Superior Limbic Keratoconjunctivitis : Introduction, Symptoms, Causes, Diagnosis, Management and Prevention - www.genericdrugscan.com

Superior Limbic Keratoconjunctivitis : Information

Superior limbic keratoconjunctivitis (SLK) is relatively an uncommon chronic disease of superior limbus/cornea, and superior bulbar and tarsal conjunctiva. It affects one or both eyes of middle-aged people, about half the patients have abnormal thyroid function (usually hyperthyroidism). About three percent of patients with thyroid eye disease develop SLK. Women are more commonly affected than men.

Superior limbic keratoconjunctivitis is believed to be due to blink-related trauma between the upper lid and the superior bulbar conjunctiva, precipitated in many cases by tear film insufficiency, and an excess of lax conjunctival tissue. With increased conjunctival movement, there is mechanical damage to the tarsal and bulbar conjunctival surfaces. It results in inflammatory response, leading to increased conjunctival oedema and redundancy, with the creation of a self-perpetuating cycle. It may be analogous to conjunctivochalasis (redundant excess fold of conjunctiva) affecting the lower bulbar conjunctiva.

Superior limbic keratoconjunctivitis has similarities to mechanically induced papillary conjunctivitis and a comparable clinical picture may be seen in:

• Contact lens wearers.
• Trauma to upper lid.
• Upper eyelid surgery.

Between 1954 and 1963, reports by Braley and Alexander (Braley AE, Alexander RC. Superficial punctate keratitis. Arch Ophthalmol, 1953; 50(2):147-154), Thygesson and Kimura (Thygesson P, Kimura SJ: Chronic conjunctivitis. Trans Am Acad Ophthalmol Otolaryngol 1963; 67: 494-517) presented information about a new clinical entity associated with filamentary keratopathy.

Superior limbic keratoconjunctivitis was first fully described by Frederick Theodore in 1963. (Theodore FH. Superior limbic keratoconjunctivitis. Eye Ear Nose Throat Mon 1963; 42: 25-28.). He suggested the term Superior limbic keratoconjunctivitis to describe a series of patients with the following presenting signs:

• Inflammation of the superior tarsal conjunctiva,
• Inflammation of the superior bulbar conjunctiva,
• Fine punctate staining of the superior cornea, limbus, and the adjacent conjunctiva, and
• Filaments on the superior limbus or upper fourth of the cornea.

SLK is probably under-diagnosed because symptoms are typically more severe than signs. The course can be prolonged over years although remission eventually occurs spontaneously.

References:

Agarwal Sunita, Agarwal Athiya, Apple David J, Buratto Lucio, Alio JorgeL, Pandey Suresh K and Agarwal Amar.Textbook of Ophthalmology Volume 1.FirstEdition. Jaypee Brothers Medical Publishers (P) Ltd. 2002. New Delhi. P. 869-871.

Holland Edward J, Mannis Mark J, Lee W Barry. Ocular Surface Disease - Cornea, Conjunctiva and Tear Film. Elsevier Saunders. 2013. P. 167-169.

Bowling Brad. Kanski's Clinical Ophthalmology - A Systematic Approach. Eighth Edition. Elsevier. 2016. P. 158-160.

Yanoff Myron, Sassani Joseph W. Ocular Pathology. Elsevier Saunders. Seventh Edition.2015. P. 238.

Copeland Jr Robert A, Afshari Natalie A. Copeland and Afsharis Principles and Practice of CORNEA Vol.1. Jaypee Brothers Medical Publishers (P) Ltd. 2013. P. 509-514.

FosterC Stephen, Azar Dimitri T, Dohlman Claes H. Smolin and Thofts The CORNEA-Scientific Foundations & Clinical Practice. Lippincot Williams &Wilkins. Fourth Edition. 2005. P. 663-667.

http://emedicine.medscape.com/article/1194578-overview

http://eyewiki.aao.org/Superior_limbic_keratoconjunctivitis

Basak Samar K, Atlas of Clinical Ophthalmology, 2nd ed. Jaypee Brothers Medical Publishers (P) Ltd, 2013, New Delhi, P.74.

