-4 weeks and then
rule out any concomitant infection with fungal tapered to to qid dose for 6-12 months.
organisms. Topical cycloplegic therapy and oral nonsteroidal
The sensitivity of this test for the diagnosis of drugs are helpful in the management of pain.
suspected Acanthamoeba keratitis in experienced hands The later the treatment is started, the deeper the
has been reported to be 98 percent, whereas its specificity Acanthamoeba cysts are in the corneal stroma and it is
is yet to be determined.17 Such a powerful tool, however, more difficult to eradicate the large abscesses . Little
requires a skilled operator, a qualified and experienced data are available in the literature about the penetration
reader, and a compliant patient. It is also a relatively of antiamoeba agents, but the deeper cysts, especially
expensive technology available only in select referral in large abscesses, are shielded from the cysticidal
centers. concentrations, necessitating longer exposure This
however may be associated with tissue toxicity from the
OTHER TESTS treating agents. It has been found helpful to reduce
antiamoeba eyedrops abruptly to four times a day and
Although Acanthamoeba can be identified because of its observe. If there is any reactivation, the eyedrops are
cystic structure and acanthopodia, species identification increased to hourly or every 2 hours, and tapered slowly
is difficult. Morphologic characteristics of cyst stage and once again. This mode of treatment may catch the
isoenzyme analysis have been used to identify different resistant cysts, especially the deeper ones, in the process
species of Acanthamoeba. More recently, restriction of converting to the more drug-vulnerable trophozoites
enzyme analysis of either mitochondrial DNA or (pulse therapy).13
cellular DNA were applied to differentiate species of According to Awwad et al, following the initial
parasites. However, these characteristics were not treatment , the clinical picture may worsen during the
correlated with morphologic identification of different first weeks in terms of infiltrate density, stromal scarring,
species. conjunctival injection, and pain, especially if topical
113
3 Types of Microbial Keratitis
steroids or nonsteroidal agents have been used before scleritis, chronic ulcers or severe anterior-chamber
diagnosis and are stopped abruptly.13 However, clinical inflammation under the cover of anti-amoebic drugs.24
worsening that develops after the first month can be Systemic immunosuppression with steroids
due to the worsening of the infection or cumulative drug combined with antiamoeba therapy has also been
toxicity. In the absence of confocal microscopy, it may described to control pain and tissue destruction for
be hard to differentiate these two entities, which require intractable Acanthamoeba sclerokeratitis. In one study,
totally different treatment approaches. The authors 20 eyes of 19 patients received systemic immunosup-
advise tapering the medications and evaluating closely.13 pression with steroids during a mean period of
Subsequent improvement denotes drug toxicity, 7 months, with two eyes remaining in severe pain and
whereas further deterioration indicates an underlying necessitating enucleation.14
intractable infection, which should be treated with more
frequent regimen and possibly higher drug concentra- SURGICAL TREATMENT
tions.
The possibility of a coinfection with bacteria or fungi Various surgical procedures for Acanthamoeba keratitis
should be constantly borne in mind, and repeat corneal which have been tried include penetrating keratoplasty,
culturing and confocal examination should be lamellar keratectomy with conjunctival flap and even
performed when in doubt. amniotic membrane transplantation.
Resistance to antiamoeba agents, such as
chlorhexidine and PHMB, has not been documented, PENETRATING KERATOPLASTY
and treatment failure is due to lack of corneal The results of therapeutic keratoplasty in eliminating
penetration and failure to reach cysticidal concentration the infection in Acanthamoeba keratitis is variable. A cure
in deeper stroma in conditions in which the entire cornea rate of 50 percent and a functional success rate of
may be involved. Hence, in vitro sensitivity testing is 50 percent have been reported.25
not routinely performed. The rate of recurrence of the infection in the graft
after therapeutic keratoplasty varies from 30-50
IMIDAZOLES percent.25 Ficker et al reported a recurrence rate of more
Topical imidazoles, when used in a 1 percent solution, than 50 percent with poor graft survival.26 Due to a high
are effective against trophozoites, but not against cysts.23 recurrence rate of Acanthamoeba in therapeutic grafts
They should never be used as monotherapy. Oral medical control of infection has been recommended first.
ketoconazole and, to a lesser extent, itraconazole pene- There should be a minimum gap of 3 months between
trate into the cornea and are used by some practitioners the complete resolution of Acanthamoeba keratitis on
as adjunctive therapy to PHMB and chlorhexidine. The medical therapy and optical penetrating keratoplasty.27
penetration of these drugs into cornea is inappropriate Meticulous management and frequent follow up of
for them to act as trophozoiticidal agents and hence cases after penetrating keratoplasty for upto 1 year is
should not be used alone.21 required as Acanthamoeba can recur in a graft.
LAMELLAR KERATOPLASTY
NEOMYCIN
Lamellar keratoplasty with a conjunctival flap has been
Most cysts are resistant to neomycin which also has a used successfully in some patients.28
high hypersensitivity rate and hence the use of neomycin
is no longer recommended.23 AMNIOTIC MEMBRANE TRANSPLANTATION
Amniotic membrane transplantation for progressive
ROLE OF CORTICOSTEROIDS
stromal lesions with persistent epithelial defects may
Corticosteroids suppress the activity of the macrophage, also be effective in controlling inflammation and
which is essential in scavenging and destroying the delaying penetrating keratoplasty with good success.29
amoeba Thus, in general, it is recommended to delay It is sometimes necessary to repeat the amniotic memb-
and limit steroid use as much as possible. They are used rane transplantation to ensure complete re-epitheliali-
in only those patients with severe pain, stromal lysis, zation.
114
Protozoal Keratitis 3
References 15. Ehlers N, Hjortdal J. Are cataract and iris atrophy toxic
complications of medical treatment of acanthamoeba
1. Seal DV. Acanthamoeba keratitis update: incidence, keratitis? Acta Ophthalmol Scand 2004;82:228-31.
molecular epidemiology and new drugs for treatment. 16. Kelley PS, Dossey AP, Patel D, et al. Secondary glaucoma
Eye 2003;17:893-905. associated with advanced Acanthamoeba keratitis. Eye
2. Hammersmith KM. Diagnosis and management of Contact Lens 2006;32:178-82.
Acanthamoeba keratitis.Curr Opin Ophthalmol 2006; 17. Parmar DN, Awwad ST, Petroll WM, et al. Tandem
17:327-31. scanning confocal corneal microscopy in the diagnosis
3. Butler TK, Males JJ, Robinson LP, et al. Six-year review of suspected acanthamoeba keratitis. Ophthalmology
of Acanthamoeba keratitis in New South Wales, 2006;113:538-47.
Australia: 1997–2002. Clin Exp Ophthalmol 2005;33:41- 18. Thebpatiphat N, Hammersmith KM, Rocha FN,
6. Rapuano CJ, Ayres BD, Laibson PR, et al. Acanthamoeba
4. Claerhout I, Goegebuer A, Van Den Broecke C, et al. keratitis: a parasite on the rise. Cornea 2007;26:701-6.
Delay in diagnosis and outcome of Acanthamoeba 19. Grossniklaus HE, Waring GO IV, Akor C, et al.
keratitis. Graefe’s Arch Clin Exp Ophthalmol 2004; Evaluation of hematoxylin and eosin and special stains
242:648-53. for the detection of acanthamoeba keratitis in penetrat-
5. Radford CF, Minassian DC, Dart JK. Acanthamoeba ing keratoplasties. Am J Ophthalmol 2003;136:520-6.
keratitis in England and Wales: incidence, outcome, and 20. Wilhelmus KR, Liesegang TJ, Osato MS, et al. Laboratory
risk factors. Br J Ophthalmol 2002;86:536-42. diagnosis of ocular infections. In: Specter SC, (Ed).
6. Sharma S, Garg P, Rao GN. Patient characteristics, Cumitech 13A. Washington DC, American Society of
Microbiology, 1994;17.
diagnosis, and treatment of noncontact lens related
21. Kaufman SC, Musch DC, Belin MW, et al. Confocal
Acanthamoeba keratitis. Br J Ophthalmol 2000;84:1103-
microscopy: A report by the American Academy of
8.
Ophthalmology. Ophthalmology 2004;111:396-406.
7. Hargrave SL, McCulley JP, Husseini Z. Results of a trial
22. Larkin DF, Kilvington S, Dart JK. Treatment of
of combined propamidine isethionate and neomycin
Acanthamoeba keratitis with polyhexamethylene
therapy for Acanthamoeba keratitis. Brolene Study
biguanide. Ophthalmol 1992;99:185-91.
Group. Ophthalmology 1999;106:952-7. 23. Seal DV, Hayt J, Kirkness CM, et al. Successful medical
8. Beattie TK, Tomlinson A, MyFayden AK, et al. Enhanced therapy of Acanthamoeba keratitis with topical
attachment of Acanthamoeba to extended-wear silicone chlorhexidine and propamidine. Eye 1996;10:413-21.
hydrogel contact lenses: a new risk factor? Ophthalmo- 24. Seal DV. Acanthamoeba keratitis update: incidence,
logy 2003;110:765-71. molecular epidemiology and new drugs for treatment.
9. Beattie TK, Tomlinson A, McFayden AK. Attachment Eye 2003;17:893-905.
of Acanthamoeba to first and second-generation silicone 25. Park DH, Palay DA, Daya SM, et al. The role of
hydrogel contact lenses. Ophthalmology 2006;113:117- corticosteroids in the management of Acanthamoeba
25. keratitis. Cornea 1997;16:277-83.
10. Hiti K, Walochnik J, Haller-Schober EM, et al. Viability 26. Sony P, Sharma N, Vajpayee RB, Ray M. CLAO J.
of Acanthamoeba after exposure to a multipurpose Therapeutic keratoplasty for infectious keratitis: A
disinfecting contact lens solution and two hydrogen review of the literature 2002;28:111-8.
peroxide systems. Br J Ophthalmol 2002;86:144-6. 27. Ficker LA, Kirkness C, Wright P. Prognosis for kerato-
11. Saviola JF. The current FDA view on overnight ortho- plasty in Acanthamoeba keratitis. Ophthalmology 1993;
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Cornea 2005;24:770-1. 28. Awwad ST, Parmar DN, Heilman M, et al. Results of
12. Moore MB, McCulley JP, Kaufman HE, Robin JB. Radial penetrating keratoplasty for visual rehabilitation after
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keratitis. Ophthalmology 1986;93:1310-5. 1080-4.
13. Awwad ST, Petroll WM, McCulley JP, Cavanagh HD. 29. Cremona G, Carrasco MA, Tytium A, et al. Treatment
Updates in Acanthamoeba keratitis. Eye Contact Lens of advanced Acanthamoeba keratitis with deep lamellar
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DF, et al. Acanthamoeba sclerokeratitis: treatment with 30. Bourcier T, Patteau F, Borderie V, et al. Amniotic memb-
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115
Pediatric Keratitis 4
11 Pediatric Keratitis
Microbial keratitis is an important cause of ocular Just like the prevalence of different organisms respon-
morbidity and blindness in children. Children and their sible for adult microbial keratitis varies in different
families are frequently unable to provide a complete regions in the world, the organisms responsible for
history of important risk factors such as previous childhood keratitis also vary.
trauma, duration of symptoms and contact lens cleaning Gram-positive cocci are the commonest isolates in
regimes. Older children may give incomplete or false pediatric keratitis in Southern California (83%),4 New
information because of fear of possible parental reprisals Orleans / Philadelphia (54.6%)5 and India 751 and 85.5
for circumstances surrounding the cause of keratitis. percent.9 However, in Florida,8 gram-negative bacilli
Poor co-operation may make the results of slit-lamp (43.2%) are the most prevalent10.
examination less reliable. In India, fungal infections were found to be relatively
more (17.2%) 1 as compared to California (4%). 4
Filamentous fungi are particularly more in Indian
Epidemiology subcontinent (14.1%)1 as compared to the Western world
(2%).4
PREVALENCE
In general children account for 11 percent of the cases Predisposing Factors
according to a review of microbial keratitis in Southern
California.4 Recent figures of World Health Organization Risk factors for the occurrence of pediatric keratitis
suggest that there are 1.5 million children blind world- include trauma, severe systemic illness, contact lens
wide and that 70,000 children annually have active wear and pre-existing external eye disease.6
corneal involvement.2 It is of a greater concern in the
developing world; 22 percent of 201 patients admitted at TRAUMA
a referral center in South Africa were under 16 years of Trauma is the leading predisposing factor of microbial
age.4 keratitis regardless of age and has been reported in
Most studies have described microbial keratitis in 24-44 percent cases (Table 11.2). The introduction of the
the age group 16 years or younger.1,4,5,9,10 It is generally organism is through an epithelial defect or gap in
believed that corneal ulceration is not very common in epithelial bridges or is concurrent with penetrating or
children younger than 5 years. However, it has been perforating corneal injury.10
reported in children younger than 5 years in one study
from Northern India9 (Table 11.1).
SYSTEMIC FACTORS
There is no predilection for any eye and an almost
equal number of right and left eye involvement has been Systemic illnesses associated with corneal ulceration
noted1, 4,10 (Table 11.1). Bilateral affections may also vary from region to region. These include eruptive fevers
occur and have been attributed to systemic illness1,4,10 such as measles, diarrhea and fever in India.1, 9 There is
(Table 11.1). a high prevalence of Vitamin A deficiency leading to
119
4 Specific Types of Keratitis
TABLE 11.1
Demographic features of microbial keratitis in children
S. Author/ (Year) No. of eyes/ Age group Male/Female Right eye Bilateral Seasonal
No. No. of Children (%) Left eye (%) (%) affection (%) pattern
TABLE 11.2
Predisposing factors for microbial keratitis in children
keratomalacia in Indian subcontinent (58.8% of factors for the occurrence of pediatric microbial keratitis.5
systemic cases)1 and is especially important in cases with In a study by Ormerod et al, systemic infections and
bilateral affection. Lower socio-economic status may be malignancies with orbital involvement were the main
significantly associated with the occurrence of corneal systemic associations of pediatric microbial keratitis.4
ulceration.9
Measles associated corneal ulceration is also an CONTACT LENS WEAR
important cause of viral keratitis in the developing
countries unlike the developed countries.11 In a study Contact lens wear as a pre-disposing factor for microbial
from Tanzania 25 percent of the unilateral cases and 57 keratitis has been reported in various western studies
percent of the bilateral corneal ulcers occurred within and varies from 6.4 to 24.1 percent.4,5,10 However, contact
one month of the measles infection.11 Keratitis in measles lens wear is not an important predisposing factor in
may occur due to superadded herpetic infection. Ulcers India1,5 (Table 11.1). Contact lenses are not routinely
associated with measles are varying from typical measles prescribed in Indian subcontinent because of tropical
induced superficial keratitis to frank ulceration, which environment and socioeconomic constraints.9
are generally epithelial and accentuated by desiccation Contact lenses predispose to keratitis especially in
due to exposure.11 aphakic children . Orthokeratology is also an important
In the Western countries, systemic aspergillosis, risk factor for contact lens induced infection.
bronchopulmonary dysplasia, Werdnig-Hoffmann’s The extended wear lenses are more prone to contact
disease, neurofibromatosis, hydrocephalous and mal- keratitis especially if the contact lens hygiene and
development of brain have been reported as the risk disinfection is not adhered to.
