JOURNAL READING

“Keratitis”

Diajukan kepada :
Pembimbing :
dr. Wahju Ratna Martiningsih, Sp.M

Disusun oleh :
Zulva Safiira
H3A022088

Kepaniteraan Klinik Departemen Ilmu Penyakit Mata

Fakultas Kedokteran Universitas Muhammadiyah Semarang
Rumah Sakit Roemani Muhammadiyah
Semarang
2023
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NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.

Keratitis
Prabhakar Singh; Abhishek Gupta; Koushik Tripathy.

Author Information and Affiliations

Last Update: November 15, 2022.

Continuing Education Activity

Keratitis is a clinical entity wherein inflammatory cells infiltrate different corneal layers in
response to noxious stimuli, either infectious exogenous agents or self-antigens. The
inflammatory reaction may result in the suppurative melting of corneal epithelium and stroma,
resulting in the formation of ulcers. This results not only in the loss of corneal clarity but also
threatens the integrity of the globe. Such cases may result in corneal blindness. This activity
helps clinicians identify the etiological agent at the earliest based on clinical features and
appropriate diagnostic tests and manage these patients with the latest treatment options. It
reviews the role of the interprofessional team.

Objectives:

Review different types of keratitis

Outline the appropriate evaluation of keratitis.

Summarize the management options available for keratitis.

Describe interprofessional team strategies for improving care coordination and

communication to advance the care of keratitis and improve outcomes.

Access free multiple choice questions on this topic.

Introduction
Keratitis is the inflammation of the cornea and is characterized by corneal edema, infiltration of
inflammatory cells, and ciliary congestion. It is associated with both infectious and non-
infectious diseases, which may be systemic or localized to the ocular surface. Amongst the types
of keratitis discussed above, "microbial keratitis" accounts for the majority and is primarily a
cause of major concern in developing countries. However, noninfectious keratitis can not be
looked down upon, especially in developed nations.

Our first line of defense is strong enough to dispel most of the infection, causing insults;
however, there exist some organisms which can evade this line and cause infection. The corneal
epithelium is one such barrier. Most of the organisms cannot penetrate intact epithelium, so they
cannot incite keratitis in the absence of cellular injury. Neisseria meningitides, N. gonorrhea,
Corynebacterium diphtheria, Haemophilus influenzae, and Listeria species are the virulent
organisms with the potential to penetrate even intact epithelium and cause keratitis.[1] This
article talks about the etiology and available current and future management options of different
types of keratitis.

Etiology
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Based on the etiological agent, keratitis can be classified as:

Infectious Keratitis

Bacterial keratitis - including Pseudomonas, Staphylococcus, Streptococcus, Moraxella,

Nocardia, and Atypical Mycobacteria

Protozoal keratitis - including Acanthamoeba

Keratitis by Oomycete - Pythium keratitis. Morphologically, very similar to fungi;

however, unlike fungi, the cell wall here contains (1-3)(1-6) beta D glucan[2][3]

Fungal keratitis - This includes infection by Aspergillus, Fusarium, Candida (yeast),

Cladosporium, Alternaria, Curvularia, and Microsporidia

Viral keratitis - This includes infection by Herpes simplex virus (HSV), Herpes zoster virus
(HZV), Adenovirus, and others.

Helminths- Onchocercal keratitis (sclerosing keratitis).

Non-infectious Keratitis

Local causes - includes trichiasis, giant papillae, foreign body in sulcus subtarsalis

Peripheral ulcerative keratitis

Collagen vascular diseases, like rheumatoid arthritis, granulomatosis with

polyangiitis, polyarteritis nodosa, relapsing polychondritis, systemic lupus
erythematosus, and others[4]

Neurotrophic corneal ulcer (post- herpes zoster ophthalmicus, trigeminal nerve damage
due to surgery or tumor)[4]

Xerophthalmia

Epidemiology
In an epidemiological study in California, the incidence of ulcerative keratitis was found to be
27.6/100000 person-years.[5] Ulcerative keratitis was significantly higher among contact lens
wearers.[5]

As per a study conducted in South India, middle-aged males were more likely to get corneal
ulcers compared to females.[6] Farmers are at high risk on account of their occupation. Fungal
corneal ulcers are very common in developing nations. However, HSV is a major concern
in developed nations.[7] In an epidemiological study at Rochester, Minnesota, the incidence of
epithelial disease was 15.6/100000 person-years, and for stromal keratitis, it was 2.6/100000
person-years.[8]

Autoimmune disorders related to keratitis accounts for an estimated incidence of 3 per million
per year.[9]

The prevalence of xerophthalmia was almost 21% in a study in rural Ethiopia and was largely
associated with other features of generalized malnutrition.[10] For xerophthalmia, the population
at risk is largely young children who are malnourished.

