Bioscience Reports, Vol. 21, No.

4, August 2001 ( 2002)

MINI REVIEW

Keratitis
Savitri Sharma
Receiûed April 12, 2001

Corneal inflammation or keratitis is a significant cause of ocular morbidity around the

world. Fortunately, the majority of the cases are successfully managed with medical ther-
apy, but the failure of therapy does occur, leading to devastating consequences of either
losing the vision or the eye. This review attempts to provide current information on most,
though not all, aspects of keratitis.
Corneal inflammation may be ulcerative or nonulcerative and may arise because of
infectious or noninfectious causes. The nonulcerative corneal inflammation may be confined
to the epithelial layer or to the stroma of the cornea or may affect both. For clarity, this
section has been divided into nonulcerative superficial keratitis and nonulcerative stromal
keratitis. While the former usually includes hypersensitivity responses to microbial toxins
and unknown agents, the latter can be either infectious or noninfectious.
In the pathogenesis of ulcerative keratitis, microorganisms such as bacteria, fungi,
parasites (Acanthamoeba), or viruses play an important role. Approximately, 12.2% of all
corneal transplantations are done for active infectious keratitis. Available world literature
pertaining to the incidence of microbial keratitis has been provided special place in this
review. On the other hand, noninfectious ulcerative keratitis can be related to a variety of
systemic or local causes, predominantly of autoimmune origin.

KEY WORDS: Keratitis; pathogenesis; infections; ulcerative; nonulcerative.

INTRODUCTION
Apart from being an important component of the refractive system of the eye the
cornea serves to protect the more delicate structure of the anterior segment of the
eye from injury. A variety of diseases may cause either specific or nonspecific altera-
tions in corneal tissues including inflammation or ketatitis. Most inflammations are
characterized by nonspecific localized or diffuse edema, which is manifested clinically
by loss of corneal transparency. The initial vascular reaction to corneal inflammation
is perilimbal hyperemia, which may extend around the entire periphery or involve
only one sector. Corneal inflammatory cells are derived from the superficial and deep
limbal vessels. The leukocytes migrate toward the site of the initiating inflammatory
stimulus, following interlamellar pathways and producing irregularities in the ana-
tomic alignment of the lamellae.

Jhaveri Microbiology Centre, Hyderabad Eye Research Foundation, L. V. Prasad Eye Institute, L. V.
Prasad Marg, Banjara Hills, Hyderabad–500 034, AP, India. E-mail: savitri@lvpeye.stph.net
419
0144-8463兾01兾0800-0419兾0  2002 Plenum Publishing Corporation
420 Sharma

The initial cellular migration consists of interlamellar polymorphonuclear leu-

kocytes that appear within 8 to 12 hr after injury [1]. During the following 12 to
16 hr, migrating macrophages (phagocytes) arising from the limbus, as well as tissue
macrophages derived from stromal cells, begin to ingest microorganisms and
inflammatory products. Experimental evidence suggests that antigen associated with
macrophages may be an important way to initiate stimulation of lymphocytic
elements and specific immune responses.
During the healing response to inflammation, neovascularization of cornea is
common which occurs in response to several factors such as, edema, cellular infil-
tration, tissue necrosis, changes in pH, oxidative processes, enzymes from inflamma-
tory cells and corneal tissue cells, etc. The extent of vascularization varies with the
severity and size of the inflammatory focus and with its duration.
Pain is commonly present with corneal inflammation because of stimulation
of the sensory ciliary branches of the ophthalmic division of the trigeminal nerve.
Inflammations that reduce corneal sensation, such as herpes simplex keratitis, may
be less painful in initial stages.
Corneal inflammation may be ulcerative (breach in corneal epithelium with
underlying infiltration of inflammatory cells) or nonulcerative. Etiologically, either
of these may be infectious or non-infectious. While detailed description of the clinical
and laboratory findings associated with all infectious and noninfectious forms of
ketatitis is beyond the scope of this review, an overall view of several of these entities
is provided.

NONULCERATIVE CORNEAL INFLAMMATIONS

Nonulcerative Superficial Keratitis
The most frequent forms of superficial keratitis include lesions that clinically
appear punctate or linear and branching (dendrites). Some of these lesions may
involve only the superficial layers of the epithelium, e.g., staphylococcal blepharo-
conjunctivitis, adenoviral keratoconjunctivitis (type 3, 7), Thygeson’s superficial
punctate keratitis etc. Others like Herpes simplex keratitis, epidemic keratocon-
junctivitis (adenovirus type 8, 19) and chlamydial infection may involve the full
thickness of the epithelium as well as the subepithelial tissues. Lesions limited to the
epithelium usually heal without residual opacity, whereas more severe infections
cause focal opacification of the superficial tissue (Fig. 1). In epidemic keratocon-
junctivitis the opacities develop late and are believed to result from subepithelial
infiltration by sensitized T lymphocytes attracted by inactive virons [2]. Similarly,
the superficial punctate corneal epithelial lesions of staphylococcal blepharocon-
junctivitis origin occur as a hypersensitivity phenomenon to Staphylococcus aureus
exotoxins.
Dendritic lesions are seen in association with Herpes simplex or Herpes zoster
infections. These viruses are neurotropic [3] and intra-axonal transport of infection
occurs along the course of sensory nerves. The dendritic lesions may be single or
multiple and may coalesce to form larger ‘‘geographic’’ lesions. Corneal scrapings
may show epithelial giant cells and acidophilic intranuclear viral inclusions (Fig. 2).
Keratitis 421

Fig. 1. Slit lamp biomicroscopy photograph of the cornea

from a case of viral keratoconjunctivitis showing subepithelial
infiltrates.

