By Louise A. Sclafani, OD
COPE Certificate 10603-AS, Expires December 1, 2006
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As optometrists, we have the opportunity to play an important role in maintaining good vision by making the correct diagnoses and initiating appropriate treatment for patients with corneal dystrophies and degenerations.
Regardless of practice emphasis, optometrists will likely encounter the corneal dystrophies and degenerations that are discussed in this course. Those involved at the primary care level may be the first to diagnose a sight-threatening condition and prevent vision loss with the aid of minor procedures or medical intervention. Those who specialize in contact lenses may be able to postpone or even prevent surgical intervention and can help with visual rehabilitation following corneal transplantation. The pediatric optometrist may make the initial diagnosis of a corneal dystrophy, and those involved with low vision may be called upon to provide optical aids for patients with otherwise untreatable degenerations or dystrophies.
After an initial orientation to the terms dystrophy and degeneration, this course will consider major degenerations and dystrophies that occur in the individual corneal layers. Management modalities will also be presented.
CORNEAL DEGENERATIONS VERSUS DYSTROPHIES
Although there is some crossover between the classifications of dystrophy and degeneration, there are certain characteristics inherent to each of these entities.
Dystrophies are primary, inherited corneal diseases that occur without prior disease or associated systemic disease. Many of the dystrophies are inherited through an autosomal dominant mode. This means that a patient's parent usually has the dystrophy and each child has a 50% chance of acquiring it. However, because some of the dystrophies vary in their penetrance and expressivity, the dystrophy may skip generations and then show up later, seemingly out of the blue.
Dystrophies are usually bilateral and symmetric. Most corneal dystrophies are progressive and have an early onset. To properly diagnose a dystrophy, it is necessary to rule out any scarring or inflammation from trauma that can sometimes mimic the appearance of a dystrophy.
In contrast, corneal degenerations are often associated with systemic diseases, which makes a careful medical history essential in these cases. Degenerations are usually unilateral, but, if bilateral, they can be asymmetric. They can manifest centrally or peripherally on the cornea. Degenerative changes are due to inflammation, aging, or systemic disease and can result in thinning, vascularization, or deposition of material into corneal tissue.
CORNEAL EVALUATION
The cornea has either 5 or 6 layers, depending on whether Bowman' is considered a separate layer. The outermost layer is a stratified, squamous epithelium. The outermost cells of this layer are connected by tight junctions that prevent the movement of tears into the stroma. The epithelium makes the next layer of the cornea, the basement membrane. This layer helps to provide adherence between the epithelium and the stroma.
The next layer is Bowman's. This layer is acellular, being composed of the same constituents of the stroma, only more condensed and tightly packed. Bowman's layer is very tought and helps to prevent foreign bodies from entering the stroma.
The next layer is the stoma. It is composed primarily of collagan fibers separated by glycosaminoglycans. The stroma needs to stay relatively dehydrated in order to maintain transparency.
Decemet's layer is next. It is the basement membrane of the endothelial cells and is constantly being produced by them. This means that Decemet's layer thickens throughout life.
The innermost layer is the endothelium. It is a single layer of cells with two functions: it maintains the barrier between the stroma and aqueous, and it contains pump mechanisms that move water from the stroma into the aqueous.
Corneal Cross Section (Slide produced by Neil VanderHorst)
Most commonly, the slit lamp is used to evaluate corneal integrity. Besides the slit lamp, other techniques can be used to assess the cornea. Confocal microscopy gives a more precise look at the corneal layers and can aid in the identification of epithelial and stromal deposits. Corneal topography is readily available and can give a useful evaluation of surface irregularities. A corneal pachymetry can measure corneal thickness. Evaluating pathology specimens harvested from corneas and stained with special dyes can aid in diagnoses of corneal problems. The potential for using optical coherence tomography to evaluate the cornea is promising and can be very helpful in making diagnoses. Special lenses and cameras are available to make specular reflection evaluation of the posterior surface possible. Electron microscopy offers very detailed views of all layers, but this method is not readily available in practice settings and requires removal of full thickness corneal specimens.
MANAGEMENT OF CORNEAL DISEASE
Treatment of corneal disease usually begins with topical management, however if the conditions involve deeper layers of the cornea, medical procedures or surgical intervention may be needed. Because degenerations may be associated with systemic diseases, these conditions must often be managed in cooperation with non-optometric specialists.
With this as a brief introduction, let us now begin our journey through the layers of the cornea
THE EPITHELIUM
The most superficial corneal layer is the epithelium. This 50 um thick layer functions to help keep the corneal stroma relatively dehydrated and thus transparent, to protect the other corneal layers, and to provide an external disease barrier.