Nema HV, Nema Nitin. Textbook of Ophthalmology. Jaypee- Highlights Medical Publishers (P) Ltd. 2012. P.156.

Khurana A. K. Ophthalmology. New Age International (P) Limited. Third edition. 2003. P.133.

BenEzra David. Blepharitis and Conjunctivitis: Guidelines For Diagnosis And Treatment. Editorial Glosa. International Ocular Inflammation Society. 2006. P. 121-122.

Braley AE, Alexander RC. Superficial punctate keratitis. Arch Ophthalmol, 1953; 50(2):147-154.

Chun YS, Kim JC. Treatment of superior limbic keratoconjunctivitis with a large-diameter contact lens and botulium toxin A. Cornea 2009; 28: 752-758.

Thygesson P, Kimura SJ: Chronic conjunctivitis. Trans Am Acad Ophthalmol Otolaryngol 1963; 67: 494-517.

Theodore FH. Superior limbic keratoconjunctivitis. Eye Ear Nose Throat Mon 1963; 42: 25-28.

Wright P: Superior limbic keratoconjunctivitis. Trans Ophthalmol Soc UK 1972; 92: 555.

The characteristic feature of the symptoms of SLK is its variability with intermittent remissions and exacerbations.

Patients may have ocular (eye) symptoms such as:

• Burning sensation.
• Redness.
• Irritation (may be more prominent when patient looks upward).
• Foreign body sensation.
• Pain.
• Itching.
• Dry eye sensation.
• Mild photophobia.
• Frequent blinking.
• Blepharospasm.
• Mucoid discharge (less common).
• Diminution of vision (rare).

The symptoms are often intermittent.

Soft contact lens wear may be associated with features like SLK. It may be attributable to preservatives especially thiomersal. Removal of lens or preservatives is usually curative.

There have been many theories about the aetiology of SLK, but still some uncertainty remains till date.

Possible aetiological theories:

Mechanical trauma:

Mechanical trauma is the most popularly assumed theory as aetiology of SLK.

There is constant abnormal movement of the superior bulbar conjunctiva during blinking due to abnormal interaction of the superior tarsal and bulbar conjunctiva. The laxity of bulbar conjunctiva because of congenital origin or due to ageing, predisposes it to get repeatedly traumatised by upper lid as the lid is opened or closed. This abnormality may be due to tight apposition of tarsal conjunctiva against the globe in the setting of:

• Thyroid eye disease e.g. endocrine exophthalmos (Some believe that when thyroid exophthalmos leads to SLK, it is of mechanical aetiology, since SLK disappears on control of endocrine exophthalmos. The upper eyelid is tensely applied against the upper bulbar conjunctiva and cornea because of thyroid abnormality,
• Scarring of the superior tarsal conjunctiva,
• Inflammation (Patients with chronic ocular inflammatory disease can develop a picture of SLK because of increased friction between the superior palpebral and bulbar conjunctiva. The chronically inflamed palpebral conjunctival surface could lead to a change in viscosity that prevents the normal maturation and replacement of bulbar conjunctival epithelium), or
• Dryness of the eyes (patients with keratoconjunctivitis sicca may have a drying effect between upper lid and bulbar conjunctiva and it increases the friction between the two).

This theory is supported by strong association of SLK with both thyroid dysfunction and dry eye disease.

There is high expression of transforming growth factor-beta 2 and tenascin, both are known to be affected by mechanical stress and injury.

The mechanical irritation induces abnormal mucous production and this abnormal mucous production is responsible for filament formation.

Biochemical abnormalities:

Alteration in expression of certain cytokeratins (CKs) is found in patients with SLK. There is decreased expression of a marker for non-keratinised stratified squamous epithelium, CK13 along with increased expression of CK10, a marker for keratinisation, which correlates with disease severity. These suggest that an abnormality of differentiation in conjunctival epithelium plays a role in the disease.

