Ophthalmology – Interstitial Keratitis (IK)

Basics

Description

Interstitial keratitis (IK), also called immune stromal keratitis, is a nonsuppurative inflammatory process involving the corneal stroma. Unlike infectious corneal ulcers, the overlying epithelium is generally intact during the active phase, and there is no primary stromal melting.

The condition is frequently accompanied by stromal neovascularization. Active disease commonly causes pain, photophobia, tearing, redness, and reduced vision.

Chronic inflammation may eventually produce:

• Corneal scarring
• Stromal thinning
• Lipid deposition
• Persistent or “ghost” stromal vessels
• Irregular astigmatism and permanent visual impairment

Many cases are associated with an underlying infectious or systemic inflammatory disorder.

Etiology

Historically, congenital syphilis was considered the classic cause of interstitial keratitis worldwide.

In contemporary ophthalmic practice, however, important causes include:

• Herpes simplex virus
• Varicella-zoster virus
• Syphilis
• Tuberculosis
• Lyme disease
• Cogan syndrome
• Sarcoidosis
• Other infectious and autoimmune disorders

In some patients, no specific cause is identified.

Risk Factors

Risk factors are primarily those associated with the underlying disease.

These include exposure to:

• Sexually transmitted infection
• Tuberculosis
• Tick-borne disease
• Herpes viruses
• Parasitic infections

Systemic inflammatory and autoimmune conditions can also predispose to stromal inflammation.

Pathophysiology

Interstitial keratitis is usually produced by an immune-mediated inflammatory reaction within the corneal stroma.

A common mechanism is a delayed-type, or type IV, hypersensitivity response against microbial antigens or other inflammatory targets within the cornea.

The inflammatory response produces:

• Lymphocytic stromal infiltration
• Corneal edema
• New blood vessel formation
• Subsequent fibrosis and scarring

In late disease, active inflammation disappears but the residual vascular channels remain as ghost vessels.

Diagnosis

History

A careful systemic and ophthalmic history is essential because IK is often a manifestation of another disease.

Ask about:

• Onset and duration of symptoms
• Unilateral versus bilateral disease
• Pain and photophobia
• Previous episodes
• Contact lens use
• Ocular trauma
• Previous herpes infection
• Sexually transmitted infections
• Travel history
• Tick exposure
• Tuberculosis exposure
• Hearing loss
• Vertigo or tinnitus
• Autoimmune disease

Review of Systems

A targeted systemic review can provide important diagnostic clues.

Constitutional Symptoms

Fever, night sweats, chills, or weight loss may suggest tuberculosis or systemic inflammatory disease.

Skin and Mucous Membranes

Look for:

• Erythema migrans in Lyme disease
• Vesicular eruptions in HSV or VZV
• Oral or genital ulceration
• Skin findings of syphilis
• Features of leprosy in endemic settings

Dental and ENT Findings

Congenital syphilis may be associated with:

• Hutchinson incisors
• Abnormal molars
• Saddle-nose deformity
• Sensorineural hearing loss

Cogan syndrome commonly produces:

• Tinnitus
• Vertigo
• Progressive hearing impairment

Respiratory Findings

Shortness of breath may suggest sarcoidosis, whereas chronic cough may suggest tuberculosis.

Musculoskeletal Findings

Migratory joint pain may occur with Lyme disease.

Neurologic Findings

Cranial nerve abnormalities can occur with:

• Herpes infection
• Lyme disease
• Syphilis
• Cogan syndrome
• Leprosy

Physical Examination

A complete ophthalmic examination should include:

• Visual acuity
• Pupillary examination
• Intraocular pressure
• Ocular motility
• Slit-lamp examination
• Dilated fundus examination

Corneal Findings

The characteristic finding is a stromal inflammatory infiltrate beneath an intact or minimally disrupted epithelium.

Other findings may include:

• Stromal edema
• Deep or superficial stromal vessels
• Corneal scarring
• Lipid deposition
• Ghost vessels
• Reduced corneal sensation
• Late stromal thinning

Scarring may be:

• Diffuse
• Sectoral
• Central
• Peripheral
• Circumferential
• Multifocal

Corneal Neovascularization

Corneal vascularization is a common feature.

During active inflammation, vessels may be engorged and accompanied by stromal haze.

Once inflammation resolves, vessels may become empty and difficult to see clinically, leaving ghost vessels embedded within the stroma.

These vessels are important because they increase the risk of corneal graft rejection if keratoplasty is later required.

Anterior Segment Findings

Associated findings may include:

• Conjunctival injection
• Scleritis
• Anterior uveitis
• Fine keratic precipitates
• Posterior synechiae
• Iris atrophy

Certain findings can suggest specific causes. For example, reduced corneal sensation and iris atrophy support a herpetic etiology.

Posterior Segment Findings

Depending on the systemic cause, the posterior segment may show:

• Retinal vasculitis
• Choroiditis
• Optic nerve abnormalities
• Salt-and-pepper retinal pigmentary changes in congenital syphilis

Diagnostic Testing

Slit-Lamp Examination

Slit-lamp examination remains the primary diagnostic method.