120
Pediatric Keratitis 4
PRE-EXISTING EXTERNAL EYE Apart from these, there are myriad of other orga-
DISEASE/SURGERY nisms, which may be isolated from cases of microbial
keratitis in children (Table 11.3).
Exposure keratitis4, 9 trichiasis,4 dry eye4 are important
Childhood microbial keratitis may also be caused by
in infancy and trauma and acquired external disease
polymicrobial infections, which varies from 6.9 to 27
are more common in the school age group.4 Other
percent (Table 11.4).
previous eye diseases include spring catarrh, dacryo-
cystitis, and conjunctivitis.9
Viruses
Prior anterior segment surgery performed on the
same eye has also been reported as a risk factor in 8.8 to Viral keratitis may also occur in children. Herpes
20.7 percent cases.1,5,10 simplex virus infection is the most common. Primary
herpetic infections as well as recurrences of the same
OTHERS may occur. 12 Herpes simplex infection has been
associated in over one third of all cases of corneal
Use of traditional eye medicines is common in develop- ulceration in children in one study.12 Primary herpes
ing countries and has been shown to be associated with manifests as typical vesiculated herpetic skin lesions,
corneal ulceration in 14 percent cases in a study from preauricular lymphadenopathy and follicular conjunc-
Tanzania.11 tivitis with or without corneal involvement.
Those with recurrences have a previous episode of
Etiology typical primary herpes and are characterized by herpetic
epithelial involvement alone, stromal keratitis or both.
MICROBIAL KERATITIS Epithelial involvement varies from punctuate epithelial
keratitis, areolar-stellate, linear dendritic or ameboid.
Just like in adults, infectious microbial keratitis in
children may be caused by bacteria, fungi, viruses or
Fungus
parasites.
In children the incidence of fungal keratitis is less as
Bacteria compared to bacterial keratitis. Fungal infections may
Gram-positive cocci are the most frequently isolated occur in 175 to 18.2 percent10 of the cases (Table 11.3).
organisms in cases of non-viral microbial keratitis in Aspergillus and Fusarium species are the most frequently
children (34-75%).5,9 However, in a series by Cruz et al identified organisms (Table 11.3).
more Gram-negative bacilli (43.2%) were identified as
compared to the gram-positive cocci.10 NON-MICROBIAL KERATITIS
Staphylococcal species and Pseudomonas species have
Nutritional
been isolated most commonly in cases of pediatric
corneal ulceration [Table 11.3]. Indigenous bacteria such Malnourished children are more prone to vitamin A
as non- coagulase positive Staphylococcus have also been deficiency and measles induced corneal ulceration.
increasingly reported in the recent times particularly Vitamin A deficiency leading to keratomalacia is the
from the Indian subcontinent.9 This occurs especially in most important cause of bilateral corneal ulceration. The
eyes, which have already been compromised by trauma, ulcers vary from small punched out, round, or oval
previous eye disease or systemic illness. Functional and ulcers involving corneal stroma to complete necrosis of
morphologic disturbances of the ocular surface in these the cornea.14
eyes facilitate infection by indigenous bacteria.
Pseudomonas aeruginosa infections are more common Vernal Keratoconjunctivitis
in younger children as compared to older children. In The abnormalities of ocular immune mechanisms found
children under 3 years of age more than 50 percent of in vernal keratoconjunctivitis predispose these patients
cases have been reported to occur due to Pseudomonas to microbial keratitis.14 Vernal keratoconjunctivitis may
unlike adults where 19 percent of the cases occurred be rarely associated with secondary bacterial infec-
due to the same.4 tion14,15 and fungal keratitis.16,17
121
4 Specific Types of Keratitis
TABLE 11.3
Non-viral microbes identified from cases of microbial keratitis in children
Organism Ormerod4 Cruz10 Clinch5 Kunimoto1 Vajpayee9
Figure 11.1: Bacterial keratitis in a child Figure 11.2: Perforated corneal ulcer in a child
123
4 Specific Types of Keratitis
TABLE 11.4
Ulcer characteristics of Microbial keratitis in children
Ulcer characteristics Ormerod4 Cruz10 Clinch5 Kunimoto1 Vajpayee9
(%)
1. Hypopyon 32 - - - 32
2. Location
Central 47 63 52 52 58
Paracentral 49 33 31 23 24
Peripheral 4 4 14 25 2
3. Size of ulcer
< 2 mm 30 25 31 31 51
2-6 mm 49 61 52 51 16
>6 mm 21 14 14 19
Topical Anesthesia
For topical anesthesia either 4 percent xylocaine or 0.5
percent proparacaine is used. The latter is preferred as
Figure 11.3: Hand-held slit lamp biomicroscope it is least epitheliotoxic.
Antibacterial agents
1. Ciprofloxacin eye drops 3 mg/ml
wet mount preparation is done to examine the smears 2. Ofloxacin eye drops 3 mg/ml
of corneal scrapings. 3. Tobramycin 14 mg/ml
The specimens obtained should be sent for inocula- 4. Gentamicin 14 mg/ml
tion onto sheep blood agar, chocolate agar and thio- 5. Amikacin 20 mg/ml
glycolate broth, all incubated at 37 deg C. Sabouraud’s 6. Cefazolin 50 mg/ml
agar plates supplemented with yeast extract and 7. Ceftazidime 50 mg/ml
50 micrograms/ml gentamicin sulphate (without 8. Chloramphenicol 3 mg/ml
cyclohexamide) should also be inoculated at 200C to 9. Vancomycin 50 mg/ml
check for fungal infection. In suspected cases for Antifungal agents
Acanthamoeba, non-nutrient agar overlaid with 10. Natamycin 50 mg/ml
Escherichia Coli should be inoculated. 11. Amphotericin B 0.1-0.25%
The culture positivity and polymicrobial involve-
ment in pediatric microbial keratitis is shown in Antiviral agents
Table 11.5. 12. Vidarabine 3 mg/ml
13. Acyclovir 3 mg/ml
Management
MEDICAL THERAPY
The management of a case of pediatric keratitis should
include not only the standard medical therapy for ocular Most ulcers respond to medical therapy alone, although
affection but also for systemic diseases. penetrating keratoplasty may be required in some eyes5,9
Attention should be particularly given to the (Tables 11.6 and 11.7). Concern for maintenance of
nutrition and vitamin A therapy especially in cases of adequate corneal antibiotic levels by topical application
keratomalacia. All children with keratomalacia should in crying, unco-operative children has led some
receive vitamin A supplement as per the WHO researchers to advocate repeated sub-conjunctival
recommendation.13 injections under chloral hydrate sedation3. However, we
Vitamin A supplementation can be given orally, do not generally recommend the use of sub-conjunctival
parenterally or both. The initial dose is 200,000IU in oil antibiotics to treat microbial keratitis.
(110 mg of retinal palmitate or 66mg retinal acetate) or,
Bacterial Keratitis
if necessary, 200,000 IU of water soluble vitamin A
intramuscularly. The next day an additional 200,000 IU We advocate that initial medical therapy should include
of vitamin A should be given. For children less than a combination of fortified antibiotic drops of cefazolin
one year of age half of these doses are given. Children sodium (5%) and tobramycin sulphate (1.3%) at frequent
who are at high risk may require a repeat dose of vitamin intervals which may vary initially from half hourly to
A at 4 to 6 months. two hourly intervals for the initial 48 hours. Subsequent
125
4 Specific Types of Keratitis
126
Pediatric Keratitis 4
acuities may be obtained, which does not commensurate logy; The cornea in health and disease. London
with the extent of the corneal involvement. This has been Academic Press, 1981;395-8.
attributed to the anisometropic or stimulus deprivation 4. Ormerod DL, Murphree AL, Gomez DS, Schanzlin DJ,
Smith RE. Microbial keratitis in Children. Ophthal-
amblyopia and permanent failure to develop stereopsis
mology 1986;449-55.
especially if the corneal opacification occurs in the early 5. Clinch TE, Palmon FE, Robinson MJ, Cohen EJ, Barron
years. Hence, the ophthalmologist should be vigilant in BA, Laibson PR. Microbial keratitis in Children. Am J
the postoperative period to institute anti-amblyopia Ophthalmol 1994;17:65-71.
therapy as and when required. 6. Gudmundsson OG, Ormerod LD, Kenyon KR, Glynn
RJ, Baker AS, Haaf J, et al. Factors influencing predilec-
tion and outcome in bacterial keratitis. Cornea 1989;
PREVENTION
8:115-21.
In general accidents and injuries in children should be 7. Ormerod LD, Hertzmark E, Gomez DS, Stabiner RG,
avoided and precautions should be undertaken to Schanzlin DJ, Smith RE. Epidemiology of microbial
keratitis in southern California. A multivariate analysis.
prevent the same. Likewise Vitamin A deficiency should
Ophthalmology 1987;94:1322-33.
be prevented. Sufficient Vitamin A should be available 8. Alexandrakis G, Alfonso EC, Miller D. Shifting trends
in the diet and supplementation should be done in bacterial keratitis in South Florida and emerging
whenever required as per the WHO guidelines. Early resistance to fluoroquinolones. Ophthalmology 2000;
diagnosis and treatment of Vitamin A should be a 107:1497-502.
priority in areas where protein energy malnutrition is 9. Vajpayee RB, Ray M, Panda A, Sharma N, Taylor HR,
prevalent. 11 Complete immunization protocol for Murthy GV, et al. Risk factors for pediatric presumed
children should be followed and children should be microbial keratitis: A case-control study. Cornea 1999;
18:565-9.
especially immunized against measles. Use of traditional
10. Cruz OA, Sabir SM, Capo H, Alfonso EC. Microbial
eye medications for minor eye ailments should be keratitis in childhood. Ophthalmology 1993;100:192-6.
discouraged. 11 Any eyes with prior ocular surface 11. Foster A, Sommer A. Corneal ulceration, measles, and
disease or anterior segment surgery should be under childhood blindness in Tanzania. Br J Ophthalmol
vigilance and an early diagnosis and prompt treatment 1987;71:331-43.
of corneal ulcers in these cases is mandatory. 12. Poirier RH. Herpetic ocular infections of childhood. Arch
In cases of contact lens wear the parents and the Ophthalmol 1980;98:704-6.
13. Sandford-Smith JH, Whittle HC. Corneal ulceration
children should be educated about the contact lens
following measles in Nigerian children. Br J Ophthalmol
hygiene and proper handling. The pediatrician and the 1979;63:720-4.
neonatologist should be made aware of the predisposing 14. Cameron JA. Shield ulcers and plaques of the cornea in
factors of keratitis. vernal kerato conjunctivitis. Ophthalmology 1995;
102:985-93.
15. Kerr N, Stern GA. Bacterial keratitis associated with
References vernal kerato conjunctivitis. Cornea 1992;11:355-9.
16. Sridhar MS, Gopinathan U, Rao GN. Fungal keratitis
1. Kunimoto DY, Sharma S, Reddy MK, Gopinathan U, associated with vernal keratoconjunctivitis. Cornea 2003;
Jyothi J, Miller Rao GN. Microbial keratitis in Children. 22:80-1.
Ophthalmology 1998;105:252-7. 17. Gupta A, Sharma A, Mohan K, Gupta A. Mycotic
2. Underwood BA. Update: Xerophthalmia, keratomalacia keratitis in non-steroid exposed vernal keratoconjunc-
and child mortality including measles. In: Kupfer C, tivitis. Acta Ophthalmol Scand 1999;77:229-31.
Gillen T (Eds): World Blindness and its Prevention . Vol. 18. Schwartz GS, Holland EJ. Oral acyclovir for the manage-
4. Oxford. ment of herpes simplex virus keratitis in children.
3. Coster DJ, Wilhelmus K, Peacock J, Jones BR. Suppu- Ophthalmology 2000;107:278-82.
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127
4 Specific Types of Keratitis
Figure 12.5: Microbial keratitis (Pseudomonas) in a contact lens Figure 12.6: Microbial keratitis (Acanthamoeba) in a contact lens
wearer wearer
131
4 Specific Types of Keratitis
techniques require a fluorescent microscope for there is no need for further treatment. However, if
visualization. discomfort or disturbed vision continues to persist, the
Corneal scrapings inoculated on a non-nutrient agar patient may demand a more rapid resolution of
with an overlay of Escherichia coli or other Gram-negative symptoms. In these rare situations, topical corticosteroid
organism enhances the recovery of Acanthamoeba. The therapy may be administered. We suggest commencing
presence of Acanthamoeba trophozoites is indicated by topical corticosteroid treatment, usually two to three
a snail-tract clearing through the layer of bacteria. drops of 1 percent prednisolone acetate daily, only after
Antibiotic therapy is instituted according to the ocular symptoms have diminished spontaneously after
isolated organism. Fortified cefazolin sodium 5 percent removal of the contact lens and there is no increase in
and tobramycin 1.3 percent is initiated after preliminary fluorescein staining, stromal edema, or infiltrate size or
corneal scraping is done. Topical antibiotic therapy is density over the course of 2-3 days after the initial
altered in accordance to the culture sensitivity reports diagnosis. It is mandatory to attempt this approach only
and clinical progress. They are given at one hourly in those patients who can be confided to comply with
frequency for the initial 48 hours. Following a clinical follow-up schedules and who can be seen daily for the
response the fortified antibiotics are tapered to 2 hourly first few days.
pregnancy and subsequently 4 hourly. Anti-acantha-
moeba treatment is initiated in cases with positive PREVENTION
Acanthamoeba cysts. The long-term maintenance of Disinfection resistant biofilms must be disrupted
anti-acanthamoeba therapy is important along with close regularly by scrubbing all internal surfaces of the contact
and regular follow-up. lens case with a cotton ball or Q-tip moistened with the
contact lens cleaner. The contact lens case should be heat
STERILE INFILTRATES disinfected with hot water exposure periodically,
followed by air-drying and the case should be replaced
If a sterile infiltrate is suspected, the contact lens should periodically. We recommend the use of daily disposable
be removed immediately. A topical antibiotic such as a contact lenses as they are associated with decreased
fluoroquidone (0.3% ofloxacin) or 0.3% ciprofloxain qic chances of infection.
should be used which is effective against Pseudomonas
and the eye should be re-examined after 24 hours. In
References
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13 Infectious Crystalline
Keratopathy
Figure 13.1: Infectious crystalline keratopathy after lamellar Figure 13.2: Multifocal Infectious crystalline keratopathy after
keratoplasty penetrating keratoplasty
Figure 13.3: Fungal crystalline keratopathy after LASIK required penetrating keratoplasty
137
4 Specific Types of Keratitis
organisms, which are usually the causative YAG Laser Application
organisms of these lesions. The nutritionally variant
Recently YAG laser is also being used by some corneal
streptococci are relatively resistant when compared
surgeons to break the protective biofilm of microorga-
to other streptococci.
nisms of ICK. This helps in achieving a better response
2. The encasement of the bacteria with biofilms limits
to antimicrobial therapy.
the bioavailability of topically administered
antibiotics.
