Ординатура / Офтальмология / Английские материалы / Ocular Periphery and Disorders_Dartt, Bex, Amore_2011

Glossary

Amyloid – Insoluble, fibrous, and primarily extracellular protein aggregates exhibiting beta-sheet structures that are deposited in many local and systemic diseases.

Anterior synechia – A pathological condition where the iris adheres to the cornea.

Corectopia – An iris defect involving displacement of the pupil from its normal position.

Corneal dystrophy – A bilateral inherited disorder of noninflammatory, progressive corneal disease. Corneal guttata – Wart-like excrescences of Descemet’s membrane that are associated with Fuchs’ corneal dystrophy.

Lamellar keratoplasty – A partial thickness corneal transplant of either the anterior or posterior corneal layers.

Penetrating keratoplasty – Full thickness corneal transplant.

Phototherapeutic keratectomy – A surgical procedure in which the epithelium is removed and then an excimer laser is used to ablate abnormal anterior stromal tissue.

Recurrent erosion – A syndrome of repeated epithelial defects due to abnormal adhesion of the epithelial basement membrane.

Introduction

The corneal dystrophies are a group of noninflammatory, inherited, and bilateral disorders characterized by pathognomonic patterns of corneal deposition and morphological changes. These heterogeneous dystrophies are defined by their clinical characteristics, histological findings, and genetics. Traditionally, they have also been grouped anatomically into three categories of anterior, stromal, and posterior dystrophies. The anterior dystrophies affect the epithelium, epithelial basement membrane (EBM), or Bowman’s layer. The stromal dystrophies primarily affect the stroma, but may extend into the anterior corneal layers and may rarely affect Descemet’s membrane and the endothelium. The posterior dystrophies are primarily disorders of endothelial cells and the posterior portion of Descemet’s membrane. They may also alter the structure of the stroma and anterior cornea.

There is a wide variation in the type and degree of symptoms caused by the corneal dystrophies. Progressive accumulation of tissue deposits can lead to vision loss from corneal opacification and astigmatism. Disruption of normal cell function can lead to abnormal epithelial adhesion with resultant painful recurrent epithelial erosions or loss of endothelial cell activity with resultant corneal edema. Several of the dystrophies are associated with vision-threatening ocular or systemic manifestations. Together, corneal dystrophies are the primary indications for approximately 10–15% of the corneal transplantations performed in the United States each year.

Anterior Dystrophies

Epithelial and EBM Dystrophies

EBM Dystrophy

Also known by the descriptive term, map-dot-fingerprint (MDF) dystrophy, or the eponym, Cogan’s dystrophy, EBM dystrophy (EBMD) is arguably the most common dystrophy, found in approximately 5% of the adult population, with a slight preponderance of women. While in rare instances an autosomal dominant inheritance pattern has been identified, in the vast majority of cases this disease is sporadic, making its designation as a corneal dystrophy controversial.

On examination, several patterns of basement membrane and epithelial involvement can be observed, including dots or microcysts, map lines, and fingerprint lines. These abnormalities may fluctuate over time but are rarely progressive.

The most common symptoms of EBMD are recurrent erosions and blurred vision. The recurrent erosions arise because of poor epithelial adhesion to the underlying basement membrane. These erosions may be triggered by the lid trauma caused by an innocuous blink and are most often noted upon eye opening in the morning – with pain sometimes – waking the patient from sleep. The pain, foreign body sensation, and blurring associated with the erosions typically last only several minutes, but for some may be prolonged and severe. In addition to these transient symptoms, the surface changes from EBMD in the visual axis may lead to irregular astigmatism and adversely affect a patient’s best-corrected visual acuity.

Recurrent erosions are managed acutely with lubricants, bandage contact lenses, patching, and prophylactic antibiotics. Medical options for prophylaxis against these recurrent erosions begin with aggressive lubrication and an

emphasis on the use of bedtime ointments to avoid epithelial dehydration which can potentiate poor epithelial adhesion. Additionally, it is beneficial to address co-existing ocular surface diseases such as blepharitis, and the use of oral tetracyclines may inhibit epithelial breakdown. Similarly, anti-inflammatory agents such as topical steroids may inhibit this breakdown, but the long-term use of these agents should be dealt with caution. If recurrent erosions persist despite medical interventions, epithelial adhesion can be improved through mechanical disruption with subsequent healing through debridement with diamond burr polishing, stromal needle puncture, or Nd:YAG laser puncture. For large or recurrent lesions in the visual axis, excimer laser phototherapeutic keratectomy may be preferred to avoid scarring due to other techniques.