The normal corneal epithelium has 5 to 6 layers of non-keratinized, stratified squamous cells centrally with 8 to 10 layers peripherally. The function of the most superficial aspect of the epithelium, the microvilli of the squamous cells, is to bind the mucous layer of the tear film, and thus the entire tear film, to the cornea. Any defects in the microvilli will produce dry eye problems. Ocular surface diseases such as keratitis sicca, allergic conjunctivitis, and blepharitis can mimic epithelial dystrophies and degenerations, so it is imperative to rule out these conditions and treat them appropriately before making a diagnosis of corneal degeneration or dystrophy
The function of the deepest layer of the epithelium, the basement membrane of the columnar basal cells, is to firmly attach the epithelium to the stroma via hemidesmosomes.
Epithelial Basement Membrane Dystrophy (EBMD)
This frequently encountered corneal dystrophy is also call map-dot-fingerprint dystrophy. In this condition, there is abnormal turnover, maturation, and production of the basement membrane, so adhesion complexes do not form properly and the epithelial attachment to the stroma is weakened.
Epithelial Basement Membrane Dystrophy Shown With Fluorescein Stain
Based on slit lamp appearance, several forms of epithelial basement membrane dystrophy are seen. Maps, the most common pattern, appear as diffuse grey patches with sharp margins that resemble the outlines of states or countries. They represent thickening of the basement membrane due to collagen formation. The tears over map areas break up rapidly so fluorescein helps to outline areas of mapping due to negative staining.
Photographically Enhanced Map Shape Patterns (Modified from Catania L. Primary Eyecare Inc., 1984.)
Fingerprints are thin, translucent, hair-like lines often arranged parallel to one another, thus giving the appearance of fingerprints. They are caused by a thickened and reduplicated basement membrane.
Dots are cysts that form as a result of intra-epithelial tissue bending and trapping debris. Patients with cysts may report photophobia, dryness, or foreign body sensations as the cysts approach and erupt on the corneal surface. The disrupted surface can produce topographical irregularities that result in blurred vision or polyopia.
A subtle pattern of dots can be seen with white light, but it will become more apparent as an immediate negative staining pattern seen with fluorescein and a cobalt blue filters.
The cysts allow debris to build-up and this creates a poor substrate for epithelial attachment to the stroma, which results in more dis-adhesion.
Recurrent Corneal Erosions
Because epithelial basement membrane dystrophy causes a weakened attachment of the epithelium to the stroma, blinking can tear off patches of the epithelium. When this occurs, we refer to the disrupted epithelium as a corneal erosion. Although many patients do not report acute symptoms with endothelial basement membrane dystrophy, a corneal erosion typically results in significant discomfort. The erosion usually occurs upon waking due to the physiologic corneal edema that occurs at night under closed-eye conditions and to mechanical shearing across the cornea when the lids are first opened.
Corneal erosion becomes recurrent when associated with epithelial basement dystrophy because the dystrophy causes the basement epithelial membrane to thicken and the hemidesmosomes to form poor attachments to the stroma. This results in incomplete healing between erosions.
Initial treatment for corneal erosions is similar to that for traumatic corneal abrasions. However, recurrent corneal erosions tend to take longer to heal and the patient reports a higher level of discomfort. Specific treatment is based on the disease severity and can include lubricants, hypertonic solutions, hot packs, bandage contact lenses or pressure patches, cycloplegics, and prophylactic antibiotics.
Because the erosions recur, patients must be treated prophylactically with lubricants, especially at night, and are told to seek care when early symptoms of erosion are detected. To prevent further erosion and damage, aggressive treatment such as anterior stromal puncture, oral antibiotic therapy, corneal debridement, and photokeratectomy will often be needed.
Meesman’s Epithelial Dystrophy
Meesman’s Epithelial Dystrophy (also known as Juvenile Epithelial Dystrophy) can develop as early as 6 months of age and produces cysts that contain a “peculiar substance” specific to this dystrophy. The substance includes debris, degenerating epithelial cells, and glycosaminoglycans. The clear, round, uniform-sized epithelial cysts extend from limbus to limbus but are more concentrated in the intra-palpebral region. They are easily viewed with retro-illumination and resemble contact lens-induced microcystic edema.
Meesman’s Epithelial Dystrophy (Modified From Spalton DJ, Hitchings RA, Hunter PA. Atlas of Clinical Ophthalmology, 1st ed. Lippincott, 1984.)
Cysts can produce symptoms of photophobia and lacrimation as they erupt on the corneal surface; however acuity is typically not affected except in the elderly who may experience opacification due to the cysts.
Treatment of Meesman's is palliative and does not include surgical intervention because the condition will recur following epithelial scraping or penetrating lamellar keratoplasty.
Thygeson’s Superficial Punctate Keratitis
Thygeson's is a bilateral recurrent disorder with corneal epithelial lesions that are often misdiagnosed as subepithelial infiltrates due to their similar appearance. The typical Thygeson's patient is female between the ages of 15 and 40 years.
