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use a humidifier while sleeping and at work if possible. Increased lubrication is often necessary during plane travel, as airplane cabins have very low humidity, and while reading or studying or driving, as the blink reflex is decreased during concentration.

Dry eye patients may better tolerate newer contact lenses with a high-DK and high water content. Daily disposable lenses are a good choice.

22.What if the patient uses tears six to eight times a day and returns with red, painful eyes and more superficial punctate keratitis?

The patient may be sensitive to the preservatives in the tears. In these patients, preservative-free tears may be necessary.

23.What if this is still not enough or the patient has a clinical exam that is worsening?

Punctal occlusion is an option. Patients who use tears every 2 hours or more may benefit from closing the lower puncta. Placement of a punctal plug can be easily done as an office procedure. Patients may notice local irritation for a short time, but this usually resolves. Occasionally, epiphora may result from overflow tearing and the plug can quickly be removed in the office. If the patient is comfortable with this, but the plug falls out, permanent closure can be done by using cautery. Between 10% and 20% of the tear film is drained through the upper puncta, and these may be closed subsequently if the lower lid punctal closure is not adequate to control symptoms. Of course, any lid contour abnormalities should be addressed as well (e.g., ectropion, lid laxity).

KEY POINTS: SEVERE DRY EYE

1. Frequent tear use may make symptoms worse if the patient is sensitive to the preservatives. 2. Occlude the lower lid puncta first and then proceed to upper lid punctal occlusion.

3. Cyclosporine may increase tear production, but it may take months to see results.

24.A patient with punctal occlusion returns with more irritation and burning since the procedure was done. The tear film meniscus is greatly improved. What happened?

If a patient has significant blepharitis, the symptoms can worsen after punctal occlusion. The debris is trapped and not drained and now has a higher concentration than before. Make sure blepharitis is treated adequately before placing punctal plugs to prevent this.

25.Is there any treatment to increase tear production?

Topical cyclosporine (Restasis) decreases cell-mediated inflammation of the lacrimal tissue and ultimately can increase tear production. Patients need to use it twice a day for 1 to 3 months to get a response and then continue for up to 6 months or more. Some practitioners are using a mild steroid four times a day for the first 2 weeks of Restasis to decrease inflammation and stinging until the cyclosporine begins to work. This is often used in patients with level 2 or 3 severity.

26.What is the role of acetylcysteine?

Acetylcysteine is a mucolytic agent used to break up mucus in patients that have filamentary keratitis and mucous plaques.

27.What other agents are used in a patient with level 4 severity of dry eye?

Other options are systemic cholinergic and anti-inflammatory agents, autologous serum tears, moisture chamber goggles, and a temporary or permanent lateral tarsorrhaphy. Rheumatologic evaluation may help elucidate the cause and coordinate systemic treatments.

Bibliography

Behrens A, Doyle JJ, Stern L, et al.: Dysfunctional tear syndrome: a delphi approach to treatment recommendations, Cornea 24(8):900–907, 2006.

Chow CYC, Gibard JP: Tear film. In Krachmer JG, Mannis MJ, Holland EJ, editors: Cornea, vol 1. St. Louis, 1997, Mosby, pp 49–60.

Fox FI: Systemic diseases associated with dry eye, Int Ophthalmol Clin 34:71–87, 1994.

Kanski J: Clinical ophthalmology: a systematic approach, Edinburgh, 2003, Butterworth-Heinemann.

Lemp MA: Report of the national eye institute/industry workshop on clinical trials in dry eyes, CLAO J 21:221–232, 1996.

1.What are corneal dystrophies?

Corneal dystrophies are bilateral, inherited, noninflammatory, commonly progressive alterations of the cornea that are usually not associated with any other systemic condition. Most corneal dystrophies are autosomal dominant disorders occurring after birth. Because each dystrophy may exhibit a spectrum of clinical manifestations, examining multiple family members frequently aids in establishing the diagnosis.

2.How do degenerations differ from dystrophies?

In contrast to dystrophies, degenerations are unilateral or bilateral aging changes that are not inherited. They are also not associated with systemic disease.

3.Discuss the general anatomic classification of corneal dystrophies.

•Anterior membrane dystrophies include disorders affecting the corneal epithelium, epithelial basement membrane (Fig. 12-1), and Bowman’s layer.

•Stromal dystrophies occur anywhere in the stromal layer of the cornea between Bowman’s layer and Descemet’s membrane.

•Posterior membrane dystrophies are primarily abnormalities of the endothelium and Descemet’s membrane.

