Superior Limbic Keratoconjunctivitis (SLK)

Superior limbic keratoconjunctivitis (SLK) is characterized as an inflammation of the superior bulbar conjunctiva with predominant involvement of the superior limbus, an adjacent epithelial keratitis, and a papillary hypertrophy of the upper tarsal conjunctiva.

In 1963, Thygeson and Kimura described it as a chronic, localized, filamentary conjunctivitis.[1] Contemporaneously, this condition was given its name, superior limbic keratoconjunctivitis (SLK), by Theodore. Five years later, Tenzel and Corwin each reported an association between thyroid abnormalities and SLK.[2, 3] A mimicking disorder has been encountered in soft contact lens (SCL) wearers, typically with exposure to thimerosal-preserved solutions.[4, 5]

In the United States, the frequency of superior limbic keratoconjunctivitis has been reported to be 3% in a cohort of ophthalmopathy patients with Graves disease, but it is much lower in the general population. Although no racial predilection exists, middle-aged people (range, 40-80 years) and women are predominantly affected.[6]

In general, the prognosis of superior limbic keratoconjunctivitis is excellent, with remission as the natural history and eventual total resolution, although symptoms may last for years.

See the following for more information:

• Acute Hemorrhagic Conjunctivitis

• Allergic Conjunctivitis

• Atopic Keratoconjunctivitis

• Bacterial Conjunctivitis

• Emergent Treatment of Acute Conjunctivitis

• Epidemic Keratoconjunctivitis

• Giant Papillary Conjunctivitis

• Keratoconjunctivitis Sicca

• Neonatal Conjunctivitis

• Viral Conjunctivitis

The cause of superior limbic keratoconjunctivitis (SLK) is unknown, but inflammatory changes from mechanical soft tissue microtrauma are the final common pathway.[7] This condition also is associated with thyroid dysfunction but has been known to develop in association with scarring of the palpebral conjunctiva in euthyroid patients.

Other potential risk factors for development of superior limbic keratoconjunctivitis include prolonged eyelid closure with associated hypoxia or reduced tear volume, as well as morphologic or functional changes in superior conjunctival apposition to the globe following upper eyelid procedures.[8]

Superior limbic keratoconjunctivitis is believed to be present secondary to superior bulbar conjunctiva laxity, which induces inflammatory changes from mechanical soft-tissue microtrauma.[9] In settings in which the physiologic tolerance of mechanical forces on the delicate ocular surface is exceeded, chronic inflammation results in thickening of the conjunctiva and keratinization, which then is cyclical in perpetuating the inflammation. Eventually, a filamentary response may be induced on the affected cornea. Factors inducing conjunctiva laxity include thyroid eye disease, tight upper eyelids, and prominent globes. Immunochemical histopathologic examination of the abnormal conjunctiva in superior limbic keratoconjunctivitis lends credence to microtrauma being of most significance to the development of superior limbic keratoconjunctivitis.

Dry eye disease also is associated with SLK, as it can exacerbate the repetitive microtrauma between the tarsal and superior palpebral conjunctiva.[7]  Studies have shown that secondary dry eye conditions, specifically the ocular form of chronic graft-versus-host disease (cGVHD), also predispose to SLK. Ocular cGVHD, similar to other forms of autoimmune-mediated ocular surface disease, creates inflammatory damage to the lacrimal glands, meibomian glands, cornea, and conjunctiva.[10] These damages increase frictional forces between conjunctival surfaces and consequently create repetitive microtrauma, leading to SLK-like inflammation.

It is speculated that SLK may be a mast cell–related disorder, as an increased number of mast cells is found in the subepithelial stroma of patients with SLK.[11] Mechanisms involving promotion of mast cell migration and activation in this disease are unclear, but recent research found an overexpression of stem cell factor (SCF) and thymic stromal lymphopoietin (TSLP) in the conjunctival epithelium of patients with SLK. Thus, it is possible that these factors are involved in promoting mast cell migration and activation, contributing to the pathogenesis of SLK.[12] Immunochemistry analysis also has shown a higher COX-2 expression in patients with SLK compared with normal conjunctiva.[13]

Superior limbic keratoconjunctivitis is more common in women than in men, by a ratio of 3:1. It also is more common in middle-aged individuals (~60 years).

It has no radical predilection.

People with thyroid dysfunction and keratoconjunctivitis sicca are at an increased risk.

In general, the prognosis of superior limbic keratoconjunctivitis is good, with remission as the natural history and eventual total resolution, although symptoms may last for years.

The natural history of superior limbic keratoconjunctivitis usually is a chronic course with gradual clearing. Patients often have seen numerous eye specialists for their symptoms. Unless the doctors have specifically examined the upper bulbar conjunctivae or everted the upper eyelids, the diagnosis previously may have been missed.

Symptoms

Patients with superior limbic keratoconjunctivitis present with complaints of tearing, burning, foreign body sensation, mild photophobia, and mucous discharge. Some patients may present with redness. There usually is no chronic visual impairment, but there may be occasional periods of transient blurred vision.

Superior limbic keratoconjunctivitis most often is bilateral, although 1 eye may be more symptomatic.