Thygeson's Keratitis. Left - Punctate Corneal Lesions Stained with Rose Bengal. Right - Epithelial Opacities shown at Higher Magnification. (Modified From Spalton DJ, Hitchings RA, Hunter PA. Atlas of Clinical Ophthalmology, 1st ed. Lippincott, 1984.)
The discreet focal lesions (usually between 12 and 20) seen in Thygeson's are typically located centrally, and are gray-white, slightly elevated, and epithelial. The lesions stain variably with fluorescein but appear to be slightly raised. They come and go and can change locations quickly. The conjunctiva is never inflamed as a result of Thygeson's.
Symptomatic patients may report photophobia, foreign body sensation, slightly reduced visual acuity, and/or epiphora.
It has been postulated that there may be a viral origin for Thygeson's, so the use of Viroptic could be beneficial. Steroids really only prolong the course of the occurrence, but some practitioners prescribe them to improve acuity in severe cases. If steroids are used, careful monitoring is required because herpes simplex can have a variety of appearances that occasionally mimic Thygeson's.
Palliative treatment with lubricants and punctal occlusion is the standard of care. Bandage contact lenses can help, but they can also cause exacerbations. It is interesting that there are many contact lens wearers who present with Thygeson's and the doctor's first instinct is to discontinue lens wear. However, lenses can be beneficial in the management of these patients and continued lens wear should be considered.
Treatment Options for Epithelial Dystrophies and Degenerations
Artificial Tears
Someone once said that artificial tear solutions and ointments can be used to treat almost any patient with a corneal problem, either because of the placebo effect or because most people with cornea-related complaints have an underlying dry eye problem anyway.
Because instillation is so frequent when treating diseased corneas, it is preferable to use non-preserved products (e.g., Bausch and Lomb Moisture Eyes and Allergan Refresh Plus) to reduce potential cytotoxic effects.
Alternatively, some of the transiently preserved formulas (e.g., Allergan Refresh Tears) that lose their preservative effects upon instillation may also be effective. However, these products require a certain tear volume to break down the preservative, and often this quantity is missing for patients with dry or diseased eyes.
Preparations are now being developed with preservatives that are activated only upon the presence of pathogens, and these would provide the ultimate in protection and safety.
It is logical that artificial lubrication should provide the necessary electrolytes such as sodium, potassium, calcium, and magnesium to help heal the eye more effectively.
The artificial tear solution or ointment medium is also important. Typically, patients enjoy longer relief with gels but they typically prefer the non-blurry effect of liquids. (Ointments are contraindicated in the presence of corneal edema because they are hypotonic and can exacerbate the edema.)
Autologous Serum Therapy
This can be likened to personalized tear replacement in which the patient's own serum (i.e., blood devoid of cells and clotting factors) is formulated into a topical supplement. These customized "artificial" tears contain epithelial growth factors, vitamin A, anti-proteases, and fibronectin to aid in the healing process. A 40 ml blood sample can be drawn to produce a three-month supply of tears that have natural bacteriostatic characteristics.
Hypertonic Agents
When corneal conditions result in edema, epithelial stroma attachments are not firmly formed. To reduce edema and promote better adhesion complexes, hypertonic agents consisting of a 2% solution of sodium chloride or a 5% solution or ointment can be used (e.g., Adsorbonac, Muro 128). Hypertonics should be used when an epithelial cover is fully formed or at least almost fully formed because these agents cause pain when instilled over an open epithelium.
Hypertonic agents can be instilled at bedtime and again in the morning. Patients should be warned that the 5% solution usually stings, but refrigeration can make instillation more comfortable. The evening dose should be in ointment form to increase contact time and improve comfort.
Punctual Occlusion
Tears are rich in buffering agents that contain nutrients and natural defense agents, all of which can provide an environment that aids in healing of the epithelium. To help retain the tears, punctal occlusion can be used.
There are many punctal plugs available on the market, including those made of thermodynamic polymers that can be conformed to the patient’s punctum shape and size. Because of the potential for “customized fits” and reduced loss, new materials and plug designs promise to revolutionize punctual occlusion and greatly increase its popularity.
However, punctal occlusion might not be appropriate for all patients. For those with ocular surface disease that might be caused by an inflammatory process, punctal occlusion would not be beneficial. If circulating cytokines from the inflammation are present in the tear layer and are not washed out, further irritation and inflammation can occur.
Adverse reactions to punctal plugs can also include an allergic reaction to silicone that can lead to discomfort. Additionally, the plug can migrate into the canulus and lead to the development of a pyogenic granuloma, or it can pull out of the punctum and become lost. This can cause significant frustration, especially for the uninsured patient. The availability of different size plugs, along with better ways to determine the correct size before insertion, have helped reduce the occurrence of punctal plug loss.
