Eliza Hoskins
Doug S. Holsclaw

BASICS

DESCRIPTION

• Interstitial keratitis (IK) or immune stromal keratitis (ISK) is nonsuppurative (nonmelting) inflammation and cellular infiltration of the corneal stroma

• Often accompanied by corneal vascularization

• Minimal primary involvement of the epithelium (non-ulcerative) or endothelium in the active stage of inflammation

• However, corneal thinning can occur as a result of chronic inflammation.

– Active disease is characterized by pain, tearing, and photophobia

– Typically associated with systemic disease

– Often diagnosed as a late sequelae of disease characterized by ghost vessels and corneal scarring

ETIOLOGY

• Congenital syphilis has been described as the most common cause of IK worldwide (1).

– Worldwide 90% of IK

– Congenital (87%) versus acquired (3%)

– F>M is 2:1 for congenital and acquired syphilis

• However, herpetic eye disease and idiopathic causes appear to be the most common causes of active IK in North America (2).

• Herpetic eye disease and syphilis comprise >50% of cases of IK in the US.

• IK is responsible for 2–5% of penetrating keratoplasties(3, 4).

RISK FACTORS

• Bacterial, viral, or parasitic infections (see Differential Diagnosis)

• Systemic diseases (see Differential Diagnosis)

PATHOPHYSIOLOGY

• Lymphocytic infiltration and neovascularizaion (typically) of the corneal stroma. Late findings of ghost vessel and corneal scarring.

• Type IV hypersensitivity response to infectious organisms or antigens in the corneal stroma

DIAGNOSIS

HISTORY

• Targeted history: onset, duration, location, quality of symptoms, associated systemic conditions (hearing loss), contact lens wear, sexually transmitted diseases, trauma, travel history, and tick or insect bites

• Unilateral or bilateral

• Active inflammation is characterized by pain, tearing, and photophobia.

Past Medical History and Medications

• Review of systems (ROS):

– Constitutional: fever, night sweats, chills [tuberculosis (TB)]

– Skin/mucocutaneous: oral ulcers (herpes simplex virus (HSV), vesicular lesions (herpetic disease), erythema migrans (Lyme’s disease), stigmata of Hansen’s (leprosy)

– Dental/ENT: incisor and molar deformation (congenital syphilis), saddle nose (syphilis), hearing loss, tinnitus, vertigo (Cogan’s syndrome), parotiditis [Epstein Barr Virus (EBV), mumps]

– Respiratory: Shortness of breath (sarocoidosis), productive cough (TB)

– Cardiovascular: AV block (Lyme’s disease)

– Musculoskeletal: Migratory joint pain (Lyme’s disease); saber shins (syphilis)

– Genitourinary: Genital ulcers (syphilis)

– Neurological: Cranial nerve palsies (CN V, VII, and VIII) (herpetic disease, Lyme’s disease, Cogan’s syndrome, leprosy)

PHYSICAL EXAM

• Visual acuity, intraocular pressure (IOP)

• Pupillary function, confrontational visual fields, and ocular motility/alignment

• External exam: Rashes (Lyme’s disease, syphilis, herpetic disease, leprosy)

• Eyelids: Vesicles (herpetic), lid chancre (syphilis)

• Conjunctiva/sclera: Conjunctival injection, scleritis, conjunctival granuloma (sarcoidosis, TB, leprosy)

• Cornea: Stromal white blood cell infiltrate, epithelium typically intact, corneal scarring (diffuse, sectoral, central, circumferential, or multifocal), decreased corneal sensation (herpetic disease, EBV, leprosy), stromal vascularization, lipid exudation/keratopathy, ghost vessels, corneal scarring, and corneal thinning (late)

• Iris: Iris atrophy (herpetic disease, syphilis), iris pearls (leprosy), posterior synechiae

• Anterior chamber: Iritis, fine keratic precipitates (KP)

• Posterior Segment: Salt and pepper fundus (syphilis), vasculitis ± choroiditis (sarcoidosis, herpetic disease, TB, syphilis)

DIAGNOSTIC TESTS & INTERPRETATION

• Slit lamp examination

• Confocal microscopy may be useful in cases where fungal or acanthamoeba infection is suspected.