The symptoms remit and exacerbate and are variable in degree, but no diurnal pattern to the worsening of symptoms exists. Typically, the usage of moisturizing medications provides only minimal symptomatic relief.

Corneal filaments increase foreign body sensation and blepharospasm, so patients with corneal filaments usually are extremely symptomatic. This also can distract the examiner's attention from the underlying condition.

Commonly, a history of thyroid dysfunction is elicited upon questioning.

Signs

Signs of superior limbic keratoconjunctivitis are marked inflammation with hyperemic papillary reaction in the upper lid tarsal conjunctiva, inflammation of the upper bulbar conjunctiva, thickening of the upper limbal epithelium and surrounding conjunctiva, punctate staining on the upper limbus, adjacent conjunctiva, and/or cornea.

The conjunctiva extending from the upper limbus to the insertion of the superior rectus muscle also demonstrates thickening, hyperemia, and typical staining with fluorescein, rose bengal, and lissamine green. Other clinical findings include erosion or micropannus in the upper cornea, diffuse corneal epithelial erosion, conjunctival hyperemia, pseudomembranes in the upper lid tarsal conjunctiva, and eyelid edema.

Approximately one third of patients present with filaments on the upper cornea or along the superior limbus.

Superior limbic keratoconjunctivitis (SLK) has been associated with thyroid dysfunction; therefore, investigations into thyroid function, including thyroid-stimulating hormone (TSH), free thyroxine (T4), thyroid-stimulating immunoglobulin, or TSH–binding inhibitory immunoglobulin, may be appropriate. An endocrinologist consultation should be obtained to aid in this workup.

To evaluate for and/or rule out dry eye syndrome, which often is present with superior limbic keratoconjunctivitis (SLK), the Schirmer test, measurement of tear lake, and tear breakup time are used.

The diagnosis of superior limbic keratoconjunctivitis (SLK) is based on clinical findings. The following laboratory studies and tests should be considered:

• Slit-lamp examination
• Fluorescein and lissamine green staining or rose Bengal staining
• Schirmer test
• Examination for thyroid orbitopathy
• Thyroid function test
• Autoimmune markers (anti-Ro [SS-A] and anti-La [SS-B] antibodies and cyclic citrullinated-peptide antibodies)

Surgical specimens taken from patients with superior limbic keratoconjunctivitis (SLK) who had not received treatment with silver nitrate demonstrate abnormal limbic epithelium with keratinized epithelial cells with dyskeratosis and acanthosis and balloon degeneration of some nuclei. The intracellular accumulation of glycogen in the epithelial cells of tissue sections of the bulbar conjunctiva has been documented. The conjunctival stroma demonstrates edema without significant inflammatory cellular infiltrate. In specimens obtained after silver nitrate treatment, significant inflammatory cells, including plasma cells, neutrophils, and lymphocytes, are also found in the epithelium and stroma.

Immunohistochemical pathologic examination of the abnormal conjunctiva in superior limbic keratoconjunctivitis demonstrates a lack of the typical mosaic pattern of the epithelium in the resulting keratinized cells before the patient undergoes treatment and upregulation of transforming growth factor-beta 2 and tenascin.[14] In separate studies, increased expression of proliferating cell nuclear antigens and altered expression of cytokines,[15] as well as the presence of involucrin,[16] was shown. More recently, heightened levels of matrix metalloproteinases 1 and 3 have been detected in specimens with the clinical manifestations of SLK.[17]

In vivo laser scanning confocal microscopy has been used to aid in diagnosing and grading the severity of the unique manifestations of SLK.[18]  Significant infiltration of inflammatory cells and dendritic cells may be seen in the upper bulbar conjunctiva by in vivo confocal microscopy [18] .

Although asymptomatic patients with superior limbic keratoconjunctivitis (SLK) do not require treatment, symptomatic patients are managed by various treatment options. However, there has been no completely effective treatment option. Therapeutic approaches have been aimed primarily toward speeding the patient's recovery and providing symptomatic relief.

See the following for more information:

• Acute Hemorrhagic Conjunctivitis

• Allergic Conjunctivitis

• Atopic Keratoconjunctivitis

• Bacterial Conjunctivitis

• Emergent Treatment of Acute Conjunctivitis

• Epidemic Keratoconjunctivitis

• Giant Papillary Conjunctivitis

• Keratoconjunctivitis Sicca

• Neonatal Conjunctivitis

• Viral Conjunctivitis

Pressure patching, placement of a bandage contact lens (primarily or as an adjunct), silver nitrate 0.5% solution application (10-20 seconds to superior tarsal and bulbar conjunctiva after topical anesthesia), topical corticosteroids, mast cell stabilizers,[11, 19]  punctal occlusion,[20]  vitamin A preparations,[21] topical cyclosporine (0.05% BID),[7] autologous serum–derived drops,[22, 23] and botulinum injection to the overlying muscle of Riolan[24] have been used with moderate success for managing superior limbic keratoconjunctivitis (SLK). Because these approaches usually offer only temporary mitigation of symptoms, more definitive treatments (eg, surgical resection of the bulbar conjunctiva) often are required.