Viral aetiology:

Some have suggested a viral cause, but cultures are found to be universally negative.

Bacterial aetiology:

In some studies, bacterial cultures have been shown to be positive, but mostly for normal ocular flora.

Autoimmune aetiology:

An autoimmune aetiology has also been proposed but this is also less likely due to:

• The lack of immunoglobulin deposition (seen on direct immune-fluorescence),
• Lack of increase in eosinophils, and
• Variable response to topical steroids.

Hyperparathyroidism has also been reported in association with SLK.

A familial association has rarely been reported but is not the norm.

History of contact lens wear, and previous eyelid surgery or trauma should be obtained from the patient.

Even in untreated patients, the natural course of disease is one of episodic intermittent relapses and gradual improvement over several years, with eventual resolution. Most patients have bilateral affection, but asymmetric and unilateral disease does occur. The disease is roughly twice more common in females. It typically presents in fourth or fifth decades of life.

Patients with SLK present with non-specific ocular complaints. Symptoms are usually much more severe if the patient has corneal filaments. Often irritation is mild in the morning but it worsens thereafter. The symptoms can be vague and intermittent and often are mistaken for other ocular surface disease, such as dry eye or blepharitis. SLK patients are often misdiagnosed or are not diagnosed for many years, because superior conjunctiva is frequently not examined or clinical findings are often missed.

A diagnosis of SLK should only be made after a thorough patient history is obtained and physical examination is performed, since diagnosis is based primarily on the clinical findings.

Clinical examination:

It requires slit-lamp (bio-microscopy) examination by an eye-specialist.

Conjunctiva/Limbus:

It is advisable in suspected SLK patient to simultaneously elevate both upper lids and look at the superior conjunctiva.

• Conjunctival injection: Conjunctival injection is best examined with un-aided eye. The classical finding associated with SLK is superior bulbar conjunctival injection. The superior bulbar and limbal conjunctiva shows sectoral congestion in the form of radial band. Vital stains, such as rose Bengal or lissamine green are the most effective way to highlight abnormal conjunctiva. These stains are especially useful in cases where the conjunctival injection may be subtle. It is important to note that vital staining of the superior bulbar conjunctiva does not guarantee a diagnosis of SLK.
• Limbal papillary hypertrophy: There may be limbal papillary hypertrophy.
• Loss of superior limbal palisades: Normally present limbal palisades of Vogt may be lost superiorly.
• Redundancy of the superior bulbar conjunctiva: Light downward pressure on the upper lid results in a fold of redundant conjunctiva crossing the upper limbus.

The thickening and hyperaemia of bulbar conjunctiva extends from upper limbus towards the insertion of the superior rectus muscle.

• Superior conjunctival filaments.
• Papillary reaction on superior tarsal conjunctiva: The papillae on superior tarsal conjunctiva are fine, small and numerous and often have a diffuse velvety appearance.
• Petechial haemorrhages: Petechial haemorrhages may be present.
• Keratinisation: Keratinisation may be demonstrated on biopsy or impression cytology of conjunctiva.

The inferior tarsal conjunctiva is typically normal.

Cornea:

• Punctate epithelial keratitis: The superior cornea is involved in one-fourth to one-third cases and shows fine epithelial staining as punctate epithelial keratitis with fluorescein sodium or rose Bengal dye. Lesions of punctate epithelial keratitis are often separated from the limbus by a zone of normal epithelium.
• Micropannus: Mild superior micropannus (superficial fibrovascular proliferation that extends 1-2 mm beyond normal vascular arcade) may be present in patients with long-standing disease.
• Superior corneal filaments: The presence of filaments on the superior cornea should alert to the diagnosis of SLK, as this is the most common cause of the finding.
• Corneal hypoesthesia: Corneal hypoesthesia is also sometimes present.
• Keratoconjunctivitis sicca: Keratoconjunctivitis sicca may be present in about half the cases of SLK.