Chlamydial disease (trachoma) characteristically affects the superior cornea and

limbal tissues as well as the conjuctiva and the lids. Limbal follicles are formed in
the active stage. Vascularization and infiltration of the limbus and cornea superiorly
produce the typical trachoma pannus. The corneal epithelial cells become edematous
and desquamative in focal areas. Polymorphonuclear lymphocytes infiltrate the area
beneath the epithelium and in the region of Bowman’s membrane. Pathogenesis is
initiated by host inflammatory responses elicited by the presence of chlamydiae and
maintained by reinfection or persistence. There is evidence to suggest that extracts
of chlamydia that contain a 60 Kda-molecular weight heat-shock protein may be
responsible for eliciting conjunctival inflammatory response [4]. In addition, chlamy-
diae attach to T cells, macrophages, and B cells and are capable of triggering cellular

Fig. 2. Corneal scraping from a case of HSV keratitis show-

ing multinucleated giant cells (arrow) and koilocytic changes
(arrow head) in the epithelial cells (Papanicolaou strain, orig-
inal magnificationB500, Courtesy: Dr. Sreedharan
Athmanathan).
422 Sharma

responses that generate a variety of cytokines, some of which are inflammatory

mediators.

Superficial Punctate Keratitis of Thygeson (SPKT)

SPKT is characterized by a coarse punctate epithelial keratitis with little or no
hyperemia of the bulbar or palpebral conjunctiva. It has often been considered as
infectious in origin, specially viral, although not proven so. Pathogenesis of SPKT
is not yet understood. Conjunctival scrapings show scant mononuclear cells, and
normal bacterial flora in culture. Corneal scrapings show abnormal epithelial cells
with vacuolated cytoplasm, occasional neutrophils, mononuclear cells, degenerating
epithelial cells, and mucus [5]. Though isolation of varicells zoster virus was reported
from SPKT [6], this was never confirmed by several subsequent studies. Therefore,
Koch’s postulates have not been satisfied. Human papilloma virus (HPV) is a poss-
ible candidate is this disease, however, polymerase chain reaction studies to evaluate
HPV as a possible infective agent have been negative so far. HLA-DW3 and
HLA-DR3 antigens have also been suggested to be associated with SPKT [7]. In yet
another attempt, involvement of a slow virus has been suggested. Despite all, SPKT
remains an enigmatic disease and is often misdiagnosed.

Filamentary Keratitis
Filaments, composed of a variable combination of degenerated epithelial cells
and mucus [8], may be found on the corneal surface in a variety of corneal con-
ditions. Filaments may differ in size, shape, composition and distribution. They
cause foreign body sensation, photophobia, watering, blepharospasm, and pain.
The relationship between tear film and corneal surface is critical to the process
of filament formation. Filamentous keratitis is believed to occur when there is dis-
ruption in the delicate balance of tear film components and ocular surface state. The
patho-physiology of filament formation is shown in Fig. 3.

Fig. 3. Pathophysiology of filament formation in the cornea.

Keratitis 423

Table 1. Conditions Associated with

Filamentary Keratitis

Ocular
Keratoconjunctivitis sicca
Superior limbic keratitis
Neurotrophic keratopathy
Prolonged patching
Ptosis
Systemic
Sarcoidosis
Diabetes mellitus
Hereditary hemorrhagic telangiectasia
Psoriasis
Atopic dermatitis

Filaments can be seen in a wide variety of clinical conditions (Table 1).

Although the causes of filamentory keratitis are many, it may occur without a cause
(essential filamentary keratitis) [9]. The location of the filaments may sometimes
provide a clue as to the cause.
The first step in the treatment of filamentary keratitis is mechanical removal.
Rose Bengal stains the filaments well and the underlying epithelial defect is stained
with fluorescein. These stains are useful in identifying the filaments. Tear substitutes,
5% sodium chloride ophthalmic solution, 10% N-Acetylcysteine etc. have been used
for treatment. Bandage contact lenses have been found to be very effective in allevi-
ating the symptoms [10].

Nonulcerative Stromal Keratitis (Interstitial Keratitis)

Nonulcerative stromal keratitis or interstitial keratitis occurs when conjunctival
and superficial corneal infections extend to the stroma, or there is an immune
response within the stroma. Stromal inflammation may also accompany systemic
diseases such as, syphilis and tuberculosis. There can be many causes of interstitial
keratitis (Table 2). The primary inflammatory stimulus may originate within the
stroma, or it may arise at the limbus or uveal tract and spread to the stroma. Charac-
teristically, the epithelium remains intact while the involved stroma becomes edemat-
ous. In severe cases, folds develop in Descemet’s membrane. Edema and cellular
infiltration causing a diffuse stromal haze is referred to as ‘‘disciform’’ keratitis when
it occupies the central portion of the cornea. Several conditions can cause ‘‘disciform
keratitis’’, however, Herpes simplex keratitis is the most common cause.

Infectious Nonulceratiûe Stromal Keratitis

Viruses
Herpes Simplex Virus (HSV): The by-products of HSV replication and immune
alteration of the cornea and iris play an important role in many destructive corneal
conditions. Intact HSV is rarely found in the cornea, therefore, it seems likely that
424 Sharma

Table 2. Causes of Nonulcerative

Stromal (Interstitial) Keratitis

Bacterial infection
Syphilis
Tuberculosis
Leprosy
Lyme disease
Brucellosis
Viral infection
Herpes simplex virus
Varicella zoster virus
Epstein–Barr virus
Mumps
Rubella
Parasitic infection
Leishmaniasis
Onchocerciasis
Trypanosomiasis
Acanthamoeba
Microsporidiosis
Systemic disease
Cogan’s syndrome
Sarcoidosis
Lymphoma