The clinician should characterize:

• Location and depth of stromal inflammation
• Presence of vessels
• Corneal sensation
• Epithelial integrity
• Associated anterior chamber inflammation
• Degree of scarring

Confocal Microscopy

Confocal microscopy may be useful when unusual infectious causes such as:

• Acanthamoeba
• Fungal keratitis

remain in the differential diagnosis.

Laboratory Evaluation

Testing should be guided by clinical suspicion.

Possible investigations include:

Syphilis

• RPR or VDRL
• Confirmatory treponemal testing such as TP-PA or another treponemal assay

Tuberculosis

• Interferon-gamma release assay or tuberculin skin testing
• Chest imaging when indicated

Lyme Disease

• Two-tier serologic testing when epidemiologically appropriate

Herpetic Disease

HSV serology is generally of limited diagnostic value because prior exposure is common. PCR or other direct testing may be more useful in selected atypical cases.

Sarcoidosis

Appropriate chest imaging and targeted laboratory evaluation may be considered.

Differential Diagnosis

Important infectious causes include:

• Syphilis
• Tuberculosis
• Lyme disease
• Leprosy
• Brucellosis
• Chlamydial disease
• HSV
• VZV
• Epstein-Barr virus
• Mumps
• Rubella
• Acanthamoeba
• Onchocerciasis
• Other parasitic disease

Important noninfectious causes include:

• Cogan syndrome
• Sarcoidosis
• Autoimmune disease
• Lymphoproliferative disease
• Idiopathic stromal inflammation

Syphilitic Interstitial Keratitis

Congenital Syphilis

Congenital syphilitic IK is classically associated with Hutchinson triad:

Interstitial keratitis + sensorineural deafness + Hutchinson teeth

Ocular disease typically appears in childhood or adolescence rather than at birth.

The disease is commonly bilateral, although one eye may be affected before the other.

Active findings can include:

• Diffuse stromal inflammation
• Deep vascularization
• Stromal edema
• Iritis

A characteristic vascularized stromal area may produce a salmon-patch appearance.

Late findings include:

• Corneal scarring
• Ghost vessels
• Irregular astigmatism
• Secondary degenerative changes

Acquired Syphilitic IK

Acquired syphilitic interstitial keratitis is much less common.

It tends to be:

• More often unilateral
• More sectoral
• Less severe than congenital disease

Diagnosis requires appropriate syphilis testing and systemic evaluation.

Tuberculous Interstitial Keratitis

Tuberculosis-associated IK is usually immune-mediated rather than caused by direct active corneal infection.

It tends to be:

• Unilateral
• Peripheral
• Sectoral
• Sometimes associated with stromal thinning

Associated ocular findings may include:

• Uveitis
• Scleritis
• Retinal vasculitis
• Choroiditis
• Conjunctival inflammation

Lyme-Associated Interstitial Keratitis

Lyme disease is caused by Borrelia burgdorferi and transmitted by Ixodes ticks.

Corneal findings may include:

• Bilateral stromal infiltrates
• Poorly defined stromal opacities
• Mild anterior uveitis
• Later vascularization and scarring

Associated systemic findings include:

• Erythema migrans
• Fatigue
• Migratory arthritis
• Cranial neuropathies
• Cardiac conduction abnormalities
• Optic neuritis in some patients

Herpes Simplex Interstitial Keratitis

HSV stromal keratitis is an important cause of IK.

It is usually:

• Unilateral
• Sectoral or diffuse
• Associated with reduced corneal sensation

Disease may initially resemble disciform keratitis and later develop:

• Stromal infiltrates
• Deep neovascularization
• Anterior uveitis
• Scarring
• Lipid keratopathy

Herpes Zoster Interstitial Keratitis

VZV-associated disease commonly develops after herpes zoster ophthalmicus.

Corneal manifestations include:

• Anterior stromal infiltrates
• Disciform keratitis
• Immune ring infiltrates
• Reduced corneal sensation
• Deep neovascularization
• Lipid deposition
• Stromal scarring

The inflammatory process is largely immune mediated.

Cogan Syndrome

Cogan syndrome is an important cause of nonsyphilitic interstitial keratitis associated with audiovestibular disease.

The classic syndrome consists of:

• Interstitial keratitis
• Vertigo
• Tinnitus
• Sensorineural hearing loss

Hearing loss may progress rapidly and can become permanent.

Typical Cogan Syndrome

Typical disease involves:

• IK
• Vestibular symptoms
• Hearing loss

The eye disease is often bilateral and may cause sudden:

• Pain
• Tearing
• Photophobia

Corneal inflammation may begin superficially and peripherally before progressing deeper into the stroma.

Atypical Cogan Syndrome

Atypical forms may include ocular inflammatory disease other than classic IK, such as:

• Scleritis
• Episcleritis
• Posterior uveitis
• Retinal vasculitis
• Optic disc edema
• Orbital inflammation

Systemic vasculitis may also occur.

Reported systemic complications include:

• Aortitis
• Aortic insufficiency
• Coronary involvement
• Cerebral ischemia

Patients with suspected Cogan syndrome should receive prompt systemic evaluation because early treatment may reduce the risk of permanent hearing loss.

