Immune Stromal (Interstitial) Keratitis

Signs and Symptoms

Active herpes simplex stromal keratitis.

Patients with active immune stromal keratitis (ISK) will present with pain, photophobia, lacrimation, and blepharospasm. Vision is typically reduced in the acute, active phase. The presentation may be either unilateral or bilateral. There will often be a history of ocular infection or systemic disease. However, ISK may be the initial manifestation of an unknown underlying systemic disease. Occasionally, ISK is idiopathic. ISK runs a chronic, indolent course and may persist for many months.

There will be a single or multiple white patches of infiltration and inflammation within the corneal stroma. There will be concurrent stromal edema as well as stromal vascularization. Typically, the overlying epithelium is intact. If there is epithelial disruption, it will be much smaller in area than the underlying inflammation. Corneal thinning may result as sequelae of the chronic inflammation; however, thinning is not a distinctive feature. There will be a secondary anterior uveitis. Endothelial folds and keratic precipitates are common.

Pathophysiology

ISK is an immune-mediated nonsuppurative stromal inflammation with an intact epithelium. ISK is typically associated with an often readily identifiable causative agent. Conditions causing SK include Epstein Barr virus, herpes zoster and simplex, mumps, measles, Lyme disease, Acanthamoeba infection, tuberculosis, syphilis, sarcoidosis and onchocerciasis. However, the most common cause of active ISK is the herpes simplex virus, accounting for over 70% of unilateral active cases.¹ Sixty percent of cases of bilateral, active ISK are idiopathic in nature. Syphilis is the cause of approximately 50% of bilateral inactive cases. Although syphilis is the leading cause of inactive, bilateral ISK, it is actually responsible for less than 20% of total cases.¹

It must be emphasized that there is no active microbial infection within the corneal stroma in ISK. Rather, microbial antigens initiate a T-lymphocytic destruction of the stroma.² Subsequent stromal vascularization and cicatrization invariably results if the underlying cause is left untreated. The stromal vascularization will begin during the acute phase and progress throughout the disease's course. However, the presence of stromal vascularization is not required in order to make this diagnosis (as was previously thought).

There are two types of ISK that may occur during herpes simplex infections: necrotizing and non-necrotizing. Necrotizing herpetic ISK is a more severe form of herpetic stromal keratitis and manifests as a dense, cheesy, yellow-white stromal infiltration often following recurrent herpetic disease. There will be epithelial ulceration, stromal edema, dense vascularization, profound corneal thinning, and possible perforation. Non-necrotizing herpetic ISK does not have the same propensity to move toward ulceration, thinning, and perforation. Untreated, non-necrotizing ISK runs an indolent, self-limiting course over several months. Fortunately, the majority of herpetic ISK cases are non-necrotizing.

Management

Immune stromal keratitis is a self-limiting condition, which will spontaneously resolve within several months. However, the result invariably will be profound stromal vascularization and scarring with subsequent visual reduction. Hence, treatment is indicated. It must be remembered that ISK is an immune stromal keratitis and not an active infectious process. Application of a strong steroid such as prednisolone acetate 1% q1h to q2h is optimal. Depending upon the etiology, the patient may need to use low doses of topical steroids indefinitely. Cycloplegia and topical lubrication will ease the patient's discomfort.

When ISK is caused by the herpes virus, therapy deviates somewhat from the above-mentioned regimen. Lower doses of topical steroids may be employed to control the patients' disease and symptoms. When topical steroids are used to treat herpetic immune stromal disease, prophylactic topical antiviral medications (trifluridine) should be used concurrently.^3,4 There has been no proven benefit for the adjunctive use of oral acyclovir in the acute management of patients with herpes simplex stromal keratitis being treated with topical corticosteroids and trifluridine.⁵

Herpes simplex ISK is a highly recurrent disease, with the risk related to the number of previous recurrences.⁶ Long-term suppressive oral therapy with acyclovir 400mg po bid has been shown to significantly reduce the recurrence rate of not only epithelial keratitis from herpes simplex, but also stromal disease.^7,8 Strong consideration should be given for long-term suppressive therapy beyond one year in herpes simplex stromal keratitis.

As ISK can result from a variety of causes, a diagnostic evaluation should be initiated. Unless the cause is obviously herpetic, medical evaluation for IK should include FTA-ABS or MHA-TP for syphilis, PPD and chest X-ray for tuberculosis, Lyme titer for Lyme disease, and rheumatoid factor and antinuclear antibodies for collagen vascular disease. Should a cause be elicited, the patient should receive medical treatment directed toward the underlying cause while he or she undergoes topical treatment.

Particular attention must be paid to patients presenting with ISK and hearing loss, signaling Cogan's syndrome. Cogan's syndrome is an idiopathic inflammatory disease, which may present as ISK, inflammation of other ocular structures, Meniere's-like attacks, audiovestibular dysfunction or systemic vasculitis. Although the ocular manifestations respond to topical steroids and are rarely serious, permanent deafness may result if systemic steroid therapy is not promptly instituted for audiovestibular dysfunction, while major morbidity and even death may occur if systemic sequelae such as vasculitis and aortic insufficiency are not recognized.⁹

Clinical Pearls

• If a patient develops ISK on the same side as a prior episode of either HSV or HZV and there is no indication of other disease in the patient's history, then no further diagnostic evaluation is necessary. In this case, it can safely be assumed that the cause of the ISK is herpetic.
• Historically, ISK has been associated with syphilis as the main causative agent. Today, however, syphilis is the main cause only in cases of bilateral, inactive ISK. By far, the main identifiable cause of active cases of ISK is herpes simplex virus.
• In cases of active herpetic ISK, topical and oral antiviral medications have been exceedingly disappointing therapeutically. The only use for either oral or topical antiviral medications in herpetic IK is prophylactically to prevent epithelial ulceration when topical corticosteroids are used and to suppress future recurrences.
• Stromal inflammatory infiltration in herpetic ISK can be difficult to differentiate from both bacterial and fungal keratitis. However, IK will have a more intact epithelium whereas the other entities will have ulceration. Further, IK runs an indolent course, whereas infectious keratitis is much more aggressive.
• As in other herpetic manifestations, corneal sensitivity is reduced on the affected side.
• Suspect Cogan's syndrome in patients presenting with ocular inflammation who develop hearing loss, vertigo, ataxia, tinnitus, vasculitis, or aortic insufficiency.

Other reports in this section

• Bacterial Keratitis
• Immune Stromal (Interstitial) Keratitis
• Dry Eye Syndrome
• Corneal Abrasion