the persistence of incomplete viral antigens and the viral immune alteration of cell
membranes in the corneal stroma incite inflammatory reactions that involve pro-
grammed host lymphocytes, antiviral antibodies, serum complement, polymorpho-
nuclear cells, and macrophages [11, 12]. Greater amount of glycoproteins have been
shown in HSV strains that cause stromal disease than those that cause epithelial
disease [13]. This suggests that stromal disease is a host immune response to the
antigenic glycoproteins produced in the ocular tissues by the infecting HSV strain.
It may be concluded that both host immune factors and viral characteristics play
key roles in determining the ultimate expression of clinical disease in ocular Herpes.
More details of this condition have been described later in this review.
Varicella Zoster Virus (VZV): During the primary illness of chicken pox caused
by VZV, the virus gains access to trigeminal ganglia (87%) and thoracic ganglia
(57%) either by hematogenous spread or retrograde neural transport and latency
can occur in multiple ganglia [14]. The virus actively infects both neural and satellite
cells, but unlike HSV establishes its latent state in the satellite cells only. Reacti-
vation results in spread back to the neural cells and ultimately spread down the
dermatomal axones.
Two thirds of the patients with Herpes zoster ophthalmicus have corneal
involvement which takes the form of punctate keratitis (51%), pseudodendrites
(51%), anterior stromal infiltrates (41%), sclerokeratitis (1%), keratouveitis-endothe-
liitis (34%), peripheral ulcerative keratitis (7%), delayed mucous plaques (13%), disci-
form keratitis (10%), neurotrophic keratitis (25%), and exposure keratitis (11%) [15].
Keratitis 425

Corneal sensation may be markedly diminished in even the mildest cases of herpes
zoster keratitis. Anesthesia is greater than that seen with simplex keratitis of compar-
able severity and is probably due to the greater severity of ganglionitis in zoster.
Stromal disciform disease may be local or diffuse and occur in association with
or without epithelial involvement. Patients may have relatively mild epithelial herpes
zoster and then months to years later develop Wessely immune rings, necrotizing
interstitial inflammation with deep neovascularization, or disciform disease. All
stromal forms of the disease are clinically indistinguishable from stromal herpes
simplex disease and may represent the same immune pathogenetic mechanisms.

Bacteria
Treponema pallidum: Syphilis, caused by T. pallidum, is a cause of corneal
inflammation that is typically nonulcerative and is referred to as interstitial keratitis.
Most cases involve the deep stroma, and neovascularization is a frequent occurrence.
Interstitial keratitis is a common ocular finding of untreated congenital syphilis and
may occur even in acquired symphilis. It may occur any time from birth to middle
age [16].
Lymphocytic infiltration most often affects the deep stromal layers in one or
more clustered foci. Bilateral nummular infiltrates at various levels can be the pre-
senting feature of congenital symphilis. On resolution of active inflammation, the
sequelae of interstitial keratitis are stromal scarring, endothelial changes, and cor-
neal ghost vessels. Bilateral involvement is common in most cases of interstitial kera-
titis caused by congenital syphilis.

Mycobacterium tuberculosis: Interstitial corneal inflammation does occur in

patients with tuberculosis, but tubercle bacilli have rarely been identified or isolated
from the corneal tissue. Hypersensitivity to tubercular protein is a postulated cause
of the inflammation. Clinically, the corneal lesions have been called ‘‘phlyctenules’’.
They begin in the deeper layers of the stroma, most often near the limbus, and may
be single or multiple. They are characterized by the separation of the corneal lamel-
lae by inflammatory cells in the absence of overlying ulceration [17].

Mycobacterium leprae: The cornea can be affected in either lepromatous or

tuberculoid form of leprosy. The latter rarely affects the eye but can cause corneal
anesthesia by affecting the trigeminal nerve. Lepromatous leprosy produces a nonul-
cerating, diffuse, granulomatous stromal inflammation characterized by infiltration
with histiocytic (foam) cells and giant cells (globi). Small collections of lymphocytes
and plasma cells are also seen, but they are not a major component of the inflamma-
tory response. The histiocytes and giant cells may contain large numbers of acid-
fast-staining lepra bacilli [18].
As the disease advances, the lesions increase in size, become confluent and there
is calcium deposition. Pannus formation ensues in the superior temporal quadrant,
with superficial limbal vessels extending between Bowman’s membrane and the
epithelium. Thus, the corneal lesions include opacification of the corneal nerves,
avascular keratitis, interstitial keratitis, pannus formation and corneal leproma.
426 Sharma

Parasites
Onchocerca ûolûulus: Ocular manifestations of Onchocerciasis (river blindness),
caused by Onchocerca ûolûulus, includes keratitis apart from chronic conjunctivitis.
The conjunctival and corneal lesions are induced by invasion and subsequent death
of the microfilariae of Onchocerca ûolûulus. The live worm usually causes no reac-
tion, but after its death, opacities may develop around the dead organism. Initially
limbitis develops followed by punctate keratitis. The keratitis can occur as either
superficial fluffy stromal opacities or discrete discoid opacities [19, 20].

Noninfectious Nonulceratiûe Stromal Keratitis

Cogan’s Syndrome. David G. Cogan was the first to report interstitial keratitis
with vestibuloauditory symptoms in 1945 and was the first to differentiate this syn-
drome from congenital syphilis [21]. Though a number of cases have been reported,
the disease is rare. Typical Cogan’s syndrome is strictly defined as nonsymphilitic
interstitial keratitis associated with vestibuloauditory disease manifested by a sudden
onset of tinnitus, vertigo, nausea, and vomiting similar to Meniere’s disease. Cogan’s
syndrome may be associated with a number of underlying systemic vasculitides such
as polyarteritis nodosa, Wegener’s granulomatosis, and rheumatoid arthritis.
The exact etiology of Cogan’s syndrome remains unknown. The clinical and
histologic findings suggest an immune response against a common antigen in the
cornea and inner ear. The trigger for the presumed immune response is unknown.
Prompt and prolonged immunosuppressive therapy is warranted in patients with
Cogan’s syndrome.
Sarcoidosis: Sarcoidosis is a multisystem disorder of uncertain etiology
characterized by the presence of noncaseating granulomas in affected tissues. It can
affect virtually any part of the body. The eyes may become involved at any time in
the course of the disease.
Corneal involvement may take the form of a calcific band keratopathy or num-
mular keratitis. The nummular keratitis consists of round, white stromal opacities
with indistinct borders and intervening clear areas. Bilateral involvement is common,
and multiple opacities may be present in each eye. Usually the patient remains
asymptomatic [22].
Diagnosis of sarcoidosis may often be difficult, especially if only the eye appears
to be involved and other evidences of systemic disease are lacking. A presumptive
diagnosis can be supported by a variety of laboratory tests such as elevated serum
angiotensin converting enzyme (ACE) and serum lysozyme. If pathologic confir-
mation is required, any clinically involved tissue may be biopsied. The most common
sites for biopsy include the skin, salivary glands, lung and mediastinal lymphnodes.
Though usefulness of conjunctival biopsy is debatable, it can be easily performed
under local anesthesia with minimal morbidity. Bilateral biopsies with examination
of multiple tissue sections have been reported to provide 55% positivity [23].