Artificial tear drops, autologous serum eye drops, and vitamin A drops which provide lubrication and nutrition to the eye and improve the ocular surface, are important adjunctive treatments in SLK [25, 26] . Autologous serum application has been shown to be beneficial in a small case series.[25]  A study reported that vitamin A drops treatment improved symptoms in 83% of patients with SLK, and no recurrence of symptoms was observed while under treatment.[26]

A 2017 study of 67 eyes showed that continuous lodoxamide 0.1% BID can be an efficacious and well-tolerated therapeutic alternative for the treatment of active and chronic SLK.[27] A 4-week course of 0.03% tacrolimus ointment has been shown anecdotally in 2 patients to alleviate symptoms.[28] Again, most do not consider these definitive treatments.

Supratarsal triamcinolone injection has had reported success in mitigating signs and symptoms and may be helpful as adjunctive therapy.[29]

Acetylcysteine 10% 3-6 times per day can be added if significant corneal filaments are present.

Topical rebamipide is suggested as a first-line treatment for SLK in patients with thyroid eye disease. The study included 33 eyes from 20 patients with thyroid eye disease, all of whom experienced significant improvement in SLK signs after treatment; 84.8% of eyes achieved complete remission.[30]

Pressure patching and bandage contact lens placement may help to improve epithelial erosions, decrease the friction of the tarsal conjunctiva on the ocular surface, heal corneal filaments, and decrease bilateral reflex blinking.[24, 31, 32]

It is important to keep in mind that inappropriate use of silver nitrate sticks (75%-95%)—which should never be used in the eyes, as opposed to preparations of topical silver nitrate solution (0.5%)—results in a severe caustic injury to the affected part of the eye where applied.

Liquid nitrogen cryotherapy as a single application or repeated for recalcitrant SLK appears to be a safe and effective therapy using a double freeze-thaw technique with the patient under topical anesthesia.[21]

When noninvasive or less invasive treatment modalities fail in the treatment of superior limbic keratoconjunctivitis (SLK), surgical intervention is an alternative.[33]

Surgical resection of the involved conjunctiva—as delineated intraoperatively by the use of rose Bengal staining—removes the affected tissue. Folds of superfluous conjunctiva are eliminated; adhesions with underlying Tenon capsule and episclera develop, which may be augmented by transplantation of cryopreserved amniotic membrane with fibrin glue;[34] and the keratinized epithelium is replaced by normal ingrowth.[35, 11] . Surgical resection of the involved conjunctiva can be performed with or without thermal cauterization of the conjunctiva. A study reported that conjunctival thermal cauterization was effective in the treatment of SLK, and improvement was observed histopathologically 2 months following treatment.[19]  Conjunctival resection can be combined with amniotic membrane grafting. In a study comparing the outcomes of conjunctival resection with and without amniotic membrane grafting, it was reported that there was no significant difference between the 2 groups and that both methods were highly effective.[36]

Surgical resection of the conjunctiva has the usual complication profile of any surgical procedure, and special care should be taken to avoid the involvement of the superior rectus muscle in the dissection.

The application of high-frequency radio-wave electrosurgery after techniques for conjunctival chalasis treatment also shortens excess conjunctiva and has been used effectively as an alternative therapy.[37]

Discussing the disease process with patients is important, because it will improve compliance with treatment modalities. This discussion will help to allay their fear of the unknown and also will help them to cope with the often prolonged symptoms of this entity.

Patients should receive follow-up care for recurrences of symptoms after treatment of superior limbic keratoconjunctivitis (SLK), and they require careful examinations for the development of thyroid ophthalmopathy.

Mast cell stabilizers and vitamin A preparations have been used with moderate success in the treatment of superior limbic keratoconjunctivitis (SLK). Preservative-free artificial tears may be helpful. However, these approaches usually offer only temporary mitigation of symptoms, and more definitive treatments often are required. 

Topical cyclosporine has been shown to provide symptom relief and to improve the signs of SLK; however, maintenance therapy is required for continued benefit.[38]

Class Summary

Mast cell stabilizers inhibit type 1 immediate hypersensitivity reactions and are used for the long-term inhibition of inflammation.

Lodoxamide tromethamine 0.1% (Alomide)

Lodoxamide is a mast cell stabilizer with reported efficacy in the treatment of superior limbic keratoconjunctivitis.

Cromolyn sodium, ophthalmic (Crolom, Opticrom)

Cromolyn is another mast cell stabilizer with reported efficacy in the treatment of superior limbic keratoconjunctivitis.

Class Summary

Topical application of cauterizing agents is used for the treatment of keratinized conjunctivae.

Silver nitrate

An application of silver nitrate to the anesthetized conjunctiva usually relieves symptoms of superior limbic keratoconjunctivitis for 4-6 weeks. Then, the treatment can be repeated safely.

Class Summary

Immunomodulatory agents modulate key factors of the immune system.

Cyclosporine A, 0.05% topical (Restasis)

Cyclosporine A is used to relieve dry eyes caused by suppressed tear production secondary to ocular inflammation. This agent is thought to act as a partial immunomodulator, but its exact mechanism of action is not known.