Epidemiology and Pathogenesis

Thygeson’s superficial punctate keratitis (TPSK) is a bilateral, epithelial keratitis of unknown cause and was first described by Phillips Thygeson in 1950. It is characterized by an insidious onset of focal corneal epithelial inflammation with a pattern of exacerbations and remissions. The disease can last from 1 month to 24 years, with an average duration of 3.5 years. TSPK usually begins in the second and third decades (mean age, 29 years), with a range of 2.5–70 years. No clear gender predilection exists, although a female preponderance has been suggested.

No established cause for this disease is known, and no clear trigger mechanisms or associated systemic illnesses have been identified. The clinical manifestations of TSPK resemble those of viral keratitis. There are conflicting reports about a viral cause.

The characteristic exacerbations and remissions of the disease may be caused by an altered immune response to an unknown exogenous or endogenous antigen. A genetic predisposition may be present because some patients demonstrate an increase in human leukocyte antigen (HLA)-Dw3 and HLA-DR3 expression, both of which are HLA loci associated with immune response genes.

Ocular Manifestations

The lesions of TSPK typically appear in the central cornea as small, round or oval, discrete, granular, white-gray, fine, dot-like intraepithelial opacities. The number of lesions ranges from 3–40, and occasionally the lesions appear stellate ( Fig. 4.17.1 ). Stromal edema and associated cellular infiltration generally are absent ( Fig. 4.17.2 ). Subepithelial opacities occur in 44% of patients. TSPK is bilateral in 96% of patients. Conjunctival inflammation is absent.

Corneal punctate lesions characteristic of Thygeson’s superficial punctate keratopathy. These typically occur in a noninflamed eye.

(Courtesy Joel Sugar, MD.)

A Patient Who Has Thygeson’s Superficial Punctate Keratopathy.

Slit-lamp appearance of the fine subepithelial haze and relative lack of corneal inflammation between lesions are shown.

Active lesions are resistant to mechanical removal and appear elevated following fluorescein staining with negative staining. During remissions, the epithelium is flat and without stain over the previous areas of keratitis. Although most lesions are central, peripheral lesions do occur and may be associated with delicate, peripheral vascularization in chronic cases.

Symptoms include tearing, foreign body sensation, photophobia, and burning. Visual acuity may be decreased by the subepithelial opacities but generally returns to normal following resolution of the keratitis.

Diagnosis

Thygeson outlined five characteristic features of TSPK: (1) chronic, bilateral punctate inflammation; (2) long duration, with remissions and exacerbations; (3) healing without significant scarring; (4) absent clinical response to topical antibiotics; and (5) striking symptomatic and clinical response to topical corticosteroids.

The diagnosis of TSPK generally can be made from the clinical history, results of slit-lamp examination, and the unusually rapid response to topical corticosteroids. No specific systemic associations have been reported for this disease.

Differential Diagnosis

One of the most characteristic features of TSPK is its lack of associated conjunctival inflammation. All the other disease entities in Box 4.17.1 have either obvious associated features or signs of local or diffuse conjunctival inflammation.

Pathology

Corneal scrapings of the lesions demonstrate atypical and degenerated epithelial cells and a mild mononuclear and polymorphonuclear cell infiltrate. Confocal microscopy has demonstrated the accumulation and aggregation of Langerhans’ cells in the basal cell layer of the corneal epithelium in association with decreased density of the subepithelial nerve plexus of affected eyes, suggesting an immune response.

Treatment

Topical low-dose corticosteroids decrease the signs and symptoms of TSPK and probably are most effective during acute exacerbations. The course of the disease may be prolonged with the chronic use of corticosteroids. Topical 2% cyclosporine or tacrolimus have been effective in the management of TSPK, with few side effects. Therapeutic bandage contact lenses may be used to improve visual acuity and improve comfort in more symptomatic patients. The use of antiviral agents has been evaluated, but no convincing evidence exists that they are effective. Photorefractive keratectomy may reduce the recurrences in the central ablated cornea, suggesting that some unknown inflammatory signal may reside in the superficial corneal stroma.