ULCERATIVE CORNEAL INFLAMMATIONS

Ulcerative keratitis may be produced by infectious organisms (microbial kerat-
itis) or by noninfectious stimuli. During the initial stages, the epithelium and the
Keratitis 427

stroma in the area of injury or stimuli become edematous and undergo necrosis.
Acute and chronic inflammatory cells infiltrate from the limbus. As the process pro-
gresses, a deep stromal abscess may form under the ulcer. Diffusion of inflammatory
mediators posteriorly may elicit an outpouring of inflammatory cells in the anterior
chamber (hypopyon). If the inflammation is severe, the superficial ulcer and the deep
abscess may meet, with resultant sloughing of the infected stroma. The remaining
cornea consisting of a few posterior lamellae of stroma and Descemet’s membrane,
may then bulge forward (descemetocele) or become necrotic and rupture, giving rise
to perforated corneal ulcer.
As the lesion begins to heal, epithelium migrates into the crater of the ulcer
from the sides. Vessels derived from the limbus and fibroblasts derived from the
stroma grow into the area beneath the epithelium. Macrophages assist in clearing
up the debris, and a connective tissue scar begins to form. The scar is usually found
to cease its growth at the level of the surrounding normal cornea. Later hyaline,
calcareous, or lipoid degeneration of the scar may occur.

Infectious Ulcerative Corneal Inflammation (Microbial Keratitis)

Microbial keratitis is a common, potentially sight-threatening ocular infection
that may be caused by bacteria, fungi, viruses, or parasites. Specific clinical signs
that suggest a particular infection are not always present, therefore, laboratory stud-
ies are required to identify the specific causative organism.

Bacterial Keratitis
Virtually any bacteria can potentially cause keratitis (Table 3). The relative
frequency of different bacteria as causative agents in keratitis may vary geographi-
cally. There has also been a change in the spectrum of bacteria causing keratitis with
time, especially in the United States. The incidence of pneumococcal keratitis, which
is commonly associated with chronic dacryocystitis [24], has decreased in developed
countries as a result of modern antibodies and refinement in techniques for dacryo-
cytorhinostomy [25]. Staphylococcus species continue to be the predominant cause
of bacterial keratitis and in several reports Staphylococcus epidermidis or coagulase
negative staphylococci (CONS) are the leading causes [26, 27]. In several series from
the southern part of the United States Pseudomonas species is reported to be the
most commonly isolated organism [28, 29], especially in association with daily or
extended wear soft contact lenses [30]. Being widely distributed in nature, Pseudo-
monas can easily contaminate ophthalmic preparations [31], cosmetics [32], and other
materials. The Moraxella group of organisms have been reported to cause keratitis
in malnourished individuals with diabetes, alcoholism or other conditions [33], how-
ever, they have also been reported from keratitis in healthy individuals [34].
Organisms less frequently reported from bacterial keratitis include Corynebac-
terium species [35], Propionibacterium acnes [36], Bacillus species [37, 38]. Neisseria
gonorrhoeae, members of Enterobacteriaceae family [39], and so on. Corneal involve-
ment with Corynebacterium diphtheriae is an event of the past since the development
of the vaccine, though the organism is known to penetrate intact corneal epithelium
428 Sharma

Table 3. Classification of Bacteria Causing Keratitis

Gram-negative aerobic兾facultative anaerobic rods

Pseudomonas
Asotobacter
Escherichia
Citrobacter
Klebsiella
Serratia
Proteus
Actinobacillus
Flaûobacterium
Haemophilus
Gram-negative anaerobic rods
Bacteroides
Fusobacterium
Gram-negative cocci and coccobacilli (aerobes)
Neisseria
Moraxella
Acinetobacter
Gram-positive aerobic and兾or facultatively anaerobic cocci
Micrococcus
Staphylococcus
Streptococcus
Pediococcus
Aerococcus
Gram-positive anaerobic cocci
Peptostreptococcus
Gram-positiûe rods
Bacillus
Clostridium
Actinomycetes and related organisms
Corynebacterium
Porpionibacterium
Actinomyces
Arachnia
Bifidobacterium
Mycobacterium
Nocardia
Streptomyces

[40]. While the association of Bacillus species in causing severe post traumatic
endophthalmitis is well established [41] corneal ulcers caused by Bacillus species are
rare and the largest series (19 eyes of 17 patients) has been described from India
[42]. Listeria monocytogenes has been infrequently isolated as a cause of corneal
ulceration [43].
Nocardia species have been linked with bacterial keratitis [44–46], most cases
being caused by Nocardia asteroides. However, they remain a rare cause of corneal
ulceration. While primary tuberculous keratitis is extremely rare, infections of the
cornea have been reported caused by atypical mycobacteria including Mycobacter-
ium fortuitum [47, 48], Mycobacterium chelonae [49, 50], Mycobacterium gordonae
Keratitis 429

[51], and Mycobacterium aûium-intracellulare [52]. Mycobacterium leprae can

occasionally be a causative agent of keratitis and invade along peripheral corneal
nerves [53, 54].
Rare nonsyphilitic spirochetal infection of the cornea may occur in Lyme dis-
ease caused by Borrelia burgdorferi [55]. Some of the other less frequently reported
organisms associated with bacterial keratitis are shown in Table 3.