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139
4 Specific Types of Keratitis
Corneal infections are known to occur after various generally begins at the incision site which in cases of
extraocular surgeries such as pterygium surgery and also phacoemulsification may be the scleral tunnel, corneal
after intraocular surgeries such as cataract surgery, tunnel or the side port.
corneal transplantation, refractive surgery, excimer laser The infection in the tunnels is related to the wound
surgery, trabeculectomy and vitreoretinal surgery. architecture with imperfect apposition which creates a
potential space between the roof and the floor of the
Keratitis after Pterygium Surgery tunnel. In cases of the scleral tunnel, it may commence
as scleritis and in cases of clear corneal incisions it
Corneal ulceration is known to occur after Pterygium manifests as keratitis.1 Clear corneal wound infection
surgery. Many cases of Scedosporium corneoscleral
(Fig. 14.3) may be associated with scleritis and
infection have been seen following Pterygium surgery
endophthalmitis.2 Simultaneous infection of the main
with beta radiation. They may be amenable to topical
wound and the side port has also been reported (Fig.
medications if the associated keratitis is mild or may
14.4).
require a large corneoscleral graft in severe cases of
melting (Fig. 14.1A and B).
PREDISPOSING FACTORS
Keratitis After Cataract Surgery The important predisposing factors in a case of wound
Infectious keratitis can occur after cataract surgery which infection include the presence of wound leak after
includes the extracapsular cataract extraction (Fig. 14.2) surgery or the occurence of infection in the adnexal
and the phacoemulsification surgery. The infection areas.
Figures 14.1A and B: Corneoscleral melting (A) in a case following pterygium surgery which was managed by (B) corneoscleral graft
140
Post-surgical Microbial Keratitis 4
Figure 14.2: Corneal ulcer after extracapsular cataract extraction Figure 14.3: Tunnel infection in a case of phacoemulsification
MICROBIOLOGIC EXAMINATION
All patients should be subjected to a detailed micro-
biology workup. Specimens should be collected through
corneal or scleral scraping by using a no. 15 surgical
blade, corneal or scleral biopsy, and anterior chamber
paracentesis. The material should be examined
Figure 14.4: Simultaneous tunnel and side port infection in a case microscopically by using Gram stain, Giemsa stain, and
following phacoemulsification surgery
potassium hydroxide and inoculated on various culture
media that facilitate the growth of fungi, bacteria, and
parasites (blood agar, chocolate agar, Sabouraud’s
The sources of microorganisms include the patient’s
dextrose agar, non-nutrient agar, thioglycolate broth,
own eyelids and conjunctiva, contaminated instruments,
and brain heart infusion broth).
lenses or irrigating solutions, airborne infections, and
At times scrapings from the corneal surface overlying
breaches in the sterile technique. Another important
the infiltrate may not reveal any organisms on micro-
predisposing factor with cases is the use of cortico-
scopy or culture and keratitis may be present in the
steroids without antibiotics.1,2
posterior part of the tunnel. Hence, it may be necessary
to a make a flap at the incision site like a trap door and
CLINICAL EXAMINATION biopsy may be taken from the visibly infected part of
The diagnostic criteria in cases of keratitis following the posterior aspect of the tunnel. In cases where scleritis
phacoemulsification surgery is the presence of an is present corneoscleral biopsy may be required and in
epithelial defect with or without infiltrates in the cases of thick exudates associated with hypopyon
surrounding stroma along the tunnel incision, i.e., anterior chamber paracentesis may be undertaken.
141
4 Specific Types of Keratitis
142
Post-surgical Microbial Keratitis 4
Figure 14.6A: Recurrence of bacterial keratitis after penetrating Figure 14.6B: Recurrence of fungal keratitis after lamellar kerato-
keratoplasty plasty
Systemic Associations
It has been reported that patients with diabetes mellitus
may have more chances of graft infection. 9,10 In
developing countries graft infection is associated with
low socioeconomic status of the patient.10,18,19 In our
study there was 2.5 times higher chances of infection in
the lower socioeconomic status as compared to higher
strata and was attributed to poor living conditions and
inadequate hygiene.18
Figure 14.9: Loose suture acts as a nidus for infection Microbiology of Graft Infection
The most common cause of graft infection is herpes
Dry Eye and Ocular Surface Problems simplex virus followed by bacterial organisms. More
cases with Gram-positive cocci (coagulase-negative
Ocular surface disorders like dry eye and dellen result staphylococci, Streptococcus pneumoniae and Staphylo-
in altered tear film dynamics and decreased tear film coccus aureus)3,4,20 have been reported as compared to
coating which increases the chances of adherence of the Gram-negative organisms (Pseudomonas aeruginosa and
microbes to the transplanted corneas. Serratia marcescens). Mycotic keratitis after corneal
transplantation has also been known to occur and fungi
Suture Related Problems of Aspergillus and Mucoraceae species 21 are most
Suture related problems are the most important commonly isolated fungal organisms from these cases.
predisposing factors for graft infection in 14 to 60 percent
cases.8,13-17 Loose or exposed sutures attract mucin (Fig. Clinical Features
14.9) and act as a nidus for microbial invasion and
proliferation and can cause graft infection. Suture Patients of graft infection in the early post-operative
abscesses may also lead to graft infection (Figs 14.10A period present with non-specific symptoms of redness,
Figure 14.10A: Suture infiltrates in a graft Figure 14.10B: Sutures abscess leading to graft infection
144
Post-surgical Microbial Keratitis 4
Gram’s stain and potassium hydroxide (KOH) wet
mount should be prepared. In cases of suture related
problems, the offending suture should be removed and
sent for bacterial and fungal culture examinations. If a
contact lens is in place, it should be removed and placed
on a separate culture plate. Initially the cultures should
be done on blood agar, chocolate agar and Sabouraud
dextrose agar. Special culture media like Lowenstein
Jensen media, non-nutrient agar with Escherichia coli and
thioglycolate broth should be used if there is clinical
suspicion of infection by unusual pathogens.
Management
Corneal graft infection requires a prompt and judicious
Figure 14.11: Mycotic keratitis in a graft (Aspergillus) management, which depends on a good clinical
judgment and an early microbiological diagnosis of the
ulcer.
photophobia, foreign body sensation and purulent
discharge. There may be a sudden or gradual decrease MEDICAL MANAGEMENT
in the visual acuity depending on the location of the We prefer to hospitalize all cases with corneal graft
lesion. Infections involving the central part of cornea infection. In all cases of suppurative infectious keratitis
cause a sudden decrease in visual acuity. Some patients of corneal graft topical corticosteroids should be stopped
with infection at the graft host junction or with infection immediately and an intensive regimen of broad-
localized to the periphery of the graft may present with spectrum combination therapy with fortified cefazolin
a normal visual acuity. sodium 50 mg/ml and fortified tobramycin 14 mg/ml
There may be a delay in diagnosis of infection in should be instituted every 30 minutes round the clock
lamellar grafts, especially in the early stages, because in the first 24 hours. Alternatively, fortified cefazolin
an infiltrate may develop in the interface and hence may 50 mg/ml and gatifloxacin 3 mg/ml may be started in
not be visualized earlier.8 the same frequency.
The ulcer should be examined under slit lamp and Antifungal medications such as 5 percent natamycin
documented with a careful detailed drawing and photo- eye drops one hourly are added only if there is
graphs (if possible). The size of the epithelial defect, microbiological evidence of presence of fungus (i.e. on
infiltrate and hypopyon, if present should be measured Gram’s smear, KOH wet mount or culture examination).
and recorded at each follow-up. Supportive topical medical therapy is given in the
The ulcers may be either peripheral or central in form of cycloplegics, lubricants and antiglaucoma
location. The former are usually associated with suture medications (if required). Topical corticosteroid may be
related problems whereas the latter are related to re-started in cases of bacterial infections only if the
exposure and tear film abnormalities. Advanced cases offending organism has been identified and there is a
may present with frank graft dehiscence or melting. significant positive response to the antimicrobial
therapy. Systemic antibiotics are indicated in cases with
frank/impending scleral involvement, graft melting,
Investigations perforation or dehiscence.
Generally, culture swabs are taken from the donor The patient should be examined daily to monitor the
corneoscleral rim and the media. This may aid in clinical response for progression of the ulcer. Once the
identification of the micro-organism especially if the clinical improvement occurs, the topical medications
infection has occurred in the early post-operative period. should be tapered.
The corneal scraping should be done under topical However, if the medical management fails, surgical
anesthesia using a slit lamp biomicroscope. Smears for options for the management of post-keratoplasty
145
4 Specific Types of Keratitis
infections should be resorted to. If the cultures are keratoplasty varies from 10 to 25 percent during the first
negative and the keratitis worsens despite medical year of follow-up.23,24
therapy, a diagnostic biopsy is indicated. Herpetic keratitis in a corneal graft may have a
variable presentation and may present as a classic
SURGICAL MANAGEMENT dendritic ulcer (Figs 14.12A and B), persistent epithelial
defect, graft rejection, or a herpetic stromal infiltration
If a loose suture is noted in the early post-operative of the graft (Figs 14.12A and B).25 A geographical
period, it should be removed and replaced immediately, herpetic ulcer has to be differentiated from a neurotro-
taking care that the exposed part of the suture does not phic ulcer by slit lamp biomicroscopy using Rose Bengal
traverse the corneal stroma. If a suture is the cause of Staining. The risk of recurrence of herpetic infection
infection during the late postoperative period i. e. after increases specially if the corticosteroids are used after
3 months it should be immediately removed and sent penetrating keratoplasty without the concomitant use
for cultures. During the late postoperative period of antiviral drugs as this enhances viral multiplication.
removal of a single interrupted suture does not adversely Hence a prophylactic dose of systemic acyclovir 800 mg
affect the wound stability. However, if infection occurs per day is recommended for up to year in cases of
due to a loose continuous suture, it should be imme- penetrating keratoplasty done for herpetic scars.24-26
diately removed and replaced with interrupted sutures.
The indications for a graft exchange include non-
resolving graft ulcers, deep-seated abscess non Graft Survival and Visual Outcome
responsive to treatment, wound dehiscence, perforation Visual prognosis in eyes with post-keratoplasty graft
or graft melting. A graft exchange using the same size infection is poor even after a successful medical therapy
graft as the one used in the prior surgery may be done due to corneal scarring after resolution of keratitis and
in cases where the infection has not spread to the host a high rate of graft decompensation. A repeat kerato-
cornea or a larger sized graft may be used in cases where plasty is required in almost half of the cases.4,10 Clear
the infection spreads to the host cornea. grafts following graft infection has been reported in
23 to 67 percent cases in various studies.5,6,15,20 A best
Associated Endophthalmitis corrected visual acuity (BCVA) of better than
Endophthalmitis may occur early or late after penetrat- 6/60 on Snellen’s acuity chart is seen in only 14 to
ing keratoplasty, often with disastrous consequences. It 30 percent of the eyes and only 6 percent of patients
may occur in 4 to 13 percent of the cases of graft achieved a best corrected visual acuity of > 6/18 at the
infection.2,3,8,13 The sources of infection are contaminated final follow up in one study.10 Infections after lamellar
donor tissue or corneal storage media or irrigating keratoplasty are associated with grave prognosis and
solutions. Ulcerative keratitis at the graft host junction may not be amenable to antimicrobial therapy.8 This
may progress to perforation and subsequent endoph- may necessitate the removal of the graft or a therapeutic
thalmitis. Anterior vitrectomy performed at the time of penetrating keratoplasty.8
penetrating keratoplasty may increase the chance of
MICROBIAL KERATITIS AFTER
endophthalmitis by 1.5 times. In cases of corneal graft
REFRACTIVE SURGERY
infection associated with endophthalmitis intravitreal
injection of vancomycin 1 mg in 0.1 ml and ceftazidime Microbial keratitis has been reported after radial
2.25 mg in 0.1 ml should be given along with topical keratotomy, photorefractive keratectomy, laser in situ
therapy for corneal ulcer. keratomileusis and laser subepithelial keratectomy.
Figures 14.12A and B: Dandrities due to herpes simplex keratitis following penetrating keratoplasty stained with Rose Bengal dye (A) and
florescien (B)
Figures 14.13A and B: Post LASIK keratitis due to Pseudomonas (A) healed on topical therapy (B)
Infectious keratitis following LASIK may be early many cases are typically treated with frequent topical
onset (occurring within the first 2 weeks of surgery) or corticosteroid therapy that may obscure the clinical
late onset (occurring 2 weeks to 3 months after surgery). picture with transient improvement in the inflammation.
The organisms seen in early-onset infectious keratitis However, unlike DLK, the inflammation associated with
are common bacterial pathogens such as staphylococcal LASIK-associated infections usually persists despite
streptococcal and Pseudomonas (Figs 14.3A and B) topical corticosteroids, and the underlying infections can
species. Gram-negative organisms are rare. The potentially worsen with corticosteroid tapering.
organisms seen in late-onset infectious keratitis are The appearance of an interface inflammation more
usually opportunistic such as fungi (Fig. 14.4), nocardia, than 1 week after LASIK should be presumed to be of
and atypical mycobacteria. an infectious etiology until proven otherwise. Diffuse
Infectious keratitis following LASIK often presents lamellar keratitis characteristically has a diffuse
with inflammation in the corneal interface, which can appearance , while infectious keratitis has a focal area
mimic diffuse lamellar keratitis (DLK). Because of this, of infiltration surrounded by diffuse inflammation
147
4 Specific Types of Keratitis
(Figs 14.13A and B) or even focal inflammation limited Topical medications are generally given for 4 months
to the area of the infiltrate. Any focal infiltrate and systemic medications are given for 2 months.
surrounded by inflammation should be presumed In cases where total melting of the cornea occurs
infectious until proven otherwise. despite amputation of the flap and maximal medical
therapy, a therapeutic keratoplasty may be required to
Microbiologic Examination save the eye.