Treatment Principles

Management requires two simultaneous strategies:

1. Control the corneal inflammation
2. Treat the underlying disease

Before using corticosteroids aggressively, active infection must be identified and appropriately treated.

Topical Corticosteroids

Topical corticosteroids are commonly used for immune-mediated stromal inflammation.

They reduce:

• Stromal inflammatory cells
• Edema
• Neovascularization
• Scarring

Treatment should be tapered slowly according to the inflammatory response.

Steroids should be used with appropriate antimicrobial coverage when an infectious cause such as herpes is involved.

Cycloplegics

Cycloplegic agents are useful when anterior uveitis accompanies IK.

They help:

• Reduce ciliary spasm
• Relieve pain
• Reduce photophobia
• Prevent posterior synechiae

Treatment of Syphilis

Ocular syphilis requires systemic antibiotic therapy, generally managed as neurosyphilis according to current infectious-disease guidelines.

Intravenous penicillin is the standard treatment in patients without contraindications.

Topical corticosteroids and cycloplegics may be added for active ocular inflammation but do not replace systemic antimicrobial therapy.

Patients should also be evaluated for other manifestations of syphilis and managed in collaboration with infectious-disease specialists when appropriate.

Treatment of Tuberculosis

Tuberculosis-associated disease requires appropriate multidrug antituberculous therapy when active or clinically relevant infection is established.

Treatment typically involves combinations of agents such as:

• Isoniazid
• Rifampin
• Pyrazinamide
• Ethambutol

The exact regimen should be directed by infectious-disease or pulmonary specialists.

Topical corticosteroids may be used to control stromal inflammation after adequate antimicrobial therapy has been established.

Treatment of Lyme Disease

Patients with untreated systemic Lyme disease require appropriate antibiotic therapy.

Depending on the clinical manifestation, treatment may involve:

• Doxycycline
• Ceftriaxone
• Other guideline-directed antibiotic regimens

Topical corticosteroids and cycloplegics may be used for associated immune-mediated ocular inflammation.

Treatment of Herpetic Stromal Keratitis

HSV stromal keratitis is usually treated with topical corticosteroids together with antiviral therapy.

Antiviral therapy may include:

• Acyclovir
• Valacyclovir
• Famciclovir
• Topical antiviral therapy in selected cases

Steroids should not be given unopposed when active herpetic infection is suspected.

Antiviral Prophylaxis

Patients with recurrent HSV stromal keratitis may benefit from long-term oral antiviral prophylaxis.

This can reduce the risk of recurrent ocular herpes, particularly in patients with repeated stromal episodes or those undergoing corneal transplantation.

Treatment of Cogan Syndrome

Cogan syndrome often requires both ocular and systemic therapy.

Treatment may include:

• Topical corticosteroids
• Cycloplegics
• High-dose systemic corticosteroids
• Steroid-sparing immunosuppressive therapy when necessary

Because hearing loss may progress rapidly, suspected cases warrant prompt:

• Audiometry
• ENT evaluation
• Rheumatologic evaluation
• Cardiovascular assessment when systemic vasculitis is suspected

Surgery

Corneal transplantation may be necessary when chronic disease causes visually significant scarring.

Options include:

• Deep anterior lamellar keratoplasty (DALK)
• Penetrating keratoplasty

DALK may be appropriate when disease is primarily stromal and the endothelium remains healthy.

Corneal Neovascularization and Graft Risk

Active or extensive corneal vascularization significantly increases the risk of corneal graft rejection.

Ideally, inflammation should be controlled before transplantation.

In herpetic disease, perioperative and postoperative antiviral prophylaxis may reduce recurrence.

Follow-Up

Patients with active disease should initially be followed closely, often weekly, until the inflammatory response is clearly controlled.

At each examination, monitor:

• Visual acuity
• Stromal inflammation
• Corneal edema
• Neovascularization
• Epithelial integrity
• Corneal thinning
• IOP
• Anterior chamber inflammation

Once stable, follow-up intervals can be extended.

Patient Monitoring

The treatment goal is to suppress inflammation with the lowest effective corticosteroid exposure while preventing:

• Progressive corneal scarring
• Stromal thinning
• Secondary glaucoma
• Cataract
• Recurrence

Patients with infectious causes should also be followed by the appropriate systemic specialist.

Prognosis

Prognosis depends strongly on the underlying cause and the degree of central corneal involvement.

Vision may recover well if:

• Inflammation is recognized early
• The underlying cause is treated promptly
• Central scarring is limited

Longstanding disease may result in permanent visual reduction from:

• Stromal scarring
• Irregular astigmatism
• Lipid keratopathy
• Corneal thinning
• Persistent vascularization

Complications

Major complications include:

• Corneal scarring
• Corneal neovascularization
• Lipid keratopathy
• Irregular astigmatism
• Stromal thinning
• Secondary uveitis
• Cataract
• Secondary glaucoma
• Permanent visual impairment
• Corneal graft rejection after transplantation

In systemic diseases such as Cogan syndrome or syphilis, nonocular complications such as hearing loss, neurologic disease, or systemic vasculitis may be more consequential than the corneal disease itself.