Pseudoptosis:

• Inflammatory pseudoptosis: Inflammatory pseudoptosis (drooping of upper eyelid) may be seen in advanced cases.

Key to the diagnosis:

Key to the diagnosis of SLK is the examination of superior bulbar conjunctiva by:

• Elevation of upper lid: Elevate upper lid to examine superior bulbar conjunctiva. It is prudent to include lid elevation as part of the eye examination. The diagnosis of SLK is missed if the upper lid is not elevated.
• Assessment of superior bulbar conjunctival injection: Superior bulbar conjunctival injection may be subtle. Subtle findings may go unrecognised, if superior conjunctiva is examined with the bio-microscope on high magnification only.

Histopathology:

Biopsy of superior bulbar conjunctiva generally shows keratinised epithelium as well as cellular infiltration (polymorphonuclear leukocytes, lymphocytes and plasma cells). Along with this, it shows acanthosis, dyskeratosis and balloon degeneration of some nuclei. The demonstration of these features on diagnostic scrapings of the superior bulbar conjunctiva stained with Giemsa, helps in diagnosis of doubtful cases.

Electron microscopy shows abnormal distribution and aggregation of nuclear chromatin, filaments in nuclei, dense accumulations of cytoplasmic filaments that surround nuclei, and formation of multi-lobed nuclei or multi-nucleated inflammatory cells.

Palpebral conjunctiva is normal but polymorphonuclear cells are often present.

Wright (Wright P: Superior limbic keratoconjunctivitis. Trans Ophthalmol Soc UK 92: 555, 1972) has stressed on the goblet cell population in SLK. Superior palpebral conjunctiva shows goblet cell hypertrophy, while bulbar conjunctiva which is thickened and keratinised shows very few goblet cells.

Diagnostic procedures:

• Test for redundancy of the superior bulbar conjunctiva: The redundancy of the superior bulbar conjunctiva can be demonstrated by using a cotton-tipped applicator to pull the conjunctiva down over the superior cornea, under local anaesthesia. This is not possible with normal conjunctiva.
• Impression cytology: Impressions of superior bulbar conjunctiva show severe squamous metaplasia, with a relative absence of goblet cells. Impressions of the superior tarsal conjunctiva show mild squamous metaplasia with inflammatory cells, while impressions of the inferior tarsal conjunctiva are essentially normal. Impression cytology aid in diagnosis, but is rarely necessary.
• Confocal microscopy: Confocal microscopy is used as an adjunctive diagnostic tool when SLK is suspected clinically. Two variables studied were mean individual epithelial cell area (MIECA) and nucleocytoplasmic (N/C) ratio. As compared to normal controls, SLK patients showed a significantly increased MIECA and a decreased N/C ratio. In addition, inflammatory cell density in SLK patients was increased, compared to controls.

Superior limbic keratoconjunctivitis should be differentiated from the conditions such as:

• Contact lens wearers: It is believed that contact lens preservative thiomersal exposure is responsible for contact lens induced changes like SLK. Only a small percentage of contact lens wearer shows keratinisation and filaments and a good number of patients had decreased vision and had more diffuse inflammation of the bulbar conjunctiva than is seen with SLK. The punctate epithelial keratitis is also more than what is observed in SLK. Contact lens-related change soon disappears with the cessation of their usage. SLK has got a very chronic course with periods of remissions and recurrences.
• Allergic conjunctivitis.
• Keratoconjunctivitis sicca.
• Epidemic keratoconjunctivitis.
• Trachoma.
• Dysthyroid ophthalmopathy.
• Episcleritis.
• Floppy eyelid syndrome.
• Viral conjunctivitis.]

Management should be carried out under medical supervision.

Medical therapy:

Initially, topical medical treatment should be attempted.