Any focal infiltrate following LASIK should be
considered infectious, and the practice of empirical References
antibiotic treatment without performing cultures of 1. Garg P, Mahesh S, Bansal AK, Gopinathan U, Rao GN.
microorganisms should be avoided. Fungal infection of sutureless self-sealing incision for
Scraping should be sent for Gram-stain, Gomori- cataract surgery. Ophthalmology 2003;110:2173-7.
methenamine silver stain, and Ziehl-Neelsen stain to 2. Cosar CB, Cohen EJ, Rapuano CJ, Laibson PR. Clear
rule out unusual pathogens such as nocardia, atypical corneal wound infection after phacoemulsification. Arch
mycobacteria, and fungi.The culture media which Ophthalmol 2001;119:1755-9.
3. Al-hazzaa SAF, Tabbara KF. Bacterial keratitis after
should be inoculated include blood agar, chocolate agar,
penetrating keratoplasty. Ophthalmology 1988;95:1504-
Sabouraud’s agar, and thioglycolate broth and 8.
Lowenstein-Jensen or Middlebrook 7H-9 agar. If these 4. Akova YA, Onat M, Koc F, Nurozler A, Duman S.
special media are unavailable, blood agar may be used Microbial keratitis following penetrating keratoplasty.
as atypical media. Mycobacteria grow quite well in this Ophthalmic Surg Lasers 1999;30:449-55.
media also. In cases in which cultures are negative and 5. Tavakkoli H, Sugar J. Microbial keratitis following
the infection continues to worsen, a corneal biopsy or keratoplasty. Ophthalmic Surg 1994;25:350-60.
polymerase chain reaction should be contemplated. 6. Bates AK, Kirkness CM, Ficker LA, Steele AD, Rice NSC.
Microbial keratitis after penetrating keratoplasty. Eye
Treatment 1990;4:74-8.
7. Lamensdorf M, Wilson LA, Waring GO III, Cavanagh
The topical corticosteroids should be discontinued. In HD. Microbial keratitis after penetrating keratoplasty.
cases of Post LASIK keratitis fortified cefazolin sodium Ophthalmology 1982;89:124.
5% eyedrops along with tobramycin sulphate 1.3% eye 8. Sharma N, Gupta V, Vanathi M, Agarwal T, Vajpayee
drops are instilled hourly. In cases where there is no RB, Satpathy G. Microbial keratitis following lamellar
keratoplasty. Cornea 2004;23:472-8.
response to above therapy and where the flap is
9. Saini JS, Rao GN, Aquavella JV. Post-keratoplasty
edematous irrigation of the flap interface with an appro- corneal ulcers and bandage lenses. Acta Ophthalmo-
priate antibiotic solution (fortified vancomycin 50 mg/ logica 1988;66:99-103.
mL for rapid-onset keratitis and fortified amikacin 10. Vajpayee RB, Boral SK, Dada T, Murthy GVS, Pandey
35 mg/mL for delayed-onset keratitis) may be helpful. RM, Satpathy G. Risk factors for graft infection in India:
In patients who work in a hospital environment, A case control study. Br J Ophthalmol 2002;86:261-5.
there is an added risk for methicillin-resistant 11. Rehany U, Balut G, Lefler E, Rumelt S. The prevalence
and risk factors for donor corneal button contamination
Staphylococcus aureus (MRSA). In these patients, fortified
and its association with ocular infection after trans-
vancomycin 50 mg/mL may be given instead of plantation. Cornea 2004;23:649-54.
cefazolin every 30 minutes to provide more effective 12. Chittum ME, Grutzmacher RD, Oiland DM, Kalina RE.
therapy against MRSA. In addition, oral doxycycline 100 Contamination of corneal tissue from infected donors.
mg twice a day may be used to inhibit collagenase Arch Ophthalmol 1985;103:802-5.
production. 13. Driebe WT, Stern GA. Microbial keratitis following
For delayed-onset keratitis, which is commonly due corneal transplantation. Cornea 1983;2:41.
to atypical mycobacteria,22 nocardia, and fungi, therapy 14. Dana MR, Goren MB, Gomes AP, Laibson PR, Rapuano
CJ, Cohen EJ. Suture Erosion after penetrating kerato-
should be commenced with amikacin 35 mg/mL every plasty. Cornea 1995;14:243-8.
hour, alternating with a fourth-generation fluoroquino- 15. Harris DJ Jr, Stulting RD, Waring GO 3rd, Wilson LA.
lone (gatifloxacin 0.3% or moxifloxacin 0.5%). Late bacterial and fungal keratitis after corneal
Clarithromycin 1 percent and Oral Clarithromycin may transplantation. Spectrum of pathogens, graft survival,
also be tried in cases which do not respond to amikacin. and visual prognosis. Ophthalmology 1988;95:1450-7.
148
Post-surgical Microbial Keratitis 4
16. Leahey AB, Avery RL, Gottsch JD, Mallette RA, Stark corneal transplants in India. Br J Ophthalmol 1997;
WJ. Suture abscesses after penetrating keratoplasty. 81:726-31.
Cornea 1993;12:489-92. 20. Tseng SH, Ling KC. Late microbial keratitis after corneal
17. Christo CG, van Rooij J, Geerards AJ, Remeijer L, transplantation. Cornea 1995;14:591-4.
Beekhuis WH. Suture-related complications following 21. Satpathy G, Vishalakshi P. Microbial profile and
keratoplasty: A 5-year retrospective study. Cornea 2001; sensitivity pattern – a five-year study. Ann Ophthalmol
20:816-9. 1995;27:301-6.
18. Dandona L, Naduviath TJ, Janarthanan H, et al. Causes 22. Daines BS, Vroman DT, Sandoval HP, Steed LL,
of corneal graft failure in India. Indian J Ophthalmol Solomon KD. Rapid diagnosis and treatment of
1998;46:149-52. mycobacterial keratitis after laser in situ keratomileusis.
19. Dandona L, Naduvilath TJ, Janarthanan M, et al. Survi- J Cataract Refract Surg 2003;29:1014-8.
val analysis and visual outcome in a large series of
149
4 Specific Types of Keratitis
Pathogenesis SIGNS
On examination, the visual acuity is decreased and may
Once endophthalmitis occurs, damage to ocular tissues
be hand motions or only light perception in fulminant
occurs due to direct effect of microbial replication as
cases. There is marked conjunctival hyperemia, chemosis
well as initiation of a fulminant cascade of inflammatory
and circumcorneal congestion. There is presence of a
mediators. Endotoxins cause direct cellular injury and
corneal ulcer and the adjacent cornea is grossly
cytokines attract neutrophils which enhance the
edematous. A limbal ring abscess or corneal melting may
inflammatory effect.
also be present. The underlying findings in the anterior
chamber and the posterior segment are not visible due
Predisposing Factors to the presence of the overlying keratitis. The anterior
chamber shows a significant degree of flare and cells,
Patients in whom keratitis is associated with endoph-
the reaction sometimes being frankly fibrinous. The iris
thalmitis give a history of frequent corticosteroid use.
pattern is lost, appears muddy and boggy and is
They may also have a concomitant systemic disorder
resistant to dilation. There may be presence of posterior
associated with relative immune dysfunction. Patients
synechiae. Pupillary response to light is absent or
in whom there is absence of an intact posterior capsule,
sluggish. In more severe cases, a dense discrete or
presence of wound abnormalities (in post surgical cases),
confluent, yellowish vitreous exudation is evident (Figs
or occurence of corneal perforation are also at a greater
15.1 and 15.2). The intraocular pressure may be elevated
risk of having endophthalmitis.3
in the early stages of endophthalmitis. The fundus glow
may be dull or absent.
Clinical Features
Investigations
SYMPTOMS The investigations in a case of keratitis with endoph-
Most patients complain of a sudden onset and a rapid thalmitis include clinical investigations such as
worsening of pain accompanied by a significant decrease ultrasonography and microbiological evaluation.
150
Keratitis and Endophthalmitis 4
Fig. 15.1: Anterior chamber exudates with endophthalmitis Fig. 15.2: Corneal melting with endophthalmitis
153
4 Specific Types of Keratitis
16 Neurotrophic Keratitis
Figure 16.1: Neurotrophic keratitis Figure 16.2: Neurotrophic keratitis in tattooed cornea
TABLE 16.3
Conversion table used with Cochet and Bonnet aesthesiometer
Selection of the treatment modality depends on the stage Despite every effort, the corneal epithelial defect may
of the ulcer which is being treated. progress to corneal ulcer with stromal lysis resulting in
158
Neurotrophic Keratitis 4
corneal thinning and perforation. During this stage it is it is now thought to act primarily through restriction of
important to maintain the integrity of the corneal the gene expression of neutrophil collagenase and
surface. epithelial gelatinase.16
Tetracycline is given in the dose of 250 mg 4 times a
Collagenase Inhibitors day or doxycycline 100 mg twice a day for 4 to 6 weeks.
Proteolytic enzymes play a major role in the formation
Tissue Adhesive
and progression of ulcer. Topical cysteine, acetyl-
cysteine 20 percent,13-15 ethylene-diaminetetra-acetic acid Tissue adhesive, particularly isobutyl cyanoacrylate
0.2 mol/L, or tetracycline16 inhibit collagenase activity (histoacryl) along with a bandage contact lens is used
and decrease stromal meltdown. These collagenase as an adjunctive treatment for filling the corneal ulcer
inhibitors are relatively nontoxic, although their efficacy and perforation (< 2 mm) and providing tectonic support
in humans has not yet been conclusively demonstrated. to the cornea. Tissue adhesives also aid in the following:
Tetracycline has also been reported to protect the 1. Exclusion of polymorphonuclear leukocytes from the
cornea against proteolytic degradation after chemical involved stroma (possibly by creating a hypoxic
burns by inhibiting matrix metalloproteinases (MMPs). environment which is not favorable to polymorpho-
Initially it was believed that tetracycline acts by inhibit- nuclear leukocytes
ing MMPs after binding with cations, i.e. Zn and Ca but 2. Antibacterial action
Figures 16.4A to D: Neurotrophic keratitis healed after multi-layered amniotic membrane transplantation
159
4 Specific Types of Keratitis
Figures 16.5A to D: Neurotrophic keratitis healed after multi-layered amniotic membrane transplantation
3. Promotion of neovascularization and postponing stromal destruction with a poor visual prognosis.21,22 For
keratoplasty in an acutely inflamed eye. a peripheral or small ulcer, a partial or bridge conjunc-
tival flap, particularly of vertical orientation, is
Conjunctival Flap performed. Along with structural support, the partial
conjunctival flap maintains good vision for the patient
Despite the prompt use of non-surgical modalities, the
by not involving the central area.
ulcer may progress, requiring surgical intervention. A
conjunctival flap halts the inflammatory process,
Amniotic Membrane Transplantation
eliminates frequent medications, improves cosmesis, and
provides an alternative to invasive surgery or Multi-layered amniotic membrane is used for filling the
enucleation.17 Several studies have been done on the use cavity of the ulcer and restoring the stromal thickness
of the conjunctival flap for persistent ocular surface and integrity of the corneal epithelium.23,24 For this
disease and its role is well established.18, 22 procedure cryo-preserved amniotic membrane is
A total conjunctival flap or partial or bridge employed. Small pieces are cut from the membrane and
conjunctival flap is indicated to prevent progression of carefully placed into the base of the ulcer. Depending
the ulcer to perforation. Total conjunctival flap on the depth and the configuration of the ulcer, two or
(Gunderson flap) is indicated for patients with extensive more of these pieces are stacked one above the other to
160
Neurotrophic Keratitis 4
fill the cavity of the ulcer (Figs 16.4A to 16.5D). Finally, 8. Karacorlu MA, Cakiner T, Saylan T. Corneal sensitivity
a larger piece of membrane is trimmed to cover the ulcer and correlations between decreased sensitivity and
and the de-epithelialized zone surrounding the ulcer. anterior segment pathology in ocular leprosy. Br J
The membrane is then secured to maintain its Ophthalmol 1991;75:117-9.
9. Mackie IA. Neuroparalytic (neurotrophic) keratitis in
physiologic orientation (epithelium up and stroma symposium on contact lenses. Transactions of the New
facing the ulcer) with six or more interrupted 10-0 nylon Orleans Academy of Ophthalmology, St. Louis, Mosby,
sutures. The knots of the sutures are cut short but not 1973.
buried. On completion of the surgery, the eye is covered 10. Van Buskirk EM. Corneal anesthesia after timolol
by a soft bandage contact lens. maleate therapy. Am J Ophthalmol 1979;88:739-43.
The advantages of using a multi-layered amniotic 11. Holland EJ, Schwartz GS. Classification of herpes
simplex virus keratitis. Cornea 1999;18:144-54.
membrane are:
12. Foster CS. Ocular surface manifestations of neurological
1. Stromal thickness is maintained even after the and systemic disease. Int Ophthalmol Clin 1979 Summer;
amniotic membrane dissolves (perhaps because the 19:207-42.
amniotic membrane modifies the proliferative and 13. Cochet P, Bonnet R. [Corneal esthesiometry. Perform-
migratory behavior of stromal keratocytes). ance and practical importance] Bull Soc Ophtalmol Fr
2. It allows rapid epithelial wound healing and long- 1961;6:541-50. French.
term stability of the corneal surface. 14. Brown SI, Weller CA. The pathogenesis and treatment
of collagenase-induced diseases of the cornea. Trans Am
3. It provides an effective barrier for inflammatory cell Acad Ophthalmol Otolaryngol 1970;74:375-83.
entry. 15. Berman MB. Collagenase inhibitor: Rationale for their
4. It downregulates the synthesis of chemotactic factors use in treating corneal ulceration. Int Ophthalmol Clin
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16. Ralpf RA. Tetracyclines and the treatment of corneal
Penetrating Keratoplasty stromal ulceration: A review. Cornea 2000;19:274-7.
17. Thoft RA. Conjunctival surgery for corneal diseases. In:
For large corneal perforations (>2 mm) an emergency SmolinG, Thoft RA (Eds). The Cornea: Scientific founda-
small lamellar (blow-out) or full thickness graft is tion and clinical practice. Boston, Little Brown, 1983;465-
required in an acutely inflamed eye.25 However, grafts 76.
18. Lugo M, Arentsen JJ. Treatment of neurotrophic ulcers
do poorly in such anesthetic corneas. with conjunctival flaps. Am J Ophthalmol 1987;103:711-
2.