Bandage Contact Lenses
Corneal dystrophies and degenerations may benefit from the use of bandage contact lenses. There are many reasons to include bandage contact lenses in the treatment regimen.
Bandage contact lenses:
The ideal bandage lens should:
Higher water content lenses tend to aid in corneal dehydration and can facilitate drug delivery by releasing the agent slowly onto the corneal surface. Full corneal coverage of the lens and minimal movement are required to avoid disrupting the healing process.
Presently, disposable silicone hydrogel lenses are a treatment of choice. They provide six times more oxygen transmissibility than standard disposable lenses and fluorescein can be used, if needed, without degrading the lens. However, these lenses can be uncomfortable for some patients.
Corneal Occlusion With the Lid
If the corneal condition does not allow bandage lens use, the lid itself can be used as a bandage because it provides natural protection, adequate pressure, and blood circulation for oxygenation and possible nutrient delivery.
Tape can be used to hold the lids together, however the use of Stamler Lid Splints (EagleVision, Memphis TN) can be more efficient.
Stamler Lid Splint
Splints have adhesive on one side and enough rigidity to hold the eyelid in a closed position. They are unobtrusive, inexpensive, and can be easily and safely applied by the patient. Splints also allow easy examination of the eye and instillation of drops.
When bandage lenses and closure with tape or splints do not work, a tarsorraphy may be required in which the palpebral fissure is fully or partially closed by suturing the superior and inferior lids at the lateral aspect. Plastic clips can also be attached to prevent tearing of the lids. Although these allow daily inspection of the cornea, most patients prefer not to have to have this done.
Anterior Stromal Puncture
Anterior stromal puncture is a technique in which a needle is used to create small punctures in the epithelial-stromal junction. This is accomplished by using a 27-gauge needle with a bent tip to puncture the cornea to about the depth of the anterior stroma (0.2 mm). The purpose of anterior stromal puncture is to disturb the epithelium and Bowman’s layer thus providing a stimulus for the formation of tighter adhesions. The punctures will produce minor scarring so the visual axis should be avoided when performing this procedure.
Anterior Stromal Puncture Needle and Procedure (From Casser L, Fingeret M, Woodcome HT. Atlas of Primary Eyecare Procedures, 2nd ed. Appleton & Lange, 1997.)
Oral Antibiotic Therapy
The tetracycline group of antibiotics has been found to have other actions beyond their antibiotic properties. Recently, it has been shown that patients with recurrent corneal erosions show a chronically increased level of metallo-proteinase enzymes (specifically MMP 2 and 9). These enzymes dissolve the basement membrane and fibrils of the hemidesmosomes. Dursan and Plugfelder have shown that doxycycline taken orally (50mg BID) for at least 2 months reduced MMP activity levels by 70%.
Corneal Debridement
Recurrent corneal erosions and other conditions that affect the anterior cornea from the epithelium to Bowman’s layer may benefit from corneal debridement. This technique involves softening the epithelium with a topical anesthetic and then using a cotton swab, spatula, spud, or jeweler's forceps to remove flaps of epithelium by pulling their edges toward the center. This creates a uniform insult anterior to Bowman's membrane with tight, firm edges. A corneal epithelial defect twice as large as the originally affected area should result, but debridement acts as a stimulus to healing in an efficient manner and this dramatically reduces the recurrence rate.
Photokeratectomy
Another treatment to enhance epithelial stroma attachment in recurrent corneal erosions is phototherapeutic keratectomy. The objective of phototherapeutic keratectomy is to remove enough of the superficial Bowman’s layer to permit formation of a new basement membrane with adhesion structures.
The usual technique is to debide the epithelium manually. Then the anterior stromal surface (Bowman’s layer) is ablated with an excimer laser using a large (e.g., 6.5 mm) spot. The depth of tissue to be ablated is selected to maximize the effect with minimal refractive change. Typically this depth is between 2 and 10 um.
After the laser ablation, a bandage contact lens with prophylactic antibiotic is used until epithelialization is complete. Patients are then instructed to continue aggressive lubrication, including nightly applications of ointment for several months.
Recurrent erosions are the most common indication for phototherapeutic keratectomy and several studies show that this procedure can improve acuity and heal the corneal so that the recurrence rate of the erosions is significantly reduced.
Superficial Keratectomy
Superficial keratectomy involves surgical removal of subepithelial fibrous tissue and/or anterior cornea opacities. The indications are the same as for phototherapeutic keratectomy, e.g., anterior cornea dystrophic and degenerative conditions. However, because the laser treatment provides an optically smooth surface and can remove deeper cornea opacities, phototherapeutic keratectomy has become the treatment of choice.