Pathophysiology
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Stages of Corneal Ulcer

Stage of progressive infiltration

Stage of active ulceration

Stage of regression

Stage of cicatrization

Infectious Keratitis

Infection incites the recruitment of polymorphonuclear leukocytes and macrophages. The

hydrolases, proteases released by these inflammatory cells are primarily responsible for corneal
stromal melt and necrosis.[11] In gram-negative infections, endotoxin plays a major role and
further adds to the inflammatory response.

Adenoviral Keratoconjunctivitis

Stage 1- It lasts for 7 to 10 days and characterized by diffuse punctate epithelial keratitis.

Stage 2- After 7 days, subepithelial to anterior stromal infiltrates appear. NK cells are the
first to come in action and further involve cell-mediated immunity.[12]

Stage 3- This is characterized by persistent subepithelial to anterior stromal infiltrates.

Onchocerca Volvulus Induced Keratitis

Corneal infection by motile worms does not per se cause blindness; however, as they die after
chemotherapy or naturally, they incite inflammation and cause corneal punctate opacification.
Repeated episodes result in complete opacification of the cornea and result in blindness.

Peripheral Ulcerative Keratitis

Exact etiology is not clear; however, both cell-mediated and humoral immunity plays an
important role. In response to a corneal antigen, the immune complex gets deposited in the
peripheral cornea. The hypersensitivity reaction to an exogenous antigen is other described
mechanisms.[13]

Xerophthalmia

Vitamin A deficiency is needed for the maintenance and integrity of the epithelial lining of the
ocular surface. Loss of epithelial lining with subsequent liquefactive necrosis of cornea results
in keratomalacia.

Histopathology
Corneal infections often start as epithelial ulceration. This is followed by stromal infiltration by
polymorphonuclear (PMN) and lymphomononuclear cells, which in turn causes the destruction
of Bowman's layer and then stromal necrosis. In severe cases, there can be perforation of the
Descemet's membrane. Suppurative infections lead to infiltrates in the anterior two-thirds of the
stroma and abscess formation. Epithelial regeneration, vascularization, edema, giant cell
reaction, myofibroblatic transformation and stromal remodeling (scarring), and round cell
infiltration can occur with chronic infections.

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History and Physical

The most common complaints of patients with keratitis include redness, pain, and irritation in the
eye. The patients may also present with photophobia, visual decline, or cosmetic blemish.

Bacterial Keratitis

Keratitis by gram-positive organisms: Staphylococcal keratitis can be either because of direct

invasion of the organism or because of staphylococcal antigen. Staphylococcal antigen-induced
keratitis is usually affecting the peripheral cornea and hence the name 'marginal keratitis.'
Marginal keratitis is invariably associated with staphylococcal blepharitis. The corneal lesions
usually start at 10, 2, 4, and 8' o'clock positions, where the lid margin is in contact with the
limbus. There is always a clear area between the limbus and the ulcerative lesion, unlike HSV
marginal keratitis.

The most common cause of Streptococcal keratitis is a blocked nasolacrimal duct. So, lacrimal
duct patency or regurgitation on pressure over the lacrimal sac (ROPLAS) should be evaluated in
corneal ulcer cases.

In early-stages of Gram-positive infection, the cuff of cellular infiltration is noted around the
corneal focus of infection and is not diffuse, unlike Pseudomonal keratitis.

Pseudomonas keratitis: In early-stage, diffuse and dense corneal cellularity is noted much beyond
the focus of infection. Pseudomonas is a gram-negative bacteria with predominantly greenish-
yellow corneal infiltrate and extensive collagenolysis. The symptoms are more acute and rapidly
progressive. Corneal melt might progress to corneal perforation or endophthalmitis if not taken
care of in the early stages.

Nocardia keratitis: Nocardia is a weakly acid-fast bacteria (Modified Kinyoun stain).