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161
4 Specific Types of Keratitis
Figure 17.1: Peripheral ulcerative keratitis due to Staphylococci Figure 17.2: Peripheral ulcerative keratitis due to Aspergillus
Figures 17.3A and B: Peripheral ulcerative keratitis due to Herpes simplex virus
Any inflammatory stimulus in the peripheral cornea leukotrienes, prostaglandins), causing dissolution and
that is caused by invasion of microbial organisms degradation of the corneal stroma. The inflamed limbal
(bacteria, virus, fungi, and parasites), immune complex conjunctiva itself is capable of producing collagenase,
deposition (in systemic immune diseases), trauma, which also causes stromal degradation.
malignancy, or dermatologic conditions may produce Systemic diseases that may cause immune complex
local and systemic immune responses, resulting in deposition at the peripheral cornea and cause PUK
neutrophil recruitment and complement activation at include collagen vascular diseases such as rheumatoid
the limbus. arthritis (RA), Wegener’s granulomatosis (WG),
Activated complement components increase vascular polyarteritis nodosa (PAN), relapsing polychondritis
permeability and further generate chemotactic factors (RP), and systemic lupus erythematosus (SLE). 5
for neutrophils (e.g. C3a, C5a), which infiltrate the peri- Infectious conditions, whether systemic (hepatitis,
pheral cornea and release proteolytic and collagenolytic syphilis) or local (herpes simplex keratitis, fungal
enzymes, reactive oxygen metabolites, and proinflam- keratitis), and noninfectious local disorders (Mooren’s
matory substances (such as platelet-activating factor, ulcer, marginal keratitis) also may cause PUK.
163
4 Specific Types of Keratitis
TABLE 17.1 HISTORY
Etiology of peripheral ulcerative keratitis The ocular symptoms vary, but patients may complaint
Infections Non-infections of a nonspecific foreign body sensation with or without
pain, tearing, photophobia, and reduced visual acuity.
Ocular • Bacterial • Mooren’s ulcer
The decrease in the visual acuity may be gradual or a
(Staphylococcus, • Terrien’s marginal
Streptococcus, degeneration sudden loss of vision may occur when PUK progresses.
Moraxella, • Pellucid marginal PUK is frequently a manifestation of an occult systemic
Haemophilus degeneration disease. Thus, a thorough systemic history is very
Gonococcus) • Blepharitis important and should include chief complaints, charac-
• Keratoconjunctivitis
teristics of present illness, past medical history, family
sicca
• Viral (Herpes • Neurotrophic and history, and a meticulous systemic history. Sometimes
simplex, herpes Neuroparalytic an underlying systemic disease may be diagnosed by
zoster) • Nutritional deficiency the presence of PUK.
• Acanthamoeba • Ocular chemical injury PUK associated with RA, WG, PAN, and RP is
• Fungal organisms • Contact lens
associated with scleritis, and may also be associated with
• Trauma
• Post-surgical significant pain.6,7 PUK in patients with Mooren’s ulcer
may also present with pain, although there is no scleral
Systemic • Tuberculosis • Rheumatoid arthritis involvement.
• Syphilis • Giant cell arthritis
The onset of ulceration should be noted as acute
• Varicella zoster • Wegener’s
granulomatosis (onset of symptoms within 2 weeks of presentation),
• Gonorrhea • Systemic lupus subacute (within 3 months) or chronic (> 3 months).
erythematosis, Past medical history should be sought especially in
• Sjögren’s syndrome relation to a systemic disease such as RA, SLE, PAN,
• Relapsing polychondritis
WG and RP. History should be taken for constitutional
• Progressive systemic
sclerosis symptoms, such as chills, fever, decreased appetite,
• Churg-Strauss recent weight loss, and fatigue, any problems related to
syndrome skin disorders, respiratory, cardiac, gastrointestinal and
• Crohn’s disease neurologic symptoms. This may elicit the presence of
• Ulcerative colitis
systemic disease, which may cause PUK.
• Rosacea
• Steven Johnson’s
syndrome Examination
• Sarcoidosis
• Behçet’s disease Examination should include a complete systemic and a
• Psoriasis thorough ocular examination.
• Malignancy
• Cryoglobulinemia
• Schönlein-Henoch SYSTEMIC
purpura
Any lesion on the skin, face, trunk, joints, and extremities
• Serum sickness
• Pyoderma should be noted. Diagnosis of PUK in a patient of colla-
gangrenosum gen vascular disease may require multiple evaluations
• Erythema devatum by a rheumatologist or clinical immunologist as clinically
diutinum detectable manifestations of these systemic diseases may
evolve slowly.8
164
Peripheral Ulcerative Keratitis 4
1. Complete blood cell count
2. Erythrocyte sedimentation rate
3. Serum creatinine, blood urea nitrogen
4. Rheumatoid factor (RF) in cases of RA (80% positive
in RA)
5. Angiotensin-converting enzyme (ACE) which may
be elevated in sarcoidosis
6. Antinuclear antibodies (ANA) which are positive
in patients with SLE and RA
7. Antineutrophil cytoplasmic antibodies (ANCA);
C-ANCA sensitivity of 96 percent for active genera-
lized WG, 67 percent for active regional disease,
and 32 percent for WG in full remission after initial
regional symptoms9
8. Anti-type II antibodies (positive in RP)
Figure 17.4: PUK with necrotizing scleritis 9. Complement - C3 and C4, CH50; in patients with
SLE
10. Hepatitis B surface antigen (HBsAg); present in
detailed results of biomicroscopic slit-lamp examination
40 percent of patients with PAN.
should be recorded. Corneal sensations and lacrimal
function by Schirmer test should also be recorded. Apart
from this the details of anterior chamber (for the Imaging Studies
presence of any inflammation), vitreous, and fundus Chest X-ray and sinus CT scan to rule out WG, sarcoi-
should also be noted. dosis, and tuberculosis should be done and other
Slit-lamp examination generally reveals a presence radiographic studies of the affected joints should also
of a crescent-shaped lesion of the juxtalimbal corneal be undertaken.
stroma associated with an epithelial defect, stromal
yellow-white infiltrates composed of inflammatory cells, Microbiology Work Up
and varying degrees of corneal stromal thinning
(minimal to full thickness) adjacent to the limbus. In Routine scraping and culture of the ulcer are
severe cases, the peripheral cornea is progressively recommended in all cases (as described for microbial
thinned out both circumferentially and centrally. The keratitis).10-12 PUK can be caused by microbial organisms
leading edge of the ulcer is infiltrated and untreated such as bacteria, fungus or herpes. Hence in all cases
PUK will eventually progress towards the visual axis. corneal scraping should be done and smears should be
Corneal ulceration should be graded as follows: prepared and cultures should be sent.
< 25 percent depth of ulceration = 1, 25-50 percent = 2,
50-75 percent = 3 and 75-100 percent = 4. Biopsy
Scleral invovement should be characterized as
diffuse, nodular or necrotizing. PUK when accompanied The conjunctival resection/biopsy is helpful in
by a necrotizing scleritis indicates the presence of an establishing an etiologic diagnosis in some cases and
underlying systemic disease (Fig. 17.4).6 also helps in removing the limbal source of collagenases
and other factors causing progressive ulceration.
Biopsies are taken from the bulbar conjunctiva adjacent
Investigations to the ulcerating cornea. In selected cases, episcleral ,
The various investigations in a case of PUK includes scleral and /or corneal tissue may also be excised and
systemic as well as ocular investigations. The tests for analyzed.
systemic evaluation should be done, wherever available.
HISTOLOGIC FINDINGS
The various laboratory tests should focus on the
suspected underlying systemic disease and include the In cases of biopsied specimens any evidence of vasculitis,
following: perivasculitis, granulomas, eosinophils, mast cells and
165
4 Specific Types of Keratitis
neutrophil and lymphocyte infiltrate should be Immunosuppressive Therapy
documented to corroborate the diagnosis of collagen
It is generally seen that in cases of PUK associated with
vascular disease. However, vasculitis may be segmental
systemic diseases, recurrences following symptomatic
and focal and hence a single negative biopsy does not
treatment are common.
rule it out.
The systemic immunosuppression therapy is
In Mooren’s ulcer, corneal thickening occurs at the
indicated in cases of PUK in the following situations:14
margin of the ulcer where inflammatory cells have
1. PUK unresponsive to aggressive conventional
invaded the anterior stromal layers. However, the
inflammation is nonspecific, and no etiologic agent can medical and surgical therapy
be identified. Necrosis of the involved epithelium and 2. Bilateral and/or progressive Mooren’s ulcer
stroma is seen. 3. PUK associated with potentially lethal systemic
vasculitic syndromes, such as PAN, RA, SLE, RP,
WG, PSS, Sjögren’s syndrome, allergic angiitis of
Treatment Churg-Strauss, and giant cell arteritis
The treatment is aimed towards promoting epithelial 4. PUK associated with necrotizing scleritis with
wound repair and limiting ulceration and supporting vasculitis based on histopathologic analysis.
the repair process.
Corticosteroids
Medical Therapy High dose oral prednisone is started, as the chemo-
The local treatment is aimed at preventing or reducing therapeutic agents begin to act optimally only after
the epithelial defect, while systemic treatment is given 4-6 weeks. Prednisone is given 1-1.5 mg/kg/d initially
to treat the underlying disease. One of the aims of (not to exceed 60-80 mg/d) (Table 17.2). The dose is
treatment is epithelization of the ulcer, which will halt adjusted on the basis of the clinical response and adverse
the progression of the corneal ulceration. effects.
Prednisone
Adult dose 1 mg/kg/d PO initially; not to exceed 60-80 mg/d
Mechanism of action Provides prompt suppression of inflammatory and immunologic reaction
FOLLOW-UP
Continued, possibly lifelong, follow-up care is necessary
even after complete resolution since relapses may occur.
Furthermore, many patients may require prolonged
systemic steroid, non-steroidal anti-inflammatory, and/
or chemotherapeutic medications for the systemic
disease despite a quiet eye. Figure 17.5: Rheumatoid melt
168
Peripheral Ulcerative Keratitis 4
scleritis is approximately 50 percent. Appropriate
systemic therapy in addition to topical treatment helps
in effective management of the disease.
WEGENER’S GRANULOMATOSIS
This is a rare multi-system granulomatous necrotizing
vasculitis characterized by respiratory and renal
involvement. Ocular involvement occurs in upto 50 to
60 percent.2 The associated conjunctivitis and scleritis
may progress to PUK or PUK may be present as an
isolated finding. The sclera is usually involved in these
cases and this differentiates it from Mooren’s ulcer in
which sclera is generally not involved.
A laboratory test, which helps in the diagnosis of
Wegener’s granulomatosis, is the serum anti-neutrophil Figure 17.6: Staphylococcal marginal keratitis
cytoplasmic antibody (ANCA) test. 9 ANCA titers
correlate with the severity and extent of the disease and detection of antibodies to double stranded (dsDNA) is
tend to decrease in remission of the disease. Two specific for SLE. No laboratory test is specific for
patterns of staining are associated with this test –the C- relapsing polychondritis. Dry eye is seen in about 70
ANCA (cytoplasmic anti-neutrophil cytoplasmic percent of systemic sclerosis patients. PUK may occur
antibody) and the P-ANCA (perinuclear anti-neutrophil unrelated to the KCS.
cytoplasmic antibody). The C-ANCA test has 99 percent
specificity and 96 percent sensitivity. This test also helps
STAPHYLOCOCCAL MARGINAL KERATITIS
to follow the clinical response to therapy and chances
of recurrence of PUK are more if these values have not Staphylococcal marginal keratitis occurs in a patient with
normalized, despite apparent clinical remission when chronic blepharitis. This presents as a peripheral
therapy has been tapered or discontinued.3 infiltrate with breakdown of the overlying epithelium
(Fig. 17.6). There is a clear zone between the infiltrate
POLYARTERITIS NODOSA and limbus. Pain is not a significant feature as in a case
Mooren’s ulcer. Immune complex mediated reactions
PAN is a rare multi-system disease with necrotizing against the microbial antigens have been attributed to
vasculitis of the small and medium sized arteries. cause the ulceration.
Histopathological identification of the vascular changes
is diagnostic of PAN. The various ophthalmic manifes- TERRIEN’S MARGINAL DEGENERATION (TMD)
tations include choroidal vasculitis (most common
ophthalmic manifestation), PUK, conjunctival lesions, TMD is usually non-inflammatory and does show
scleritis, choroiditis, central retinal artery occlusion are features of corneal ulceration. It is more common in
the various ophthalmic manifestations. The clinical males and is asymmetrical. TMD begins superiorly as
characteristics of PUK in this disease are similar to those fine punctate stromal opacities and a clear zone exists
of Mooren’s ulcer. Hepatitis B surface antigen is positive between the limbus and the infiltrate. Superficial
in about 50 percent patients with PAN. Systemic vascularization is also present. However, the epithelium
immunosuppressive therapy is the key to retard the overlying is intact. The peripheral thinned zone is
progression of PUK. determined by a white lipid line at its central edge (Fig.
17.7). Slowly progressive thinning spreads circum-
ferentially and causes irregular astigmatism. An oblique
OTHER COLLAGEN VASCULAR DISEASES (CVD)
pseudopterygium is associated in about 20 percent of
PUK is rarely seen in other CVD such as systemic cases and perforation may occur due to trivial trauma.
sclerosis, SLE and RP. The clinical profile and the Recurrent inflammation, scleritis/episcleritis is rarely
laboratory tests help in confirming the diagnosis. The seen.
169
4 Specific Types of Keratitis
SENILE FURROW DEGENERATION (SFD) Males have a greater predilection for this disorder
(1.6 times).16
SFD is thinning of the interval between the limbus and
the arcus senilis and occurs in the elderly.
Types of Mooren’s Ulcer
ROSACEA KERATITIS Mooren’s ulcer has been classified into 2 groups accord-
ing to the age of onset and the clinical characteristics.17
Ocular rosacea is a relatively common disorder. The Type I is benign and usually unilateral with mild to
diagnosis largely rests on its association with the moderate symptoms. It occurs in older people (over 35
cutaneous disease characterized by persistent erythema, years) and usually responds well to medical and surgical
telangiectasia, papules and pustules and hypertrophic treatment (Fig. 17.9). Type II is malignant and occurs in
sebaceous glands of the face and neck. Ocular involve- younger patients (< 35 years) and is more likely to be
ment is seen in upto 58 percent of cases and ranges from bilateral (in 75% cases) with relatively more pain and
chronic blepharoconjunctivitis to neovascularization and poor response to therapy (Fig. 17.10).
thinning. PUK is rarely associated with ocular rosacea.