ANTERIOR STROMA (BOWMAN’S LAYER)
Moving through the cornea, the next structure that we encounter is Bowman’s layer, an 8 to 14 micron thick layer of modified stromal collagen. The function of this layer is in question because many primates and post-photo-refractive keratectomy patients lack the layer but still have normal visual acuity with no evidence of swelling. However, if this layer is diseased or damaged in certain ways, severe scarring and vision loss can result. The following dystrophies and degenerations affect the anterior stroma (Bowman’s Layer).
Reis-Buckler Dystrophy
Reis-Buclker is a symmetrical bilateral autosomal dominant condition that manifests at about 5 years of age and can cause significant acuity loss by the age of 20 years. Initially, the cornea shows an irregular epithelium with diffuse, irregular patchy geographic opacities at the level of Bowman’s layer. With time, central opacities develop as a reticulated or honeycomb pattern spreads into the midperiphery along with a diffuse, superficial stromal haze. Concomitant abnormalities in the epithelial basement membrane account for painful recurrent corneal erosions. Marked acuity loss is typically due to superficial stromal haze.
Reis-Buckler Dystrophy (Modified From Spalton DJ, Hitchings RA, Hunter PA. Atlas of Clinical Ophthalmology, 1st ed. Lippincott, 1984.)
A superficial keratectomy is helpful in managing the visual aspects of this disorder and should be attempted before penetrating keratoplasty is suggested. Recurrences after keratoplasty have occurred.
Honeycomb Dystrophy
This condition might be a variant of Reis-Buckler Dystrophy, but the corneal surface remains smooth and the patient maintains normal corneal sensitivity.
Anterior Mosaic Dystrophy/Degeneration
Anterior mosaic dystrophy/degeneration (AKA, Grayson-Wilbrandt Disease) produces breaks in Bowman’s layer that resemble the skin of a crocodile with gray-white opacities in a polygonal pattern with clear intervening spaces. Its late onset suggests that it is a degeneration rather than a dystrophy. Most patients with anterior mosaic dystrophy/degeneration are asymptomatic.
Anterior Mosaic Dystrophy
Band Keratopathy Degeneration
Band Keratopathy is the result of calcium salt deposition in the inter-palpebral region of the epithelial basement membrane, Bowman’s layer, and the superficial stroma. It generally starts at the periphery, both nasally and temporally, and then spreads centrally. A lucid interval separates the calcific band from the limbus.
Band Keratopathy
Band keratopathy occurs secondary to chronic ocular inflammation or systemic disease. It often affects patients with a history of uveitis, interstitial keratitis, prolonged glaucoma, long-standing corneal edema, or severe corneal injury. The chronic anterior uveitis of juvenile rheumatoid arthritis is also frequently associated with band keratopathy. Systemic disease associations include hypercalcemia caused by such conditions as hyperparathyroidism and vitamin D toxicity as well as the elevated serum phosphorus found in kidney failure. Gout can also cause band keratopathy.
The use of a chemical to chelate (bind) calcium and pull it out of the epithelial tissue has been used to treat band keratopathy. A preparation of 2% or 3% EDTA applied with a wick cell sponge to the de-epithelialized cornea can aid in decreasing the amount of calcium that is causing opacification.
Band Keratopathy Following Chelation Treatment
Other treatments include superficial keratectomy, phototherapeutic keratectomy, and penetrating keratoplasty.
When the calcium density has become so severe that vision is reduced to light perception, cosmesis and comfort become the goals of treatment. In this case, the role of the optometrist may be to design cosmetic lenses with a black under-print to mask the opacification and a top surface colored to match the fellow eye.
Salzmann’s Nodular Degeneration
Salzmann’s Degeneration is noninflammatory and creates elevated, smooth, bluish-white nodules, usually in the midperiphery. The nodules are typically associated with chronic keratitis and can follow phlyctenular disease, trachoma, interstitial keratitis from syphilis, or vernal disease.
This degeneration can cause minimal to extreme pain and acuity loss depending on the nodules location and severity. The nodules represent focal areas where excess collagen or hyaline material replaces Bowman’s layer leading to a destruction of the layer and subadjacent stroma.
Salzmann’s Nodular Degeneration (Modified From Spalton DJ, Hitchings RA, Hunter PA. Atlas of Clinical Ophthalmology, 1st ed. Lippincott, 1984.)
Treatment begins with lubrication and a bandage contact lens but may eventually require phototherapeutic keratectomy or a corneal transplant. Phototherapeutic keratectomy utilizing localized spot ablations has become a common treatment and can produce excellent results.
THE STROMA
The stroma is an avascular structure comprised of uniform layers of type I collagen with intervening keratocytes. It provides approximately 90% of the corneal thickness.
Although four-fifths of the stroma is comprised of water, relative dehydration must be maintained. The transparency of the cornea is controlled by the hydration state of the stromal proteins called glycosaminoglycans. When too much water is present, stromal edema occurs with resultant pain and acuity loss.