Lab

• VDRL or RPR (syphilis)

• FTA-ABS or MHA-TP (syphilis)

• Lyme’s Ab (ELISA IgG and IgM)

• Lyme’s Western Blot

• HSV-1, HSV-2 (herpetic disease)

• Purified protein derivative (PPD) or quantiferon, chest X-ray [CXR (TB)]

• Cogan’s syndrome: Leukocytosis and mild eosinophilia

• EBV (positive heterophil antibody test)

DIFFERENTIAL DIAGNOSIS

• Bacterial

– Syphilis

– Tuberculosis

– Lyme’s disease

– Leprosy

– Brucellosis

– Chlamydia trachomatis

• Viral

– Herpes simplex virus (HSV)

– Varicella zoster virus (VZV)

– Epstein–Barr Virus (EBV)

– Mumps

– Rubella

• Parasitic

– Leishmaniasis

– Onchocerciasis

– Trypansomiasis

– Acanthamoeba

– Microsporidiosis

• Systemic disease

– Cogan’s syndrome

– Sarcoidosis

– Lymphoma

– Idiopathic

DESCRIPTION OF ETIOLOGIES¹

Syphilitic Interstitial Keratitis

• Triad of Hutchinson [IK, deafness (CN VIII), Hutchinson’s incisors (dental deformation]

• Congenital Syphilitic IK

– Treponema pallidum

– Crosses placenta in primary, secondary, or early latent phase

– Clinical disease is rarely present at birth

– Age of onset: 5–20 years; Peak incidence 9–11 years; rare after age 30

– 80% bilateral; unilateral disease at presentation, diffuse stromal disease, deep stromal vessels with overlying “salmon patch” edema, associated iritis in active disease

– Second eye involved after days to years (∼1 year)

– Corneal involvement in 40% of congenital IK

– Late phase characterized by ghost vessels ± corneal scarring, guttae-like excrescences on Descemet’s membrane

• Acquired Syphilitic IK

– Very uncommon and less severe

– 10 years after primary infection

– Probable corneal invasion of spirochetes

– Bulbar conjunctival, limbal, or lid chancre

– Unilateral in >60%

– Often remains sectoral with vascularization

– Regresses rapidly with anti-syphilitic therapy

TUBERCULOSIS

• Mycobacterium Tuberculosis

• Infection enters body via inhalation

• Granulomatous inflammation; 2% of IK cases

• Typically, unilateral, sectoral, and peripheral; frequently involves inferior cornea

• Stromal vascularization (minimal)

• Dense sectoral scar ± thinning

• Associated conditions: uveitis, choroiditis, retinal vasculitis, conjunctivitis, and scleritis

• Host response to antigen rather than active disease and natural course is weeks to months.

LYME’S DISEASE

• Borrelia burgdorferi

• Spirochete; Ixodes scapularis from tick

• Bilateral, focal, and avascular

• Poorly defined nebulous lesions seen in all stromal levels; iritis and fine KP may be present

• May progress to vascularization and scarring

• IK is a late manifestation and is immune- mediated

• Associated disease: Erythema migrans rash, constitutional symptoms, migratory joint and muscle pain, cranial nerve palsies, and optic neuritis

HERPETIC INTERSTITIAL KERATITIS

• Herpes Simplex Virus

– Unilateral, diffuse or sectoral

– Frequently begins as disciform keratitis

– Followed by deep corneal infiltrates associated with iritis

– Deep and superficial vessels

– Reduced corneal sensation

– HSV serologies useful only for exclusion

• Hepes Zoster Virus (Varicella Zoster Virus)

– Develops 2–3 weeks after acute epithelial keratitis or dermatitis (shingles)

– Unilateral, anterior stromal infiltrates, disciform keratitis, Wessely ring (immune ring infiltrate)