[14] There may be a history of either trauma or intraocular surgery with corneal infiltrates
usually starting adjacent to the surgical incision site. The infiltrates are granular, superficial to
mid-stromal with the wreath-like pattern often in the mid-peripheral cornea.[15]

Atypical mycobacteria: The Atypical mycobacteria are acid-fast bacilli causing keratitis with a
protracted course. There may be a history of trauma with corneal foreign bodies or a history of
corneal surgery (LASIK).[16] The onset of keratitis in trauma cases can vary from days to
weeks; however, the post-LASIK cases usually have an average time of presentation of 3.4
weeks.[17] The disease has a waxing and waning course.[18] The corneal infiltrate has a typical
cracked windshield appearance with radiating lines in the middle one-third of the corneal stroma.
[19]

Viral Keratitis

Adenoviral keratitis: Adenoviral keratitis often has associated conjunctivitis, so the exact
terminology would be Epidemic adenoviral keratoconjunctivitis (Human adenovirus types
8,19,37 and 54). Presentation is usually unilateral to start with; however, it becomes bilateral
later. A predominantly follicular reaction is noted.[20] It may or may not be associated with
conjunctival hemorrhages.[21] At times the inflammation can be severe enough, resulting in the
formation of pseudomembranes. Clinically, corneal epitheliopathy develops manifesting as
punctate corneal erosions, which over a week develops into multiple, punctate to nummular
anterior stromal infiltrates.[21][22] Preauricular lymphadenopathy is an important finding in
adenoviral keratoconjunctivitis. In the pharyngoconjunctival variant (human adenovirus types 3,4
and 7), the patient may have systemic findings like pharyngitis and fever. The corneal findings in
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the early-stage (subepithelial to anterior stromal infiltrate) are considered to be due to active viral
replication; however, in the chronic stage, the infiltrates are the result of an immunological
reaction.[21] In the chronic stage, symblepharon can also be seen.[23][24] The patients at this
stage often complain of photophobia, glare, and haloes.

Herpes simplex keratitis: HSV keratitis can present as epithelial disease, stromal keratitis, and
endotheliitis.[25] HSV epithelial disease manifestation may vary from multiple punctate
erosions to dendritic ulcers and geographical ulcers. The early vesicular stage is often missed,
because of delayed presentation to the ophthalmic clinic. The ruptured vesicles coalesce together
to form dendrites with a terminal bulb.[26] Inappropriate and indiscriminate use of topical
steroids may result in geographical ulcer formation. In epithelial disease, the virus is actively
involved in the causation of the ulcer.[27] HSV epithelial disease is usually unilateral, but the
bilateral disease is more commonly seen in immunodeficient and patients with a history of atopy.
[28] HSV stromal keratitis can either be secondary to epithelial disease due to contiguous spread,
or immune-mediated. If stromal keratitis develops secondary to epithelial disease, an overlying
epithelial defect is present. However, the primary stromal involvement manifests as localized
stromal edema with or without signs of previous similar episodes. On resolution, these result in
scar formation. These scars with vascularization are the telltale signs and are also called
'footprint scars' with or without superficial or deep vascularization. HSV endotheliitis manifests
as localized or diffuse stromal edema with underlying keratic precipitates.

HSV necrotizing stromal keratitis is a variant where both the viral load and the inflammatory
component play roles simultaneously.[29][30] It manifests as corneal stromal infiltrate with
extensive collagenolysis and corneal thinning. If not treated early, corneal perforation is likely.
[31]

Herpes zoster keratitis: The diagnosis of Herpes zoster ophthalmicus (HZO) is very obvious.
Associated unilateral rashes over the forehead and eyelids with rashes reaching the tip of the
nose (Hutchinson's sign) suggest likely involvement of the corresponding eye also.[32] Corneal
dendritiform lesions with absent terminal bulbs are very characteristic.[33][34] These lesions are
due to direct invasion of epithelial cells.[35] It can also manifest as
stromal involvement corresponding to the areas of epithelial pseudodendrites or deep stromal
involvement. Isolated stromal involvement is largely an immunological reaction. It may or may
not be associated with anterior chamber reaction. Associated trabeculitis manifests as raised
intraocular pressure. Corneal sensations decrease significantly after HZO, resulting in recurrent
corneal erosions in the chronic phase. The epitheliopathy may result in persistent epithelial
defects and subsequent stromal ulceration. The ulcer is called 'neurotrophic ulcer.'[35]

Thus, the absent terminal bulbs and poor fluorescein uptake by the ulcer base differentiate HZO
keratitis from HSV keratitis.

