Corneal Atlas: Part IV
 How to Detect and Deal With Dystrophies and Degenerations

What Causes Keratoconus?

Corneal breakdown comes in many forms. Your diagnostic skill is key to managing
the problem effectively.

by Alan G. Kabat, O.D. and Joseph W. Sowka, O.D, Contributing Editors

Any number of predisposing factors can lead to a progressive degradation of the corneal tissue. Certain patterns of corneal breakdown are associated with well-documented systemic or ocular conditions. Others remain something of a mystery even to this day.

A patient suffering from vision loss and pain cares less about the cause than about your ability to diagnose the problem and ameliorate his symptoms. No doubt in any given year the typical optometric practice will encounter numerous incidents of corneal degenerations and dystrophies. Here's how you can recognize and manage these conditions.

Keratoconus
Keratoconus is a chronic, progressive, non-inflammatory corneal ectasia. After all this time, we're still not clear on its etiology and pathogenesis (see the sidebar, "What Causes Keratoconus?"). Whatever the root cause, the cornea loses its spherical configuration and becomes cone-shaped due to thinning and protrusion. These changes are irreversible. They can impair vision mildly or significantly.

In most keratocones the disorder begins to show up around puberty. Patients usually notice progressive blurring and distortion in their mid-teens or early 20s. Some tolerate these symptoms until their 30s or even later. Glare and photophobia, monocular diplopia and ocular discomfort characterize the other common complaints. The rate at which keratoconus progresses and its severity varies among patients. Keratoconus is mostly bilateral yet often asymmetric.

A host of classic clinical signs are associated with keratoconus. The most obvious is Munson's sign, in which the lid margin protrudes in downgaze. Another common finding is an abnormal red reflex in which a dark annular shadow surrounds the cone's bright reflex. The same phenomenon causes a "scissors-type" reflex on retinoscopy. Refractively, keratocones manifest irregular, high-myopic astigmatism. Biomicroscopy reveals a focal protrusion of the cornea, either centrally or slightly inferiorly. Fleischer's ring often marks the cone's base. The iron deposits reside at the basal epithelium.

Another classic finding is Vogt's striae. These are vertical streaks in the posterior stroma. These folds of tissue disappear with digital pressure. You may notice fine anterior stromal scars due to breaks in Bowman's membrane. Other less common findings include enlarged corneal nerves, clear spaces in the anterior stroma and subepithelial fibrillary lines.1-3

Corneal topography is the best way to identify the early stages of keratoconus. But even with standard keratometry, irregular mires should prompt further investigation. Educate patients with keratoconus about the progressive nature of the disorder and its potentially poor visual prognosis. Initial refractive correction usually consists of spectacles. Rigid contact lenses are indicated when spectacles can't provide acceptable vision. While contact lenses cannot prevent progression of the cone, they can often compensate for the irregular astigmatism.

Early keratocones may succeed with a large-diameter aspheric RGP lens. More advanced cases may require a nipple-cone lens or a lens designed specifically for keratoconus, such as the Soper or McGuire lenses. Often, a contact lens specialist is the best clinician to handle these advanced cases. Due to the progressive corneal thinning, refractive procedures such as LASIK are contraindicated.

Corneal hydrops is a severe late complication of keratoconus. The stromal edema results from ruptures in Descemet's membrane. It brings reduced acuity, discomfort, redness and photophobia. Treatment aims at relieving the discomfort through cycloplegia and a bandage, either a pressure patch or contact lens. Hyperosmotic agents such as 5 percent sodium chloride ointment may help, although their primary effect is in the epithelium; they do little to reduce stromal edema. In rare cases the patient may need topical NSAIDs or steroids for severe discomfort. Hydrops usually resolves within weeks or months. See the patient every one or two weeks in the meantime.