The lesion begins as vascularized marginal subepithelial Pathogenesis
infiltrates, which are initially small and round. Untrea-
ted cases progress to ulcers spreading towards the center Autoimmunity is suspected to be involved in the
of the cornea (Fig. 17.8). Oral tetracycline (250 mg pathogenesis of Mooren’s ulcer based on evidence of
4 times/day) or doxycycline (100 mg bd) is effective circulating antibodies18,19 to the corneal stroma and
along with topical corticosteroids which is given for 4 specific cell mediated immune reaction toward a
to 6 weeks duration. partially purified corneal antigen (Co-Ag). Reports have
described the presence of inflammatory cells,
immunoglobulin and increased expression of HLA class
MOOREN’S ULCER
II molecules in the cornea and conjunctiva, adjacent to
Definition the ulcers.20
The triggering factor instigating this autoimmune
Mooren’s is a chronic. It is characterized by the presence response is not clearly known. Privileged corneal
of an overhanging edge overlying central and leading antigens may become the target of the patient’s immune
edge that starts in the periphery and may progress system by local exposure of these antigens due to corneal
centrally or circumferentially to involve the entire cornea trauma, surgery or infection.21,22 It has been proposed
(Fig. 17.9). that organisms such as a helminth 23 stimulate the
170
Peripheral Ulcerative Keratitis 4
Figure 17.9: Mooren’s ulcer Figure 17.10: Mooren’s ulcer malignant preoperatively
production of antibodies that cross-react with corneal spreads circumferentially and then centrally to involve
antigens and cause ulcer. Mooren’s ulcer has occurred the entire cornea eventually. The anterior 1/3 to 1/2 of
following corneal trauma and eye surgery.22 the stroma is involved characteristically with a steep
overlying central and leading edge. Healing and
Histopathology vascularization occurs slowly over 4-18 months. Parts
Pathological examination of the specimens of involved of the ulcer may be quiescent while the remaining may
corneal tissue have shown presence of plasma cells, be active (Fig. 17.11). The end stage is a typical scarred,
neutrophils, mast cells and eosinophils in the involved vascularized thinned cornea with the patient experienc-
regions.24 There was destruction of the collagen matrix. ing sudden relief from the excruciating pain.
Epithelium and Bowman’s layer were absent. Midtroma Adjacent conjunctiva may be inflamed and viritis is
showed hyperactivity of fibroblasts with disorganization sometimes associated with Mooren’s ulcer. Hypopyon
of the collagen lamellae. The deep stroma was intact is rare unless secondary infection is present. Sometimes
but contained heavy macrophage infiltration. Heavy there may be associated glaucoma and cataract.
neutrophil infiltration and dissolution of the superficial Perforation is rare, though it can occur, especially follow-
stroma were present at the leading edge of the ulcer. ing trivial trauma due to the presence of weakened
Adjacent conjunctiva shows epithelial hyperplasia and cornea (Fig. 17.12).
a subconjunctival lymphocytic and plasma cell
infiltration. Diagnosis
Clinical Features Investigations include laboratory investigations to rule
Patients with Mooren’s ulcer will complain of redness out several systemic diseases leading to PUK. These
of the eye, tearing and photophobia, but pain is typically include immunology and dermatology workup, X-ray
the outstanding feature. The pain is excruciating and chest and sinus X-ray, Mantoux, hemogram, liver and
may seem well out of proportion the corneal inflam- renal function tests, rheumatoid factor, autinuclear
mation. Decreased visual acuity may be secondary to antibody (ANA), antineutrophil cytoplasmic antibody
associated iritis irregular astigmatism due to the (ANCA), complement fixation, angiotensin converting
peripheral corneal thinning. enzyme, VDRL, hepatitis B, hepatitis C and HIV antigen
The disease may begin as several patchy peripheral detection, serum protein electrophoresis and stool
stromal infiltrates that then coalesce, commonly in the examination. Scrapings should be done to rule out
region of the palpebral fissure. Generally there is infectious pathology per se or secondary infection due
involvement upto the limbus. The ulcerative process to Mooren’s ulcer.
171
4 Specific Types of Keratitis
Figure 17.11: Healing Mooren’s ulcer Figure 17.12: Mooren’s ulcer with perforation
Figure 17.13A: Mooren’s ulcer preoperatively Figure 17.13B: Mooren’s ulcer after crescentic patch graft
The lenticules form a biological barrier between the host 4. Carson DA. Rheumatoid factor. In: Kelley WN, Harris
cornea and the conjunctiva which is the source of ED Jr, Ruddy S, Sledge CB (Eds): Textbook of Rheuma-
immunological mediators. This procedure can be tology. 3rd ed. Philadelphia: WB Saunders Co; 1989;664-
79.
combined with a corneoscleral lamellar graft.
5. Foster CS, Forstot SL, Wilson LA. Mortality rate in
rheumatoid arthritis patients developing necrotizing
Superficial Keratectomy scleritis or peripheral ulcerative keratitis. Effects of
Superficial lamellar keratectomy along with conjunctival systemic immunosuppression. Ophthalmology 1984;
91:1253-63.
resection including the resection of the overhanging lip
6. Gregory JK, Foster CS. Peripheral ulcerative keratitis in
of the ulcerating cornea and application of tissue the collagen vascular diseases. Int Ophthalmol Clin 1996;
adhesive with bandage soft contact lens application or 36:21-30.
amniotic membrane has been described. 7. Hoang-Xaun T, Foster CS, Rice BA. Scleritis in relapsing
polychondritis. Response to therapy. Ophthalmology
Keratoplasty 1990;97:892-8.
8. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for
In advanced cases surgery may be done in two stages, the use of immunosuppressive drugs in patients with
that is initial lamellar tectonic grafting followed by ocular inflammatory disorders: Recommendations of an
central penetrating keratoplasty. Lamellar keratoplasty expert panel. Am J Ophthalmol 2000;130:492-513.
removes antigenic targets of the cornea, prevents 9. Ludemann G, Gross WL. Autoantibodies against
immunological reactions, reconstructs the anatomical cytoplasmic structures of neutrophil granulocytes in
structure, prevents perforation and improves vision (Figs Wegener’s granulomatosis. Clin Exp Immunol 1987;
69:350-7.
17.13A and B).
10. Messmer EM, Foster CS. Vasculitic peripheral ulcerative
keratitis. Surv Ophthalmol 1999;43:379-96.
References 11. Mondino BJ. Inflammatory diseases of the peripheral
cornea. Ophthalmology 1988;95:463-72.
1. Brown SI, Grayson M. Marginal furrows. A characteristic 12. Robin JB, Schanzlin DJ, Verity SM, et al. Peripheral
corneal lesion of rheumatoid arthritis. Arch Ophthalmol corneal disorders. Surv Ophthalmol 1986;31:1-36.
1968;79:563-7. 13. Shiuey Y, Foster CS. Peripheral ulcerative keratitis and
2. Bullen CL, Liesegang TJ, McDonald TJ, DeRemee RA. collagen vascular disease. Int Ophthalmol Clin 1998;
Ocular complications of Wegener’s granulomatosis. 38:21-32.
Ophthalmology 1983;90:279-90. 14. Tauber J, Sainz de la Maza M, Hoang-Xuan T, Foster
3. Foster CS, Sainz de la Maza M. Immunological consi- CS. An analysis of therapeutic decision making regard-
derations of the sclera. In: Foster CS (Ed): The Sclera. ing immunosuppressive chemotherapy for peripheral
1st ed. New York: Springer-Verlag 1993;33-58. ulcerative keratitis. Cornea 1990;9:66-73.
173
4 Specific Types of Keratitis
15. Atchia II, Kidd CE, Bell RW. Rheumatoid arthritis- 23. Zelefsky JR, Srinivasan M, Kundu A, Lietman T,
associated necrotizing scleritis and peripheral ulcerative Whitcher JP, Wang K, et al. Hookworm Infestation as a
keratitis treated successfully with infliximab. J Clin Risk Factor for Mooren’s Ulcer in South India.
Rheumatol 2006;12:291-3. Ophthalmology 2006.
16. Lewallen S, Courtright P. Problems with current 24. Young R, Watson P. Light and electron microscopy of
concepts of the epidemiology of Mooren’s corneal ulcer. corneal melting syndrome (Mooren’s Ulcer). Br J
Ann Ophthalmol 1990;22:52-5. Ophthalmol 1982;66:341-56.
17. Wood TO, Kaufman HE. Mooren’s ulcer. Am J
25. Wakefield D, McCluskey P, Penny R. Intravenous pulse
Opthalmol 1971;71:417-22.
methylprednisolone therapy in severe inflammatory eye
18. Brown SI, Mondino BI, Rabin BS. Autoimmune pheno-
disease. Arch Ophthalmol 1986;104:847-51.
menon in Mooren’s ulcer. Am J Ophthalmol 1976; 82:
835-40. 26. Zhao J, Jin X. Immunological analysis and treatment of,
19. Gottsch ID, Liu’SH, Minkovitz IB, et al. Autoimmunity Mooren’s ulcer with cyclosporine A applied topically.
to a cornea-associated stromal antigen in patients with Cornea 1993;12:481-8.
Mooren’s ulcer Invest Ophthalmol Vis Sci 1995;36:1541- 27. Wakefield D, Robinson LP. Cyclosporin therapy in
7. Mooren’s ulcer. Br J Ophthalmol 1987;71:415-7.
20. Zhao JC, Jin XY. Immunological analysis and treatment 28. Agrawal V, Kumar A, Sangwan V, Rao GN. Cyanoacry-
of Mooren’s ulcer with cyclosporin A. Cornea 1993; late adhesive with conjunctival resection and superficial
12:481-8. keratectomy in Mooren’s ulcer.Indian J Ophthalmol
21. Wilson SE, Lee WM, Murakami C, Weng J, Moninger 1996;44:23-7.
GA. Mooren’s corneal ulcers and hepatitis C virus 29. Kinoshita S, Ohashi Y, Ohji M, Manabe R. Long-term
infection. N Engl J Med 1993;329:62. results of keratoepithelioplasty in Mooren’s ulcer.
22. Mondino BJ, Hofbouer JD, Foos RY. Mooren’s ulcer after Ophthalmology 1991;98:438-45.
penetrating keratoplasty. Am J Ophthalmol 1987;103:53-
6.
174
Intracameral Antibiotics 5
18 Intracameral Antibiotics
177
5 Surgical Management
cornea is seen which aids in visualization of the track of taken not to damage the corneal endothelium, especially
the needle. A 22 gauge needle is usually used. when endothelial plaque is being aspirated. Further,
Viscoelastic such as hydroxypropyl methylcellulose may sometimes it may become necessary to leave a part of
be used for viscoexpression of the anterior chamber the exudate, especially if the anterior capsule is involved,
exudates. If the exudate cannot be removed, the anterior as this may injure the lens and cause cataract.
chamber may be entered with no. 11 surgical blade and Smears should be prepared for KOH wet mount
the exudate removed with forceps or a Simcoe cannula preparation, Gram’s and Giemsa stains and culture
may be used to aspirate the exudate. Care should be media such as blood agar, chocolate agar, non-nutrient
TABLE 18.1
Summary of cases who received intracameral amphotericin B for mycotic keratitis
Author, year No. Age/ Initial Ulcer size Dose of No. of Final VA Organism Outcome
sex VA (mm) amphotericin injec-
B (μg) tions
178
Intracameral Antibiotics 5
agar, and thioglycollate broth should be inoculated. Acanthamoeba, Aspergillus species and Cryptococcus
Intracameral injection of amphotericin B 7.5 mg in species.
0.1 ml is prepared as described previously and injected.
The wound is then closed with a 10-0 monofilament Summary
nylon suture.
Presently, the intracameral injection of antimicrobials is
Repeat Injections used only to treat some cases of deep mycotic keratitis.
Repeat injections are given based on the clinical
References
response. In cases of non-responding cases, a repeat
injection may be considered after a time interval of 1 to 1. Naumann G, Green WR, Zimmerman LE. A histo-
5 days. pathologic study of 73 cases. Am J Ophthalmol
Generally the response to intracameral amphotericin 1967;64:668-82.
2. Abad JC, Foster CS. Fungal keratitis. Int Ophthalmol
B is monitored by the following parameters: A clinical
Clin 1996 Summer;36:1-15.
response is present when the size of the epithelial defect, 3. O’Day DM, Head WS, Robinson RD, Clanton JA.
ulcer infiltrates and hypopyon decreases. The corneal Corneal penetration of topical amphotericin B and
infiltrates become rounded, there is visible shrinking of natamycin. Curr Eye Res 1986;5:877-82.
the endothelial plaque and pigmentation on the surface 4. Kaushik S, Ram J, Brar GS, Jain AK, Chakraborti A,
of the endothelial plaque (Figs 18.1 and 18.2). Although Gupta A. Intracameral amphotericin B: initial experience
a maximum of 13 injections have been reported, we in severe keratomycosis. Cornea 2001;20:715-9.
5. Kuriakose T, Kothari M, Paul P, Jacob P, Thomas R.
prefer not to give more than 4 injections. These injections
Intracameral amphotericin B injection in the manage-
are given from the site of the first injection. ment of deep keratomycosis. Cornea 2002;21:653-6.
6. Sridhar MS, Sharma S, Gopinathan U, Rao GN. Anterior
RESULTS chamber tap: Diagnostic and therapeutic indications in
the management of ocular infections. Cornea 2002;21:
In the various studies in literature as well as in our
718-22.
experience intracameral amphotericin B is safe and 7. Bharadwaj PC, Shrivastava KN, Lall K, Varma V.
efficacious in treating deep keratomycosis and non- Intracameral injections of framycetin sulphate
responsive mycotic keratitis (Table 18.1). The patients (Soframycin) in fulminating corneal infections. A clinical
may complain of pain immediately after the injection trial. Br J Ophthalmol 1969;53:185-7.
and there may be transient uveitis and an exudative 8. Agarwal LP, Malik SR, Dhir SP. Intracameral injection
membrane during the first 24 hours. The time from the of Framycetin (soframycin). Ophthalmologica 1962;
first injection to the complete resolution of the 144:311-5.
endothelial plaque ranges from 13 to 52 days. The 9. Foster JB, Almeda E, Littman ML, Wilson ME. Some
intraocular and conjunctival effects of amphotericin B
various organisms, which have been isolated from the
in man and in the rabbit. AMA Arch Ophthalmol 1958;
anterior chamber tap, include Cladosporium species, 60:555-64.
179
5 Surgical Management
19 Glue Application
METHOD OF APPLICATION
MODIFICATION OF THE TECHNIQUE
The cyanoacrylate glue may be applied with various
The adherence of the glue is limited by the size of the
devices, which include tuberculin syringe, applicators
defect and the condition of the surrounding tissue to
and aerosol application.9-12
which the glue is bonding (Fig 19.2). Reapplication may
Materials Required be required in case of continued corneal stroma melting
or persistent wound leak. Various modifications have
Histoacryl glue
been made in the application of the glue. These include
1 mL syringe and 26 gauge needle
the following:
Weckcel sponges
Direct Application method: Overlapped Applications
• The glue is loaded in a 1ml tuberculin syringe with Larger defects can be treated with multiple applications
a fresh 26 G needle. overlapped if necessary.
