Corneal Degenerations and Dystrophies
Degenerations and dystrophies: Learn their telltale signs and symptoms and how to diagnose and treat them.
BY LOUISE SCLAFANI, OD, FAAO

Whatever your practice mode, you will likely encounter patients who have corneal dystrophies and degenerations. Primary care practitioners may be the first to diagnose a sight-threatening condition and to minimize or prevent vision loss with the help of appropriate intervention or procedures. Contact lenses may defer surgical intervention or help rehabilitate vision following surgery.

To identify various corneal conditions, you must be comfortable with differentiating normal corneas from abnormal corneas. It is essential to understand the various layers of the cornea and to keenly observe patients. This article will help you distinguish between corneal degenerations and dystrophies, overview corneal anatomy, describe specific corneal conditions and discuss the use of bandage contact lenses (BCLs) and lubrication techniques.

Degenerations vs. Dystrophies

Degenerations are tissue changes that cause deterioration and may impair function. They may result from a specific disease or simply from aging. It is rare for degenerations to stem from family history or genetic disposition. Because corneal degenerations are commonly associated with systemic diseases such as rheumatoid arthritis, syphilis and Crohn's disease, make sure you take a careful medical history. Degenerations are usually unilateral, asymmetric and often peripheral. Changes caused by inflammation, maturity or systemic disease result in deposition, thinning or vascularization of the corneal tissue.

Dystrophies are rare conditions and may not present in a primary setting. They often have an autosomal dominant inheritance, with many found on chromosome 5. Although they vary in frequency and expressiveness, most slowly progress with onset by age 20 and stabilize by age 40. One exception is Fuch's Dystrophy, which becomes more difficult to manage as patients age.

Dystrophies are not associated with systemic or ocular disease, so rule out any scarring or inflammation from trauma before making your diagnosis. Dystrophies are bilateral and may vary in severity. They usually have a central location and primarily involve a single corneal layer, so knowing corneal anatomy is important. Pathogenesis of corneal changes is sometimes unknown, often making them difficult to strictly classify as a degeneration or dystrophy. Table 1 can help guide you.

Corneal Anatomy Overview

To evaluate the cornea, first observe the most anterior layers, then scan posteriorly with slit lamp microscopy and perhaps specular microscopy to see deeper layers. Pathology images that use specific dyes may help the pathologist post-operatively because the images are usually harvested from the whole cornea rather than from biopsies. Electron microscopy offers detailed views of all corneal layers, but this method is not readily available. Researchers are currently investigating use of optical coherence tomography (OCT) to evaluate the cornea. Although not available, visualizing the cornea in this manner is promising and hopefully viable.

The epithelium contains five to six central layers of non-keratinized squamous epithelium and eight to 10 peripheral layers. Microvillae found on the most superficial of these dome-shaped cells attach to the tear layer to maintain a uniform surface. The deepest layer, the basement membrane, firmly attaches the epithelium via hemi-desmosomes to the fibrils of the stroma. If ocular surface disease disrupts the epithelium, then treat these conditions so that you can detect other abnormalities. Many dry eye conditions can mimic more serious disease.

Bowman's Layer is extremely important, but its function is unclear. Other primates and even photorefractive keratectomy (PRK) patients lack this layer but still have normal vision with no evidence of corneal swelling. If damaged, this 8µm to 10µm layer of modified stromal collagen causes severe scarring and vision loss.

The stroma represents approximately 90 percent of the corneal area. It is an avascular structure comprised of uniform layers of type I collagen with intervening keratocytes. Although 80 percent of the stroma is water, accurate hydration must be maintained and controlled by stromal proteins and glycosa-minoglycans (GAGS). Altered hydration may affect the stroma's thickness and transparency, which causes pain and vision loss. Many stromal dystrophies and degenerations result from abnormal substances accumulating within the keratocytes or collagen fibrils. Pathology specimens show distinct staining patterns with specific dyes.

Descemet's layer and the endothelium comprise the deepest corneal layers. Mitochondria within the cytoplasm of these cells helps them function as a hydration pump. Many diseases within these layers are associated with aging, and genetic predisposition makes them more dystrophic in nature. The normal maturity process causes Descemet's layer to thicken from 3µm to 17µm. We lose 50 percent of our endothelial cells by the time we reach age 60. Because this is a single layer that is incapable of mitosis, the cells spread out. The correlation between disruption in the fluid pump and the rate of thinning is unknown.

Degenerations

To simplify the discussion, we can divide degenerative corneal conditions into involutional and noninvolutional. Involutional degenerations are common and primarily related to age, while noninvolutional degenerations are uncommon and are usually related to local or systemic conditions (Table 2). Following are overviews of some significant degenerations.