Advanced keratoconus and cases that manifest corneal hydrops can bring significant scarring. Surgery is suggested when scarring reduces visual acuity beyond a functional level or when a stable contact lens fit is no longer feasible. Procedures include simple lamellar keratoplasty, epikeratophakia, thermokeratoplasty or a complete penetrating keratoplasty.18,19

Salzmann's Nodular Degeneration
This corneal degeneration may ensue after episodes of keratitis, particularly corneal phlyctenule. Other predisposing conditions are vernal keratoconjunctivitis, trachoma, interstitial keratitis, Thygeson's superficial punctate keratitis, exposure keratopathy and keratitis sicca. Patients with a history of epithelial basement membrane dystrophy, RGP wear, keratoconus or corneal surgery may have a greater risk. The most recent report suggests that SND is most often bilateral. It occurs more frequently in women than men.

SND appears clinically as an accumulation of bluish-white superficial nodules in the mid-peripheral cornea. The nodules are not vascularized, although the underlying stroma may be. Generally, the eye is not inflamed unless there's associated corneal erosion. If so, there'll be limbal injection, corneal edema and an anterior chamber eaction.

Most cases remain asymptomatic until the later stages. Recurrent corneal erosion may then ensue. Patients typically report photophobia, blepharospasm, tearing and decreased acuity. Between bouts of erosion, patients often complain of burning and grittiness.

The nodules of Salzmann's nodular degeneration are clumped masses of collagen fibrils anterior to Bowman's membrane. Fibroblasts within the conjunctiva or limbal vessels may produce these accumulations.20 Interestingly, transmission electron microscopy has shown duplication of the epithelial basement membrane in some cases. Descemet's membrane and the corneal endothelium usually remain unchanged.

You can manage mild, asymptomatic cases of SND with topical lubricants and/or a bandage contact lens. Use antibioitics if there are significant epithelial defects. You may be tempted to use topical steroids in symptomatic cases, but remember that SND is non-inflammatory; steroids will have little effect. Also, steroids introduce an unnecessary risk in patients with a compromised epithelium.

In more severe cases, debridement will remove the nodules. Phototherapeutic keratectomy (PTK) is another option. If there's significant scarring or if chronic epithelial breakdown makes the condition unmanageable, lamellar or penetrating keratoplasty may be the only recourse.

Band Keratopathy
In this corneal degeneration, calcium salts deposit at the level of the anterior stroma and Bowman's layer. It's typically due to hypercalcemia resulting from hyperparathyroidism. Chronic inflam- mation from anterior uveitis also can cause it.

Band keratopathy frequently accompanies juvenile rheumatoid arthritis, presumably due to the associated uveitis. Other causes of band keratopathy are severe superficial keratitis, interstitial keratitis, corneal edema, trachoma, prolonged glaucoma, toxicity (mercury, silicone, preservatives) and trauma.21-23 Band keratopathy has been associated with a number of systemic diseases.21,24,25

Visual acuity typically decreases as the calcium deposits become denser and more abundant. As epithelial erosions develop in advanced cases, significant pain may ensue. Biomicroscopy reveals a dense, white accumulation of material in the superficial stroma within the interpalpebral aperture. The appearance has been likened to frosted glass. Initially there's a sharp demarcation with a small band of normal cornea separating the peripheral edge of the band from the limbus. The band typically begins in the limbal area and progresses centrally from both the nasal and temporal directions. The band spreads slowly and extends over months to years. The material appears densest near the limbus. You'll see areas where clear cornea shows through the opalescence (the so-called "Swiss cheese" appearance). Advanced cases can become nodular.

Initial management calls for topical lubricants, particularly if there are surface wetting problems. More aggressive management is needed as the symptoms worsen. Chelation with EDTA may help resolve advanced cases of band keratopathy. Phototherapeutic keratectomy is another option.

Beyond management of their ocular symptoms, these patients should be tested for abnormal calcium metabolism. Refer to an endocrinologist for evaluation of the parathyroid gland. Younger patients should see a rheumatologist—particularly if there's also cataract and uveitis (Still's triad)—to check for juvenile rheumatoid arthritis. Band keratopathy in patients under 16 is highly diagnostic of JRA. Also, remember that malignant disease can cause abnormal calcium metabolism. Unusual cases may merit oncologic evaluation.