Protozoal Keratitis

Acanthamoeba keratitis: History of exposure to soil or contaminated water is very often seen in
Acanthamoeba keratitis in the developing world. However, in developed countries, contact lens
wear has been found to have a strong association with Acanthamoeba keratitis. The spectrum of
clinical features can vary from superficial punctate keratitis, pseudo-dendrites to peri-neuritis in
the early stages.[36] Ring infiltrates are very characteristically seen in Acanthamoeba keratitis;
however, this is not present in all cases.[36] As the disease progresses, the infiltrates extend from
anterior to mid to full-thickness infiltrate and become indistinguishable from bacterial and fungal
keratitis.[37]
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Keratitis by Oomycetes

Pythium keratitis: This keratitis is caused by an oomycete, a distinct phylogenetically related

lineage of fungus-like eukaryotic micro-organism. Pythium insidiosum species causes disease in
human. The corneal lesions often mimic fungal infiltrate, and careful examination reveals dry-
looking corneal infiltrates denser in the periphery of the whole infiltration with hyphate edges.
Pin-head like lesions and tentacular extensions of the main lesion is very characteristic
for Pythium keratitis.[38]

Fungal Keratitis

Microsporidial keratitis: Previously, microsporidia was considered to be a primitive protozoan.

[39] However, subsequently, molecular phylogenetic studies revealed that it belonged to fungi.
[40][41] Microsporidial keratitis can be classified as 'keratoconjunctivitis' and 'deep stromal
keratitis.' The former being more commonly seen in immunocompromised but can also be seen
in immunocompetent.[42][43][44] The onset of keratoconjunctivitis is usually acute. A rise in
keratoconjunctivitis cases is noted during the rainy season.[45][46] Exposure to muddy water is
an important predisposing cause.[47] In keratoconjunctivitis, multiple punctate, coarse, and
raised epithelial lesions with stuck-on appearance are noted. During its course, subepithelial
infiltrates might appear, mimicking adenoviral keratoconjunctivitis. The conjunctiva shows
predominantly follicular response, though papillary reactions are also apparent. Mild anterior
chamber reaction with keratic precipitates can be seen.[48] The deep stromal variant has a
chronic course with waxing and waning. The stromal infiltrates are deep with intact overlying
epithelium. The course can vary from months to years.[49][50]

Filamentous fungal keratitis: History of trauma with vegetative matter is very often
noted. Corneal infiltrates in fungal keratitis is usually dry-looking and having feathery edges
with the presence of multiple satellite lesions. Plaque-like (with or without pigmentation) or
fungal ball-like surface lesions can also be very commonly seen. At times, retained corneal
vegetative foreign body lies in close association with the infiltrate. Endothelial plaque or
exudates in the absence of anterior stromal infiltrate can also be seen. In such a scenario, careful
examination often reveals a track from the anterior corneal surface to endothelium. This track is
usually the path of entry for fungal infection and usually follows penetrating trauma. The
hypopyon is usually thick and does not shift with a change in head position. The course of the
disease is usually longer. Compared to bacterial keratitis, the outcomes of fungal keratitis is poor.
[51][52]

Alternaria sp., Bipolaris sp., Curvularia sp. are the pigmented fungal species causing infections
in humans. The infiltrate may have pigmentation (brown) in dematiaceous fungal keratitis.[53]

Candida keratitis: Clinical features are indistinguishable from fungal keratitis.

Onchocerca volvulus keratitis: This results in sclerosing keratitis. Corneal opacity starts from the
periphery, and the visual axis gets affected at last. Deep vascularization is noted 360 degrees.

Non-infectious Keratitis

Local Causes

Trichiatic eyelashes, giant papillae, or any foreign body lodged in sulcus subtarsalis can result in
persistent epithelial denudation mechanically and subsequent stromal ulceration. To start with,
these corneal epithelial defects are usually sterile; however, they can get secondarily infected.
Ulcers due to trichiatic lashes are very often seen as sequelae of cicatrizing conjunctivitis. The
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corneal ulcers in trichiatic lashes of the lower lid are usually present in, the lower half of the
cornea.[54]

Patients with severe allergic conjunctivitis often develop giant papillae and can result in the
formation of an ulcer on superior half of cornea called "Shield ulcer." Patients will give a history
of previous allergic eye disease.

In both the above-mentioned cases, the onset of ulcer development will be gradual.

Patients with a foreign body in sulcus subtarsalis often come with a short history and acute onset
of symptoms. Patients usually give a history of the fall of the foreign body in the eye. On careful
examination, multiple linear abrasions in superior cornea may also be very obvious.
[55] Fluorescein stain accentuates the appearance and may show these abrasions clearly.

Systemic Causes

Various systemic causes can result in alteration of the local ocular surface milieu and subsequent
development of severe dry eye and keratitis.[56] Connective tissue diseases are an important risk
factor for the development of keratitis.

