Keratitis, Fungal Author: Daljit Singh, MBBS, MS, DSc, Professor Emeritis, Department of Ophthalmology, Guru Nanak Dev

University, Amritsar, India; Director, Daljit Singh Eye Hospital Coauthor(s): Arun Verma, MD, Senior Consultant, Department of Ophthalmology, Dr Daljit Singh Eye Hospital, India Contributor Information and Disclosures Updated: Jun 12, 2008 Background Fungal keratitis was first described by Leber in 1879. This entity is not a common cause of corneal infection, but it represents one of the major causes of infectious keratitis in tropical areas of the world. Considering fungus as a possible cause of infectious keratitis is important because devastating ocular damage can result if it is not diagnosed and treated promptly and effectively. Fungal keratitis is a general term meaning any inflammation of the cornea. Fungi can infect (and therefore inflame) the cornea. The term fungal keratitis refers to a corneal infection caused by fungi. One type of fungus that can infect the cornea is Fusarium. When Fusarium infects the cornea, the eye disease is referred to as Fusarium keratitis. Fungal keratitis remains a diagnostic and therapeutic challenge to the ophthalmologist. Difficulties are related to establishing a clinical diagnosis, isolating the etiologic fungal organism in the laboratory, and treating the keratitis effectively with topical antifungal agents. Unfortunately, delayed diagnosis is common, primarily because of lack of suspicion; even if the diagnosis is made accurately, management remains a challenge because of the poor corneal penetration and the limited commercial availability of antifungal agents. Moreover, the incidence of fungal keratitis has increased over the past 30 years. This increased occurrence of fungal keratitis is a result of the frequent use of topical corticosteroids and antibacterial agents in treating patients with keratitis, the rise in the number of patients who are immunocompromised, and better laboratory diagnostic techniques that aid in its diagnosis. Classification Of the 70 different fungi that have been implicated as causing fungal keratitis, the 2 medically important groups responsible for corneal infection are yeast and filamentous fungi (septate and nonseptate). Yeast produces characteristic creamy, opaque, pasty colonies on the surface of culture media. Candida is the most representative pathogen in this group, primarily affecting those corneas already compromised by topical steroids, surface pathology, or both. A feathery or powdery growth on the surface of culture media is produced by septate filamentary fungi, which are the most common cause of fungal keratitis. Pathophysiology Many fungal organisms associated with ocular infections are ubiquitous, saprophytic organisms and have been reported as causes of infection only in the ophthalmic literature. Fungal isolates have been classified into the following groups: Moniliaceae (nonpigmented filamentary fungi, including

Fusarium and Aspergillus species), Dematiaceae (pigmented filamentary fungi, including Curvularia and Lasiodiplodia species), and yeasts (including Candida species). Fungi gain access into the corneal stroma through a defect in the epithelium, then multiply and cause tissue necrosis and an inflammatory reaction. The epithelial defect usually results from trauma (eg, contact lens wear, foreign material, prior corneal surgery). The organisms can penetrate an intact Descemet membrane and gain access into the anterior chamber or the posterior segment. Mycotoxins and proteolytic enzymes augment the tissue damage. Fungal keratitis also has been described to occur secondary to fungal endophthalmitis. In these cases, fungal organisms extend from the posterior segment through the Descemet membrane and into the corneal stroma. Fungi are not a common cause of microbial keratitis. Fungi cannot penetrate the intact corneal epithelium and do not enter the cornea from episcleral limbal vessels. They need a penetrating injury or a previous epithelial defect to enter the cornea. Once within the cornea, however, they are able to proliferate. Organisms that infect preexisting epithelial defects belong to the normal microflora of the conjunctiva and adnexa. The most common pathogen that invades a preexisting epithelial defect is Candida. Filamentous fungi are the principal causes of posttraumatic infection. The intrinsic virulence of fungi depends on the fungal substances produced and the host response generated. Filamentous fungi proliferate within the corneal stroma without release of chemotactic substances, thereby delaying the host immune/inflammatory response. In contrast, Candida albicans produces phospholipase A and lysophospholipase on the surface of blastospores, facilitating the entrance to the tissue. Fusarium solani, which is a virulent fungus, is able (as are other filamentous fungi), to spread within the corneal stroma and penetrate the Descemet membrane. Corneal trauma is the most frequent and major risk factor for fungal keratitis. In fact, the physician should have a high level of suspicion in a patient with a history of corneal trauma, particularly with plant or soil matter. The trauma that accompanies contact lens wear is miniscule; contact lenses are not a common risk factor of fungal keratitis. Candida is the principal cause of keratitis associated with therapeutic contact lenses, and filamentous fungi are associated with refractive contact lens wear. Topical steroid use has definitively been implicated as a cause of increased incidence, development, and worsening of fungal keratitis. Other risk factors to consider are foreign bodies, corneal surgery, chronic keratitis, and immunosuppressive diseases. Frequency United States