Microscopic examination of EBMD reveals a thickened epithelial layer with a thickened or redundant basement membrane that has extended into the epithelium in either linear propagations or sheets, representing the map and fingerprint lines, respectively. The dots are microcysts formed by these abnormal extensions of basement membrane that have entrapped degenerated epithelial cells.

Meesman’s

This rare anterior dystrophy is an autosomal dominant disorder characterized by the development of intraepithelial vesicles in the central cornea that appear as early as in the first few years of life. Over time, there is progressive involvement of the mid-peripheral cornea and an increase in the number and density of vesicles. As the disease progresses, vision may slowly deteriorate and the eye may become irritated as the intraepithelial vesicles rupture. In contrast to EBMD, recurrent erosions are uncommon in this dystrophy. While most patients are asymptomatic, those who have ocular irritation from ruptured vesicles are treated with lubricants or soft contact lenses to manage these microerosions.

The pathologic changes in the epithelium are thickening of the basement membrane and the formation of small epithelial cysts containing a material composed of degenerated keratin with cytoplasmic and nuclear debris, known as peculiar substance. Consistent with the epithelial nature of this dystrophy, Meesman’s lesions are known to recur in cornea transplants as the host epithelium repopulates the surface of the donor button.

Genetic analysis has elicited responsible mutations in two genes (KRT3 and KRT 12) on chromosomes 12q13 and 17q12, respectively, which code for two corneal keratins (k3 and k12).

Bowman’s Layer Dystrophies

Reis-Buckler’s

Also known as corneal dystrophy of Bowman’s type 1 (CDB-1) and granular dystrophy type III (GD-3), this is

Figure 1 External photograph of Reis-Buckler’s dystrophy (corneal dystrophy of Bowman’s type 1 or granular dystrophy type 3) demonstrating geographic opacification of Bowman’s layer.

an autosomal dominant dystrophy that is marked by geographic opacification of Bowman’s layer, beginning as fine granular deposits that evolve into confluent opacities over time. Reis-Buckler’s arises during childhood or adolescence and often leads to frequent recurrent erosions and marked, progressive visual loss (Figure 1). The recurrent erosions can be managed in a manner similar to in EBMD, but the progression of opacification may necessitate extensive excimer laser phototherapuetic keratectomy. Despite initial clearing of the visual axis, these patients often have recurrence of opacities requiring additional treatment.

Histological examination demonstrates that the normally acellular collagenous Bowman’s is disrupted, noncontiguous, or absent and is replaced with fibrocellular tissues. The opacities in Bowman’s layer are band-shaped, granular, and stain red with Masson’s trichrome. Similar to other granular dystrophies, these lesions appear as rodshaped bodies under electron microscopy.

Multiple mutations of the human transforming growth factor inducible gene (TGFBI) – previously known by the misnomer, keratoepithelin – on chromosome 5q31 may lead to the Reis-Buckler’s phenotype. The most common mutations are Arg124 or Arg555 which are both thought to affect the solubility and stability of the TGFBI protein.

Thiel-Behnke

Initially classified as a variant of Reis-Buckler’s, ThielBehnke, or corneal dystrophy of Bowman’s type 2 (CDB-2), at times is similar in its clinical appearance but is always distinct in its histological and electron microscopic appearance. Also autosomal dominantly inherited, ThielBehnke has a slightly later onset of recurrent erosions, typically in the second decade of life, and vision loss is more slowly progressive. At the slit lamp, this dystrophy typically appears as honeycombed-shaped subepithelial

opacities. It can be managed similarly to Reis-Buckler’s and recurrence after keratectomy is infrequent.

Examination of pathologic specimens reveals only weakly positive Masson’s trichome staining, in contrast to the strongly positive staining of Reis-Buckler’s. The pathognomonic features are the 8–10 nm curly fibers identified by electron microscopy.

Similar to Reis-Buckler’s, this dystrophy is sometimes linked to the TGFBI gene. However, there is genotypic heterogenicity for Thiel-Behnke as evidenced by the discovery that mutations on chromosome 10q23-q24 can also lead to this phenotype.

Stromal Dystrophies

Lattice

There are three major types of lattice dystrophy and all are unified by the appearance of lattice lines on slit-lamp examination and amyloid deposition on histological examination.