Many stromal dystrophies and degenerations are the result of abnormal substances accumulating within the keratocytes or collagen fibrils. Pathology specimens of the stroma show distinct and diagnostic staining patterns for the different corneal dystrophies.
Macular Dystrophy
Macular dystrophy is a rare autosomal recessive condition that is found predominately in the Virginia area of the United States. It represents a build-up of mucopolysaccharides; the lesions associated with this condition stain with Alcian blue.
Macular Dystrophy (Modified from www.eyesearch.com, 2003)
Macular dystrophy begins in the central region of the cornea during the first decade of life and then spreads aggressively to the limbus. The stroma becomes generally cloudy with superimposed dense, gray-white spots. Initially the lesions are in the superficial layers of the cornea, but with time they extend throughout the entire stromal thickness. Even the endothelium becomes involved with gutatta formation. As more of the stroma becomes involved in the dystrophic process, vision undergoes progressive deterioration. Because this condition can result in severe vision loss, management typically requires a penetrating keratoplasty.
Lattice Dystrophy
Lattice dystrophy is characterized by branching filaments of amyloid deposits in the stroma. The deposits stain with Congo Red and show birefringence when exposed to polarized light. Symptoms usually begin in the first decade of life with decreased acuity.
Lattice Dystrophy (Modified from insight.med.utah.edu)
Amyloid accumulation under the epithelium gives rise to poor epithelial-stromal adhesions so recurrent erosions are a part of this disease process. In time, the condition progresses to produce marked opacification of the axial stroma as well as the superficial corneal layers.
By 40 years of age or earlier, severe acuity loss and discomfort from the corneal erosions occur. Treatment of lattice dystrophy depends on visual acuity loss and patient discomfort. Penetrating keratoplasty carries an excellent prognosis for this condition.
Systemic amyloidosis may be associated with lattice dystrophy. Manifestations include progressive cranial and peripheral neuropathy and skin changes, such as thickened facial skin, protruding lips, and floppy ears. A systemic workup may be indicated along with genetic counseling for patients with lattice dystrophy.
Granular Dystrophy
Granular dystrophy is a relatively common autosomal dominant condition that is characterized by deposition of hyaline. The hyaline within the stromal tissue stains with Masson Trichrome.
Granular dystrophy manifests during the first decade of life as sharply demarcated, milky, opaque lesions resembling snowflakes or bread crumbs. The lesions are located in the axial portion of the superficial stroma. Between the dense opacities, the intervening cornea is characteristic clear.
Granular Dystrophy Before Treatment
Granular dystrophy does not require keratoplasty as often as the other familial dystrophies because visual acuity may be good if the clear spaces align with the visual axis. Some patients get a beneficial pinhole effect based on the pattern of lesions.
Recurrent erosions may occur when the basement membrane is involved, but this happens less frequently than in lattice dystrophy. If the lesions coalesce and occlude the visual axis, phototherapeutic keratectomy or penetrating keratoplasty may be necessary.
Granular Dystrophy After Phototherapeutic Keratectomy
Central Crystalline Dystrophy of Schneider
Central crystalline dystrophy is an autosomal dominant genetic disease that occurs early in life. The main feature of the disease is a bilateral, axial, ring-shaped corneal opacity consisting of cholesterol, lipid, and triglyceride deposits in Bowman’s layer and the anterior stroma. Acuity is much better than would be predicted by the appearance of the deposits. Both limbal girdle of Vogt and corneal arcus are associated with dystrophy.
It is important to perform cholesterol and lipid studies on these patients. However, because this can be a localized abnormality of cholesterol metabolism, many patients will have a normal serum lipid profile.
Corneal Arcus
Corneal arcus appears as a whitish ring on the peripheral cornea with a clear zone between it and the limbus. The white ring is an accumulation of cholesterol, triglycerides, and phospholipids. Arcus affects over 60% of the population between 40 and 60 years of age and can be associated with abnormal serum lipid profiles. Although bilateral arcus is a common finding, when it presents unilaterally a carotid workup is indicated to check for plaque deposits.
Corneal Arcus
Furrow Degeneration
Furrow Degeneration is a benign peripheral thinning in the clear zone of arcus. There is no associated inflammation; visual consequence and perforation are rare.
White Limbal Girdle of Vogt
The white limbal girdle of Vogt is another peripheral degeneration, affecting more then 50% of the population over 40 years of age. It is a white opacity in the medial and temporal limbal regions and may have a clear zone separating it from the limbus. In this condition, subepithelial degeneration occurs and calcium deposits may or may not be present. The degeneration is considered an aging change and has no ocular health or visual consequences.
Limbal Girdle of Vogt (Modified from Spalton DJ, Hitchings RA, Hunter PA. Atlas of Clinical Ophthalmology, 1st ed. Lippincott, 1984.)