The incidence of fungal keratitis varies according to geographical location and ranges from 2% of keratitis cases in New York to 35% in Florida. Fusarium species are the most common cause of fungal corneal infection in the southern United States (45-76% of fungal keratitis), while Candida and Aspergillus species are more common in northern states. In a large series of fungal keratitis from south Florida, Rosa et al reported that Fusarium oxysporum was the most common isolate (37%), followed by, in order of decreasing frequency, Fusarium solani (24%), Candida, Curvularia, and Aspergillus species.1 Fusarium species are commonly found in soil, in water, and on plants throughout the world, particularly in warmer climates. Past studies of Fusarium keratitis have found that most

incidences of Fusarium keratitis have been caused by an eye injury with vegetative matter (eg, being hit in the eye with a palm branch). An estimated 30 million persons in the United States wear soft contact lenses. The annual incidence of microbial keratitis is estimated to be 4-21 per 10,000 soft contact lens users, depending on whether users wear lenses overnight. A number of individuals have contracted Fusarium keratitis from contact lens wear, especially through the use of the Bausch & Lomb ReNu with Moisture Lock contact lens solution. This number is generally very small, particularly in the northern part of the United States. On March 8, 2006, the Centers for Disease Control and Prevention (CDC) received a report from an ophthalmologist in New Jersey regarding 3 patients with contact lensassociated Fusarium keratitis during recent months. Initial contact with several corneal disease specialty centers in the United States revealed that other centers also had seen recent increases in Fusarium keratitis. The CDC began an investigation of the Fusarium keratitis outbreak. There were 130 confirmed cases of Fusarium keratitis. Over 60% of people with confirmed Fusarium keratitis had used Bausch & Lomb ReNu with Moisture Lock contact lens solution, and 37 of these cases resulted in cornea transplant surgery. The US Food and Drug Administration (FDA) recalled Bausch & Lomb ReNu with Moisture Lock contact lens solution. According to Bausch & Lomb, "unique characteristics of the formulation of the ReNu with Moisture Lock product in certain unusual circumstances can increase the risk of Fusarium infection."

International

Aspergillus species is the most common isolate in fungal keratitis worldwide. Large series of fungal keratitis from India report that Aspergillus species is the most common isolate (2764%), followed by Fusarium (6-32%) and Penicillium (2-29%) species.

Mortality/Morbidity Fungal organisms can extend from the cornea into the sclera and intraocular structures. Fungi can cause severe infections, such as scleritis, endophthalmitis, or panophthalmitis. These infections are usually very difficult to treat and may result in severe visual loss or even loss of the eye. Sex Fungal keratitis is more common in males than in females and often occurs in patients with a history of outdoor ocular trauma. Clinical History

A history of outdoor eye trauma often is reported. In patients presenting with possible fungal keratitis, inquire about possible risk factors (see Causes). Symptoms include the following: o Foreign body sensation o Increasing eye pain or discomfort o Sudden blurry vision o Unusual redness of the eye

o o

Excessive tearing and discharge from the eye Increased light sensitivity

Physical The clinical diagnosis of fungal keratitis is based on risk factor analysis and characteristic corneal features.

The most common signs on slit lamp examination are nonspecific and include the following: o Conjunctival injection o Epithelial defect o Suppuration o Stromal infiltration o Anterior chamber reaction o Hypopyon Presenting clinical features that are specific to fungal keratitis include an infiltrate with feathery margins, elevated edges, rough texture, gray-brown pigmentation, satellite lesions, hypopyon, and endothelial plaque. o Fine or coarse granular infiltrate within the epithelium and anterior stroma o Gray-white color, dry, and rough corneal surface that may appear elevated o Typical irregular feathery-edged infiltrate o White ring in the cornea and satellite lesions near the edge of the primary focus of the infection o In advanced cases, suppurative stromal keratitis associated with conjunctival hyperemia, anterior chamber inflammation, hypopyon, iritis, endothelial plaque, or possible corneal perforation Although these highly characteristic signs may be present, obtaining a sample of the lesion by scraping or corneal biopsy is important before initiating treatment with antifungal therapy (see Procedures). Several unfortunate cases have been reported in which antifungal therapy had been initiated before fungi were seen or isolated, with resultant misdiagnosis and progression of the process. A deep stromal infiltrate with an intact epithelium also may be present. However, many fungal ulcers demonstrate no striking morphologic pattern, and it often is not possible to differentiate clinically between fungal keratitis and bacterial keratitis. Advanced severe filamentous fungal and yeast keratitis are indistinguishable and resemble keratitis caused by virulent bacteria, such as Staphylococcus aureus and Pseudomonas aeruginosa.

Causes

Aspergillus is the most common cause of fungal keratitis worldwide. However, the epidemiology of fungal keratitis is climate specific. In the southern United States, Fusarium species are the most common cause of fungal keratitis, with an especially high incidence in Florida. In contrast, Candida and Aspergillus species are the most common pathogens in the northern United States. Common risk factors for the development of fungal keratitis include the following: o Trauma (eg, contact lenses, foreign body); in a study of fungal keratitis from south Florida, trauma with vegetable matter was the major risk factor in 44% of patients. o Topical corticosteroid use o Corneal surgery such as penetrating keratoplasty, clear cornea (sutureless) cataract surgery, or laser in situ keratomileusis (LASIK) o Chronic keratitis due to herpes simplex, herpes zoster, or vernal keratoconjunctivitis o Young males

Healthy No significant ocular disease Previous history of trauma (vegetable matter) Agricultural occupations Risk factors for Candida keratitis are as follows: o Older patients o Preexisting ocular disease o Exposure keratopathy o Chronic keratitis o Long-term steroid use o Immunosuppressive disease
o o o o

Keratitis, Herpes Simplex

Author: Jim C Wang, MD, Retina/Vitreous Fellow, Department of Ophthalmology, West Virginia University; Cornea/Anterior Segment Subspecialist, Department of Ophthalmology, Kaiser Permanente Fontana Medical Center Coauthor(s): David C Ritterband, MD, Assistant Director of Cornea & External Disease, Clinical Assistant Professor, Department of Ophthalmology, New York Eye and Ear Infirmary, New York Medical College Contributor Information and Disclosures Updated: Dec 19, 2007

Background
Herpes simplex virus (HSV) keratitis encompasses a variety of disease processes that HSV can cause in the human cornea. A variety of clinical manifestations of infectious and immunologic etiologies, such as infectious epithelial keratitis, neurotrophic keratopathy, necrotizing stromal keratitis, immune stromal keratitis (ISK), and endotheliitis, can affect all levels of the cornea. Although more common as a manifestation of recurrent HSV infection, HSV keratitis may also be seen during a primary infection.