Band Keratopathy Degeneration This condition results from calcium salt deposition in the interpalpebral region of Bowman's layer. It often affects patients who have a history of uveitis, interstitial keratitis, long-standing glaucoma, severe injury, renal failure, syphilis or juvenile rheumatoid arthritis.

The density of the deposition is often so severe that vision reduces to light perception (Figure 1). Therefore, preserving cosmesis and comfort is the goal of treatment. Chelation with a preparation of ethylenediamine tetra acetate (EDTA) can help decrease opacification and improve light transmission. In preserving cosmesis, the practitioners' role may be to design cosmetic lenses. To achieve the maximum benefit, use a lens with a black underprint to mask the scar and match the color of the fellow eye on the top surface.

Salzmann's Nodular Degeneration This condition usually follows an inflammatory or noninflammatory event such as trauma, and results when excess collagen or hyaline replaces Bowman's layer (Figure 2). These superficial, bluish nodules can cause minimal to extreme pain and vision loss depending on the location and severity. Treatment begins with lubrication and BCLs but may require a corneal transplant. Phototherapeutic-keratectomy (PTK) has become a more common treatment. PTK performs localized spot ablations of 3mm to 6mm diameters with excellent success.

White Limbal Girdle of Vogt Many age-related corneal stromal degenerations result from thinning in the periphery. The White Limbal Girdle of Vogt affects more than 50 percent of the population over age 40. It represents subepithelial degeneration and may include calcium deposits. It occurs only in the horizontal meridian and may have a clear zone separating it from the limbus.

Furrow Degeneration This condition is a benign peripheral thinning with a lucid interval of arcus and no inflammation or visual consequence.

Terrien's Marginal Degeneration This slow, painless, progressive thinning leaves the epithelium intact and may result in some vascularization of the gutter. It usually begins in the super-nasal quadrant. The main treatment goal is to correct oblique astigmatism that results, which presents on topographical analysis.

Mooren's Ulcer This differs from Terrien's because it is a more ulcerative process with an elevated de-epithelialized leading edge that spreads circumferentially and centrally. It produces mild to severe pain and is associated with autoimmune disease, such as Crohn's, and previous surgery or trauma. Recent evidence shows a relationship to Hepatitis C. Rheumatoid arthritis is also associated with ulcerative keratitis because of decreased tear production and limbal vascular compromise. Artificial lubricants, mechanical protection (such as tarsorrhaphy, conjunctival resection and lid taping) and steroids are the main treatments.

Dystrophies

Corneal dystrophies usually affect only one corneal layer. Table 3 shows how corneal dystrophies are anatomically classified. Following are overviews of some significant dystrophies.

Epithelial Basement Membrane Disorder (EBMD) This is the most frequently encountered dystrophy. It is closely related to recurrent corneal erosion because trauma can aggravate the condition and it then becomes exacerbated. However, because it has demonstrated an inheritance pattern and it affects a single corneal layer, we may consider it a dystrophy. Abnormal turnover, maturation and production of the basement membrane cause adhesion complexes to form improperly, which weakens the epithelium.

Often referred to as Fingerprint Keratopathy, this condition results from reduplication of the basement membrane and resembles the concentric pattern of the fingertips. Maps, which represent multilamination of the membrane and collagen, are the most common pattern. Dots that intervene between these designs are cysts that form because the tissue bends intra-epithelial and traps debris (Figure 3).

Patients may report photophobia, dryness or foreign body sensation when the cysts approach and erupt at the surface. The disrupted surface may result in topographical irregularities and blurred vision or polyopia. White light reveals a subtle pattern, but fluoroscein and a cobalt blue filter reveal an immediate negative staining pattern, which you should not confuse with a rapid tear break-up time (TBUT). These cellular changes allow debris to build up, which creates a poor substrate for epithelium attachment to stroma and causes more dysadhesion.

Many patients do not report any acute symptoms, but recurrent corneal erosions could result. When this happens, patients become symptomatic upon waking because of the physiologic post-sleep edema and the mechanical shearing of opening the lids.

Treatment is similar to that for a corneal abrasion, but healing usually takes longer and patients report greater discomfort. Treatment depends on disease severity and can include lubricants, hypertonic solutions, hot packs, BCLs, anterior stromal puncture and PTK.

Meesman's Dystrophy (Juvenile Epithelial Dystrophy) This condition can develop in children as young as six months old. Cysts specific to this dystrophy contain a "peculiar substance," which includes debris, degenerating epithelial cells, and GAGS. These clear, round, uniform epithelial vesicles extend from limbus to limbus, but they are more concentrated in the intra-palpebral region. You can easily view them with retroillumination, and they resemble contact lens-induced microcystic edema. Symptoms of photophobia and lacrimation may occur as the cysts erupt through the surface. Vision is often unaffected except in the elderly, who may experience cyst opacification. Treatment is palliative and does not require surgical intervention. The condition recurs following epithelial scraping or penetrating lamellar keratoplasty.