Terrien’s Marginal Degeneration
Terrien's is a slow, painless, progressive thinning of the peripheral stroma that usually begins in the superior nasal quadrant and spreads circumferentially. It leaves the epithelium intact but may result in some vascularization of the gutter. A yellow border of lipid is characteristically present at the lesion's advancing edge. Therapy for Terrien’s Degeneration involves grafting to prevent or to repair perforation of thinned areas.
Optometric treatment should include compensation for the marked corneal astigmatism that typically results from this deterioration.
Mooren’s Ulcer
Mooren’s ulcer differs from Terrien’s marginal degeneration in that Mooren's is an autoimmune, inflammatory process producing a peripheral thinning with ulceration. The ulcer, which can produce from mild to severe pain, spreads circumferentially and centrally. Its leading edge often undermines the more central corneal stroma. The lesion usually resolves when it encompasses the entire cornea, but in younger blacks it can proceed centrally destroying the entire cornea and possibly causing perforation.
Mooren's Ulcer
Mooren's can be associated with autoimmune disease such as Crohn’s disease, previous surgery, trauma, or hepatitis C. Rheumatoid arthritis is also associated with ulcerative keratitis, but this is due to decreased tear production and limbal vascular compromise.
Mooren's ulcer can spread rapidly, so aggressive therapy may be indicated. Artificial lubricants, mechanical protection (such as tarsorrhaphy, conjunctival resection, and lid closure), and steroids have been the main treatment options. If perforation occurs, tissue adhesive or lamellar grafting may be necessary. Systemic immunosuppression may be of some value for patients with progressive disease.
Mooren's Ulcer Following Lamellar Keratoplasty in Which Only the Epithelium and Part of the Stromal Layer are Replaced
Treatment Options for Stomal Disease
Phototherapeutic Keratectomy
In the past, penetrating keratoplasty (full thickness corneal transplant) was the only option for many of the vision threatening stromal dystrophies and degenerations. However, use of photo-therapeutic keratectomy has now become more common. Using an excimer laser in the phototherapeutic keratectomy mode, central ablation of 3 to 6 mm can be performed to remove superficial opacities. This can markedly improve central corneal clarity and visual acuity.
Phototherapeutic keratectomy also produces a corneal flattening effect and a resultant hyperopic shift. This may be beneficial if the patient was initially myopic, but it may require refractive correction if significant anisometropia or hyperopia results.
After phototherapeutic keratectomy, subepithelial corneal haze can develop within several weeks. The haze peaks within 1 to 2 months and then resolves during the next 6 to 12 months. It is often asymptomatic, being more noticeable to the examiner than the patient. However, sometimes the haze can contribute to loss of best corrected visual acuity.
For conditions such as Salzmann’s nodular degeneration, smaller ablation spots are used to produce in a debulking effect and prevent hyaline from encroaching onto the visual axis.
Systemic Medications
Many corneal degenerations are associated with systemic conditions that cause inflammation. For example, Crohn’s Disease is a chronic inflammatory bowel disease that affects all layers of the bowel wall due to the presence of non-caseating granulomas. It is thought that there is constant stimulation of the mucosal and systemic immune systems by luminal bacteria secondary to a defective mucosal barrier. This produces a poorly regulated immune response causing an accumulation of acute and chronic inflammatory cells.
Up to 10% of Crohn's patients have ocular complications such as keratoconjunctivitis, infiltrative keratitis, uveitis, papillitis, retinal detachment, and macular edema presumably due to circulation of these antigen and antibody complexes.
When ulcerative keratitis due to Crohn's or other causes can no longer be managed with palliative lubricants and bandage contact lenses, topical steroids should be applied in conjunction with cycloplegia and prophylactic antibiotics (which also offer anticollagenolytic activity). Instillation should be frequent (QID to q 2 hours) depending on the severity; daily monitoring is required for these patients.
If the condition is not resolving, systemic steroids should be considered. A typical oral regimen consists of 60-100 mg prednisone daily. If the condition is still not resolving, immunosuppressive therapy (e.g., oral cyclo-phosphamide or methotrexate) can be considered. There are serious side-effects, such as anemia, alopecia, nausea, nephrotoxicity, and hepatotoxicity, to consider with these drugs so they are usually reserved for severe conditions that do not respond to other treatments.
Cyclosporine is available in a 0.05% emulsion that can be used for the treatment of dry eye. It is an immune modulator that inhibits T-lymphocytic activity thereby reducing chronic inflammation. It may, therefore, have the potential for use in the treatment of corneal diseases that have inflammatory components. Of note is its high level of safety as demonstrated by the fact that no detectable amounts of the cyclosporine are found in the blood following topical application.
DESCEMET'S LAYER AND THE ENDOTHELIUM
Descemet’s layer is produced by the endothelium and together they make up the deepest layers of the cornea. The endothelial cells contain a dehydration pump powered by the mitochondria found within the cytoplasm.