Rheumatoid arthritis (RA): RA is known to cause the spectrum of ocular abnormalities. Severe
dry eye, scleritis, sclerokeratitis, and peripheral ulcerative keratitis are various manifestations of
the disease.[57] History of small joint pain with or without finger deformities are important clues
to reach the diagnosis.[56] If systemic findings are not picked up in time, these cases can land up
in corneal perforations or severe systemic disease.

Wegner granulomatosis (WG)/granulomatosis with polyangiitis: WG is a connective tissue

disorder (necrotizing vasculitis) that is known to cause keratitis, episcleritis, and scleritis.
[58] The patient can present with peripheral ulcerative keratitis.[59][60] A careful examination
might reveal a depressed nasal bridge or destruction of the pinna of the ear.[61] History of nasal
bleed, hemoptysis can also be elicited. Here, early diagnosis is important to decrease not only
morbidity but also mortality.

Other systemic conditions resulting in keratitis are also known, like systemic lupus
erythematosus, relapsing polychondritis, and polyarteritis nodosa. Careful history taking helps to
reach the diagnosis.

Xerophthalmia: The keratolysis in xerophthalmia results in a punched out corneal ulcer and have
a high propensity to perforate, if left untreated.[62] The fellow eye will have dull and lustreless
cornea with conjunctival signs like Bitot's spot and conjunctival xerosis. History of recent onset
exanthematous fever or diarrhea can be elicited. Other evidence of malnutrition may be present.

Evaluation
Regurgitation on pressure over the lacrimal sac area (ROPLAS) and/or sac syringing constitute
important routine investigation in all corneal ulcer patients to rule out obstructed nasolacrimal
duct induced keratitis. The routine protocol for any corneal ulcer is to look for the characteristic
features of the ulcer, followed by corneal scraping to identify the causative organism.[63] The
sample is sent for slides and culture with sensitivity. Commonly two slides are prepared, one
each for Gram staining and 10% KOH mount.[64]

The patient is started on medications based on direct microscopy findings, and subsequently, the
treatment is further modified based on culture reports. Commonly used culture media are blood

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and chocolate agar for bacterial growth. Potato dextrose agar and Saboraud's dextrose agar are
used for fungal growth and non-nutrient agar with E. coli for Acanthamoeba.
[65] Specific microbiological features have been discussed in the management section.

Serology forms the basis for the diagnosis of autoimmune diseases. However, the diagnosis of
xerophthalmia is largely clinical.

Treatment / Management
Bacterial Keratitis

For bacterial keratitis, patients are started on fortified topical antibiotics empirically until culture
reports are available. Fortified cefazolin 5% or vancomycin and fluoroquinolones or tobramycin
or gentamicin give complete coverage against both gram-positive and gram-negative organisms.
For keratitis caused by methicillin-resistant Staphylococcus aureus (MRSA), topical vancomycin
is the drug of choice.[66] Topical linezolid 0.2% can also be used for MRSA.

Pseudomonas Keratitis: Direct smears on Grams staining shows gram-negative rods and culture
grows Pseudomonas aeruginosa. The patient is started on topical fluoroquinolones
hourly. Treatment is modified once the culture and sensitivity report is available. Oral
doxycycline is added to halt the progression of collagenolysis.[67] For resistant strains, topical
imipenem-cilastatin (1%) or colistin (0.19%) is being used.[68]

Nocardia Keratitis: Corneal smears are subjected to routine Gram staining and 1% acid-fast
staining.[69] Nocardia is a gram-positive, aerobic bacillus with thin beaded filaments exhibiting
extensive branching at 90°.[70] Nocardia grows well on conventional culture media, though
slower than other organisms. Topical fortified amikacin (2.5%) is the treatment of choice.
[15] Pre-treatment with topical steroids worsens the prognosis.[71]

Atypical mycobacteria: Ziehl Neelsen stain is used to identify the organism in smears. Topical
fortified amikacin (4%) is the treatment of choice.[18] Clarithromycin (2%) is the second line of
management. However, fluoroquinolones (ciprofloxacin 0,3%) can also be used.