Lattice type 1. In type 1 lattice, or Biber–Haab–Dimmer corneal dystrophy, amyloid is deposited in the cornea but is not found elsewhere in the body. It can vary in its appearance, and there is often progression from round, ovoid and white, or small, filamentous, and refractile anterior stromal lesions to more nodular, threadlike, and thicker linear lesions that extend into deep stroma (Figure 2(a)). Initially, the stroma between lesions remains clear, but over time these spaces opacify and assume a ground-glass appearance. The limbus is typically spared. Signs of lattice dystrophy most often appear in early childhood, but symptoms of surface erosions, irregular astigmatism, and vision loss usually begin in the second or third decades of life.

Recurrent erosions can be frequent and can be managed as described previously. Some authors believe that phototherapeutic keratectomy should be avoided (as well as laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK)) because excimer laser, within the UV light spectrum, may trigger activation of TGFB and exacerbate this condition. For severe vision loss due to opacification, penetrating and lamellar keratoplasty may be warranted. Recurrence may occur in these grafts but presents differently than the primary lesions.

Specimens are positive for amyloid and stain with Congo red, periodic acid-Schiff ’s reagent (PAS), Masson’s trichrome, and thioflavine-T fluorochrome, and are metachromatic with crystal violet (Figure 2(b)). As with all amyloid, they demonstrate apple-green birefringence under polarized light.

Lattice type 2. Type 2 lattice, also known as Meretoja’s, familial, or Finnish amyloidosis syndrome, is characterized by both systemic and corneal amyloid deposition. Typically seen in families of Finnish, European, or Japanese origin, it is usually asymptomatic until early adulthood. Corneal slit-lamp examination shows more peripheral

Figure 2 (a) Slit-lamp photograph of lattice type 1 dystrophy. Arrow indicates amyloid deposition. (b) Congo red stain of cornea in lattice type 1 demonstrating amyloid deposition. Afshari, N. A., Mullally, J. E., Afshari, M. A. et al. (2001). Survey of patients with granular, lattice, avellino, and Reis-Bu¨cklers corneal dystrophies for mutations in the BIGH3 and gelsolin genes. Archives of Ophthalmology 119: 16–22. ã 2001 American Medical Association. All rights reserved.

deposits, with fewer and finer lattice lines, and a primarily sub-Bowman’s location of deposition.

Patients begin to experience corneal changes in the third decade of life, but symptoms of reduced corneal sensation and frequent recurrent erosions are uncommon until the fifth decade. Overall, the visual prognosis is better than in type 1 with many patients not developing visual loss until late in the course of disease. While there is a decreased severity of corneal disease, the systemic manifestations can be serious and include dry, itchy skin, intermittent proteinuria, and cardiac abnormalities. Patients may develop severe mask-like facial paresis (loss of facial muscle motor function), blepharochalasis (inflammation

of eyelid), protruding lips, and pendulous ears from amyloid deposition and secondary muscular dysfunction.

Unique among the lattice dystrophies, type 2 does not arise from a mutation in the TGFBI gene. Instead, it has been linked to a dominant mutation of the gelsolin gene on 9q32–34 that encodes an amyloid precursor.

Lattice types 3 and 3a. Type 3 lattice is the least severe and has an autosomal recessive pattern of inheritance. The lattice lines in type 3 are thicker and ropier in appearance, and later in onset. Vision is often not affected until the sixth or seventh decade of life, and recurrent erosions are rare. Like type 1, type 3 is associated with a defect in the TGFBI gene. Type 3a is similar in presentation to type 3 but follows an autosomal dominant inheritance pattern.

Granular

Granular type 1

The most common of the stromal dystrophies, granular dystrophy is named for its typical appearance as crumblike, discrete, grainy opacities in the anterior stroma. Initially, these opacities are fine dots or lines and with time they assume their more characteristic appearance of anterior stromal drops, rings, or crumbs with intervening clear spaces. As the dystrophy progresses, the lesions coalesce and extend into deeper stroma, and the intervening spaces take on a ground-glass appearance. The lesions rarely extend to the limbus (Figure 3). Symptoms of vision loss do not usually occur until the fifth decade. Despite the anterior location of the dystrophy, recurrent erosions are rare. There are exceptions to this mild course, and some variants of the disease cause earlier and more severe vision loss.