Pathophysiology
HSV is a DNA virus that commonly affects humans. Infection occurs by direct contact of skin or mucous membrane with virus-laden lesions or secretions. HSV type 1 (HSV-1) is primarily responsible for orofacial and ocular infections, whereas HSV type 2 (HSV-2) generally is transmitted sexually and causes genital disease. HSV-2 may rarely infect the eye by means of orofacial contact with genital lesions and occasionally is transmitted to neonates as they pass through the birth canal of a mother with genital HSV-2 infection. Primary HSV-1 infection occurs most commonly in the mucocutaneous distribution of the trigeminal nerve. It is often asymptomatic but may manifest as a nonspecific upper respiratory tract infection. After the primary infection, the virus spreads from the infected epithelial cells to nearby sensory nerve endings and is transported along the nerve axon to the cell body located in the trigeminal ganglion. There, the virus genome enters the nucleus of a neuron, where it persists indefinitely in a latent state. Primary infection of any of the 3 (ie, ophthalmic, maxillary, mandibular) branches of cranial nerve V can lead to latent infection of

nerve cells in the trigeminal ganglion. Interneuronal spread of HSV within the ganglion allows patients to develop subsequent ocular disease without ever having had primary ocular HSV infection. Recurrent ocular HSV infection has traditionally been thought of as reactivation of the virus in the trigeminal ganglion, which migrates down the nerve axon to produce a lytic infection in ocular tissue. Evidence suggests that the virus may also subsist latently within corneal tissue, serving as another potential source of recurrent disease and causing donor-derived HSV disease in transplanted corneas. However, corneal HSV latency as a cause of recurrent disease remains controversial. A prospective multicenter trial failed to find an association between anecdotal environment triggers (eg, stress, systemic infections, sunlight exposure, menstruation, contact lens wear, eye injury) and ocular HSV recurrence.

Frequency
United States Approximately 20,000 new cases of ocular HSV occur in the United States annually, and more than 28,000 reactivations occur in the United States annually. It is one of the most frequent causes of blindness in the United States with 500,000 people experiencing HSV-related ocular disease. International HSV infection is ubiquitous, with an estimated one third of the population worldwide suffering from recurrent infections.

Mortality/Morbidity
HSV keratitis is the most frequent cause of corneal blindness in the United States and is a leading indication for corneal transplantation. HSV keratitis is also the most common cause of infectious blindness in the Western world.

Age
Most HSV eye disease occurs in adults, and it occurs many years after the primary infection. However, herpetic keratitis in children almost always involves the corneal epithelium and is marked by a disproportionate risk of binocular disease, a high recurrence rate, and amblyopia.

Clinical
History

Patients with HSV keratitis may complain of the following: o Pain o Photophobia o Blurred vision

Tearing Redness A history of prior episodes in patients with recurrent disease may exist. Among patients with ocular HSV, those with previous stromal involvement have a significantly higher risk of subsequent stromal keratitis; in contrast, patients with epithelial keratitis have no increased rate of recurrent HSV disease.
o o

Physical
HSV keratitis may be divided into 4 categories: infectious epithelial keratitis, neurotrophic keratopathy, stromal keratitis, and endotheliitis.

Infectious epithelial keratitis is characterized by corneal vesicles, dendritic ulcers, and geographic ulcers. o The earliest sign of active viral replication in the corneal epithelium is small, raised, clear vesicles that are analogous to the vesicular eruptions seen in mucocutaneous herpes infection elsewhere in the body. These infectious epithelial vesicles are rarely seen or recognized during a patient's first presentation. However, in patients with a known history of HSV keratitis, infectious epithelial vesicles may be observed even in the absence of any clinical symptoms. o Within several hours, these corneal vesicles coalesce into a dendritic pattern. In some patients, particularly patients who are immunocompromised, the recurring infection may be arrested at the vesicle stage. As the disease progresses, a central epithelial defect develops. The resultant dendritic ulcer is the most common presentation of HSV keratitis. o Prominent features of a HSV dendritic ulcer include branching terminal bulbs, swollen epithelial borders that contain live viruses, and central ulceration through the basement membrane. o If the infectious ulcer enlarges, its shape is no longer linear. It is then referred to as a geographic ulcer. The swollen epithelial cells and the scalloped or geographic borders differentiate this infectious lesion from the smooth borders of a neurotrophic ulcer. Neurotrophic keratopathy develops in patients with previous HSV epithelial disease. Traditionally thought of as neither infectious nor immunologic in origin, neurotrophic keratopathy arises from impaired corneal innervation and decreased tear formation, exacerbated by long-term use of topical medications, especially antiviral agents. However, evidence suggests that HSV replication may occur in persistent epithelial defects. o The earliest signs of neurotrophic keratopathy include an irregular corneal surface and punctate epithelial erosions. These erosions may progress to a persistent epithelial defect and eventual stromal ulceration. o In contrast to the irregular shape and scalloped borders of an infectious geographic ulcer, a neurotrophic ulcer is typically oval with smooth borders and often lies within the interpalpebral fissures, located in the central or inferior paracentral area of the cornea. Decreased corneal sensitivity helps confirm the diagnosis. o Complications of neurotrophic keratopathy include stromal scarring, neovascularization, necrosis, and perforation.