Epithelial Basement Membrane Disease 
There's some debate over whether epithelial basement membrane disease is a dystrophy or degeneration. It's similar to other dystrophies in many respects. It often has an autosomal dominant inheritance pattern, it's bilateral, it affects only one layer of the cornea, it's centrally located, and it's not a sequela of associated systemic or ocular diseases. Yet some consider EBMD a degeneration because it typically starts after age 30 and in some cases it occurs sporadically without a family history.26,27

Whatever you call it, we do know that EBMD represents a continuum of progressive epithelial basement membrane dysfunction. The progression may include Cogan's microcystic epithelial dystrophy, map-dot-fingerprint dystrophy, anterior basement membrane dystrophy, fingerprint dystrophy, and net- and bleb-like patterns.28

Patients with EBMD usually present without symptoms. Others report mild, transient corneal irritation on awakening, with photophobia or glare. About 10 percent develop transient blurred vision with painful recurrent epithelial erosions. Most patients have fluctuating visual acuity without discomfort. Look for these three signs under the slit lamp:

  • Maps. The earliest clinical findings in EBMD, maps are sharply demarcated areas with hazy, white centers. Oval lacunae may appear within these areas. Sodium fluorescein will exhibit negative staining over the maps, particularly in elevated areas.
  • Dots. These gray or white opacities appear within the epithelium. David G. Cogan, M.D., described these as microcysts in a condition later named for him. Dots often form within or adjacent to maps. These opacities show positive fluorescein staining when superficial.
  • Fingerprints. These are concentric, usually curved parallel lines in the central or mid-peripheral cornea. They often surround the maps and are best seen in retroillumination. Groups of fingerprints are sometimes called "mare's tails."
  • Blebs. Small uniform vacuoles that usually cluster in the central cornea, blebs may form refractile lines that follow the normal anterior corneal mosaic. These lines are known as nets.

In EBMD, the basal epithelial cells manufacture finger-like projections that protrude off the thickened basement membrane. These irregularities migrate forward, causing corneal surface abnormalities. The epithelial layer cannot regenerate basal lamina, and this results in poor epithelial adherence. This ultimately leads to recurrent corneal erosion, the most common reason patients seek care.

Patients who present without symptoms can simply be educated and monitored. Patients with mild irritation in the morning may require management with supportive therapies such as lubricating drops or ointments at bedtime and in the morning. Punctal occlusion may alleviate discomfort from dry eye. Some clinicians recommend hypertonic solutions and ointments for significant presentations. Yet studies have shown little difference between hypertonic preparations and bland ointments in managing EBMD.29 Soft contact lenses may help smooth surface disturbances in cases of significant visual acuity loss.

Patients with EBMD and a history of traumatic abrasions have the highest incidence of recurrent corneal erosion.30 Corneal erosion may require debridement of the loose epithelium, topical cycloplegia, topical antibiotics and hypertonic drops or ointment. Pain management may call for cold compresses, oral analgesics or topical NSAIDs. Recurrent corneal erosion that resists medical management may require surgical intervention such as anterior stromal puncture using a 25-gauge needle or Nd:YAG laser. Phototherapeutic keratectomy is an effective alternative in some cases.

Fuchs' Endothelial Dystrophy 
This bilateral, often asymmetric condition rarely causes symptoms before age 50. Fuchs' endothelial dystrophy is more prevalent and usually more severe in women.49 Hyperopes and those with shallow anterior chambers have a greater incidence also.31

Fuchs' endothelial dystrophy stems from a malfunction of the corneal endothelium. There's a disruption of the endothelial pump mechanism that maintains normal stromal hydration. This results in excessive influx of aqueous and stromal edema.

Patients with Fuchs' dystrophy may present with decreased vision, foreign body sensation and pain or discomfort upon awakening. The key biomicroscopic finding is central corneal guttata, which appear as gold refractile bodies on the posterior corneal surface under direct illumination. With retroillumination they resemble small bubbles or holes in the endothelium. You'll commonly see fine endothelial pigment dusting. In later stages, you may observe stromal edema with folds in Descemet's membrane. Severe presentations bring corneal pannus and bullous keratopathy. Those with Fuchs' endothelial dystrophy may be especially prone to open angle glaucoma, although there have been conflicting reports in the literature.

