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.

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 noninfectious 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 that 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 virulent organisms with the potential to penetrate even intact epithelium and cause keratitis.[1] This article discusses the etiology and available current and future management options for different types of keratitis.

Etiology

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 - include 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 in 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 account 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

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 and 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 adds to the inflammatory response.

Adenoviral Keratoconjunctivitis

• Stage 1 lasts 7 to 10 days and is characterized by diffuse punctate epithelial keratitis. 
• Stage 2- After 7 days, subepithelial to anterior stromal infiltrates appear. NK cells are the first to come into 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

The exact etiology is not clear; however, both cell-mediated and humoral immunity play 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 is needed for the maintenance and integrity of the epithelial lining of the ocular surface. The loss of epithelial lining with subsequent liquefactive necrosis of the 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.

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 usually affects the peripheral cornea, 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 a 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, 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; 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 develop 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 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 a '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: A 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 and 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] 

Keratitis by Oomycetes

Pythium keratitis: This keratitis is caused by an oomycete, a distinct phylogenetically related lineage of fungus-like eukaryotic microorganisms. Pythium insidiosum species causes disease in humans. 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 are very characteristic of 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 is 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 of 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: A history of trauma with vegetative matter is very often noted. Corneal infiltrates in fungal keratitis are usually dry-looking and have 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, the 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 the 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 are poor.[51][52]

Alternaria sp., Bipolaris sp., and 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 at 360 degrees. 

Non-infectious Keratitis 

Local Causes

Trichiatic eyelashes, giant papillae, or any foreign body lodged in the 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 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 cases mentioned above, the onset of ulcer development will be gradual.

Patients with a foreign body in the sulcus subtarsalis often have a short history and an acute onset of symptoms. They usually give a history of the foreign body's fall into the eye. On careful examination, multiple linear abrasions in the 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 alter the local ocular surface milieu and subsequently cause severe dry eye and keratitis.[56] Connective tissue diseases are an important risk factor for keratitis. 

Rheumatoid arthritis (RA): RA is known to cause a spectrum of ocular abnormalities. Severe dry eye, scleritis, sclerokeratitis, and peripheral ulcerative keratitis are various manifestations of the disease.[56] A history of small joint pain with or without finger deformities are important clue to reach the diagnosis.[57] If systemic findings are not picked up in time, these cases can end 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 bleeding and 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, such as systemic lupus erythematosus, relapsing polychondritis, and polyarteritis nodosa. Careful history-taking helps to diagnose these conditions.

Xerophthalmia: The keratolysis in xerophthalmia results in a punched-out corneal ulcer that has a high propensity to perforate if left untreated.[62] The fellow eye will have a dull and lustreless cornea with conjunctival signs like Bitot's spot and conjunctival xerosis. A 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 an 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.[62] The sample is sent for slides and culture with sensitivity. Commonly, two slides are prepared, one each for Gram staining and 10% KOH mount.[63] 

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 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.[64] 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.[65] Topical linezolid 0.2% can also be used for MRSA. 

Pseudomonas Keratitis: Direct smears on Grams staining show 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.[66] For resistant strains, topical imipenem-cilastatin (1%) or colistin (0.19%) is being used.[67]

Nocardia Keratitis:  Corneal smears are subjected to routine Gram staining and 1% acid-fast staining.[68] Nocardia is a gram-positive, aerobic bacillus with thin beaded filaments exhibiting extensive branching at 90°.[69] 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.[70]

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.[71] 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.[72] The role of endosymbiont bacteria (Pseudomonas aeruginosa) in the development of acanthamoeba keratitis has also been described.[73] The role of the addition of levofloxacin to the anti-protozoal treatment regimen might facilitate treatment in resistant cases.[74] 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.

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.[75] 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 hours) and oral azithromycin (500mg daily for 3 days in a week) was found to be effective in treating keratitis in the earliest report.[76] The favorable role of these agents in Pythium keratitis was further substantiated by Bagga et al. in their study of these agents over 3 years.[77] However, in-vitro susceptibility of Pythium insidiosum to minocycline and tigecycline was also fairly acceptable.[78]

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.[79] 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.[80] 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).[81][82][81] 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 reveals 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.[83] 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.[83] 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.[84] However, it had some role in Fusarium keratitis.[85] 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.[86] 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 the 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.[87] Corneal scraping for polymerase chain reaction for HSV viral DNA is done in doubtful cases.[88] 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 mainstay of treatment. However, oral antiviral (acyclovir 400 mg, 5 times daily) is also added to prevent further recurrence.[89] 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.[90]

The diagnosis of HZO is clinical. The skin lesions associated with corneal dendritiform lesions are very characteristic. Unlike chickenpox lesions, 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.[91] 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.[92]

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.[93] 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.[94] 

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.[95][96]

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.[97] Control of ocular allergy itself helps improve shield ulcers. Supratarsal triamcinolone injection in refractory cases helps.[98] However, surgical excision of giant papillae and conjunctival autologous graft or mucous membrane graft has also been described in refractory cases.[99][100][95]

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 (anti-CCP) are important serological markers.[57] Anti- CCP antibodies help in making an early diagnosis.[57][101][102] 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.[103] Perforated corneal ulcers are managed either with cyanoacrylate glue or a multi-layered amniotic membrane graft, provided the perforation is amenable to closure.[104][105] For large perforations, either a corneal patch graft or penetrating keratoplasty with simultaneous immunosuppression is done.[57]

Granulomatosis with polyangiitis: The clinical features are suggestive; however, the serological test is diagnostic. C-ANCA is the serological marker.[106] GPA not only adds to the morbidity but is a life-threatening condition if left untreated.[106] 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.[106] Topical steroids, along with oral immunosuppressive (steroids), can be used to treat peripheral ulcerative keratitis. 

Xerophthalmia: Vitamin A supplementation, as per WHO guidelines, needs 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.[107][108] 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 the early stages, Acanthamoeba keratitis and HSV stromal keratitis are often indistinguishable; however, the late stages of Acanthamoeba keratitis may simulate fungal keratitis.

• Atopic keratoconjunctivitis
• Bacterial endophthalmitis
• Band keratopathy
• Blepharitis
• Corneal ulcer
• Entropion
• Epidemic keratoconjunctivitis
• Fungal keratitis
• 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 to heal. Bacterial ulcers heal relatively earlier than fungal ulcers, and Acanthamoeba keratitis might take months for complete remission. Corneal scarring is the most common outcome following corneal ulcers. These cases can be managed later with glasses, 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 the lens
• Anterior capsular cataract
• Corneal fistula
• Purulent uveitis
• Intraocular hemorrhage
• Corneal scarring- nebula, macula, leucoma, adherent leucoma
• Keratectasia
• Disorganized anterior chamber
• Autoevisceration
• 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.[90]

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.