KEY POINTS: DIFFERENCES BETWEEN CORNEAL DYSTROPHIES AND DEGENERATIONS

1. Corneal dystrophies are always bilateral.

2. They are inherited.

3. They may occur shortly after birth.

4.What is the International Committee for Classification of Corneal Dystrophies?

The International Committee for Classification of Corneal Dystrophies (IC3D) was created in 2008 to study what genetic analyses had brought to light and the relations between genetic abnormalities and their phenotypic description available at the time. Members of The Cornea Society assigned a category number from 1 to 4 to each one of the known dystrophies, reflecting the “level of evidence” of its existence. All dystrophies were given a name, alternative names, and eponyms; their Mendelian

inheritance in humans, inheritance, genetic locus, and gene; their onset, signs, symptoms, and course; their light microscopy, transmission electron microscopy, immunohistochemistry, and confocal microscopy results; and a category.

Figure 12-1.  Typical mare’s tail sign in epithelial basement membrane dystrophy.

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All anterior membrane dystrophies are autosomal dominant. Examples are Meesmann’s juvenile epithelial dystrophy, epithelial basement membrane dystrophy, and corneal dystrophies of Bowman’s layer.

5.Which is the most common anterior membrane dystrophy? Which is strictly epithelial?

Epithelial basement membrane dystrophy is by far the most common anterior membrane dystrophy. In fact, it has the highest prevalence of all of the corneal dystrophies. Areas of extra basement membrane result in maplike and/or fingerprint changes as well as intraepithelial microcysts. Five percent of otherwise normal corneas have been observed to have such changes.

Second in prevalence are the corneal dystrophies of the Bowman’s layer (CDBs): Reis-Bücklers (CDB-I) and Thiel-Behnke honeycomb-shaped dystrophy (CDB-II). These disorders consist of gray reticular opacities beneath the epithelium.

Meesmann’s dystrophy is the rarest of the three and is strictly epithelial. This disorder, noted in the first few years of life, presents as a bilaterally symmetric pattern of microcysts or vesicles seen strictly in the epithelial layer of the cornea, usually in the interpalpebral fissure.

6.What are the most common presenting symptoms of anterior membrane dystrophies?

First are the symptoms associated with corneal erosions—pain, foreign body sensation, photophobia, and tearing, especially with opening of the lids during sleep or upon awakening in the morning. Erosions are most common in the setting of epithelial basement membrane dystrophy. The second symptom is blurred vision secondary to either irregularity of the surface, seen in epithelial basement membrane dystrophy, or corneal clouding, frequently seen in the dystrophies of the Bowman’s layer or Meesmann’s dystrophy

7.Discuss treatment options for recurrent corneal erosions associated with anterior membrane dystrophies.

The conservative approach includes the generous use of lubricating eyedrops during the day and ointments at night. Some physicians advocate the use of topical steroids to stabilize the basement membrane, and others advocate hypertonic saline, especially in ointment form at night to dehydrate the epithelium and aid in its attachment to the underlying layers. Patching, either conventional or with collagen or bandage contact lenses, hypothetically decreases the mechanical effect of lid movement on the already weakened corneal epithelium. Recalcitrant cases may require surgical intervention.

KEY POINTS: RECURRENT CORNEAL EROSIONS

1. Recurrent corneal erosions may be associated with anterior membrane and stromal dystrophies. 2. They have common symptoms: pain, blurred vision, and photophobia.

3. Recurrent corneal erosions are frequently amenable to medical therapy with lubrication and hyperosmotic agents.

4. They can be treated surgically with mechanical or laser keratectomy or stromal puncture.

8.Discuss the role of surgery in the treatment of anterior membrane dystrophies.

In the setting of recalcitrant corneal erosions, mechanical debridement of the loose epithelium and basement membrane or anterior stromal puncture, together with the use of a bandage lens, may aid in reepithelialization of the surface and adherence of the epithelium to the underlying layers. Mechanical debridement also may be used to remove an irregular epithelial basement membrane if an associated visual decline is noted. Typically these patients do not have symptoms of corneal erosion but complain of blurred vision. Topography reveals marked irregularity of the Placido rings. Removal of the abnormal epithelium and basement membrane can restore normal anterior corneal anatomy paralleled by improvement in vision. For the Bowman’s layer dystrophies a more aggressive superficial or lamellar keratectomy may be required. This may be microkeratome assisted. Lamellar keratoplasty may also be considered.

9.Do lasers have a role?