Protozoal Keratitis

A clinician needs to have strong suspicion for making a diagnosis of Acanthamoeba keratitis
based on the history and clinical features. Previous topical steroid use might increase the yield of
the organism in smears and culture; however, it worsens the prognosis. As the clinical picture
often mimics viral keratitis, pre-treatment with antivirals may alter the clinical picture. In Gram
staining, the cysts are visible as multiple double-walled cysts with inner polyhedral lining. 10%
KOH-mount and 10% KOH with 0.1% calcofluor white also
demonstrate Acanthamoeba cysts. Non-nutrient agar seeded with E.coli is used for culture.
Biguanides and pentamidine are the mainstays of treatment.[72] Polyhexamethylene biguanide
(PHMB) (0.02%) and chlorhexidine (0.02%) are commonly used biguanides. Monotherapy with
one drug is quite effective. Studies suggest a synergistic effect of biguanide (PHMB and
chlorhexidine) and pentamidine. The role of voriconazole and BAK (preservative) is under
investigation.[73] The role of endosymbiont bacteria (Pseudomonas aeruginosa) for the
development of acanthamoeba keratitis has also been described.[74] The role of the addition of
levofloxacin to the anti-protozoal treatment regimen might facilitate treatment in resistant cases.
[75] For non-responding cases, deep anterior lamellar keratoplasty is a valid option. For cases
with perforation, penetrating keratoplasty is the only option, but with poor prognosis.

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Keratitis by Oomycete

Pythium insidiosum on Gram staining and 10% KOH with 0.1% calcofluor white show fungus-
like broad aseptate filaments with ribbon-like folds.[38] Zoospore induction helps in
identification, and Internal Transcribed Spacer DNA sequencing helps in confirmation.
[38] Iodine-potassium-Iodide-sulphuric acid stain (IKI-H2SO4) has been described as
another way of staining that is said to be exclusive for Pythium insidiosum and may help in early
diagnosis.[76] Various studies are being done to establish diagnosis using confocal microscopy;
however, results are inconclusive. Hourly administration of topical linezolid (0.2%) along with
topical (1% every 2 hourly) and oral azithromycin (500mg daily for 3 days in a week) was found
to be effective in treating keratitis in the earliest report.[77] The favorable role of these agents
in Pythium keratitis was further substantiated by Bagga et al. in his study with these agents over
3 years.[78] Though, in-vitro susceptibility of Pythium insidiosum to minocycline and tigecycline
was also fairly acceptable.[79]

Fungal Keratitis

Microsporidial keratitis: Microsporodial spores stain well with Grams, silver, and 10% potassium
hydroxide (KOH) with 0.1% calcofluor white. The keratoconjunctivitis variant has a self-limiting
course.[80] Topical lubricants can be added to palliate the foreign body sensation. Epithelial
debridement is also a valid option for the early resolution of corneal lesions.[81] The deep
stromal variant is unlikely to respond to conservative management with oral albendazole (400
mg twice daily for 3-4 weeks) and topical fumagillin (topical, 70 mcg/ml, 2 drops every 2 h for 4
days and then 2 drops 4-times daily).[82][83][82] Therapeutic penetrating keratoplasty is the
treatment of choice.[50]

Filamentous fungal keratitis: Routine microscopy with 10% KOH alone or 10% KOH with 0.1%
calcofluor white reveal hyaline/ pigmented, septate (Aspergillus, Fusarium)/ aseptate (Mucor,
Rhizopus) fungal filaments. Preferred culture media for fungal growth are Saboraud's and potato
dextrose agar. Topical natamycin (5%) is the drug of choice for filamentous fungal keratitis.[84]
Topical voriconazole (1%) is added as an adjunct to natamycin in Aspergillus keratitis, not
responding to natamycin alone. Voriconazole is not given as a primary drug for fungal keratitis.
[84] Systemic anti-fungal is added for large and deep corneal ulcers. As per the MUTT II
trial, the use of oral voriconazole does not make a significant difference compared to placebo in
severe fungal keratitis.[85] However, it had some role in Fusarium keratitis.[86] Repeated
superficial corneal ulcer debridement is an important component of treatment. Repeated
debridement not only decreases fungal load but also facilitates penetration of hydrophilic
natamycin into the corneal stroma. The role of intrastromal voriconazole for non-responding
lesions cannot be ignored.[87] Topical amphotericin-B (0.15%) is the drug of choice in candida
keratitis. Therapeutic penetrating keratoplasty is indicated in keratitis threatening limbus or
perforated corneal ulcer not amenable to tissue adhesive application.