Corneal stromal inflammation may be the primary manifestation of HSV keratitis or may be seen secondary to infectious epithelial keratitis, neurotrophic keratopathy, or endotheliitis. The 2 forms of primary stromal involvement are necrotizing stromal keratitis and ISK. o Necrotizing stromal keratitis, characterized by dense stromal infiltrate, ulceration, and necrosis, is believed to result from viral replication in stromal keratocytes and severe host inflammatory response. This destructive intrastromal inflammation may lead to thinning and perforation within a short period. The use of topical corticosteroids without antiviral coverage may be a possible risk factor for its development. o ISK is a common manifestation of chronic recurrent ocular HSV disease. An antibody-complement cascade to retained viral antigen within the stroma is believed to be the underlying mechanism. ISK may present clinically with focal, multifocal, or diffuse cellular infiltrates; immune rings; neovascularization; or ghost vessels at any level of the cornea. o Significant anterior chamber inflammation may accompany stromal keratitis. o Permanent stromal scarring may lead to profound visual loss. In addition, all stromal keratitis types may develop uveitis, trabeculitis, and secondary glaucoma. Endotheliitis o Clinical signs of endotheliitis include keratic precipitates (KP), overlying stromal and epithelial edema, and absence of stroma infiltrate or neovascularization. A mild-to-moderate iritis is frequently seen. o Immunologic reaction to viral antigens within corneal endothelial cells has been proposed as the underlying pathogenesis; however, active viral replication may also play a role. The inflammation directed at the endothelium may cause endothelial decompensation and overlying stromal and epithelial edema. o HSV endotheliitis can be classified as disciform, diffuse, or linear. Disciform endotheliitis presents with a round area of corneal edema in a central or paracentral region with a clear demarcation between involved and uninvolved cornea. Diffuse endotheliitis shows scattered KP and may stem from a previous disciform area of involvement. Linear endotheliitis appears as a line of KP progressing centrally from the limbus, with peripheral corneal edema trailing the migrating line of KP. The line of KP can be sectoral or circumferential; it may take on either a straight pattern or a more serpiginous pattern.

Causes

Infectious epithelial keratitis results from active viral replication within the corneal epithelium. Neurotrophic keratopathy is poorly understood. The cause is thought to be multifactorial and includes decreased corneal innervation and tear secretion (as a result of prior HSV infection of the sensory nerves), toxicity from topical agents, and underlying stromal inflammation. Evidence suggests that active HSV reproduction may also play a role. Necrotizing stromal keratitis arises from direct infection of the corneal stroma and the resultant severe host inflammatory response.

ISK is an antibody-complement cascade triggered by a retained viral antigen within the stroma. Endotheliitis is believed to be primarily an immunologic reaction to an antigen in endothelial cells; however, the role of live virus has been speculated.

Keratitis, Interstitial
Author: Parag A Majmudar, MD, Fellowship Co-Director, Department of Ophthalmology, Cornea and Refractive Surgery Service, Assistant Professor, Rush-Presbyterian-St Luke's Medical Center Contributor Information and Disclosures Updated: Dec 14, 2007

Background
Interstitial keratitis (IK) is a broad, descriptive term that has become synonymous with syphilitic disease. Although syphilis remains the leading cause of IK, various bacterial, viral, parasitic, and autoimmune causes of IK exist.

Pathophysiology
By definition, IK is a nonsuppurative inflammation, which is characterized by cellular infiltration of the corneal stroma. In general, no primary involvement of the corneal epithelium or endothelium occurs. Inflammation may be either the direct result of an infectious process or, more commonly, secondary to an immunologic response to a specific foreign antigen. This immunological response may take the form of antigen-antibody complex deposition, complement-mediated disease, or a delayed-type hypersensitivity reaction.

Frequency
United States IK generally is seen in the context of syphilis and, less commonly, in the context of herpes and Cogan syndrome. International In various countries in which mycobacterial diseases (eg, tuberculosis, leprosy) are endemic, these and other parasitic causes of IK may be seen with greater frequency.

Mortality/Morbidity
Ocular morbidity generally is in the form of corneal scarring, which can interfere with visual acuity.

Race

No known racial predilection exists.

Sex
No gender predilection exists.

Age
IK generally is a disease that manifests in the third to fifth decades of life.

Clinical
History

In the acute phase, IK typically causes decreased vision, photophobia, tearing, pain, and blepharospasm. Late phase symptoms consist of decreased visual acuity but little ocular discomfort. Congenital syphilis tends to cause acute symptoms in childhood. Patients may give a history of one or both eyes being red and painful for months as a child. They may remember being admitted to the hospital or confined to bed, and they may not have been allowed to go to school for many months. They may give a history of prolonged intravenous antibiotics or multiple shots as treatment.

Physical

Clinically, IK is characterized by areas of dense, white, stromal necrosis and vascularization in the acute phase, which may be either diffuse or focal and typically results in scarring and thinning in the later phases of inflammation. The active vascularization contributes to the pinkish color of the cornea and is termed the salmon patch of Hutchinson. These vessels often regress, leaving behind remnants known as ghost vessels. Once the initial inflammation has resolved, which may take many months, the cornea may exhibit mild-to-severe scarring and thinning. The scarring tends to be in the mid to posterior corneal stroma.

