AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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
• • 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.
  • 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.
  • 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.
• • 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.
  • 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.
  • 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.
  • 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.
  • 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
• • 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.
  • 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.
  • Mumps typically causes lacrimal gland inflammation, but cornea involvement may occur with a variable presentation, ranging from punctate epithelial keratopathy to nummular keratitis.
  • 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
• • 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.
  • Corneal findings are very similar to those seen in syphilitic IK, with lymphocytic infiltration of the deep stroma with variable neovascularization.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Corneal dystrophies
Metabolic corneal disorders
Cogan syndrome

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• A diagnosis of syphilitic IK is often based on the clinical findings and by serologic testing.
• • Other nonocular findings of syphilis may be helpful in establishing the diagnosis of syphilis. These include dental abnormalities (Hutchinson teeth), facial asymmetry, saddle-nose deformity, saber shins, deafness, and mental retardation.
  • Serologic testing of syphilis can be performed by a treponemal test and nontreponemal test. The treponemal test detects immunoglobulin to Treponema pallidum. The two treponemal tests are the fluorescent treponemal antibodies absorption (FTA-ABS) test and the microhemagglutination-T pallidum (MHA-TP) test. These tests always remain positive once an exposure to the causative agent of syphilis has occurred. In contrast, the nontreponemal test detects immunoglobulin to phospholipids (anticardiolipin antibodies); these are nonspecific tests, and the titers will decrease once adequate treatment has been initiated. The two most commonly used nontreponemal tests include the Venereal Disease Research Laboratory (VDRL) test and the rapid plasma reagin (RPR).
• To diagnose tuberculosis, a purified protein derivative (PPD) test with anergy panel should be placed. Lyme titers and enzyme-linked immunosorbent assay (ELISA) may be helpful in establishing the diagnosis of Lyme disease.
• Serologic testing may assist in the diagnosis of Cogan syndrome, although this remains largely a diagnosis of exclusion. Lymphocytosis and an elevated erythrocyte sedimentation rate (ESR) have been described in those patients with an active systemic vasculitis. There have been variable reports of human leukocyte antigen B17 (HLA-B17) more prevalent in patients with Cogan syndrome, although the results are equivocal.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Treatment of IK is dependent on the specific underlying disorder.

• The use of topical corticosteroids has markedly changed the natural history of IK due to congenital syphilis. Without the use of these anti-inflammatory modifiers, the typical scenario was permanent corneal opacity with variable visual outcome. Due to its anti-inflammatory properties, topical corticosteroids reduce inflammation and neovascularization and often result in better visual acuity than if the condition were left untreated.
• Treatment of syphilitic IK includes antibiotic therapy for untreated cases. Intravenous penicillin is the preferred treatment, and the dosages vary depending on the stage of disease. Most commonly, tertiary syphilis or neurosyphilis dosages of intravenous penicillin are administered. Ocular therapy is concentrated on reducing the local inflammatory reaction, as well as controlling the other sequelae of the inflammation, most commonly elevated intraocular pressure. While the corneal inflammation associated with IK resolves spontaneously, the use of topical corticosteroids shortens the duration and the severity of the corneal inflammation. Studies have shown that the visual outcome is better and recurrences are fewer in patients who are treated with topical corticosteroids in a tapering fashion over a long period of time. The usual antiglaucoma medications may be used as needed to control intraocular pressure.
• Tuberculous IK also responds well to topical corticosteroid treatment. Systemic therapy is indicated using the recommended multidrug regimens.
• For patients with lepromatous IK, in addition to systemic treatment using dapsone, clofazimine, and rifampin, local treatment, including topical corticosteroids, may be used with caution due to the presence of neurotrophic disease and its deleterious effect on the corneal epithelium and wound healing.
• Treatment of Lyme disease includes the appropriate systemic antibiotic therapy, which is based on the stage of the illness and topical anti-inflammatory medications (eg, corticosteroids), which act to reduce the local morbidity as in the other forms of IK.
• Treatment of Acanthamoeba keratitis includes discontinuation of infected contact lenses, as well as using various antibiotic, antifungal, and antiparasitic topical and systemic medications. The medications may need to be continued for a significant length of time, and, typically, Acanthamoeba remains a very difficult infection to treat.
• The various parasitic causes of IK share systemic antiparasitic therapy as the basis of treatment. In cases of onchocerciasis, systemic treatment with ivermectin is the accepted standard of care.
• Leishmania requires systemic treatment with sodium stibogluconate, or meglumine antimonate may be combined with the same medications topically to treat keratitis.
• Treatment of IK due to trypanosomiasis is via the systemic antiprotozoal agents (eg, suramin, nifurtimox).
• Microsporidia remains a very rare cause of IK, and treatment options vary from systemic antiparasitic agents to surgical reconstruction with penetrating keratoplasty.
• Treatment of herpetic stromal disease has been described as part of the Herpetic Eye Disease Study (HEDS). Topical steroids were found to be beneficial when combined with topical antiviral agents in the treatment of herpetic stromal disease, but oral acyclovir was not found to have any additional benefit when combined with topical corticosteroids and topical antiviral agents (eg, trifluridine). Oral acyclovir does appear to reduce the likelihood of recurrent herpetic disease.