• Topical anesthesia with 0.5 percent proparacaine
eye drops is instilled. Using a Suture
• The lid speculum is inserted gently as the eye is A running 10/0 nylon suture is used to create a
perforated and soft. reticulum over the defect on which the glue is applied
• The surface is dried completely. in case of larger defects (> 3 mm).13 This is followed by
• The adjacent epithelium is scraped. the application of the bandage contact lens.
• If the anterior chamber is flat and the defect is large
(>2 mm), the anterior chamber may be reformed Viscoelastics
with air or viscoelastic to enable easier application The sodium hyaluronate can be used as a visco-
of the glue. maintainer/retainer prior to application of the corneal
• The syringe is then gently screwed in small turns glue in situations where anterior chamber is com-
(for controlled release) to express the glue onto the promised and/or intraocular contents are tending to
26 G needle tip. Alternatively the bead of the glue prolapse through the perforation site.9 The viscoelastic
may be dripped on to a fresh 26 G needle tip for is useful as it prevents the intraocular structures from
better results. adhering to the glue.
• The region to be treated is touched with the tip of
the needle containing the glue drop. Corneal Patch
• After waiting for 2 minutes, a bandage contact lens A dermatological punch is used to cut three or four
is applied. circular patches of the non-stick portion of opsite plastic
181
5 Surgical Management
Figures 19.3A and B: Glue application in perforated corneal ulcer (Corneal patch technique) (Courtesy: Medical Photographic Imaging
Centre, Royal Victorian Eye and Ear Hospital, Melbourne)
or the steridrape. The opsite is picked with a stick, which more than 6 weeks especially with the therapeutic
is dipped in a K-Y jelly and the cyanoacrylate glue is contact lenses. Rare report of retinal toxicity, cataracts
applied over the patch with a 26 gauge needle which is and granulomatous keratitis are also there.15
mounted on a tuberculin syringe and this patch is then
applied at the site of the perforation (Figs 19.3A and B). References
This procedure is effective in healing of the small
1. Hirst LW, Smiddy WE, Stark WJ. Corneal perforations;
corneal perforations. In larger perforations such as in
changing methods of treatment, 1960-1980.
cases of sterile melts this procedure helps in delaying Ophthalmology 1982;89:630-4.
surgery which can be performed as an elective proce- 2. Refojo MF, Dohlman CH. The tensile strength of
dure at a later date under more optimal conditions of adhesive joints between eye tissues and alloplastic
controlled inflammation. materials. Am J Ophthalmol 1969;68:248-55.
3. Refojo MF, Dohlman CH, Ahmad B, Carroll JM, Allen
POSTOPERATIVE MANAGEMENT JC. Evaluation of adhesives for corneal surgery. Arch
Ophthalmol 1968;80:645-56.
Topical prophylactic antibiotic drops should be used at
4. Hirst LW, Stark WJ, Jensen AD. Tissue adhesives: New
2 hourly intervals for the first three days followed by perspectives in corneal perforations. Ophthalmic Surg
four times daily. Additionally, lubricants should also 1979;10:58-64.
be given. One should monitor the degree and time to 5. Weiss JL, Williams P, Lindstrom RL, Doughman DJ. The
epithelialization, vascularization, and corneal thickeness. use of tissue adhesive in corneal perforations. Ophthal-
Any evidence of extrusion of the glue or infection, mology 1983;90:610-15.
especially at 3 to 5 weeks should also be be monitored. 6. Kim JC, Bassage SD, Kempski MH, et al. Evaluation of
tissue adhesives in closure of scleral tunnel incisions. J
ADVERSE EFFECTS Cataract Refract Surg 1995;21:320-5.
7. Eiferman RA, Snyder JW. Antibacterial effect of
Application of cyanoacrylate glue to the conjunctiva, cyanoacrylate glue. Arch Ophthalmol 1983;101:958-60.
sclera or skin causes greater tissue reaction than to the 8. Hirst LW, De Juan Jr E. Sodium hyaluronate and tissue
corneal epithelium and stroma. The tissue histotoxicity adhesive in treating corneal perforations. Ophthal-
is generally less with the newer cyanoacrylates. The side mology 1982;89:1250-3.
9. Wessels IF, Mcneill JI. Applicator for cyanoacrylate
effects of the glue application include the scarring of
tissue adhesive. Ophthalmic Surg 1989;20:211-4.
the conjunctiva and giant papillary conjunctivitis.14,15 10. Quillen DA, Rosenwasser GO. Aerosol application of
Inadvertent instillation of cyanoacrylate glue into the cyanoacrylate adhesive. J Refract Corneal Surg 1994;10:
anterior chamber can result in polymerization of the 149-50.
corneal endothelium and iridocorneal and iridolenti- 11. Erdey RA, Lindahl KJ, Temnycky GO, Aquavella JV.
cular adhesions.16 Close monitoring for infection/corneal Techniques for application of tissue adhesive for corneal
infiltrate is essential when the glue has been present for perforations. Ophthalmic Surg 1991;22:352-4.
182
Glue Application 5
12. Vote BJT, Elder MJ. Cyanoacrylate glue for corneal 15. Leahey AB, Gottsch JD, Stark WJ. Clinical experience
perforations: A description of a surgical technique and with N-butyl cyanoacrylate (Nexacryl) tissue adhesive.
a review of literature 2000;28:437-42. Ophthalmology 1993;100:173-80.
13. Moschos M, Droutsas D, Boussalis P, Tsioulias G. 16. Markowitz GD, Orlin SE, Frayer WC, Andrews AP,
Clinical experience with cyanoacrylate tissue adhesive. Prince RB. Corneal endothelial polymerisation of
Doc Ophthalmol 1996-97;93:237-45. histoacryl adhesive: A report of a new intraocular
14. Carlson AN, Wilhelmus KR. Giant papillary conjuncti- complication. Ophthalmic Surg 1995;26:256-8.
vitis associated with cyanoacrylate glue. Am J
Ophthalmol 1987;104:437-8.
183
5 Surgical Management
20 Conjunctival Flaps
Advancement Flaps
Indications
An advancement conjunctival flap is be used to cover a
A conjunctival flap is principally used to treat recalci- peripheral limbal or paralimbal corneal lesion such as
trant sterile corneal ulcers.2 Conjunctival flaps provide following a limbal dermoid excision.2 A limbal incision
a smooth ocular surface and also help in tectonic support with relaxing incisions is made and the flap is advanced
and nutrition to a chronic, non-healing corneal ulcer. over the peripheral lesion and sutured onto the
The major indications of conjunctival flaps are: conjunctiva (Fig. 20.1). Peripheral patch grafts and
1. Neurotrophic corneal ulcers3 sclerocorneal grafts may also be covered by these
2. Neuroparalytic keratitis4 advancement flaps. However, such flaps usually retract
3. Exposure keratitis and gape over a period of time.
4. Peripheral ulcerative keratitis
Conjunctival flaps may be rarely used in non- Single Pedicle Flaps (Racquet Flaps)
responding fungal and bacterial keratitis with damage The flaps were advocated for peripheral and paracentral
to epithelial basement membrane damage, which lesions, which are not large enough to require a complete
hinders the surface healing. However, most corneal flap. Subconjunctival lidocaine with 1: 100,000
specialists do not like to perform conjunctival flaps due epinephrine may be used to balloon the area of the
to the following reasons: conjunctiva to be undermined.The adjacent pedicle of
1. Conjunctival flaps obscure the view of the ulcerated conjunctiva is fashioned and is placed on the peripheral
area hindering the monitoring of the progression of corneal lesion and sutured. Although technically more
corneal ulcer. difficult than a simple advancement flap, it has the
2. Penetration of the antimicrobial agents may be advantage that the retraction of the flap does not occur.
suboptimal.
Bipedicle Flaps (Bucket Handle Flaps)
CONTRAINDICATIONS
These are used for small paracentral or limbal corneal
The contraindications of conjunctival flaps include the lesions that do not require the coverage of the whole
following: cornea2. The width of the flap should be 1.3 to 1.5 times
184
Conjunctival Flaps 5
Figure 20.1: Advancement flap (Courtesy: Medical photographic Figure 20.2: Gunderson flap (Courtesy: Medical photographic imaging
imaging centre, Royal Victorian Eye and Ear Hospital, Melbourne) centre, Royal Victorian Eye and Ear Hospital, Melbourne)
the width of the lesion. The flap is fashioned with two times a day for one week along with a cycloplegic agent.
pedicles from the limbal conjunctiva spanning the width The suture removal is done at one month.
of the lesion and placed on the lesion and fixed with
sutures. Complications
The complications may occur intraoperatively or post-
Total Conjunctival Flap (Gunderson Flap)
operatively.
This is performed for large lesions requiring coverage
of the total cornea.6 The superior bulbar conjunctiva is Intraoperative
ballooned with injection of 2 ml of 2 percent lignocaine
with 1 in 100,000 dilution of adrenaline into the Intraoperatively, button-holing of the conjunctiva may
subconjunctival space anterior to the Tenon’s capsule. occur which should be avoided by careful and meti-
This aids in easy dissection. The bulblar conjunctiva culous dissection of the conjunctiva. In case a button-
starting from the superior fornix is dissected free from hole occurs, it should be sutured with a non-absorbable
the Tenon’s capsule upto the 10 and 2 O’ clock positions. suture.
All tension on the flap is relieved by dissection.
After debridement of the corneal epithelium, the
Postoperative
pedicle is placed over the cornea. In cases of irregular
corneal surface a superficial keratectomy may be Postoperatively, retention of the conjunctival cyst may
required. The cornea is then irrigated meticulously with occur due to in curling of the conjunctival edges.
balanced salt solution and care is taken to maintain the However, these do not cause too much of a problem
correct orientation of the flap. The flap is then positioned and may be left alone.
on the cornea and anchored to the limbus or sclera with Further, occurrence of the herpetic infection in the
interrupted 7-0 silk or other non-absorbable material conjunctival flap has also been reported.7,8
sutures (Fig. 20.2). The superior sclera is left bare which
re-epithelialises rapidly. An inferior flap can be similarly
fashioned if required.
Summary
Conjunctival flaps have limited usefulness in the modern
Postoperative Therapy
day era. They may be used in cases of indolent painful
Postoperatively, a broad-spectrum fluoroquinolone such corneal ulcers. Successful keratoplasty is possible after
as 0.3 percent ciprofloxacin or ofloxacin is given four performance of these flaps.
185
5 Surgical Management
References 5. Nichols BD. Conjunctival flaps. In: Krachmer JH, Mannis
MJ, Holland EJ (Eds): Cornea: Surgery of the Cornea
and Conjunctiva. Vol III. Mosby St. Louis 1997 Chapter
1. Gunderson T. Conjunctival flaps in the treatment of
155;1903-10.
corneal disease with reference to a new technique of
6. Maguire LJ, Shearer DR. A simple method of conjunc-
application. Arch Ophthalmol 1958;60:880-8.
tival dissection for Gunderson flaps. Arch Ophthalmol
2. Mannis MJ. Conjunctival flaps. Int Ophthalmol Clin
1991;109:1168-9.
1988;28:165-8.
7. Rosenfeld SI, Alfonso EC, Gollamudi S. Recurrent herpes
3. Lugo M, Arentsen JJ. Treatment of neurotrophic ulcers simplex infection in a conjunctival flap. Am J Ophthal-
with conjunctival flaps. Am J Ophthalmology 1987;103: mol 1993;116:242-4.
711-2. 8. Lesher MP, Lohman LE, Yeakley W, Lass J. Recurrence
4. Donzis PB, Mondino BJ. Management of noninfectious of herpetic stromal keratitis after a conjunctival flap
corneal ulcers. Surv Ophthalmol 1987;94-110. surgical procedure. Am J Ophthalmol 1992;114:231-3.
186
Therapeutic Keratoplasty 5
21 Therapeutic Keratoplasty
FUNGAL KERATITIS
Therapeutic keratoplasty is more often required as
compared to cases bacterial keratitis in the management Figure 21.3: Perforated corneal ulcer
of refractory fungal corneal ulcers. 3-5,7,10,11,15 The
incidence of cases requiring a therapeutic keratoplasty
in fungal keratitis varies from 18-29 percent.3,5,11,15 OTHER INDICATIONS
Apart from infectious keratitis, therapeutic keratoplasty
ACANTHAMOEBA KERATITIS is also undertaken in large corneal perforations
Due to the availability of effective and newer anti- secondary to keratoconjuctivitis sicca as in Sjögren’s
acanthamoebic medications early and moderately syndrome, Rosacea, ocular cicatricial pemphigoid, riley
advanced cases may be successfully treated with medical day syndrome, post-radiation dry eye and collagen
treatment alone.16-20 In the management of advanced vascular diseases such as rheumatoid arthritis4,39,40
cases, which are unresponsive to medical therapy a (Figs 21.3 and 21.4). It may also be undertaken in cases
therapeutic corneal transplantation alone or in combi- of perforation secondary to persistent epithelial defect,
nation with cryotherapy of the host cornea has been which may become secondarily infected such as in cases
recommended.2,16-19 Although some surgeons recom- of neurotrophic keratitis, chemical burns, Stevens-
mend early keratoplasty in cases of Acanthamoeba Johnson syndrome, neuroparalytic keratitis and
keratitis to remove the bulk of infiltration and to reduce recurrent erosion syndrome.4,40
the risk of scleral extension,17 presently a therapeutic
penetrating keratoplasty in Acanthamoeba keratitis is Timing of Surgery
performed for advanced cases that are unresponsive to
medical management.18, 20 A review of 38 case reports Timing of the surgery also relates to the success of the
of Acanthamoeba keratitis in various studies of different therapeutic graft. A few reports suggest that a delay in
authors showed that 29 patients required a transplant the surgery improves the surgical outcome. Nobe et al
surgery.16-36 obtained a graft clarity rate of 17 percent with emergency
surgery (within 24 hours), 57 percent with intermediate
surgery(within 2-6 days) and 31 percent with a delayed
HERPES KERATITIS
surgery (1 week-2 months). Failure rate was highest if
A therapeutic keratoplasty may need to be performed the surgery was an emergent one. In a study by Foster
for necrotizing herpetic keratitis leading to extensive et al a graft clarity rate of 85 percent was achieved in
corneal melting and perforation37,38 (Figs 21.2 and 21.3). eyes that were initially managed with lamellar
Therapeutic keratoplasty is also performed in patients kerato-plasty or glue and bandage contact lens and a
who develop corneal perforations secondary to delayed penetrating keratoplasty compared to 17 percent
persistent epithelial defect with little or no stromal in eyes treated with a early penetrating graft for a
inflammation.4,37,38 perforation.38 Polack et al reported clear grafts in all the
188
Therapeutic Keratoplasty 5
involvement and size of the infiltrates particularly in
relation to the limbus.2-4 This facilitates planning of
surgical details such as size of trephine that has to be
used and its optimal placement in the recipient’s bed.