Thygeson's Superficial Punctate Keratitis This is one of the most underdiagnosed corneal conditions. It is chronic, often bilateral and characterized by discreet focal lesions, which resemble subepithelial infiltrates and are often misdiagnosed as infectious keratitis or conjunctivitis. The differentiating features of Thygeson's include a lack of inflammation and many patients are asymptomatic. These pearl-like opacities may surface, and the resultant elevations have a positive staining pattern surrounded by dark areas. Some patients may report photophobia, epiphora, foreign body sensation and blurred vision.

Although this condition is selflimiting, it can be quite disturbing and it usually recurs. Typical patients are female from 15 to 40 years of age. Etiology is unclear, although it may be viral and you should rule out other viral cause. Practitioners have prescribed topical steroids to improve vision, but this may prolong its course. Palliative treatment with lubricants and punctal occlusion is the standard of care, and BCLs also help. Because this conditions affects many contact lens wearers, your first instinct might be to discontinue lens wear. However, lens wear is beneficial to managing this condition.

Reis-Buckler Dystrophy This symmetrical, bilateral autosomal-dominant condition presents at about age five and can cause significant vision loss by age 20. It obliterates Bowman's layer and replaces it with randomly arranged collagen, producing an irregular, rough surface that appears opacified and honeycombed. It can cause marked vision loss because of superficial stromal haze and pain if recurrent erosions result. The pain can last several weeks. Treatment includes hyperosmotic agents and BCLs. As the disease progresses, corneal sensation may decrease. Superficial keratectomy or penetrating keratoplasty (PK) may help, but the latter may cause recurrences.

Honeycomb Dystrophy This condition may be a variant of Reis-Buckler dystrophy in which the corneal surface remains smooth and the patient maintains normal corneal sensation.

Anterior Mosaic Dystrophy or Degeneration (Grayson-Wilbrandt Disease) This condition results in breaks in Bowman's layer that resemble the skin of a crocodile because they have a polygonal pattern with clear central spaces. Most patients are asymptomatic, and its late onset may lend itself to the category of degeneration.

Macular Dystrophy This is a rare autosomal-recessive condition. It causes a buildup of mucopolysaccharides and it stains with alcian blue. It begins in the central and superficial layers of the stroma during the first decade of life and spreads aggressively to the limbus. It results in severe vision loss and requires a PK.

Granular Dystrophy This is a more common autosomal-dominant condition characterized by hyaline deposits and staining with masson trichrome. Its appearance varies from discreet spots to a diffuse powdery presentation with intervening clear zones (Figure 4). It develops centrally in the anterior to mid-stroma, and erosions often break through the basement membrane.

Some patients benefit from a pinhole effect, but surgical intervention may become necessary if the depositions coalesce. PK had been the only option, but now PTK can ablate the superficial anterior stromal layers, which reduces the granules. The surgery flattens the cornea, which affects refractive correction. You can treat this with contact lenses, especially if anisometropia results.

Lattice Dystrophy or Degeneration The branching filaments of amyloid in this condition stain with congo red, which shows birefringence when exposed to polarized light. Recurrent erosions may occur and could cause scars that blur visual acuity.

Avellino Dystrophy This condition is a combination of granular dystrophy and discreet linear opacities (Figure 5).

Central Crystalline Dystrophy of Schneider This condition represents a collection of cholesterol, lipids and triglycerides in the anterior stroma. It is autosomal-dominant with variable expressiveness. The deposits appear gray or golden, and vision is much better than you would predict by the appearance of the deposits. Many patients have a normal serum lipid profile because this condition is a localized abnormality of cholesterol metabolism.

Arcus Senilis This condition differs from central crystalline dystrophy because the lipid deposits are located more peripherally in all quadrants. This degeneration affects more than 60 percent of the population between the ages of 40 and 60.

Posterior Polymorphous Dystrophy In this autosomal or recessive condition, vesicles intervene between the normal endothelial cells (Figure 6). These vesicles may contain collagenase material and can result in stromal edema or glaucoma if they spread into the trabecular meshwork. Patients may experience no visual symptoms or perhaps polyopia if the vesicles or edema are located at or near the visual axis.

Fuch's Dystrophy This bilateral, asymmetric condition begins in the fifth or sixth decade and predominantly affects women. The endothelium secretes guttata, which are clear vesicles, and projects them into the potential space between the endothelium and Descemet's membrane. Biomicroscopically they resemble bubbles, but specular reflection reveals that they are missing cells. Guttata interrupt the epithelium's normal pumping mechanism, which may result in stromal and epithelial edema as well as great discomfort and visual compromise. The treatment is palliative and includes glaucoma agents to reduce edema, hypertonic solutions and BCLs to draw fluid out and PK if corneal opacification results.