The yttrium–aluminum–garnet laser has been used instead of a needle to accomplish anterior stromal puncture but does not offer a clear advantage. The excimer laser has been used

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Figure 12-2.  Slit lamp appearance of granular dystrophy.

for treatment of recurrent erosions associated with basement membrane dystrophies and for removal of deeper layers in conditions such as Reis-Bücklers and Thiel-Behnke dystrophies (phototherapeutic keratectomy). Although in the first instance the excimer laser may not offer a clear advantage over debridement, in the second it has supplanted manual lamellar keratectomy as the treatment of choice. Microkeratome-assisted lamellar keratectomy may be equally effective.

10.What controversy surrounds the dystrophies affecting the Bowman’s layer?

Until recently there has been some confusion over dystrophies affecting the Bowman’s layer, because they present with two different sets of characteristics, but historically they have been lumped under Reis-Bücklers dystrophy. The first set was described by Reis in 1917 and later by Bücklers in 1949 and the second by Thiel and Behnke in 1967. Küchle et al. divided the Bowman’s membrane dystrophies into two classifications: corneal dystrophy of the Bowman’s layer type I and type II. Type I is synonymous with the original Reis-Bücklers dystrophy and equivalent to what also has been described as superficial variant of granular dystrophy. Type II is honeycomb-shaped and is also known as the Thiel-Behnke corneal dystrophy. The two dystrophies have slightly different characteristics on light microscopy. Transmission electron microscopy, on the other hand, differentiates them unequivocally.

11.Describe the inheritance patterns of the stromal dystrophies.

•Autosomal dominant: Granular (Groenouw type I; Fig. 12-2), lattice, Avellino granular–lattice, Schnyder’s crystalline, fleck, central cloudy dystrophy of François, pre-Descemet, congenital hereditary (stromal), and posterior amorphous dystrophies

•Autosomal recessive: Macular (Groenouw type II) and possibly gelatinous droplike dystrophies

12.Match the stromal dystrophy with the histochemical stain for the accumulated substance.

•Granular: Masson trichrome stains hyaline

•Lattice: Congo red stains amyloid (amyloid deposits exhibit polarized light birefringence and dichroism)

•Macular: Alcian blue stains mucopolysaccharides (glycosaminoglycans)

•Lattice and macular dystrophies also stain with periodic acid–Schiff stain.

13.Describe the clinical features of the three major stromal dystrophies.

See Table 12-1.

14.Is lattice dystrophy associated with systemic amyloidosis?

There are three types of lattice dystrophy. Only type II (Meretoja’s syndrome or familial amyloid polyneuropathy type IV), which has less corneal involvement than type I or III, is associated with systemic findings, including blepharochalasis, bilateral facial nerve palsies, peripheral neuropathy, and systemic amyloidosis.

15.What is the differential diagnosis of corneal stromal crystals? What systemic findings are associated with Schnyder’s crystalline dystrophy?

The differential diagnosis of corneal stromal crystals includes Bietti’s peripheral crystalline dystrophy, cystinosis, and dysproteinemias, such as multiple myeloma, Waldenstrom’s macroglobulinemia, and benign monoclonal gammopathy.

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Table 12-1.  Clinical Features of the Three Major Stromal Dystrophies

Figure 12-3.  Schnyder’s crystalline stromal dystrophy.

Schnyder’s dystrophy (Fig. 12-3) is strongly associated with hypercholesterolemia with or without hypertriglyceridemia. There is no direct association with primary hyperlipidemias, and serum lipid levels do not correlate with the density of the corneal opacities. The dystrophy more likely represents a localized defect in cholesterol metabolism. Of importance, not all patients with Schnyder’s dystrophy have clinical evidence of corneal crystalline deposits.

16.How does central cloudy dystrophy of François differ from posterior crocodile shagreen?

Although some physicians have argued that the location of the lesions differs in the two conditions, the lesions are clinically the same. It is generally accepted that the polygonal “cracked-ice” lesions of the central cloudy dystrophy of François are more central, deeper, and, by definition, bilateral with an inheritance pattern. On the other hand, posterior crocodile shagreen is more commonly peripheral and anterior stromal and is classified as degeneration. Of importance, both conditions are associated with normal corneal thickness and no recurrent erosions or significant visual compromise.

17.What characterizes Avellino dystrophy?

Avellino dystrophy also has been called granular–lattice dystrophy. The granular deposits occur in the anterior stroma early in the progression of the condition, followed later by lattice lesions in the midto posterior stroma and finally by anterior stromal haze. More patients with Avellino dystrophy experience recurrent erosions than patients with typical granular dystrophy. The disease-causing genes

of lattice dystrophy type I, granular dystrophy, Avellino dystrophy, and Reis-Bücklers dystrophy have been mapped to chromosome 5q, suggesting one of the following possibilities:

1.A corneal gene family exists in this region.