Course and Outcome

Most patients with TSPK recover completely with no loss of visual acuity, although up to 44% may be left with faint subepithelial opacities.

Epidemiology and Pathogenesis

Superior limbic keratoconjunctivitis (SLK) is a chronic, focal, ocular surface disease characterized by episodes of recurrent inflammation of the superior cornea and limbus, as well as of the superior tarsal and bulbar conjunctiva. It occurs primarily in adults age 30–55 years and is more common in women (3 : 1). It typically is bilateral, but unilateral disease may occur.

Although the pathophysiology is unclear, mechanical trauma from tight upper lids or loose redundant conjunctiva could lead to the known disruption of normal epithelial development. This mechanical hypothesis is supported by the increased lid apposition in patients with exophthalmic thyroid disease, who are known to have an increased incidence of SLK, as well as increased lubrication being an effective treatment modality.

Ocular Manifestations

The classic sign of SLK is bilateral local hyperemia of the superior bulbar conjunctiva ( Fig. 4.17.3 ), which also appears keratinized, thickened, and redundant. The opposing superior palpebral conjunctiva demonstrates a delicate papillary reaction with associated hyperemia. Fine fluorescein or Rose Bengal punctate staining usually is present. Keratoconjunctivitis sicca occurs in 25%–50% of patients and must be evaluated in all patients with SLK. A fine filamentary keratitis of the superior cornea and limbus may be present ( Fig. 4.17.4 ). A delicate superior corneal pannus suggests more long-standing disease.

Superior Limbic Keratoconjunctivitis.

Slit-lamp appearance of focal superior bulbar conjunctival injection is shown with Rose Bengal staining.

Superior Limbic Keratoconjunctivitis.

Slit-lamp appearance of superior filamentary keratitis is shown.

Characteristic symptoms include a gradual onset of burning, tearing, foreign body sensation, mild photophobia, and sometimes mucus discharge. Patients may notice pain and decrease in vision if the filamentary component is severe or occurs within the visual axis.

Diagnosis

The diagnosis of SLK is made from the history of irritation, photophobia, and the specific pattern of superior corneal and conjunctival inflammation and staining. Superior filamentary keratitis supports the diagnosis.

Differential Diagnosis

The differential diagnosis of SLK is shown in Box 4.17.2 . Filamentary keratitis may occur in up to 40% of patients with SLK. The distribution of filaments on the upper cornea and limbus may help differentiate SLK from dry eye disease (DED), in which filaments occur more typically on the lower half of the cornea.

An inflammatory condition associated with soft contact lens wear may resemble SLK. Although many signs and symptoms of this contact lens–related SLK are similar to those of SLK of Theodore, filaments are usually absent, vision may be decreased (unusual in SLK), and no female predilection or associated thyroid dysfunction exists. More importantly, symptoms generally improve with discontinuation of contact lens wear. Contact lens–induced keratoconjunctivitis may be a more appropriate term for this entity, with SLK reserved for the specific condition described by Theodore.

SLK-like inflammation can occur in patients with chronic ocular graft-versus-host disease (GVHD). These patients present with the typical signs of SLK, including conjunctival injection and staining of the superior conjunctiva and cornea. They also tend to show good response to the common treatments for SLK. If this type of inflammation goes undiagnosed in patients with chronic GVHD, they can develop limbal stem cell deficiency, scarring, and loss of vision.

Systemic Associations

Systemic associations include thyroid disease and collagen vascular disease. In one study in a referral university setting, 65% of patients who had SLK were found to also have thyroid dysfunction. Of those patients who had SLK and thyroid disease, 90% had ophthalmopathy, and 49% had severe thyroid disease necessitating orbital decompression. SLK is a strong negative prognostic factor for patients who have thyroid disease.