Fuchs' endothelial dystrophy progresses through three stages over a period of about 10-20 years. At first the patient is asymptomatic but manifests central guttata and some pigment dusting. You may see diffuse brown pigmentation of the central posterior surface. At this stage the endothelial cells show degeneration and Descemet's membrane material displays abnormal deposition.

In the second stage the patient develops stromal and epithelial edema, with symptoms of glare and hazy vision. Visual acuity is usually 20/30 or better. Patients may be more symptomatic in the morning when the edema is most pronounced. But the vision quickly clears as the cornea deturgesces under open-eye conditions. As the edema increases, the stroma thickens centrally and epithelial bullae develop. Descemet's membrane develops folds and vision worsens. As the epithelium becomes more bullous, the patient experiences pain and photophobia.

In the third phase, subepithelial connective tissue appears centrally. Clinically this appears as an irregular, dense, gray, swirling sheet of scar tissue. Histologically, it consists of active fibroblasts and collagen fibrils between Bowman's layer and the epithelium. In advanced cases the stromal edema and epithelial bullae disappear as the stroma scars. The patient becomes more comfortable even though the visual acuity is severely reduced.

Treatment for Fuchs' endothelial dystrophy varies depending on the severity. Patients with early stromal or epithelial edema may be treated conservatively at first with 5 percent sodium chloride solution three to four times daily and 5 percent sodium chloride ointment at bedtime. Some practitioners advocate using a hair dryer held at arm's length to diminish the edema. Therapeutic soft contact lenses may alleviate discomfort. A flat, high-water lens will decrease the irregular astigmatism and the pain from ruptured epithelial bullae.

Remember that any elevation of intraocular pressure will force more fluid into the stroma across the compromised endothelium. IOP reduction with topical or, especially, oral agents may decrease the progression and symptoms of corneal edema.

Penetrating keratoplasty is the treatment of choice for patients with significant vision reduction and discomfort. Fuchs' dystrophy accounts for 10 percent of all corneal grafts. 32,33 If the graft is done before the peripheral cornea is involved, there's an 80 percent likelihood it will remain clear for at least two years.34 Patients with both Fuchs' endothelial dystrophy and cataracts will do well with a combined penetrating keratoplasty and cataract extraction.

Dellen
Dellen are focal areas of corneal thinning typically located at the limbus. They're a transient form of corneal degeneration that results from stromal dehydration secondary to poor wetting by the tear film. Dellen are often linked to an adjacent elevation of the conjunctival tissue such as a pinguecula or episcleritis nodule. Other conditions that can predispose to dellen are pterygia, conjunctival chemosis, scarring from cataract or extraocular muscle surgery, filtering blebs and scleritis.35 Certain drugs with anticholinergic properties can incite or exacerbate the problem.35

Patients with corneal dellen may be asymptomatic but often report mild ocular discomfort or a foreign body sensation. Their histories may involve a period of redness and irritation that suddenly got worse. Biomicroscopy demonstrates a "saucer-like" depression at the limbus. The lesion's center usually appears lackluster while the edges are sharply defined. The overlying epithelium is intact. That distinguishes dellen from ulcers and stromal necrosis. Sodium fluorescein will show central pooling with or without staining. Rarely are these lesions larger than 2mm.

Therapy aims at rehydrating the cornea. Usually you can resolve the problem simply with copious lubrication (artificial tears every one or two hours and bland ointment at night). You'll often see complete reversal of dellen within 24-48 hours.35,36

More significant presentations may require a bandage contact lens along with lubrication therapy. Topical antibiotics usually aren't necessary, except in extreme cases involving significant epithelial compromise.

If the dellen are due to a primary inflammation of the conjunctiva, episclera or sclera, it's critical to address that condition initially. Topical corticosteroids often help in managing episcleritis or conjunctivitis. But they're not indicated for the dellen themselves, which are non-inflammatory.