The presence of iris prolapse is diagnostic of a corneal
perforation. Topical fluorescein and a positive Seidel’s
test should be done to evaluate the size of a small
perforation (Figs 21.5A to C). The amount of anterior
segment inflammation is assessed carefully and the eye
is examined for other associated conditions like dry eye,
exposure, secondary glaucoma and endophthalmitis.39,40
INVESTIGATIONS
A and B scan ultrasonography is mandatory when the
Figure 21.4: Peripheral melt with secondary infection in rheumatoid integrity of globe is not compromised by a large
arthritis perforation, to assess the posterior segment involvement
and to rule out endophthalmitis especially when retina
is not visualized adequately.2
eyes with inactive herpes compared to a rate of 45
percent in grafts with active disease.37 PREOPERATIVE TREATMENT
Preoperatively, the patients may be given antibiotic
Preoperative Evaluation agents, antiglaucoma medications and some surgeons
even recommend the use of corticosteroids.
HISTORY TAKING
Anti-microbial Therapy
History taking should include a detailed assessment of
onset of symptoms, duration of symptoms, prior medical Both systemic and topical anti-microbial treatment is
therapy and /or any surgical intervention, information recommended preoperatively in all the patients2. The
about the type of organism isolated (if the records are treatment should be directed against the offending
available) and the response to medical therapy. agent. If preoperatively an etiologic diagnosis has not
been established, broad-spectrum antibiotic or a
OCULAR EXAMINATION combination therapy should be given.2 Donnenfeld et
al recommend use of topical ofloxacin at hourly
Prior to the surgery a detailed ocular examination is frequency in all cases undergoing therapeutic kerato-
mandatory. Initial assessment includes determination plasty regardless of the cause of infection to prevent
of best-corrected visual acuity and slit-lamp evaluation bacterial superinfection. They also recommend use of
to determine the depth and extent of the corneal Ofloxacin 400 mg every 12 hours before admission and
Figures 21.5A to C: Seidel’s test reveals presence of perforation (note the dark spot which is the site of the florescien leek)
189
5 Surgical Management
intravenous vancomycin and tobramycin after glycerin-preserved corneas and even sclera has been
hospitalization.3 suggested.44-46
conduit of the infectious organism from cornea to the given until the corneal epithelium has healed.3 Fungal,
anterior chamber.3 Longer sutures bites on the host side Acanthamoeba and viral keratitis may require
with moderate tension are preferred to avoid cheese antimicrobial treatment for several months post-
wiring of the suture through a potentially necrotic bed.3 operatively.2-4
All suture knots should be trimmed and buried on the In cases of bacterial keratitis we give topical fluoro-
host side2 (Figs 21.6A and B). Meticulous wound closure quinolones such as 0.3 percent ciprofloxacin or 0.3
is recommended even if it requires greater number of percent ofloxacin eye drops are given 2 to 4 hourly
sutures.2,3 Care should be taken to avoid any pressure initially along with systemic antibiotics.
over the globe through out the surgery. In cases of fungal keratitis, in addition to the above
regime, 5 percent natamycin eye drops five times a day
Microbiological and Pathological Examination are also added.
In cases of herpetic keratitis, in addition to the
In all cases, the corneal specimen is divided into two antibiotic, topical acyclovir 3 percent ointment is added
pieces and sent for microbial and histopathological 5 times a day in cases of keratitis subsequent to herpes
investigations. Material should be inoculated on blood simplex and systemic acyclovir is added in case of
agar, chocolate agar, Sabouraud’s agar without keratitis subsequent to herpes zoster.
cyclohexamide and blood agar coated with E.coli, for In cases of acanthamoeba keratitis, in addition to the
plating.3 The corneal specimen should also be sent for antibiotics, polyhexamethyl biguanide or brolene eye
histopathological evaluation for identification of the drops are given.
offending organisms.
STEROIDS
The use of topical steroids following a therapeutic
Postoperative Management keratoplasty for infectious keratitis is controversial.
The postoperative therapy consists of the use of Killingsworth et al and O’Day et al suggested that as
the infection is cured by surgery in virtually all the
antimicrobial agents and cycloplegics.
patients, aggressive use of both topical and systemic
steroids can be considered postoperatively in all cases
ANTIMICROBIAL THERAPY
to decrease the postinflammatory sequel and improve
There is a general consensus to give antimicrobial the visual outcome.4,41
postoperatively following therapeutic keratoplasty.2-4 As most of the bacterial corneal infections are
The duration of therapy depends on the severity of responsive to antibiotics therefore concomitant use of
infection and the causative organism and should be corticosteroids may be justified in an inflamed eye.4,41
192
Therapeutic Keratoplasty 5
Figures 21.7A to C: (A) Hypopyon corneal ulcer (B) No response maximal medical therapy (C) Therapeutic graft associated with hemorrhage
We give topical steroids in cases of bacterial keratitis Mild to moderate anterior uveitis is encountered in
in reduced frequency (8 hourly doses). However, in cases almost all cases (40-100%)6,7,51-53 and can be controlled
of recurrence of infection, and in cases of active fungal by judicious use of topical corticosteroids and cyloplegics
or Acanthamoeba infection after therapeutic (Figs 21.8A and B). O’Day et al advocates use of steroids
keratoplasty steroids should be avoided.4 In therapeutic even in fungal corneal ulcers.6,7,41 Severe iritis may lead
keratoplasty for herpetic keratitis, topical corticosteroids to formation of pupillary membrane in 3 to 9 percent
may be given without significant risk, as long as the cases.7,52
patient is managed with concomitant topical or oral
SECONDARY GLAUCOMA
antiviral therapy.41
Early postoperative increase in IOP(14-20%) occurs
Complications secondary to anterior chamber reaction and may require
topical and systemic anti-glaucoma treatment along with
The complications seen after therapeutic keratoplasty
anti-inflammatory therapy.2
include severe uveal inflammation, and reinfection of
Late onset secondary glaucoma results from
the graft along with other usual complications seen after
extensive peripheral synechiae and may lead to graft
a standard full thickness corneal transplantation surgery.
failure. The incidence of secondary glaucoma has been
reported to vary from 3 percent in keratoplasty for
HEMORRHAGE/HYPHEMA
Pseudomonal keratitis6 to 50 percent after keratoplasty
Postoperative hyphema results from inflamed iris and in fungal corneal ulcer.6,52,53 Our study showed a 19.46
if associated with raised intraocular tension requires percent incidence of glaucoma following therapeutic
evacuation2 (Figs 21.7A to C). keratoplasty.
UVEITIS
Figure 21.8A: Perforated corneal ulcer due to herpes Figure 21.8B: Postoperative uveitis after therapeutic graft
193
5 Surgical Management
Figures 21.9A and B: (A) Recurrence of infection in a therapeutic graft (B) Uncontrolled infection in the same case
196
Phototherapeutic Keratectomy 5
22 Phototherapeutic Keratectomy
198
Index
A B Clinical investigations 51
Clostridium 71
Acanthamoeba 13 Bacillus 18 Clotrimazole 29
Acanthamoeba infection 110 Bacterial keratitis 65, 125, 187 Coagulase negative staphylococci 17
Acanthamoeba keratitis 107, 126, 188 clinical features Cochet and Bonnet aesthesiometer 157
corneal involvement 108 signs 69 Collagen vascular diseases 169
cataract and glaucoma 110 symptoms 69 Collagenase inhibitors 159
iritis and hypopyon 110 contact lens use 66 Collection of samples 52
lids and conjunctiva involvement 110 etiologic organisms 67 Confocal microscopy 60, 72, 84, 113, 137
scleral involvement 110 microbiologic work up 71 Congenital ocular herpes 92
differential diagnosis 110 regional differences 67 Conjunctiva 41
epidemiology 107 risk factors 65 Conjunctival flap 160, 184
etiology 107 specific features complications 185
laboratory diagnosis alpha hemolytic streptococci 69 contraindications 184
anaerobes 71 indications 184
corneal scraping 111
gram-negative organisms 69 postoperative therapy 185
staining 111
other gram-negative rods 70 types
wet smear 111
specific organisms 67 advancement flaps 184
risk factors 107
actinomycetes 68 bipedicle flaps 184
contact lens wear 108
gram-positive aerobic bacilli 68 Gunderson flap 185
non-contact lens wearer 108
less common organisms 68 single pedicle flaps 184
signs 108 Connective tissue diseases 40
nonspore-forming anaerobic
symptoms 108 Contact lens 37
organisms 68
treatment 112 non-tuberculous mycobacteria 68 Contact lens induced keratitis 128
combination therapy 112 spore forming anaerobic bacteria 68 clinical features 129, 135
surgical treatment 114 staphylococcal organisms 67 management 130
Acetazolamide 31 systemic defense mechanisms 66 organisms 129
Acquired immunodeficiency syndromes 40 treatment 71 pathogenesis
Acridine orange 55 adjunctive therapy 73 altered tear dynamics 128
Actinomycetes 68 medical therapy 72 contact lenses 128
Acyclovir 30 specific drugs 73 contamination of contact lens care
Adenoviral infections 104 surgical therapy 74 systems 129
Adjuvants 31 systemic therapy 74 risk factors 128
Alpha blockers 167 Bacteriology 16 Contact lens induced peripheral ulcer 130
Aminoglycosides 26 Basal cells 4 Contact lens induced red eye 130
Amniotic membrane transplantation 114, 160 Basement membrane 4 Contact lens wear 78
Amphotericin B 28 Beta lactam antibiotics 25 Cornea 3
injection 177 Blood agar 22, 57 applied physiology 6
Anterior chamber 48 Bowman’s layer 4 blood supply 5
Anterior vitrectomy 191 Brain-heart infusion 58 defense mechanism 6
Antibacterial agents 25 broth 23 innervation 5
Antibiotic therapy 72 Bullous keratopathy 38 oxygen and nutritional supply 5
Antibiotics 166 structure 3
Antifungal agents 28 transparency 6
Antimicrobial susceptibility testing 60
C Cornea 41
Corneal biopsy 61, 113
Antiviral agents 30 Calcofluor white 55, 83 Corneal injuries 37
Aspergillus 15 Cataract surgery 140 Corneal scraping 52, 53, 111
Asymptomatic infiltrates 130 Cephalosporins 25 Corneal sensations 45, 156
Asymptomatic infiltrative keratitis 130 Chocolate agar 23, 57 Corneal stroma 4
Atropine 31 Chronic corneal inflammation 78 Corneal surgery 79
Azoles 29 Circulating antibodies 99 Corneal thinning/perforation 46
200 Corneal Ulcer: Diagnosis and Management
surgical therapy 152 Microbiology of graft infection 144 Ocular surface disorder 66
systemic therapy 152 clinical features 144 Ophthalmic varicella zoster 104
topical therapy 152 investigations 145 Orthokeratology 108
Keratoepithelioplasty 172 management 145
Keratoplasty 173 medical management 145
Ketoconazole 29 surgical 146 P
Kimura’s spatula 52 Micrococcus species 17
Microsporidia 13 Patch grafts 74
KOH wet mount preparation 82
Modified Grocott-Gomori methenamine-silver Pediatric keratitis 119
nitrate stain 21, 56 bacteria
L Moniliaceae 15 fungus 121
Monotherapy 72 nutritional 121
Lacrimal SAC 41
Lactophenol cotton blue 83 Mooren’s corneal ulcer 44 vernal keratoconjunctivitis 121
Mooren’s ulcer 170 viruses 121
Lamellar keratoplasty 114
clinical features 171 clinical examination 123
Lens surgery 191
Lid and adnexal infections 38 diagnosis 171 diagnosis 122
pathogenesis 170 etiology 121
Light microscopy 136
treatment 172 investigations 123
Limbal conjunctivectomy 172
Linear endothelitis 98 types 170 laboratory investigations 124
Moraxella 19 systemic investigations 124
Listeria monocytogenes 71
Moraxella species 68 management
Löwenstein-Jensen media 23, 58
Moraxella ulcers 70 medical therapy 125
Mycobacterium 18 post-resolution management 126
M Mycology 14 surgical therapy 126
predisposing factors 119
Macrolides 26 contact lens wear 120
Mannitol 31 N pre-existing external eye disease/
Marginal keratitis 94
surgery 121
Methotrexate 166 Natamycin 28 systemic factors 119
Miconazole 29
Necrotizing stromal keratitis 102 trauma 119
Micro-antimicrobial removal device 59
Necrotizing stromal keratitis 97 prevalence 119
Microbial keratitis 35, 129, 131
Neomycin 114 prevention 127
clinical examination and signs 40
Neonatal HSV keratitis 92 regional differences 119
external ocular examination 41
Neurotrophic epithelial keratitis 95 Penetrating keratoplasty 102, 114, 161
history and symptoms
Neurotrophic keratitis 154 Peripheral ulcerative keratitis 162
decreased visual acuity 35
discharge 35 diagnosis 155 clinical picture 164
pain 35 differential diagnosis 157 complications 168
redness and photophobia 35 etiology 154 epidemiology 162
onset of disease 36 ocular causes 154 etiology 162
predisposing factors 36 systemic causes 154 examination
occupational factors 40 investigation 158 ocular 164
ocular factors 37 ocular examination 155 systemic 164
systemic factors 39 corneal sensations 156 investigations
record of visual acuity 41 dilated fundus examination 157 biopsy 165
slit-lamp biomicroscopy 41 slit-lamp biomicroscopy 155 histologic findings 165
Microbial keratitis after keratoplasty systemic examination 157 imaging studies 165
predisposing factors 142 pathogenesis 155 microbiology work up 165
contact lens 143 treatment 158 pathogenesis 162
donor factors 142 Neurotrophic keratopathy 100 treatment
dry eye and ocular surface problems Nocardia 18 medical therapy 166
144 Non-fermenters 19 surgical treatment 168
indication for keratoplasty 142 Nutrient agar 22 Phototherapeutic keratectomy
persistent epithelial defect 143 Nystatin 28 complications 197
recurrence of host infection 143 laser characteristics 197
suture related problems 144 mechanism of action 197
systemic associations 144 O Pneumococcal ulcers 69
Microbial keratitis after refractive surgery 146 Polyarteritis nodosa 169
micribiologic examination 148 Ocular investigations 51 Polyenes 28
treatment 148 Ocular lubricants 158 Polymerase chain reaction 84, 99, 113
Microbiological investigations 51 Ocular surface diseases 38 Polymicrobial keratitis 59
202 Corneal Ulcer: Diagnosis and Management