Pathogenesis
The ocular surface is constantly exposed to a large number of bacteria, however,
only a few succeed in causing a corneal infection. Several mechanisms protect the
surface of the eye from infectious agents. The eyelids provide a physical barrier to
protect against organisms. Apart from irrigating the ocular surface, the tear film is
bactericidal or bacteriostatic by virtue of containing immunoglobulins, complement,
various enzymes such as, lysozyme, lactoferrin, betalysins, and ceruloplasmin [25].
The mucin layer is a mechanical protective barrier. The normal ocular flora provide
a balance to help prevent the growth of exogenous organisms. The cell mediated
immunity (CMI) has an important role in the ocular defense system against bacteria.
Subepithelial mucosal-associated lymphoid tissue (MALT) present in the conjuctiva
and Langerhans cells present mostly at the sclerocorneal limbus are specialized type
of dendritic cells which initiate cell mediated immune response on the ocular surface.
Langerhans cells are rarely present at the central cornea but can be brought in
rapidly from the limbus with slightest of insult to the cornea [56]. They express
HLA-DR antigen (Class II histocompatibility antigen), receptors for complement
and the Fc portion of immunoglobulins and play an important role in the processing
of bacterial antigens and presentation to T cells [56]. The use of topical cortico-
steroids may cause localized immunosuppression predisposing to bacterial and fun-
gal keratitis. Patients with Acquired Immunodeficiency Syndrome (AIDS) develop
more fulminant clinical course [57].
Apart from corneal abrasion, foreign body, or erosion, which may precipitate
bacterial keratitis, surgical trauma may also predispose to bacterial keratitis. A study
reporting microbial keratitis in the elderly patients found prior surgery as one of the
leading risk factors [58]. Recently popularized keratorefractive surgery, excimer laser
photorefractive keratectomy (PRK), and excimer laser in situ keratomilieusis
(LASIK) have resulted in disastrous bacterial keratitis cases [59–63]. Patients who
have undergone penetrating keratoplasty are also at increased risk for bacterial
keratitis.
The pathogenesis of bacterial keratitis initially requires the adherence of bac-
teria to disrupted corneal epithelium. But a few bacteria, such as Neisseria
gonorrhoeae, Corynebacteria diphtheriae, Shigella and Listeria may penetrate an
intact corneal epithelium [25]. Many bacteria display several adhesions on fimbriae
(pili) and nonfimbriated structures. Such adhesive proteins may recognize receptors
on host cells and promote bacterial entry into the host cell as well as activate leuko-
cyte migration and induce cytokine production. Most bacteria can display a number
of adhesions. Although the cognate oligosaccharides for bacterial adhesins are
known, the molecules bearing these determinants are not well characterized.
430 Sharma

Intergrins are a family of glycoproteins mediating cell–cell and cell–extracellular

matrix recognition [25].
Once the bacterial pathogen has adhered to the corneal epithelial surface, the
next step is the invasion into stroma, which is facilitated by proteinases that degrade
basement membrane and extracellular matrix. Proteinases may be derived from bac-
teria, corneal cells, and migrating leukocytes. Corneal matrix metalloproteinases are
excreted in an inactive form but are activated during infection by bacteria. The
invasion of bacteria is facilitated by a number of exotoxins, such as phospholipase
(Pseudomonas aeruginosa), heat-stable hemolysin, and exotoxin-A. Interruption in
the host immune response occurs once the bacteria invade deeper tissues. Certain
bacteria with capsular polysaccharide have immunosuppressive properties including
interference with phagocytosis. Bacterial proteases and elastases cause severe corneal
damage [64, 65]. The proteases contribute to the pathogenesis of keratitis by degrad-
ing basement membrane [66], laminin, proteoglycans, extracellular matrix [67] and
collagen [68]. Bacterial exotoxins and endotoxins persist in the cornea for a protrac-
ted period and continue to cause stromal destruction after the death of the pathogen.

Fungal Keratitis
Fungi are ubiquitous, saprophytic and occasionally a part of the normal exter-
nal ocular flora. They gain access into the corneal stroma through a defect in epi-
thelial barrier which may be due to external trauma, a compromised ocular surface,
or previous surgery. Once in the stroma, they multiply and cause tissue necrosis and
a host inflammatory reaction. Organisms can penetrate deep into the stroma and
through an intact Descemet’s membrane (Fig. 4). It is believed that once the organ-
isms gain access into the anterior chamber or to the iris and lens, eradication of the
organism becomes extremely difficult. The possible role of fungal derived enzymes
(proteases) has been shown in the pathogenesis of fungal keratitis [69, 70]. Degra-
dation of laminin in the basement membrane of the cornea has been shown to be
caused by the conidia of Aspergillus fumigatus [71].
Overall, the incidence of fungal keratitis is low in temperate climates, while
higher incidence is reported from Southern United States [72, 73] and tropical
regions of the world including India [74]. A wide variety of species have been
reported [75] from different parts of the world (Table 5). Prevalent species vary from
one geographical area to the other [75].