The normal aging process leads to thickening of Descemet’s layer and loss of half the endothelial cells by the time patients reach 60 years of age. Because the endothelial layer is only one cell thick and the cells are incapable of mitosis, the remaining cells spread out and thin to maintain a continuous layer. It is not clear whether the fluid pumping ability of endothelial cells is affected by this thinning.
Many of the diseases found within Decemet's and the endothelial layers are associated with the ageing process, however a genetic predisposition makes them classifiable as dystrophies.
Posterior Polymorphous Dystrophy
Posterior polymorphous dystrophy is an autosomal or recessive condition characterized by polymorphous vesicles located at the level of Descemet’s membrane. Numerous histologic studies have demonstrated endothelial cells that morphologically and immunopathogically resemble epithelial cells. Therefore, abnormal developmental differentiation of the endothelial cells has been suggested as a cause of this condition.
Posterior Polymorphous Dystrophy. Left – Generalized corneal opacity. Right – profound endothelial cell depletion and many other abnormal features. (Modified from Spalton DJ, Hitchings RA, Hunter PA. Atlas of Clinical Ophthalmology, 1st ed. Lippincott, 1984.)
This dystrophy can be stationary or slowly progressive so that patients may not notice any visual symptoms. If significant endothelial decompensation with resultant stromal edema occurs, a keratoplasty may be required.
Fuch’s Dystrophy
Fuch's is a bilateral, asymmetric condition that begins in the fifth or sixth decade of life and is more common in women. Guttata, which are deposits on Descemet’s membrane produced by the endothelium, are characteristic of this dystrophy. With biomicroscopy, the guttata appear to be bubbles but using specular reflection they appear like black areas on the endothelial mosaic.
Fuch’s Dystrophy. Top – Ground glass appearance of the guttata. Bottom – guttata seen as black areas in specular reflection. (Modified from Spalton DJ, Hitchings RA, Hunter PA. Atlas of Clinical Ophthalmology, 1st ed. Lippincott, 1984.)
Guttata stretch the endothelial cells and interrupt the normal pumping mechanism. The compromised endothelial hydration pump permits aqueous fluid to enter the cornea causing stromal and epithelial edema with bullae formation. Consequences of this process include decreased acuity from the edema, pain from ruptured bullae, and subepithelial scarring.
Corneal Edema Associated with Fuch's Dystrophy
Treatment is palliative. It can include anti-glaucoma agents and hypertonic solutions to reduce edema, and bandage contact lenses to relieve patient discomfort. Penetrating keratoplasty may be required for restoration of patient comfort and visual function.
Treatment Options for Descemet’s Layer And Endothelial Diseases
Corneal Transplant
For some patients, there comes a time when a corneal transplant is indicated. There are several types of transplant procedures, most requiring the use of healthy human donor tissue.
Depending on the disease, the transplant may require a full thickness penetrating keratoplasty or a lamellar keratoplasty in which only the epithelium and part of the stromal layer are replaced. The latter procedure offers less risk for rejection, glaucoma, and endophthalmitis.
The entire cornea may be replace or just a specific area. For example, a doughnut shaped tissue section can be used to replace sclera and limbal stem cells in the case of peripheral marginal disease.
Finally, a keratoprosthesis may be required. This artificial mechanical implant is reserved for multiple graft failures and is used largely as last resort therapy.
CONCLUSION
This ends our journey through the cornea and a review of the more “common” dystrophies and degenerations that affect these layers. Selected treatment strategies have been described for most of the diseases, but their application will vary based on prescribing authority andlevel of comfort for each individual optometrist.
Each of us may have the "benefit" of seeing only a few of the corneal degenerations and dystrophies in our careers, but the medical model says, “see one, do one, teach one.” Hopefully some of the illustrations and descriptions in this course will count as your “see one” and your first “do one" treatment will be challenging, yet rewarding.
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Note: Some of the material and photos presented have been re-formatted from previous publications by the same author: Corneal Degenerations and Dystrophies, Contact Lens Spectrum, August 2003 and Corneal Degenerations and Dystrophies: Diagnosis and Treatment, BCI Vision Care CE Online Continuing Education
Contact this author:
Louise A. Sclafani, OD, FAAO, Associate Professor of Clinical Ophthalmology University of Chicago Center for Advanced Medicine 5758 S. Maryland – MC 9005 Suite 1B, Chicago, Illinois 60637 lsclafan@bsd.uchospitals.eduPacific University College of Optometry provides On-Line CE as a service to optometrists. The college does not endorse or recommend any products, equipment, or services that might be discussed in the courses. Courses are prepared by individuals believed to be experts in their areas of specialization who are compensated for their efforts. The College relies on their expertise to produce accurate and timely courses. Questions or concerns about courses should be directed to the individual authors and/or the Continuing Education Department at the College of Optometry at kundart@pacificu.edu .
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