• Artificial tears: Aggressive lubrication with artificial tears (preservative-free may be preferred) of the ocular surface may be done, either alone or in conjunction with occlusion of lacrimal punctum. It reduces friction between the tarsal and bulbar conjunctiva.
• Acetylcysteine: Acetylcysteine breaks down filaments and provide lubrication to the ocular surface.
• Rebamipide: Rebamipide, a mucin-inducing and secretion-promotive eye drop has shown promising results.
• Autologous serum tears: Autologous serum tears may be more beneficial than artificial tears, providing objective and subjective improvement, but it requires more frequent instillation during the day.
• Topical corticosteroids: Topical corticosteroids may produce symptomatic improvement in some cases, but the overall results have been variable. Corticosteroids may be best used in short intensive courses with rapid tapering, and should be reserved for severe cases.
• Topical cyclosporine A: Topical cyclosporine A, an immune-modulator, may have very good success with resolution of symptoms in patients. It may be used as primary or adjunctive therapy, particularly in the presence of co-existing keratoconjunctivitis sicca. However, maintenance therapy is required for continued benefit.
• Retinoic acid: Retinoic acid retards keratinisation.
• Topical mast cell stabilisers: Topical mast cell stabilisers inhibit type I immediate hypersensitivity reactions and are used for long-term inhibition of inflammation (e.g. lodoxamide tromethamine and sodium cromoglycate).
• Topical ketotifen fumarate: Topical ketotifen fumarate , a mast cell stabiliser and selective H1-blocking antihistamine (dual acting drug), addresses any inflammatory component and help in resolution of symptoms; but objective signs do not always improve.
• Topical vitamin A: Topical vitamin A also helps in resolution of symptoms.
• Supra-tarsal triamcinolone injection: When topical treatment is unsuccessful, injection of medication may break the inflammatory cycle. Supra-tarsal triamcinolone injection decrease symptoms and corneal/ conjunctival staining.
• Large-diameter contact lenses: Chun and Kim used large-diameter contact lenses to decrease trauma to the superior bulbar conjunctiva, and hence, improved symptoms. In addition, injection of botulinum toxin A in pre-tarsal orbicularis muscle further improved results (Chun YS, Kim JC. Treatment of superior limbic keratoconjunctivitis with a large-diameter contact lens and botulium toxin A. Cornea 2009; 28: 752-758).

Surgical therapy:

Hallmark of SLK is redundancy of the superior bulbar conjunctiva. Different methods have been employed to attempt to tighten the redundant superior bulbar conjunctiva.

Tightening procedures for redundant superior bulbar conjunctiva:

• Silver nitrate: Initial attempts with silver nitrate were effective, but severe ocular burns may result, especially when using a solid applicator. Silver nitrate application usually results in relief of symptoms for 4 to 6 weeks. Any residual remnant of silver nitrate is irrigated after a minute. It may be reapplied in cases with recurrence of disease.
• Cryotherapy: Liquid nitrogen cryotherapy as a single application or repeated for recalcitrant cases is a safe and effective therapy, using the double freeze-thaw technique under topical anaesthesia.
• Thermocautery: Use of thermocautery to tighten the superior bulbar conjunctiva may result in resolution of symptoms with increase in density of goblet cells.
• Conjunctival fixation sutures: Conjunctival fixation sutures placed in superior fornix, results in complete resolution of symptoms as well.

Resection of the superior bulbar conjunctiva: Resection of the superior bulbar conjunctiva is used in cases where medical treatment and/or conjunctival tightening are not successful. This technique has been most successful, predictable and usually gives immediate as well as permanent relief of symptoms. This is the preferred and initial surgical treatment. Conjunctival resection alleviates symptoms and results in resolution of squamous metaplasia of conjunctiva. In rare cases, redundant conjunctiva can recur, necessitating further conjunctival resection or application of silver nitrate.

Temporary superior and/or inferior punctal occlusion: Temporary superior and/or inferior punctal occlusion may be done for concomitant lacrimal insufficiency, and it may be combined with instillation of artificial tears.

Management of associated thyroid dysfunction may improve SLK.

Prognosis:

In general, prognosis for superior limbic keratoconjunctivitis is excellent. With increasing age, exacerbations tend to diminish in frequency with eventual total resolution, though symptoms may last for years.