Causes
IK may be attributed to a number of systemic illnesses, including bacterial, viral, and parasitic infections, as well as Cogan syndrome, which can be associated with various systemic vasculitides.

Bacterial infections o Syphilis: IK in syphilis may be due to an immune-mediated reaction to an unknown treponemal antigen. IK may be seen in congenital and acquired syphilis. o Congenital syphilis IK due to congenital syphilis is commonly a late finding. Most cases of IK develop in patients aged 5-20 years. Acute IK may be triggered by ocular surface inflammation and following intraocular surgery. Corneal

inflammation most often affects the deep stromal layers either as multifocal infiltrates or as a diffuse process. Corneal stromal edema may result from the inflammation, resulting in the ground glass cornea. Variable corneal stromal neovascularization depending on the severity of the inflammation may be present. Typically, the neovascularization begins at the corneal limbus and may occur in the level, although it most commonly is seen in the deeper stromal layers. Stromal inflammation overlying the vessel often causes the salmon-colored patch due to the pinkish color imparted by the stromal vessels. Intrastromal hemorrhage also may occur. IK may progress to the regression phase, during which scarring of the corneal stromal and collagen remodeling occur. The superficial vessels resorb, and the deeper vessels may constrict, resulting in the ghost vessels that are seen as a late finding of syphilitic IK. Congenital syphilitic IK is typically bilateral in 80% of cases. However, the two eyes are very rarely involved simultaneously; usually, the contralateral eye is affected after an interval of time, which may be as short as 2 months or as long as 15 years, following inflammation of the first eye. Acquired syphilis Corneal disease in acquired syphilis is rare, although IK may be seen. Typically, IK is unilateral in the context of acquired syphilis. IK may occur relatively soon following the primary general infection, but it more often occurs many years later with the onset of pain, photophobia, tearing, and blurred vision, similar to the symptoms seen in acute IK in congenital syphilis. In general, the symptoms are less severe and of shorter duration. Clinical findings of IK in acquired syphilis very closely resemble those seen in IK in congenital syphilis. Late findings of IK in acquired syphilis include opacification of the stroma with ghost vessels and thinning. Endothelial changes in the form of redundant basement membrane at the level of the Descemet membrane also may be present. Endothelial decompensation may follow, resulting in central corneal edema later in life. Mycobacterial infections: Tuberculosis and leprosy are two mycobacterial infections that may be causative agents in the pathogenesis of IK. Internationally, tuberculosis remains an important public health issue, and, in the United States, tuberculosis has become a relevant topic due to increased immigration from endemic areas, as well as due to the human immunodeficiency virus (HIV). Although primary tuberculosis infection of the eye is extremely rare, IK may be associated with pulmonary tuberculosis. Even in this setting, it is extremely rare and, when present, usually is unilateral. In keeping with the other types of IK, the pathogenesis seems to be an immune reaction to tuberculous antigens within the cornea. Clinical findings are similar to IK due to other disorders. Leprosy is caused by Mycobacterium leprae and characteristically infects the skin and peripheral nerves. Two forms of leprosy exist, tuberculous and lepromatous. IK also may be an ocular finding of leprosy (Hansen disease), and, in contrast to that seen in tuberculosis,

lepromatous IK usually is bilateral. Another distinguishing characteristic of lepromatous IK is that the organisms have been found throughout the stroma, implying that a direct infectious etiology may occur, in contrast to an immunologic etiology. Clinical findings of IK are similar to that in tuberculous IK; however, prognosis may be poor due to the widespread involvement of the corneal nerves in lepromatous IK. o Lyme disease: The causative organism in Lyme disease is the spirochete Borrelia burgdorferi and typically is transmitted by the deer tick vector, Ixodes. Lyme disease clinically is distinguished by 3 stages, and ocular involvement typically occurs in stage 2 and stage 3. Stage 1 represents the viral prodrome with a flulike illness and the typical bull's eye lesions on the skin, erythema chronicum migrans. Stage 2 is characterized by neuro-ophthalmologic manifestations. Keratitis along with uveitis and vasculitis may occur in stage 3. Keratitis is a rare feature of Lyme disease, but, when present, it carries a typical finding of IK with the exception of stromal edema, which is not a common factor in Lyme IK. Lyme keratitis also can appear as large nummular infiltrates in various levels of the stroma without corneal neovascularization. Parasitic infections: Parasitic infections are rare causes of IK commonly seen in the United States. o Acanthamoeba is a free-living amoeba, which may cause a severe keratitis, especially in patients with a history of contact lens wear and more typically contact lens abuse. In prior decades, the use of homemade saline solutions was found to be a cause of Acanthamoeba keratitis. The use of contact lenses while swimming, typically in a fresh water environment, also is another risk factor. Acanthamoeba keratitis may have a variety of presenting characteristics, but the most significant symptom is pain out of proportion to clinical findings. Although epitheliopathy may exist, primary stromal involvement, including inflammation edema, may be seen, which resembles IK. In typical Acanthamoeba keratitis, stromal neovascularization is not an early finding. o Onchocerciasis (river blindness) is the result of infection by the nematode Onchocerca volvulus. Ocular involvement is the result of the migration of the microfilariae to the ocular tissues. IK caused by onchocerciasis has been described as beginning in the peripheral cornea, followed by progressive spread centripetally. Vascularization and complete opacification of the cornea may result, but corneal thinning is not a significant feature in this condition. o Leishmania is a protozoan agent commonly seen in Asia, Africa, and South America. It is carried by the sand fly vector and is divided into cutaneous and visceral forms. Typically, 2 types of keratitis are seen. Necrotizing keratitis may progress to corneal necrosis and perforation. However, a second presentation is that of typical IK with late corneal scarring and thinning. o Trypanosoma cruzi is responsible for the American form or Chagas disease, and Trypanosoma brucei is responsible for the African form, also known as African sleeping sickness. IK may be seen in the African form with the typical features described previously. o Microsporidia are small intracellular protozoans, which have been isolated from patients with acquired immunodeficiency syndrome (AIDS) who had