Pathology

The superior bulbar conjunctiva demonstrates keratinization of the epithelium with intracellular accumulation of glycogen and abnormal chromatin. A predominantly polymorphonuclear infiltrate occurs. Acanthosis, squamous metaplasia, dyskeratosis, balloon degeneration of nuclei, and decreased goblet cell density, and conjunctival stromal edema occur. Upregulation of transforming growth factor-β ₂ and tenascin support an increase in mechanical stress. Altered expression of cytokeratins also suggests an abnormality of epithelial differentiation. One study found elevated levels of matrix metalloproteinases (MMP-1 and MMP-3) in surgical specimens from patients with SLK compared with controls, suggesting a possible role of MMP imbalance in the pathogenesis.

Changes in the superior palpebral conjunctiva are somewhat different, with an increase in polymorphonuclear neutrophil leukocytes, lymphocytes, and plasma cells. The overlying epithelium contains hypertrophic goblet cells.

Treatment

Because a large proportion (25%–50%) of patients who have SLK also have DED, care must be taken to treat any concurrent aqueous tear deficiency with unpreserved teardrops and, if indicated, punctal occlusion. Associated blepharitis also must be managed. Any lid surgery, especially ptosis repair, should be evaluated carefully because possible exacerbation of SLK may be caused by lid tightening and possible secondary exposure.

Surgical approaches to treatment involve the destruction or resection of the presumed abnormal conjunctival epithelium. Simple resection or recession of the conjunctiva with Tenon’s capsule can be very effective. Use of cryotherapy and thermocautery has been reported, with symptom improvement in 75% of patients treated with the latter.

Bandage contact lenses and pressure patching have been used to manage severe symptoms of photophobia, ocular discomfort, and associated filamentary keratitis. SLK often recurs, however, after lens wear has been discontinued.

Topical hypertonic saline solutions may help reduce the excessive mucus production and associated filaments. N -acetylcysteine (Mucomyst), in 10%–20% solution, may offer relief in severe cases. Topical cromolyn or lodoxamide may offer symptomatic relief of itching.

The chronic use of topical corticosteroids should be discouraged. Topical cyclosporine A and autologous serum have been reported to be effective in some cases. Topical vitamin A eyedrops may be variably effective during inflammatory periods. Topical tacrolimus 0.03% ointment has been successful in the treatment of cases refractory to the above treatment modalities. Topical rebamipide, a medication initially used to increase gastric mucosa mucin, has been shown to improve SLK in patients with thyroid disease.

Course and Outcome

Many of the proposed therapies have been effective, and the overall prognosis is excellent because the visual axis usually is not affected.

Epidemiology and Pathogenesis

Mooren’s ulcer, a rare, chronic, painful, peripheral ulcerative keratitis (PUK), was first described in detail as a clinical entity by Mooren in 1867. Two clinical types of primary Mooren’s ulcer have been described. The limited type is typically unilateral, occurs in the fourth decade or later, and is more responsive to local surgical and medical therapy. The second type, which is more resistant to systemic immunosuppression, involves a bilateral, painful, relentless, progressive destruction of the cornea, usually in younger individuals (third decade), many of whom are of African descent.

The pathogenesis of Mooren’s ulcer is unknown but appears to involve an autoimmune reaction against a specific target molecule in the corneal stroma, which may occur in genetically susceptible individuals. Both cellular and humoral mechanisms have been postulated. The conjunctival epithelium demonstrates increased levels of several inflammatory mediators.

Interestingly, there have been several reported cases of Mooren’s ulcer in patients with concurrent hepatitis C whose corneal inflammation responded to systemic interferon-α (IFN-α). These cases suggest a common antigenic source.

Ocular Manifestations

Mooren’s ulcer is characterized by a progressive, crescentic, peripheral corneal ulceration that is slightly central to the corneoscleral limbus. It is associated with a characteristic extensive, undermined, “overhanging” edge ( Fig. 4.17.5 ). It progresses with an anterior, stromal, yellow-white infiltrate at the advancing margin. An overlying epithelial defect then develops. Progressive stromal melting follows, which affects first the deeper and subsequently the anterior stroma. The ulcer progresses circumferentially and centrally. A re-epithelized, conjunctivalized, thinned cornea remains. Patients in whom Descemet’s membrane has a minimal overlying stroma may be predisposed to perforation either spontaneously or following minor trauma.