You'll see corneal degenerations and dystrophies regularly in your practice. The conditions may develop over many years, or they may present abruptly. You need to be familiar with these disorders and be ready to manage whatever complications may arise. Educate patients about the natural course of their condition and how to recognize symptoms that may require medical management.

Drs. Kabat and Sowka are associate professors at Nova Southeastern University College of Optometry. Both serve as referees for the Review of Optometry Editorial Review Board.

1. Kinoshita S, Tanaka F, Ohashi Y, et al. Incidence of prominent corneal nerves in multiple endocrine neoplasia type 2A. Am J Ophthalmol 1991;111:307-11.
2. Shapiro MB, Rodrigues MM, Mandel MR, et al. Anterior clear spaces in keratoconus. Ophthalmology 1986;93: 1316-9.
3. Bron AJ, Lobascher DJ, Dixon WS, et al. Fibrillary lines of the cornea. A clinical sign in keratoconus. Br J Ophthalmol 1975;59:136-40.
4. Sawaguchi S, Yue BY, Sugar J, et al. Lysosomal enzyme abnormalities in keratoconus. Arch Ophthalmol 1989;107:1507-10.
5. Sawaguchi S, Twining SS, Yue BY, Wilson PM, Sugar J, Chan SK. Alpha-1 proteinase inhibitor levels in keratoconus. Exp Eye Res 1990;50:549-54.
6. Zhou L, Sawaguchi S, Twining SS, Sugar J, Feder RS, Yue BY. Expression of degradative enzymes and protease inhibitors in corneas with keratoconus. Invest Ophthalmol Vis Sci 1998;39:1117-24.
7. McKusick VA. Heritable Disorders of Connective Tissue, 3rd edition.  St. Louis: Mosby, 1966.
8. Wolter FR. Bilateral keratoconus in Crouzon's syndrome with unilateral acute hydrops. J Pediatr Ophthalmol 1977;14:141-3.
9. Rados A. Conical cornea and mongolism. Arch Ophthalmol 1948;40:454-78.
10. Austin MG, Schaefer RF. Marfan's syndrome, with unusual blood vessel manifestations. Arch Pathol 1957; 64:205-9.
11. Tuft SJ, Kemeny DM, Dart JK, et al. Clinical features of atopic keratoconjunctivitis. Ophthalmology 1991;98:150-8.
12. Street DA, Vinokur ET, Waring GO, et al. Lack of association between keratoconus, mitral valve prolapse, and joint hypermobility. Ophthalmology1991;98:170-6.
13. Cameron JA, Al-Rajhi AA, Badr IA. Corneal ectasia in vernal keratoconjunctivitis. Ophthalmology 1989;96:1615-23.
14. Shapiro MB, France TD, The ocular features of Down's syndrome. Am J Ophthalmol 1985;99:659-63.
15. Lipman RM, Rubenstein JB, Torczynski E. Keratoconus and Fuch's corneal endothelial dystrophy in a patient and her family. Arch Ophthalmol 1990;108:993-4.
16. Weissman BA, Ehrlich M, Levenson JE, et al. Four cases of keratoconus and posterior polymorphous corneal dystrophy. Optom Vis Sci 1989;66:243-6.
17. Smith SG. Rabinowitz YS. Sassani JW. Smith RE. Keratoconus and lattice and granular corneal dystrophies in the same eye. Am J Ophthalmol 1989;108:608-10.
18. Feder RS. Noninflammatory ectactic disorders. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. St. Louis: Mosby, 1997:1091-1106.
19. Maguire LJ. Ectatic corneal degenerations. In:  Kaufman HE, Barron BA, McDonald MB, eds. The Cornea, 2nd Edition. Boston: Butterworth-Heinemann, 1998:525-49.
20. Wood TO. Salzmann's nodular degeneration. Cornea 1990;9:17-22.
21. Klintworth G. Degenerations, depositions, and miscellaneous reactions of the cornea, conjunctiva, and sclera. In Garner A, Klintworth G, eds. Pathobiology of Ocular Disease. New York: Marcel Dekker, 1982:1431-60.