developed superficial keratoconjunctivitis. They are rare causes of keratitis in immunocompetent individuals. Viral infections o Herpetic infections of the cornea comprise a myriad of clinical findings. A complete discussion is beyond the scope of this section. Herpetic stromal disease may take the form of IK and represents an important entity in the differential diagnosis. Typical findings of IK may be present along with an immune ring, which may be diagnostic. o Epstein-Barr virus also belongs to the herpes family of viruses and may have variable presentation in corneal disease. Unilateral or bilateral, multifocal or discrete infiltrates may be present, which may benefit from topical corticosteroids. o Mumps typically causes lacrimal gland inflammation, but cornea involvement may occur with a variable presentation, ranging from punctate epithelial keratopathy to nummular keratitis. o Cornea involvement in measles typically is a superficial keratitis and generally is self-limiting. However, measles has been associated with vitamin A deficiency in malnutrition, and the combination of these factors may promote stromal infiltration and perforation. Cogan syndrome o The triad of nonsyphilitic IK, vestibuloauditory disease, and associated autoimmune vasculitis is known as Cogan syndrome and was first described in 1945. In this condition, a sudden onset of vestibuloauditory symptoms (eg, tinnitus, vertigo, nausea, vomiting) occurs, along with corneal inflammation and often an association with autoimmune disorders (eg, polyarteritis nodosa, Wegener granulomatosis, rheumatoid arthritis). In contrast to the deafness associated with syphilitic IK, the hearing loss in Cogan syndrome also has the vestibular symptoms described earlier. Although the exact pathogenesis is unknown, the disease process probably represents an immune reaction against the common antigen found in the cornea and in the inner ear. o Corneal findings are very similar to those seen in syphilitic IK, with lymphocytic infiltration of the deep stroma with variable neovascularization.

Keratoconjunctivitis, Atopic
Author: Anne Chang-Godinich, MD, Assistant Clinical Professor, Department of Ophthalmology, Baylor College of Medicine Coauthor(s): Michael B Raizman, MD, Associate Professor, Department of Ophthalmology, Tufts School of Medicine; Consulting Staff, Ophthalmic Consultants of Boston, Inc Contributor Information and Disclosures Updated: Jan 16, 2009

Background
Atopic keratoconjunctivitis (AKC) is a relatively uncommon but potentially blinding ocular condition. In 1952, Hogan described AKC as a bilateral conjunctivitis occurring in 5 male

patients with atopic dermatitis. Originally described to flare with worsening dermatitis, Foster et al noted that some patients' ocular involvement evolves independent of dermatitis.1 AKC is associated with a 95% prevalence of concomitant eczema and an 87% prevalence of asthma. Other than AKC, common ocular atopic phenomena include allergic conjunctivitis, giant papillary conjunctivitis, and vernal keratoconjunctivitis.

Pathophysiology
Atopy refers to hypersensitivity in patients with familial histories of allergic disease. Individuals with atopy often have environmental allergies, allergic asthma, rhinitis, and atopic dermatitis or eczema. Less commonly, they exhibit food allergies, urticaria, and nonhereditary angioedema. Immunoglobulin E (IgE) is the serum mediator of the exuberant responses. Hypersensitivity reactions associated with types I and IV contribute to the inflammatory changes of the conjunctiva and the cornea that are found in AKC. During exacerbations, patients have increased tear and serum IgE levels and increased numbers of circulating B cells; T-cell levels are depressed.

Frequency
International Atopy affects 5-20% of the general population. AKC occurs in 20-40% of individuals with atopic dermatitis.

Mortality/Morbidity
Decreased vision and blindness result from chronic superficial punctate keratitis, persistent epithelial defects, corneal scarring or thinning, keratoconus, cataracts, and symblepharon formation. The use of corticosteroids to medically treat AKC can further promote the development of cataracts, glaucoma, and secondary corneal infections.

Sex
This condition is more prevalent in men than in women.

Age
Peak age of incidence is in persons aged 30-50 years. The age range is from the late teenaged years to 50 years.

Clinical
History
Look for the following in past medical history:

Chronic or chronically relapsing atopic disease o Dermatitis

Asthma Rhinitis Ocular symptoms with little or no seasonal variation (as opposed to vernal conjunctivitis that is seen only in warm weather) o Itching o Tearing o Ropy discharge o Burning o Photophobia o Decreased vision
o o

Physical

Periorbita - Dennie-Morgan folds (linear lid folds secondary to chronic eye rubbing) and Hertoghe sign (absence of lateral eyebrows) Lids - Thickening and tylosis, crusting, edema, fissures, ptosis, and staphylococcal blepharitis Conjunctiva o Small- or medium-sized papillae, hyperemia, edema, excessive mucin, and limbal Trantas dots (clusters of necrotic eosinophils, neutrophils, and epithelial cells) o Formation of keratinization, cicatrization, and symblepharon in advanced disease Cornea o Punctate epitheliopathy and keratitis, persistent epithelial defects, shieldshaped ulcers, anterior stromal scarring, and micropannus o Extensive peripheral corneal vascularization in later stages o Higher incidence of keratoconus (16%) and recurrent herpes simplex keratitis associated with AKC Lens - Posterior or anterior subcapsular shield-shaped cataracts Fundus - Degenerative vitreous changes and retinal detachment