Viral Keratitis

Dual staining with Rose-Bengal and fluorescein stain is a very important clinical tool to make a
diagnosis of HSV epithelial disease. Fluorescein stain makes the dendrites and geographical
ulcers more evident by staining the base of ulcer, and Rose-Bengal stains the cells at the margin
of the ulcer, which are loaded with viruses. The diagnosis of epithelial disease is mostly clinical.
[88] Corneal scraping for polymerase chain reaction for HSV viral DNA is done in doubtful
cases.[89] Topical antiviral (acyclovir 3%- 5 times a day) is the mainstay of treatment for
epithelial disease.[27] For HSV stromal disease and endotheliitis, a topical steroid is the
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mainstay of treatment. However, oral antiviral (acyclovir 400 mg, 5 times daily) is also added to
prevent further recurrence.[90] For HSV necrotizing stromal keratitis, treatment has to be given
at the earliest to avoid corneal melt and subsequent perforation. The loading dose of antiviral
both topical acyclovir (3%) and oral (acyclovir 400 mg 5 times daily ) is given for the initial
three days.[31] Topical steroid is added on the third day. For cases presenting as severe thinning
or perforation, tissue adhesive (cyanoacrylate glue) and bandage contact lens are applied.
Preferably, a topical steroid is started after applying tissue adhesive to avoid steroid-induced
further stromal lysis. For recurrent HSV keratitis, a prophylactic dose of oral antiviral (acyclovir
400 mg twice daily) is given for a year.[91]

The diagnosis of HZO is clinical. The skin lesions associated with corneal dendritiform lesion is
very characteristic. Unlike the chickenpox lesions, here, the skin lesions are in the same stage.
The ends of dendritiform lesions are tapering, unlike in dendritic ulcers in HSV epithelial
keratitis. The pseudodendrites are because of swollen epithelial cells, so they do not take up
fluorescein stain. Oral acyclovir (800 mg, 5 times daily for 1 week) is very effective in its
treatment in the early stages.[92] The recurrent epithelial erosions should largely be managed
with lubricants and prophylactic antibiotics. Neurotrophic ulcers are managed with serum,
amniotic membrane transplantation, and tarsorrhaphy. The role of long term prophylaxis with
oral antivirals is not clear and needs to be evaluated.[93]

Adenoviral keratitis: The diagnosis of adenoviral keratoconjunctivitis is primarily clinical.

However, wherever in doubt, it can be confirmed using PCR techniques. Considering the
contagious nature of the disease, maintenance of personal hygiene has a very important role in
preventing its transmission. Topical 1% povidone-iodine, in combination with 0.1%
dexamethasone, has shown good results.[94] The role of steroids in the early stages is
controversial.[20]. Topical cyclosporine 2%, when added in the acute stage in combination with
topical steroids, resulted in inhibition of subepithelial infiltrates.[95]

Non-infectious Keratitis

Local Causes

Patients with ulcers related to trichiatic lashes, entropion, or distichiasis need early correction of
pathology. The diagnosis is largely clinical. Either electrolysis of eyelash hair root follicle, lid
everting procedures, or lid splitting procedures, respectively, need to be done without
compromising the gross anatomical relationship.[96][97]

Shield ulcer is an ulcer due to the mechanical effect of giant papillae. Diagnosis is obvious on lid
eversion. Topical steroids, along with topical cyclosporine (0.05%) and lubricants, are sufficient
enough to control the disease.[98] Control of ocular allergy itself helps improving shield ulcers.
Supratarsal triamcinolone injection in refractory cases helps.[99] However, surgical excision of
giant papillae and conjunctival autologous graft or mucous membrane graft has also been
described in refractory cases.[100][101][96]

Patients with corneal ulcers related to sulcus subtarsalis foreign body needs immediate removal
of a foreign body under topical anesthesia either on slit lamp or under the microscope in the
operating room.

Systemic Causes

Rheumatoid arthritis: The diagnosis is largely by serological methods; however, clinical findings
like finger deformities are suggestive. RA factor and anti-cyclic citrullinated peptide antibodies

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(anti-CCP) are important serological markers.[56] Anti- CCP antibodies help in making an early
diagnosis.[56][102][103] The cause of keratitis is immunological. Topical and oral steroids are
the mainstay of initial treatments. The patient is started on oral or subcutaneous methotrexate
(steroid-sparing agent) under the rheumatologist's supervision.[104] Perforated corneal ulcers are
managed either with cyanoacrylate glue, or multi-layered amniotic membrane graft provided the
perforation is amenable to closure.[105][106] For large perforations, either corneal patch graft or
penetrating keratoplasty with simultaneous immunosuppression are done.[56]

Granulomatosis with polyangiitis: The clinical features are suggestive; however, the serological
test is diagnostic. C-ANCA is the serological marker.[107] GPA not only adds to the morbidity
but is a life-threatening condition if left untreated.[107] So, early diagnosis and initiation of
treatment at the earliest are important. Routine urine examination is also important to look for
renal involvement at the presentation—earlier, the renal involvement poorer the prognosis. Pulse
cyclophosphamide is the drug of choice.[107] Topical steroids, along with oral
immunosuppressive (steroids), can be used to treat peripheral ulcerative keratitis.