Surgical Care

In cases of permanent corneal opacity, corneal transplantation is an option, but it should be performed only when the ocular inflammation has become quiescent to prevent postoperative complications, such as rejection and graft failure.

Consultations

Rheumatologic and ear, nose, and throat (ENT) consultations should be obtained in suspected cases of Cogan syndrome. Infectious disease consultation may be beneficial in cases of unusual infections.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

A wide variety of medications may be used to treat IK, with the specific agent selected based on the particular etiology of the condition. It is strongly recommended that systemic treatment be initiated and maintained by an internist, an infectious disease specialist, or a rheumatologist.

Although parasites are unusual causes of IK in the United States, in developing countries, the incidence is higher. Antiparasitic agents have been shown to be helpful in eradicating the immunologic stimulus and in preventing other associated ocular morbidity. Consultation with an infectious disease specialist is recommended in cases of suspected parasitic keratitis.

Drug Category: Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Antibiotics, such as penicillin, may be used in cases of IK secondary to untreated tertiary syphilis.

Drug Category: Antivirals

Antiviral medications, such as trifluridine and acyclovir, and its derivatives, valacyclovir and famciclovir, have shown activity against herpes simplex.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• The topical steroid medications are tapered slowly, over weeks to months, depending on the clinical response.

In/Out Patient Meds

• See Medication.

Complications

• Complications related to IK generally are due to corneal thinning and perforation. Although these occur rarely, perforations of the cornea may be treated urgently with conventional penetrating keratoplasty surgical techniques.

Prognosis

• With appropriate treatment, visual acuity in IK generally can be preserved. In case of permanent corneal scarring, surgical therapy often is successful provided that the underlying cause of inflammation is controlled.

Patient Education

• For excellent patient education resources, visit eMedicine's Sexually Transmitted Diseases Center. Also, see eMedicine's patient education article Syphilis.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• It is important to recognize that IK may develop in persons who have untreated syphilis. Practitioners should attempt to determine whether or not a patient has been treated appropriately in the past to prevent the development of neurosyphilis.
• Another important association to keep in mind is that patients with Cogan syndrome are more likely to have a history of systemic vasculitides, and prompt referral to a rheumatologist may be critical.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• Cogan DG, Dickersin GR. Nonsyphilitic interstitial keratitis with vestibuloauditory symptoms. A case with fatal aortitis. Arch Ophthalmol. Feb 1964;71:172-5. [Medline].
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• Orsoni JG, Zavota L, Manzotti F, Gonzales S. Syphilitic interstitial keratitis: treatment with immunosuppressive drug combination therapy. Cornea. Jul 2004;23(5):530-2. [Medline].
• Pepose JS. Herpes simplex keratitis: role of viral infection versus immune response. Surv Ophthalmol. Mar-Apr 1991;35(5):345-52. [Medline].
• Rabb MF, Fine M. Penetrating keratoplasty in interstitial keratitis. Am J Ophthalmol. Jun 1969;67(6):907-17. [Medline].
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• Tamesis RR, Foster CS. Ocular syphilis. Ophthalmology. Oct 1990;97(10):1281-7. [Medline].
• Taylor HR, Semba RD, Newland HS, Keyvan-Larijani E, White A, Dukuly Z, et al. Ivermectin treatment of patients with severe ocular onchocerciasis. Am J Trop Med Hyg. May 1989;40(5):494-500. [Medline].
• Zaidman GW. The ocular manifestations of Lyme disease. Int Ophthalmol Clin. 1993;33(1):9-22. [Medline].

Article Last Updated: Dec 14, 2007