Keratoconjunctivitis, Superior Limbic

Author: James H Oakman Jr, MD, Partner, Southern Eye Center, Augusta, Georgia Contributor Information and Disclosures Updated: Nov 6, 2008

Background
This disorder is characterized as an inflammation of the superior bulbar conjunctiva with predominant involvement of the superior limbus, an adjacent epithelial keratitis, and a papillary hypertrophy of the upper tarsal conjunctiva. In 1963, Thygeson and Kimura described it as a chronic, localized, filamentary conjunctivitis.1 It was given its name, superior limbic keratoconjunctivitis (SLK), by Theodore, contemporaneously. Five years later, Tenzel and Corwin reported an association

with thyroid abnormalities and SLK.2,3 A mimicking disorder has been encountered in soft contact lens wearers, typically with exposure to thimerosal-preserved solutions.

Pathophysiology
SLK is believed to be present secondary to superior bulbar conjunctiva laxity, which induces inflammatory changes from mechanical soft tissue microtrauma4 In settings where the physiological tolerance of mechanical forces on the delicate ocular surface is exceeded, chronic inflammation results in thickening of the conjunctiva and keratinization, which is then cyclical in perpetuating the inflammation. Eventually, a filamentary response may be induced on the affected cornea. Factors inducing conjunctiva laxity include thyroid eye disease, tight upper eyelids, and prominent globes. Immunochemical histopathologic examination of the abnormal conjunctiva in SLK lends credence to microtrauma being of most significance to the development of SLK.

Frequency
United States The frequency of SLK has been found to be 3% in a cohort of Graves ophthalmopathy patients, but it is much lower in the general population. International The international frequency is unknown.

Mortality/Morbidity
The natural history of the disorder is remission and eventual total resolution but only after a prolonged clinical course.

Race
No racial predilection exists.

Sex
Women are predominantly affected.

Age
Typically, middle-aged people are affected; however, this entity has been reported to occur in patients aged 4-81 years.

Clinical
History

Patients present with complaints of burning and irritation of the affected eye. o Some patients may present with redness. Upgaze may elicit these symptoms. o Typically, usage of moisturizing medications only provides minimal relief. o Symptoms remit and exacerbate and are variable in degree, but no diurnal pattern to the worsening of symptoms exists. In most cases, the condition is present bilaterally, although one eye may be more symptomatic. Patients with filaments are usually extremely symptomatic. Commonly, a history of thyroid dysfunction is elicited upon questioning. The natural history of SLK is prolonged, with gradual clearing. Patients often have numerous eye specialists for their symptoms. Unless the doctors have specifically examined the upper bulbar conjunctivae or everted the upper eyelids, they may have missed the diagnosis.

Physical

Marked inflammation of the upper lid tarsal conjunctiva, adjacent inflammation of the upper bulbar conjunctiva, and punctate rose bengal staining of the cornea at the upper limbus are signs of SLK. The conjunctiva extending from the upper limbus to the insertion of the superior rectus muscle also demonstrates thickening, hyperemia, and typical rose bengal staining. It stands out in stark contrast to the normal appearance of the inferior conjunctiva and cornea. Approximately one third of patients present with filaments on the upper cornea or along the superior limbus.

Causes

The cause of SLK is unknown, but inflammatory changes from mechanical soft tissue microtrauma are the final common pathway. SLK is associated with thyroid dysfunction. SLK has also developed in association with scarring of the palpebral conjunctiva in euthyroid patients. Prolonged eyelid closure with associated hypoxia or reduced tear volume may be a risk factor for SLK development. Morphological or functional changes in superior conjunctival apposition to the globe following upper eyelid procedures may induce SLK.5

Keratoconjunctivitis, Sicca
Author: Fernando H Murillo-Lopez, MD, Senior Surgeon, Unidad Privada de Oftalmologia CEMES Contributor Information and Disclosures Updated: Apr 21, 2006

Background

This condition is characterized by inadequate tear film protection of the cornea because of either inadequate tear production or abnormal tear film constitution, which results in excessively fast evaporation or premature destruction of the tear film.

Pathophysiology
The tear film is constituted by 3 layers, as follows: (1) a lipid layer (0.11 m thick), produced by the Meibomian glands; (2) an aqueous layer (7.0 m thick), produced by the main and accessory lacrimal glands of Krause and Wolfring; and (3) a hydrophilic mucin layer (0.020.05 m thick), produced by the conjunctival goblet cells. Any abnormality of 1 of the 3 layers produces an unstable tear film and symptoms of keratitis sicca. The tear layer affected most frequently is the aqueous layer, resulting in aqueous tear deficiency (ATD) or lacrimal hyposecretion. The classification scheme proposed by the 2 workshops held in December 1993 and December 1994 at the National Eye Institute (NEI) stratified patients with dry eye into those with aqueous tear deficiency and those with increased evaporative loss. Sjgren syndrome is characterized by the combination of aqueous tear deficiency and dry mouth (xerostomia). Women comprise 90-95% of patients with this syndrome that has been classified into 3 different subsets, as follows:

Patients with systemic immune dysfunction but no defined connective tissue disease (primary Sjgren syndrome) Patients who lack evidence of systemic immune dysfunction or a defined connective tissue disease Patients who have a defined connective tissue disease, most commonly rheumatoid arthritis (secondary Sjgren syndrome). Dry eye is common in patients with rheumatoid arthritis, including those without Sjgren syndrome. Dry eye should always be taken into consideration regardless of the rheumatoid arthritis activity, because the severity of dry eye is independent of the rheumatoid arthritis activity.