Xerophthalmia: Vitamin A supplementation, as per WHO guidelines, need to be done at the

earliest.

Some patients do require surgical interventions, like the application of tissue adhesives, amniotic
membrane transplantation, patch graft, or penetrating keratoplasty, to maintain the integrity of
the globe. This holds for all keratitis reaching a fate of severe corneal thinning or
perforation. Therapeutic penetrating keratoplasty is planned for limbus threatening infective
keratitis.

Apart from various diagnostic and treatment modalities discussed above, now nanoparticles and
antimicrobial peptides are being devised for sustained and targeted drug delivery.[108][109] In
addition to PCR, genotyping, and confocal microscopy, many other modalities are being worked
on.

Differential Diagnosis
Making a diagnosis of keratitis is not difficult; however, finding the etiology is not always easy.
Many times the direct microscopy and culture reports are unremarkable, and the patient has to be
treated based on clinical findings. In early-stage, Acanthamoeba keratitis and HSV stromal
keratitis are often indistinguishable; however, late stages of Acanthamoeba keratitis may
simulate fungal keratitis.

Atopic keratoconjunctivitis

Bacterial endophthalmitis

Band keratopathy

Blepharitis

Corneal ulcer

Entropion

Epidemic keratoconjunctivitis

Fungal keratitis

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Herpes simplex virus keratitis

Herpes Zoster

Interstitial keratitis

Neurotrophic keratitis

Nasolacrimal duct obstruction

Ocular rosacea

Pseudophakic bullous keratopathy

Scleritis

Viral conjunctivitis

Prognosis
Overall corneal ulcers take longer for healing. Bacterial ulcers heal relatively early than fungal
corneal ulcers. Acanthamoeba keratitis might take even months for complete remission. Corneal
scarring is the most common outcome following corneal ulcers. These cases can be managed
later with glasses or with optical iridectomy or optical keratoplasty to restore vision. Perforated
corneal ulcers often tend to have a worse prognosis. The use of prior topical steroids in fungal
and Acanthamoeba keratitis worsens the prognosis.

Complications
Complications

Toxic iridocyclitis

Secondary glaucoma

Descemetocele

Perforation of corneal ulcer

Sequelae of Corneal Perforation

Iris prolapse

Anterior dislocation of lens

Anterior capsular cataract

Corneal fistula

Purulent uveitis

Intraocular hemorrhage

Corneal scarring- nebula, macula, leucoma, adherent leucoma

Keratectasia

Disorganized anterior chamber

Autoevisceration
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Phthisis bulbi

Deterrence and Patient Education

Considering the majority of cases of keratitis due to agricultural trauma in developing nations, it
is advisable to use eyeshields during harvest season in fields. Apart from these, cases with
recurrent HSV keratitis (more than 3 episodes in a year) should take oral antiviral prophylaxis for
1 year.[91]

Pearls and Other Issues

To conclude, comprehensive treatment for keratitis would be first to find the etiology using
various clinical and/or microbiological findings and serological markers and then to address it. It
can be addressed with topical and/or systemic drugs. In the case where globe integrity is
compromised, measures like tissue adhesive application, amniotic membrane transplantation,
patch graft, or penetrating keratoplasty are done. Each treatment modality has to be tailored as
per the requirement. This article tries to bring out a comprehensive idea about keratitis and its
management.

Enhancing Healthcare Team Outcomes

It is always good to have an inhouse microbiologist so that reporting of direct smears can be
done at the earliest. Ophthalmologist and a rheumatologist should also work hand in hand. Many
patients are referred to a rheumatologist by an ophthalmologist for systemic evaluation and
starting immunomodulators. The patients need to follow at both places. An ophthalmologist can
suggest a rheumatologist for titrating the dose of immunomodulators based on clinical response.
Apart from these, patients are also evaluated for any adverse effect profile. These kinds of work
models not only ensure better clinical outcomes and patient safety but also a healthy work
atmosphere.

Review Questions

Access free multiple choice questions on this topic.

Comment on this article.

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