2.These corneal dystrophies represent allelic heterogeneity (i.e., different mutations within the same gene manifest as different phenotypes).

3.They are the same disease.

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Figure 12-4.  Appearance of eye after penetrating keratoplasty.

18.How are stromal dystrophies treated?

To the extent that some dystrophies, such as lattice and Avellino, are associated with recurrent erosions, they are treated as discussed earlier. When the lesions obscure vision and are restricted to the anterior third of the stroma, they are usually amenable to manual lamellar, microkeratome-assisted lamellar, or phototherapeutic keratectomy with the excimer laser. If the lesions are deeper, lamellar or penetrating keratoplasty is necessary.

19.Is keratoplasty a definitive treatment?

Deep anterior lamellar keratoplasty (DALK) offers the advantage of preserving the host Descemet’s membrane and endothelium. Penetrating keratoplasty may be considered as well, especially if the surgeon is not comfortable with the DALK technique. Both keratoplasty techniques are associated with recurrence of the pathology in the graft as early as 1 year after surgery. The recurrent pathology is sometimes milder than in the original cornea but may require regrafting not infrequently (Fig. 12-4).

KEY POINTS: KERATOPLASTY

1. Deep anterior lamellar keratoplasty (DALK) is the procedure of choice for stromal dystrophies with deep stromal involvement not amenable to surgical or phototherapeutic keratectomy.

2. Endothelial keratoplasty (Descemet stripping endothelial keratoplasty or Descemet membrane endothelial keratoplasty) is the procedure of choice for posterior membrane dystrophies.

3. Penetrating keratoplasty (PK) may also be considered for stromal or posterior membrane dystrophies, especially when the surgeon is not familiar with anterior and posterior keratoplasty techniques.

4. DALK and PK do not prevent recurrence of stromal dystrophies in the donor graft.

20.Name the three posterior membrane dystrophies.

•Posterior polymorphous dystrophy (PPMD)

•Fuchs’ endothelial dystrophy

•Congenital hereditary endothelial dystrophy (CHED)

21.What is their common clinical manifestation?

All three essentially share the pathway of corneal edema and increased thickness, resulting in visual compromise.

22.Describe the inheritance patterns of the three posterior membrane dystrophies.

Posterior polymorphous and Fuchs’ dystrophies have an autosomal dominant inheritance pattern. Two forms of congenital hereditary endothelial dystrophy exist. The autosomal dominant form presents in early childhood and is slowly progressive and frequently symptomatic. The autosomal recessive form presents at birth and is nonprogressive, but it is associated with significant visual compromise and nystagmus due to marked corneal edema.

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Table 12-2.  Main Clinical Characteristics of the Three Posterior Membrane

Dystrophies

ICE, Iridocorneal endothelial.

A B

Figure 12-5.  A, Slit lamp photo of cornea with advanced Fuchs’ dystrophy. B, Confocal microscopy of guttate changes in Fuchs’ dystrophy.

23.Describe the main clinical characteristics of the three posterior membrane dystrophies.

See Table 12-2.

24.How does Fuchs’ dystrophy differ from cornea guttata?

Cornea guttata basically refers to a pattern of corneal guttae that are usually found on the central cornea. They sometimes coalesce, produce a beaten-metal appearance, and are associated with increased pigmentation. This condition does affect vision, although not significantly. In 1910 Fuchs described a more severe form of the condition associated with stromal thickening and epithelial edema with secondary marked visual compromise (Fig. 12-5, A and B ). This represents an advanced stage of the same dystrophy.

25.Describe the workup of a patient with Fuchs’ dystrophy

•History: Ask about previous intraocular surgery

•Biomicroscopic examination: Guttae on the posterior corneal surface, increased stromal thickness, and epithelial edema with possible subepithelial bullae

•Intraocular pressure measurement

•Ultrasound or optical pachymetry

•Specular microscopy to evaluate number, size, and shape of endothelial cells

•Anterior segment optical coherence tomography (OCT)

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26.What overlapping features are seen in posterior polymorphous dystrophy and iridocorneal endothelial syndromes?

Overlapping features of PPMD and ICE are abnormal corneal endothelium, peripheral anterior synechiae, corectopia, and glaucoma.

27.What is unique about the congenital hereditary endothelial dystrophy cornea?

The CHED cornea shows markedly increased corneal thickness, unlike any other corneal dystrophy.