Viral Keratitis
Herpes simplex ûirus (HSV): The spectrum of ocular disease caused by HSV is
broad. The clinical sequelae of HSV infection are largely a result of recurrent disease
and the immunologic response associated with each episode. Many factors have
been implicated in the activation of recurrent HSV ocular disease. Sunlight, trauma
(including surgery), heat, abnormal body temperature, menstruation, other infec-
tious diseases, and emotional stress have all been implicated in the activation of
HSV infection. Although some type of immunoregulation may exist in all of these
Keratitis 431

Table 4. Etiological Agents in Mycotic

Keratitis

1. Hyaline filamentous fungi

Aspergillus spp
Acremonium spp
Beauûeria spp
Cylindrocarpon spp
Fusarium spp
Geotrichum candidum
Neurospora spp
Penicillum spp
Paecilomyces spp
Pseudallescheria boydii
Sphaeropsis subglobosa
Scopulariopsis
Ustilago spp
Volutella spp
2. Dematiaceous filamentous fungi
Alternaria spp
Bipolaris spp
Curûularia spp
Cladosporium spp
Drechslera spp
Exserophilum spp
Exophiala jeanselmei
Lasiodiplodia theobromae
Phialophora spp
3. Yeasts and yeast—like fungi
Candida spp
Cryptococcus spp
Rhodotorula spp
Trichosporon spp
4. Dimorphic fungi
Blastomyces dermatitidis
Paracoccidoides brasiliensis
Sporothrix schenkii
5. Others
Mycelia sterilia
Rhizopus
Mucor

circumstances, it has not been clearly demonstrated. The severity and frequency of
disease also depend on the viral genome and its virulence.
The pathogenesis of HSV keratitis has already been discussed in the Viruses
section under nonulcerative stromal keratitis caused by HSV. As mentioned earlier,
a variety of clinical manifestations of not only infectious keratitis but also immunol-
ogic disease can affect all levels of the cornea (Table 5).
Recurrent epithelial keratitis are caused by reactivation of live virus, the most
commonly recognized clinical manifestation of which are dendritic and geographic
432 Sharma

Fig. 4. Histologic section of the corneal button showing fragmented

and folded Descemet’s membrane (arrow) with multiple branching
fungal filaments. Note the penetration of fungal filaments (arrow
head) to the posterior surface of the cornea (Gomori Methenamine
Silver Stain, original magnificationB500, Courtesy: Dr. Geeta K.
Vemuganti).

ulcers. The features of a dendritic ulcer include a branching, linear lesion with ter-
minal bulbs and swollen epithelial borders that contain live virus (Fig. 5). This lesion
represents a true ulcer in that it extends through the basement membrane. An
enlarged dendritic ulcer that is no longer linear is referred to as a geographic ulcer.
The dendritic or geographic ulcer may be completely resolved without residual
evidence but more commonly it leads into sight-threatening sequel of stromal scar-
ring. Another sequel is a stromal disease, which may develop in 25% of patients [76].
The stromal disease may be either infectious or of immune etiology. Necrotizing
keratitis represents true viral infection of the stroma, whereas immune stromal kera-
titis is complement mediated antibody reactions to viral antigen.

Table 5. Classification of HSV Keratitis

I. Infectious epithelial keratitis

Corneal vesicles
Dendritic ulcer
Geographic ulcer
Marginal ulcer
II. Neurotrophic keratopathy
III. Stromal keratitis
Necrotizing stromal keratitis
Immune stromal (interstitial) keratitis
IV. Endotheliitis
Disciform
Diffuse
Linear
Keratitis 433

Fig. 5. Slit lamp biomicroscopy photograph of the cornea from

a case of HSV keratitis showing dendritic lesions in the central
area (Courtesy: Dr. Prashant Garg).

Immune stromal (interstitial) keratitis has been discussed earlier in this review.
Many patients with HSV disease develop corneal stromal edema without stromal
infiltrate, which is believed to be due to endotheliitis. The exact pathogenesis of this
is unknown. The reaction at the level of the endothelium appears to be immunologic
because of the clinical findings of keratic precipitates (KP) and iritis. The role of live
virus also has been speculated as contributing [77, 78].
Varicella Zoster Virus (VSV): The pathogenic mechanisms of Herpes Zoster
Ophthalmicus (HZO) have been described earlier in this review. Table 6 outlines the
variety of corneal changes that may be seen in HZO. Several groups of patients with
altered immunity are at particularly high risk for zoster including HZO. Some clini-
cal conditions associated with an increased risk of zoster include organ transplan-
tation, HIV infection, and immunosuppressive drug therapy for autoimmune or
hematologic disorders. There is an association between the development of HZO in
otherwise healthy young adults and underlying HIV seropositivity. HZO in young
Africans, where there is a high seroprevalence of HIV and limited availability of
therapy, has a poor visual outcome [79]. Complications of HZO in HIV-positive

Table 6. Corneal Changes in Herpes

Zoster Ophthalmicus (HZO)

Punctate epithelial keratitis

Anterior stromal infiltrates
Keratouveitis兾endotheliitis
Serpiginous ulceration
Sclerokeratitis
Corneal mucous plaques
Disciform keratitis
Neurotrophic keratopathy
Exposure keratopathy
Lipid keratopathy
Permanent corneal edema
434 Sharma

patients include a chronic VZV keratitis and VZV retinitis. In most situations, the
diagnosis of HZO can be made from the characteristic rash and laboratory tests are
usually superfluous.

Acanthamoeba Keratitis
The first case of Acanthamoeba keratitis was reported [80] in 1973 and a few
cases were recognized between 1973 and 1983. The first case diagnosed in India [81]
was in 1987. The reported incidence of Acanthamoeba keratitis all over the world
increased dramatically through 1989 and then it reached a plateau, especially in the
United States. While the incidence continues to increase in developing countries it
is reported to have declined in the U.K. [82].
Acanthamoeba keratitis occurs in immunocompetent, healthy young individuals.
Several important risk factors have been identified which are associated with Acan-
thamoeba keratitis. In a series of 189 cases of Acanthamoeba keratitis from the U.S.
85% of cases were contact lens related [83]. In contrast, the commonly identified risk
factor in patients of Acanthamoeba keratitis seen in developing countries is history
of corneal trauma or exposure to contaminated water [84, 85].
Adhesion of Acanthamoeba trophozoites and cysts to a variety of contact lenses
has been shown in ûitro [86–88]. Adhesion of the parasite to abraded corneal buttons
rather than to the intact cornea in an animal model [89], and to corneal epithelial
cells in ûitro [90] have also been demonstrated, which highlight the importance of
initial attachment to corneal epithelium in the pathogenesis of Acanthamoeba kera-
titis. Using pig and Chinese hamster models, the immune mechanisms that may be
involved in Acanthamoeba keratitis have been studied [91, 92]. Protection to the eye
is dependent on mucosal immune mechanisms and does not seem to correlate with
either high IgG antibody titre or blastogenic potential of peripheral blood
lymphocytes.
Major reviews have dealt with the clinical features and treatment of Acantha-
moeba keratitis in contact lens related [93] as well as non-contact lens related [85]
Acanthamoeba keratitis. The epithelial breakdown and stromal involvement may
resemble either Herpes simplex keratitis or fungal keratitis, however, a characteristic
form of the stromal disease occurs late as a typical ring infiltrate (Fig. 6).