Anterior Keratoconus This ectatic corneal dystrophy may be congenital but is most commonly diagnosed when patients are between 10 and 30 years of age. Computer-assisted videokeratography is the most sensitive method of detection. The majority of keratoconics manifest para-inferior steepening. Keratoconics may be associated with vernal keratoconjunctivitis, atopic dermatitis and other atopic conditions.

Treatment

Practitioners can treat many of these conditions or co-manage them if surgery becomes necessary. You can treat some on an individual layer basis, but treatment often can affect multiple layers.

The most effective way to treat anterior corneal conditions is to provide a good surface environment. Lubricating drops are often the initial treatment and ease most patients, whether by a placebo effect or because most of these patients have an underlying dry eye.

Lubricating drops are not created equal. Patients often state that one type of drop works better for them than another. Instillation is frequent for patients who have diseased eyes, so prescribe non-preserved drops to reduce potential cytotoxic effects. Some transiently preserved formulas, which lose their preservative effect upon instillation, may be effective. However, they require sufficient tear volume to break down the preservative compound, and this tear quantity is often missing in patients who have diseased eyes. Preparations that contain preservatives that activate only when pathogens are present seem to make the most sense.

Artificial lubrication should also provide electrolytes that help the eye heal more effectively, such as sodium, potassium, calcium and magnesium. Finally, the media makes a difference. Patients enjoy longer relief with gels, but they often prefer the non-blurry effect of liquids. Incorporating characteristics that react favorably and biologically with the ocular surface into a solution should provide the best relief.

Several new treatment modalities are available for advanced cases of ulcerative keratitis, including cyclosporine (Allergan's Restasis) and autologous serum treatment.

Cyclosporine is an immune modulator that inhibits T-lymphocytic activity, which reduces inflammation. It recently became commercially available by prescription. Cyclosporine facilitates apoptosis of lacrimal gland lymphocytes while suppressing apoptosis of lacrimal and epithelial cells.

Autologous serum therapy resembles personalized tear replacement in which the patient's own serum (blood devoid of cells and clot factors) is formulated into a topical supplement. These customized tears contain epithelial growth factors, vitamin A, anti-proteases and fibronectin that help the healing process. A 40-mL blood sample can produce a three-month supply of "artificial tears" that have natural bacteriostatic characteristics.

Tear retention via punctal occlusion may also help these patients. Remember that using punctal plugs is a responsibility. Written consent may be warranted just as with other procedures, and proper followup is essential. Allergy to silicone can result in an uncomfortable patient. Plug downward migration may result in a pyogenic granuloma, while upward migration might cause much frustration. Recent advancements in punctual occlusion include a thermodynamic acrylic polymer that reacts to body temperature and changes shape to conform to the patient's puncta.

Use BCLs to treat corneal conditions that affect both the anterior and posterior surfaces. BCLs protect the eye from mechanical irritation, provide comfort, act as a mechanism for dehydration and improve vision by providing a more uniform surface. Make sure that the lenses have sufficient oxygen permeability to allow for continuous wear. The lenses should not interfere with the healing process or hinder the use of therapeutic agents. They should be comfortable for the patient, allow you to see corneal structures without removal and be cost effective.

BCLs technically should also have approval for treating corneal disease, but the standard of care and accountability of the practitioner are important deciding factors. Higher water content lenses may help with dehydration and may serve as a drug delivery device for some agents by releasing them slowly onto the corneal surface. Full corneal coverage with minimal movement helps prevent disruption of the healing process. Disposable silicone hydrogel lenses may best meet the overall requirements.

It is well accepted that contact lenses are the best treatment for most keratoconics, whose irregular anterior corneal surface does not properly focus light. Replacement of this irregular corneal surface with a more regular contact lens surface significantly improves the focusing of light on the retina and patients' visual acuity. Gas permeable (GP) corneal lenses are most often used. Other options are GP scleral lenses, piggyback GP lenses on a soft lens carrier, GP lens in a well in a soft lens, a central rigid lens with a soft lens skirt combination (Softperm, CIBA Vision) and specially designed contact soft lenses.

Conclusion

Many types of corneal degeneration and dystrophy exist. Their appearance, progression and treatment vary, as described in this article. Practitioners should be aware of these conditions so they can provide proper detection, management and/or co-management.

Dr. Sclafani is director of Optometric Services and associate professor of clinical ophthalmology at the University of Chicago Medical Center, Chicago, IL.

References are available upon request to the editors of Contact Lens Spectrum. To receive references via fax, call (800) 239-4684 and request document #96.