All cases are characterized by progressive lymphocytic (predominantly B and CD4 lymphocytes) infiltration of the lacrimal and salivary glands that leads to disorganization of the normal gland architecture and consequent loss of function. At this time, the most comprehensive criteria for a diagnosis of Sjgren syndrome include the following:

Abnormally low Schirmer test Objective evidence of low salivary flow Biopsy-proven lymphocytic infiltration of the labial salivary glands Dysfunction of the immune system as manifested by the presence of serum autoantibodies (eg, antinuclear antibodies, rheumatoid factor, anti-Ro [SS-A] and anti-La [SS-B] antibodies)

It has recently been shown that patients with keratoconjunctivitis sicca show elevated levels of tear nerve growth factor (NGF); these levels were decreased with 0.1% prednisolone. Data suggest that ocular surface NGF may play an important role in ocular surface inflammation processes associated with dry eyes.

Frequency

United States Keratitis sicca is a relatively common condition, especially in older patients.

Mortality/Morbidity
Keratitis sicca can range from mild or barely symptomatic to moderate and severe cases, which can produce some of the following complications:

Punctate keratopathy, epithelial defects, sterile corneal ulcer, and infectious corneal ulcer Corneal vascularization and corneal scarring Corneal perforation

Race
No racial predilection exists.

Sex
Sjgren syndrome and keratitis sicca associated with this condition are significantly greater in women (9:1). Milder forms of keratitis sicca also are more common in females than in males.

Age
Decreased tearing is associated with increased age.

Clinical
History

The following are the most common complaints in patients who are experiencing keratitis sicca depending on the severity of this problem: o Foreign body sensation and ocular dryness and grittiness, typically worse toward the end of the day o Hyperemia o Mucoid discharge o Ocular irritation (exacerbated by smoky or dry environments, indoor heating systems, prolonged reading, or computer use) o Excessive tearing (secondary to reflex secretion) Documenting the history of exacerbating or alleviating factors and a systemic past medical history is important, including history of connective tissue disease, thyroid disease, and rheumatoid arthritis. A review of systems focused on rheumatological disease, history of neoplasias, and GI and ear, nose, and throat (ENT) symptoms should be documented. History of dry mouth should be requested. A list of systemic and topical medications is important.

Physical
The following are the most important findings that are present in the external and slit lamp examination of patients with keratitis sicca before placement of any drops in the eye:

Perform a slit lamp examination to document some of the following: o Decreased tear meniscus o Increased debris in the tear film o Conjunctival pleating o Superficial punctate keratopathy (with positive fluorescein, lissamine green and/or rose bengal staining) o Conjunctival hyperemia o Mucous plaques and discharge o Xerostomia (in association with Sjgren syndrome) o Corneal filaments o Corneal epithelial defects or ulceration in more severe cases Determine tear breakup time after placing a drop of fluorescein in the cul-de-sac. Use rose bengal staining to look for conjunctival and corneal staining, particularly at the nasal and temporal limbus and/or inferior paracentral cornea. Perform the 5-minute Schirmer test with and without anesthesia using a Whatman #41 filter paper 5 mm in width and 35 mm in length. (Wetting <5 mm with anesthesia and <10 mm without anesthesia are considered abnormal.) Measure reflex secretion with a Schirmer II test if the initial Schirmer test is abnormal. The Schirmer II test is performed by irritating the nasal mucosa with a cotton-tipped applicator prior to measuring tear production with a Whatman #41 filter paper. (Wetting <15 mm after 5 min is considered abnormal.)

Causes
The causes for keratitis sicca are multiple and can be multifactorial. They can be classified into 3 categories by the element of the tear layer that is mostly affected, as follows: (1) those affecting the aqueous tear layer, (2) those affecting the lipid tear layer, and (3) those affecting the mucin tear layer.

The following include the most common conditions associated with aqueous tear deficiency: o Idiopathic o Congenital alacrima o Systemic vitamin A deficiency (xerophthalmia) Lacrimal gland ablation Sensory denervation Collagen vascular diseases, including rheumatoid arthritis, Wegener granulomatosis, and systemic lupus erythematosus Sjgren syndrome Autoimmune disorders associated with Sjgren syndrome, as follows: o Rheumatoid arthritis o Scleroderma o Polymyositis o Polyarteritis nodosa

Hashimoto thyroiditis Chronic hepatobiliary cirrhosis Lymphocytic interstitial pneumonitis Thrombocytopenic purpura Hypergammaglobulinemia Waldenstrm macroglobulinemia Progressive systemic sclerosis Dermatomyositis Interstitial nephritis Conjunctival scarring secondary to the following: o Ocular pemphigoid o Stevens-Johnson syndrome o Trachoma o Chemical/thermal burns o Atopic disease Drugs, including the following: o Oral contraceptives o Antihistamines o Beta-blockers o Phenothiazines o Atropine Infiltration of the lacrimal glands by sarcoidosis or tumors Postradiation fibrosis of the lacrimal glands The most common disorders associated with abnormalities of the lipid tear layer are as follows: Blepharitis Rosacea The most common conditions resulting in abnormalities of the mucin tear layer are as follows: o Vitamin A deficiency o Trachoma o Diphtheric keratoconjunctivitis o Mucocutaneous disorders o Topical medications
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