Noninfectious Ulcerative Corneal Inflammations

Neurotrophic Keratitis
Neurotrophic keratitis is characterized by absence of corneal sensitivity.
Reduced corneal sensation renders the corneal surface vulnerable to occult injury
and decreased reflex tearing. Vulnerability and poor healing secondary to corneal
sensory denervation favor the formation of nonhealing epithelial defects that tend
to be ulcerative and perforate if not treated appropriately and timely.
Table 7 shows the causes of corneal hypesthesia [94]. The molecular basis of
neurotrophic keratitis is based on the theory that the corneal epithelial proliferative
system has bidirectionally regulated controls linked to the sensory and sympathetic
Keratitis 435

Fig. 6. Slit lamp biomicroscopy photograph of the cornea from

a case of Acanthamoeba keratitis showing a ring infiltrate.

nerves and their neurotransmitters [95]. There is evidence to suggest that the sensory
neurons directly affect the development of corneal epithelial cell characteristics that
are critical to the maintenance of good epithelial layer integrity. A decrease in epi-
thelial cells mitosis eventually leads to a deficit in corneal epithelial cells even in the
absence of a preexisting defect or accelerated cell death. Role of substance P as a
direct trophic molecule on corneal epithelial growth has been demonstrated. Sub-
stance P is a neuropeptide present in the cornea, which is depleted with sensory
denervation specifically with capsaicin [96]. Research continues along these lines to
solve the mystery of neutrotrophic keratitis.

Mooren’s Ulcer
Mooren’s ulcer is a rare inflammatory disorder of presumed autoimmune etiol-
ogy consisting of peripheral corneal ulceration with a variable clinical course. It
begins as a gray-white infiltrate in the peripheral cornea (Fig. 7) followed by epi-
thelial breakdown and stromal melting. The leading edge of the ulcer is undermined,
infiltrated, and de-epithelialized. The ulcer progresses circumferentially and centrally
creating an overhanging edge at its central border. Behind the advancing edge of
the ulcer, healing may take place. Vision is affected due to irregular astigmatism and
involvement of central cornea.
The etiology of Mooren’s ulcer is unknown. It can be primary of idiopathic
variety or may be secondary following cataract surgery, penetrating keratoplasty,
corneal trauma, chemical burns, Herpes zoster, syphilis, tuberculosis, and corneal
foreign bodies. The secondary variety is usually unilateral, however, the primary
Mooren’s ulcer may be bilateral in 25% of patients.

Several immunologic abnormalities have been reported in order to explain the

pathogenesis of Mooren’s ulcer. Conjunctival biopsy has been shown to contain
plasma cells, lymphocytes, and histiocytes [97]. The conjunctiva adjacent to the cor-
neal ulcer has been shown to produce circulating antibodies to both the conjunctival
436 Sharma

Table 7. Causes of Corneal Hypesthesia [94]

Infection
Herpes simplex
Herpes zoster
Leprosy
Fifth nerve palsy
Surgery (trigeminal neuralgia)
Neoplasia (acoustic neuroma)
Aneurysms
Facial trauma
Congenital
Familial dysautonomia (Riley–Day syndrome)
Goldenhar-Gorlin syndrome
Mobius syndrome
Familial corneal hypesthesia
Topical medications
Anesthetics
Timolol
Betaxolol
Sulfacetamide
Diclofenac sodium
Corneal dystrophies
Lattice
Granular (rare)
Systemic disease
Diabetes mellitus
Vitamin A deficiency
Iatrogenic
Contact lens wear
Trauma to ciliary nerves by laser and surgery
Corneal incisions
Toxic
Chemical burns
Carbon disulfide exposure
Hydrogen sulfide exposure

and corneal epithelium and also binding of IgG, IgM and C3 to the conjunctival
epithelium adjacent to the ulcer has been demonstrated [98]. Cellular as well as
humoral phenomena have been demonstrated. All evidences suggest that trauma,
infection, or systemic disease alters the normal corneal antigens which leads to acti-
vation of complement, infiltration of neutrophils, and release of collagenases.
Necrosis of the cornea seems to liberate more altered corneal antigens and the pro-
cess continues until the corneal stroma is destroyed. Recently an association between
Mooren’s ulcer and hepatitis C virus infection has been reported [99].

Marginal Staphylococcal Keratitis

Also called marginal catarrh or catarrhal infiltrates and ulcers, marginal staphy-
lococcal keratitis occurs secondary to the host’s antibody response to the staphylo-
coccal antigen present in cases of chronic blepharoconjunctivitis. Its presentation as
Keratitis 437

Fig. 7. Slit lamp biomicroscopy photograph under diffuse

illumination showing an area of epithelial defect with marked
thinning accompanied by vascularization. The central edge of
the lesion is concentric to the limbus and is having edematous
overhanging edges suggestive of Mooren’s ulcer (Courtesy: Dr.
Prashant Garg).

superficial corneal infiltrates has been mentioned in the Nonulcerative Superficial

Keratatis section of this review. The infiltrates are usually peripheral and are separ-
ated from the limbus by a thin strip of clear cornea (lucid interval). With progressive
inflammation the corneal epithelium overlying the stromal infiltrates breaks down,
leading to ulceration or thinning of the underlying stroma.
The condition is usually associated with chronic staphyloccal (S. aureus) ble-
pharoconjuctivitis, however, the organisms have not been isolated from the corneal
lesions. Topical corticosteroids are the mainstay of the treatment after infectious
causes for the corneal ulcer are excluded by laboratory investigations. Concomitant
treatment of blepharoconjunctivitis with warm compress, lid hygiene, topical and
systemic antibiotics is recommended.

