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.
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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 is also 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 is then 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 is also associated with SLK, as it can exacerbate the repetitive microtrauma between the tarsal and superior palpebral conjunctiva.[7] Recent 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 has also 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 is also 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 excellent, with remission as the natural history and eventual total resolution, although symptoms may last for years.
The natural history of superior limbic keratoconjunctivitis is usually 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 may have been previously missed.
Patients with superior limbic keratoconjunctivitis present with complaints of tearing, burning, foreign body sensation, mild photophobia, and mucous discharge. Some patients may also present with redness.
Superior limbic keratoconjunctivitis is most often bilateral, although one 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, usage of moisturizing medications provides only minimal symptomatic relief.
Patients with corneal filaments are usually extremely symptomatic, which may distract the examiner from the underlying condition.
Commonly, a history of thyroid dysfunction is elicited upon questioning.
Marked inflammation of the upper lid tarsal conjunctiva, adjacent inflammation of the upper bulbar conjunctiva, and punctate rose Bengal staining of the cornea at the upper limbus are signs of superior limbic keratoconjunctivitis.
The conjunctiva extending from the upper limbus to the insertion of the superior rectus muscle also demonstrates thickening, hyperemia, and typical rose Bengal staining. This finding stands out in stark contrast to the normal appearance of the inferior conjunctiva and cornea.
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 is often present with superior limbic keratoconjunctivitis (SLK), the Schirmer test, measurement of tear lake, and tear breakup time are used to evaluate for.
The following laboratory studies and tests should be considered:
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 numbers of inflammatory cells, including plasma cells, neutrophils, and lymphocytes, also are 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 the diagnosis and grading of severity of the unique manifestations of SLK.[18]
Superior limbic keratoconjunctivitis (SLK) is managed by various treatment options, none of which has been completely effective. Therapeutic approaches have been aimed primarily toward speeding the patient's recovery and providing symptomatic relief.
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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), mast cell stabilizers,[11, 19] vitamin A preparations,[20] topical cyclosporine (0.05% BID),[7] autologous serum–derived drops,[21, 22] and botulinum injection to the overlying muscle of Riolan[23] 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) are often required.
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.[24] A 4-week course of 0.03% tacrolimus ointment has been shown anecdotally in two patients to alleviate symptoms.[25] 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.[26]
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 of SLK signs after treatment; 84.8% of eyes achieved complete remission.[27]
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.[20]
When noninvasive or less invasive treatment modalities fail in the treatment of superior limbic keratoconjunctivitis (SLK), surgical intervention is an alternative.[28]
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,[29] and keratinized epithelium is replaced by normal ingrowth.[30, 11] Thermocautery accomplishes 2 of these treatment objectives.[19] Autologous serum application has been shown to be beneficial as an alternative therapy in a small case series.[31] Adjunctive superior lacrimal punctal occlusion,[32] bandage contact lens application,[33, 34] and amniotic membrane grafting[35] have been advocated but are not widely used.
Surgical resection of the conjunctiva has the usual complication profile of any surgical procedure, and special care should be taken to avoid involvement of the superior rectus muscle in the dissection.
Application of high-frequency radiowave electrosurgery after techniques for conjunctival chalasis treatment also shortens excess conjunctiva and has been used effectively as an alternative therapy.[36]
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 will also 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). However, these approaches usually offer only temporary mitigation of symptoms, and more definitive treatments are often required. Preservative-free artificial tears may also be helpful.
Topical cyclosporine has been shown to provide symptom relief and to improve the signs of superior limbic keratoconjunctivitis; however, maintenance therapy is required for continued benefit.[37]
Clinical Context: Lodoxamide is a mast cell stabilizer with reported efficacy in the treatment of superior limbic keratoconjunctivitis.
Clinical Context: Cromolyn is another mast cell stabilizer with reported efficacy in the treatment of superior limbic keratoconjunctivitis.
Mast cell stabilizers inhibit type 1 immediate hypersensitivity reactions and are used for the long-term inhibition of inflammation.
Clinical Context: 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.
Topical application of cauterizing agents is used for the treatment of keratinized conjunctivae.
Clinical Context: 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.