– Sequelae: lipid deposition, scarring, deep neovascularization

– Immune-mediated

– Reduced corneal sensation

– May be seen in inactive stage

COGAN’S SYNDROME

First described by Cogan in 1945 as nonsyphilitic IK with vestibuloauditory symptoms

• Typical Cogan’s

– IK and vestibuloauditory symptoms (vertigo, tinnitus, and hearing loss)

• Atypical Cogan’s:

– Vestibuloauditory disease (as above)

• Ocular inflammatory disease other than IK

– Posterior uveitis, subconjunctival hemorrhage, scleritis, episcleritis, retinal hemorrhage, disk edema, conjunctivitis, and orbital inflammation

• Systemic associations

– 10% systemic large vessel vasculitis:

– Polyarteritis, aortic insufficiency, coronary stenosis, and brain infarcts

– Underlying rheumatologic disease in up to 50% of patients with atypical Cogan’s

– Polyarteritis nodosum, Wegener’s granulomatosis, rheumatoid arthritis, Crohn’s disease, and relapsing polychondritis

• Usually bilateral, sudden-onset severe pain, tearing, and photophobia

• Early: peripheral subepithelial keratitis with faint nummular lesions; begins peripherally and superficially

• Late: involves deep stroma; ± uveitis; variable mild late vascularization

• Vestibuloauditory symptoms develop within 1 month (before or after IK)

• Autoimmune hypersensitivity reaction to antigen present in corneal stroma and inner ear; can be preceded by upper respiratory infection (URI)

• Can progress to deafness in 3 months if untreated.

Other

Epstein–Barr Virus (EBV)

• Bilateral nummular keratitis

• Vascularization variable (usually avascular)

• Parotiditis

• Mononucleosis confirmed by positive heterophil antibody test

TREATMENT

SYPHILIS

• Topical corticosteroids and cycloplegics

• Primary, secondary, and early latent stages:

– 2.4 million units PCN G IM × 1

• Late congenital:

– 2.4 million units PCN G i.v. or i.v. for 10 days

• Lumbar puncture to r/o neurosyphilis:

– 24 million units PCN G i.v. for 10–14 days

TUBERCULOSIS (TB)

• Topical corticosteroid and cycloplegics

• Treat underlying TB: usually multidrug Rx

– Isoniazid

– Rifampin

– Pyrazinamide

– Streptomycin or ethambutol

LYME’S DISEASE

• Topical corticosteroid and cycloplegics

• Systemic antibiotics if no prior treatment:

– i.v. penicillin

– Ceftriaxone

– Cefotaxime

– Tetracycline/doxycycline

HERPETIC DISEASE

• Topical corticosteroid ± trifluridine 1% and cycloplegics³

• Oral antiviral agents:

– Acyclovir (ACV)

– Valcyclovir

– Famciclovir

• Although oral antivirals did not reduce established stromal inflammation, in the treatment group of topical steroid and trifluridine, the addition of oral antiviral was superior to placebo in causing visual improvement at 6 months follow-up (5).

• Prophylactic treatment of HSV stromal keratitis patients with oral acycolvir resulted in a statistically significant reduction of ocular (14% treated vs. 28% placebo) and orofacial recurrences during a 12-month treatment and 6-month follow-up period. Consider antiviral prophylaxis ACV 400 mg b.i.d if >1 episode (6).

COGAN’S DISEASE

• Topical corticosteroids and cycloplegics

• Prednisone 2 mg/kg for first week; slow taper

• Systemic immunosuppression for underlying systemic disease or disease unresponsive to corticosteroids alone.

• Check MRI inner ear, audiogram, and echocardiogram if diagnosis is suspected and start high-dose steroids.

SURGERY/OTHER PROCEDURES

• Penetrating keratoplasty (PKP)

• Deep anterior lamellar keratoplasty (DALK) (7)

• High-risk of graft rejection with active corneal neovascularization

• Consider antiviral prophylaxis in herpetic disease and PKP (8).

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

• Follow patients weekly until inflammation is controlled.

• Goal is to have patients on least amount of topical corticosteroid to control inflammation and permanent corneal scarring

• Infectious Disease consult when indicated

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