Keratomalacia
Vitamin A deficiency results in changes in mucosal surfaces throughout the
body including the eye. Apart from night blindness there may be conjunctival
xerosis, corneal xerosis or the most serious manifestation—keratomalacia or corneal
ulceration. Vitamin A is known to be involved in corneal metabolism [100] and
specific retinal binding proteins are present in the epithelium, keratocytes and endo-
thelium. Animal studies suggest that there may be reduction in hemidesmosomes
[101], which may lead to sloughing of cornified epithelium by lid action. Polymor-
phonuclear leukocytes are brought in and are known to release destructive proteases
such as collagenases. However, Sommer noted relative lack of inflammatory changes
in humans compared to animal models [102]. Though sterile to start with many cases
of keratomalacia may get secondarily infected with bacteria.
438 Sharma

Rosacea Keratitis
Rosacea is a chronic inflammatory eruption of the flush areas (forehead, nose)
of the face occurring mostly in middle aged women. Corneal involvement is seen in
about 5% of rosacea patients. A superficial punctate keratopathy is common with
meibomitis or blepharitis. A marginal vascular infiltration can occur. As the keratitis
progresses, subepithelial infiltrates may appear and rarely ulceration and perforation
may occur. Histopathologically; conjunctival and corneal infiltration with chronic
inflammatory cells including lymphocytes, epithelial cells, plasma cells, and giant
cells; suggesting type IV hypersensitivity is seen.

Keratitis Associated with Collagen-Vascular Diseases

Collagen vascular diseases include a variety of immune-mediated systemic dis-
orders including Rheumatoid arthritis, and Wegener’s granulomatosis, which are
associated with a variety of ocular manifestations including keratitis.
Rheumatoid arthritis (RA), is a chronic systemic inflammatory disease of
unknown etiology. The most common associated ocular disorder is keratoconjuncti-
vitis Sicca (KCS) which is found in 15–25% of RA patients. RA patients with KCS
are at increased risk of developing ulcerative keratitis, particularly when concurrent
blepharitis is present [103]. Keratitis in RA occurs most often contiguous with adja-
cent scleritis but it may occur as an isolated finding. It may first develop as stromal
opacities at any level of the cornea with accompanying stromal edema. The opacities
may coalesce and the overlying epithelium may break with resultant peripheral ulcer-
ative keratitis (PUK). The autoimmune phenomenon is obvious from the demon-
stration of lymphocytes and macrophages in the perilimbal conjunctiva, and
antibodies to corneal antigens [104]. Secondary bacterial or fungal keratitis of PUK
may occur. Wegener’s granulomatosis is a systemic vasculitis of unknown etiology
and is characterized by necrotizing and granulomatous inflammation of the vessels
of various organs in the body. Ocular complications may occur in 58% of patients.
Scleritis and keratitis are often the presenting findings of Wegener’s granulomatosis
[105]. In areas of scleral necrosis there may be contiguous corneal guttering which
may extend both centrally and circumferentially. The etiology of the corneal and
scleral disease is presumably the same as that for systemic disease. Vasculitis with
limbal ischemia may lead to corneal changes. Antibodies to corneal epithelial
antigens have been demonstrated [104].

Keratitis Associated with Atopy

Atopy refers to hypersensitivities in persons with a hereditary background of
allergic diseases. Apart from many conjunctival disorders atopic ocular diseases
include vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC)
affecting the cornea. In VKC the sequence of occurrence of corneal findings have
been described [106]. To start with, mediators from the inflamed tarsal conjunctiva
cause a punctate epithelial keratitis. Coalescence of these areas leads to frank epi-
thelial erosion, leaving Bowman’s membrane intact. In the absence of treatment,
Keratitis 439

this epithelial defect may contain deposits of mucus and fibrin giving rise to what is
called a shield ulcer (Fig. 8). This shield ulcer usually has its lower border in the
upper half of the visual axis. With resolution, the ulcerated area leaves a subepi-
thelial ring like scar.
The conjunctival epithelium in VKC contains large numbers of mast cells and
eosinophils and eosinophil major basic protein (EMBP) is found diffusely deposited
throughout the conjunctiva. The corneal epithelium of VKC patients has been
shown to express ICAM-1, an important cell adhesion molecule [107]. EMBP and
cationic protein (ECP) are pro-inflammatory and EMBP has been shown to be cyto-
toxic to corneal epithelium. Specific IgE, IgG along with histamine and tryptase are
elevated in tears of VKC patients. VKC is reported to occur in patients with the
hyperimmunoglobulin E syndrome.
In atopic dermatitis, 15–40% of patients may have ocular involvement, usually
AKC. Punctate epithelial defect, scarring and secondary bacterial infections of the

Fig. 8. Clinical photographs of a patient of vernal keratocon-

junctivitis showing 8a-Giant papillae on the upper tarsal con-
junctiva, 8b-a punched out oval epithelial defect with a
plaque at the base (shield ulcer). The surrounding cornea is
devoid of inflammatory reaction (Courtesy: Dr. Prashant
Garg).
440 Sharma

cornea may occur. AKC is thought to consist of both type I and type IV hypersensi-
tivity mechanisms. Mast cells and eosinophils are found in the conjunctival epi-
thelium of AKC patients. Upregulation of antigen presentation has been suggested
by various experiments involving antibodies to HLA-DR, Langerhans cells, and
CD4兾CD8 ratio in conjunctiva.

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