22. Kennedy RE, Roca PD, Landers PH. Atypical band keratopathy in glaucomatous patients. Am J Ophthalmol 1971;72:917-22.
23. Brazier DJ, Hitchings RA. Atypical band keratopathy following long-term pilocarpine treatment. Br J Ophthalmol 1989;73:294-6.
24. Porter R, Crombie AL. Corneal and conjunctival calcification in chronic renal failure. Br J Ophthalmol 1973;57:339-43.
25. Goodfriend AN, Ching SST. Corneal and Conjunctival Degenerations. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. St. Louis: Mosby, 1997: 1119-35.
26. Werblin TP, Hirst LW, Stark WJ, et al. Prevalence of map-dot-fingerprint changes in the cornea. Br J Ophthalmol 1981;65:401-9.
27. Laibson PR. Microcystic corneal dystrophy. Trans Am Ophthalmol Soc 1976;74:488-531.
28. Miller CA, Krachmer JH. Epithelial and stromal dystrophies. In: Kaufman HE, Barron BA, McDonald MB, eds. The Cornea, 2nd Edition. Boston: Butterworth-Heinemann, 1998: 525-49.
29. Williams R, Buckley RJ. Pathogenesis and treatment of recurrent erosion. Br J Ophthalmol 1985;69:435-7.
30. Hykin PG, Foss AE, Pavesio C, et al. The natural history and management of recurrent corneal erosion: a prospective randomized trial. Eye 1994;8:35-40.
31. Pitts JF, Jay LJ. The association of Fuch's corneal endothelial dystrophy with axial hypermetropia, shallow anterior chamber and angle closure glaucoma. Br J Ophthalmol 1990;74:601-4.
32. Brady SE, Rapuano CJ, Arentsen JJ, et al. Clinical indications for and procedures associated with penetrating keratoplasty. Am J Ophthalmol 1989;108:118-22.
33. Mamalis N, Craig MT, Coulter VL, et al. Penetrating keratoplasty 1981-1988: clinical indications and pathologic findings. J Cat Ref Surg 199;17:163-7.
34. Price FW Jr, Whitson WE, Marks RG. Graft survival in four common groups of patients undergoing penetrating keratoplasty. Ophthalmology 1991;98:322-8.
35. Casser L, Lingel NJ. Diseases of the cornea. In: Bartlett JD, Jaanus SD, eds. Clinical Ocular Pharmacology, 3rd Edition. Boston: Butterworth-Heinemann, 1995: 679-745.
36. Baum JL, Mishima S, Boruchoff A. On the nature of dellen. Arch Ophthalmol 1968;79:657-62.

What Causes Keratoconus?

There's been much debate on what actually causes keratoconus. One popular theory blames it on increased lysosomal enzymes in the basal epithelium and reduced levels of proteinase inhibitors.4-6 This may degrade the underlying stromal tissue, leading to the characteristic degenerative changes.

Keratoconus has been linked to several connective-tissue disorders. Among these are Ehlers-Danlos syndrome, osteogenesis imperfecta, Down's syndrome, Apert's syndrome, Crouzon's syndrome, Marfan's syndrome and Turner's syndrome.7-10

Both atopic disease and eye rubbing may play a role in keratoconus.11-13 A significant incidence of atopy, especially hay fever and asthma, has been noted in those with keratoconus. Perhaps when these individuals rub their eyes to relieve the itching they may induce or enhance the degeneration and ectasia of keratoconus. Patients with Down's syndrome rub their eyes a lot too. These individuals likewise have a high incidence of keratoconus. 14

Other ocular conditions have been linked to keratoconus. These include tapetoretinal degenerations (especially Leber's congenital amaurosis), floppy eyelid syndrome, axenfeld-Rieger syndrome, Fuch's dystrophy, posterior polymorphous dystrophy and granular and lattice dystrophies.15-17

top

| | | | | |