28.Discuss the management and prognosis of posterior membrane dystrophies

Conservative management has a role, especially in the earlier stages of Fuchs’ dystrophy. Topical hypertonic saline solution, dehydration of the cornea with a blow dryer, and reduction of intraocular pressure may decrease corneal edema and improve vision. Bandage contact lenses may be used in the setting of recurrent erosions or subepithelial bullae. However, when vision is significantly

compromised by Fuchs’ or other posterior membrane dystrophies, the definitive solution is endothelial keratoplasty (Descemet stripping endothelial keratoplasty (DSEK) or Descemet membrane endothelial keratoplasty (DMEK)). DSEK involves transplantation of a layer of donor posterior stroma with Descemet’s membrane (DM) and endothelium (Fig. 12-6, A–C). DMEK is a pure anatomic replacement of

the host DM and endothelium with healthy donor tissue. This is surgically challenging because of the very thin nature of the donor tissue (15 to 20 μm) (Fig. 12-6, D–G). Keratoplasty, endothelial or penetrating, has the best prognosis in Fuchs’ dystrophy, especially in the absence of glaucoma; a fairly good prognosis in PPMD in the absence of glaucoma; and a guarded prognosis in CHED, especially in the early pediatric age group.

29.Can PPMD recur in the graft?

Recurrence of PPMD has been reported.

30.Discuss considerations for combined cataract extraction and corneal transplantation in patients with Fuchs’ dystrophy.

•First scenario: Visually significant cataract and borderline corneal function. The decision whether to perform corneal transplantation at the time of cataract extraction may be based on a number of factors, including appearance of the corneal endothelium by specular microscopy,

corneal thickness, visual variation throughout the day, and postoperative visual requirements of the

patient. Patients with no evidence of frank stromal edema, including absence of morning blur and a stable central corneal thickness less than 620 μm, are likely to tolerate cataract extraction alone. The risk of corneal decompensation is outweighed by the advantage of rapid visual rehabilitation

from cataract surgery alone. On the other hand, in patients with frank stromal edema, central corneal thickness greater than 650 μm, or an increase of more than 10% in corneal thickness in the morning compared with later in the day, the cornea is unlikely to tolerate routine cataract extraction. The patient will benefit from a triple procedure (i.e., cataract extraction with implant combined with keratoplasty, usually DSEK or DMEK). Having said that, most surgeons are opting

to offer their patients with early but visually significant Fuchs’ dystrophy and cataract the modern triple procedure, which includes endothelial keratoplasty (DSEK or DMEK) combined with cataract extraction and intraocular lens implantation, because of the high success of and the rapid visual rehabilitation after this combined procedure.

•Second scenario: Corneal edema requiring corneal transplantation and mild-to-moderate cataract. With the wide acceptance of DSEK and the recent emergence of DMEK as the preferred procedures for the surgical management of visually significant Fuchs’ dystrophy, together with the predictability of the refractive outcome when combined with cataract extraction (CE) and intraocular lens (IOL) implantation, more triple corneal procedures (DSEK or DMEK + CE/IOL) are being performed for corneal endothelial disease and even early cataract. Some surgeons, however, especially when treating prepresbyopic patients, prefer to stage the procedures, starting with endothelial keratoplasty followed a few months later, when the cornea is stable physiologically and refractively, with CE/IOL. This may give the patient the best chance for good unaided vision especially with the increased popularity of toric IOLs. The incidence of graft decompensation after secondary CE/IOL is small.

31.List some interesting trivia about corneal dystrophy.

•The apostrophe in Fuchs’ dystrophy is after the “s,” not before.

•In cornea guttata, guttata is the adjective describing the cornea. The actual excrescences of ­Descemet’s membrane between the endothelial cells are corneal guttae, not corneal guttata.

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E

A

F

B

G

C

D

Figure 12-6.  A, One day after Descemet stripping endothelial keratoplasty (DSEK). Postoperative bubble allows­ one to check the border and adherence of the graft. B, DSEK 1 week postoperative. The border of the graft is visible. C, Anterior segment OCT of cornea after DSEK. D, One day after Descemet’s membrane endothelial keratoplasty (DMEK). E, Anterior segment OCT 1 day after DMEK with Descemet’s membrane almost indistinguishable, showing in complete adherence of the graft. F, One month after DMEK. G, Anterior segment OCT 1 month after DMEK.

•Although keratoconus is usually bilateral and may have an inheritance pattern, it is considered an ectasia, not a dystrophy.

•Dua’s layer is a structure in the posterior stroma, 5 to 8 collagen lamellae and 5 to 16 μm thick, devoid of keratocytes, and with a high bursting pressure reaching 750 mm Hg.

•When the Descemet’s membrane is stripped off the posterior stroma it always scrolls endothelial side out!

WEBSITES

1.www.corneasociety.com/links.cfm

2.www.nkcf.org

3.www.cornealdystrophyfoundation.org