Acute Mooren’s Ulcer.

Peripheral thinning and an overlying epithelial defect are present in an inflamed eye.

(Courtesy Joel Sugar, MD.)

In the more aggressive form of Mooren’s ulcer, the inflammation may affect the entire cornea and perilimbal tissue. Perforation is not uncommon in this form, occurring in about one third of patients. Associated cataract, secondary glaucoma, and uveitis may be seen.

Chronic Mooren’s ulcer ultimately results in a central island of hazy stromal tissue with severe peripheral thinning ( Fig. 4.17.6 ). No scleral involvement occurs, although associated conjunctival and episcleral inflammation may be seen. No clear zone exists between the ulcer and the limbus, which distinguishes Mooren’s ulcer from other forms of PUK. Visual loss as a result of severe, irregular corneal astigmatism and scarring is common.

Mooren’s Ulcer.

Peripheral thinning is present in a relatively quiet eye in this patient who had a history of Mooren’s ulcer, now in remission.

Diagnosis

Mooren’s ulcer is, by definition, not associated with any systemic abnormality, except for the occasional association with hepatitis C. Collagen vascular disease must be excluded. Patients should also be tested for hepatitis C virus. Patients who have other systemic diseases, including leukemia, pyoderma gangrenosum, and syphilis, also may develop PUK.

Patients complain of severe ocular pain, photophobia, and tearing. The overlying epithelium in other degenerative corneal lesions remains intact.

Differential Diagnosis

Although there are many other causes of PUK ( Box 4.17.3 ), Mooren’s ulcer is an unusual and severe inflammatory disease without known associated systemic disease (except perhaps hepatitis C).

Pathology

Three zones of corneal involvement have been described. The superficial stroma contains lymphocytes, plasma cells, polymorphonuclear leukocytes, disrupted collagen lamellae, and neovascular elements. The midstroma demonstrates an increase in the number of fibroblasts, and the deep stroma is infiltrated primarily by macrophages. The epithelial basement membrane is disrupted at the leading edge, and the characteristic infiltrate contains primarily neutrophils.

Conjunctival resections from patients with Mooren’s ulcer demonstrate increased levels of inflammatory mediators, including vascular cell adhesion molecule-1 (VCAM-1), very late activation-4, intercellular adhesion molecule-1 (ICAM-1), and lymphocyte function–associated antigen-1.

Treatment

A stepladder approach to manage this aggressive disease has been proposed. This includes local, systemic, and surgical therapies. Initial treatment should begin with topical corticosteroids, followed by conjunctival resection if the inflammation is not controlled. Topical cyclosporine drops and tacrolimus ointment have been effective in some cases. In addition, bandage contact lenses, as well as amniotic membrane transplantation, may reduce discomfort and promote epithelial healing in refractory cases. Topical administration of IFN-α may be helpful.

Systemic immunosuppression with cyclophosphamide followed by azathioprine may be initiated if treatment with conjunctival resection fails. Systemic immunosuppressive treatment of the more aggressive bilateral disease has included corticosteroids, cyclosporine, methotrexate, and infliximab. Systemic IFN-α _2b has been effective in the treatment of patients who are positive for hepatitis C virus and have Mooren’s ulcer.

Systemic workup for vasculitis or collagen vascular disease is mandatory for patients who are suspected of having Mooren’s ulcer. The primary goal of therapy is to slow the severe progression of the corneal loss, although 50% of cases may be unresponsive to all medical therapy.

Small perforations can be managed with cyanoacrylate adhesive but large perforations require lamellar or full-thickness keratoplasty.

Surgical management for visual rehabilitation is a challenge as penetrating keratoplasty is usually associated with disease recurrence, graft rejection, and melting.

Course and Outcome

Most patients who have unilateral disease respond fairly well to topical corticosteroids and conjunctival resection. For more severe bilateral cases, the prognosis is poor.