For patients with severe vision loss, management options include superficial keratectomy, phototherapeutic keratectomy, and lamellar or full thickness keratoplasty depending on the depth of involvement. Recurrence may occur even in full thickness grafts necessitating repeat procedures. With recurrence, the lesions may appear similar to primary disease or may consist of subepithelial lesions emanating from the graft periphery.

The pathology of granular type 1 shows eosinophilic, rod-shaped, trapezoidal hyaline deposits in the stroma that are bright red on Masson’s trichome and weakly PAS positive. On electron microscopy, the amorphous material appears rod or trapezoidal in shape.

Granular dystrophy type 1 is also due to a defect in the TGFBI gene and at least two causative mutations have been identified.

Granular type 2

Previously known as Avellino dystrophy (because the initial reports were of families from Avellino, Italy) this variant of granular dystrophy is characterized both by granular deposits and lattice lines or stellate deposits. Early lesions are often ring-like and anterior and can appear similar to type 1 granular lesions. As the disease

(a)

(b)

(c)

Figure 3 Slit-lamp photographs of mild (a) and moderate (b) granular type 1 corneal dystrophy. (c) Masson’s trichrome staining of hyaline deposits in granular dystrophy. Afshari, N. A., Mullally, J. E., Afshari, M. A. et al. (2001). Survey of patients with granular, lattice, avellino, and Reis-Bu¨cklers corneal dystrophies for mutations in the BIGH3 and gelsolin genes. Archives of Ophthalmology 119: 16–22. ã 2001 American Medical Association. All rights reserved.

progresses, deeper lesions appear and the lattice-like lesions are observed. With progression, the intervening clear spaces between lesions assume a hazy appearance.

Symptoms may be more severe and the onset earlier than in type 1 granular dystrophy. Many patients experience vision loss by adolescence, but vision rarely drops below the 20/70 level. Recurrent erosions and related ocular discomfort occur in a minority of patients, but more frequently than in type 1 granular patients.

Not every patient displays clinical evidence of both granular and lattice lesions, but on histologic examination these patients uniformly demonstrate both hyaline and amyloid deposits, the distinguishing pathologic findings of the two respective diseases.

As both granular and lattice dystrophies can arise from dominant TGFBI gene defects, it is not surprising that TGFBI mutations have been found to be responsible for this dystrophy which displays characteristics of both diseases. The autosomal dominant inheritance of type 2 granular dystrophy has a high penetrance, but phenotypic expressivity is quite variable between family members.

Macular

The least common of three major stromal dystrophies, the autosomal recessive Macular dystrophy is also the most severe. Its clinical appearance is unique, seen at the slitlamp as diffuse, cloudy, gray–white lesions that begin superficially and centrally and then spread downward and outward. By late adolescence, these lesions may progress to involve the entire cornea from limbus to limbus and from anterior stroma to the endothelium. Anteriorly protruding nodules may cause highly irregular astigmatism, and Descemet’s membrane involvement may produce corneal guttata.

Vision loss can begin in the first decade of life and may be severe by the third decade. Recurrent erosions are more frequent and may also begin at an early age. Due to photophobia, many patients seek treatment with tinted lenses, phototherapeutic keratectomy, or lamellar and penetrating keratoplasty. Unfortunately, recurrence is common and may lead to significant vision loss even in penetrating keratoplasty recipients. This recurrence most often begins in the periphery near the graft–host junction, and has been found to be more common in smaller-sized grafts.

The key histopathologic finding of Macular dystrophy is glycosaminoglycan accumulation. This accumulation may occur both intracellularly and extracellularly and is found between stromal lamellae, subepithelially, and within keratocytes and endothelial cells. The deposits stain with Alcian blue, colloidal iron, metachromatic dyes, and PAS. The cornea may have decreased overall thickness with a thinned or absent Descemet’s membrane and an epithelium that is stretched thin over anterior stromal deposits.

Unique in its autosomal recessive inheritance, Macular dystrophy is linked to various mutations on chromosome

16q2 and the CHST6 gene that encodes enzymes of keratan sulfate synthesis. This keratan sulfate defect is systemic and the varied expression of keratan sulfate in serum and cornea has led to the classification of several types of Macular dystrophy. In type 1, keratan sulfate is completely undetectable in the cornea and serum. In type 1a, the only detectable keratan sulfate is found within keratocytes, and in type 2 corneal keratan sulfate is present but levels are diminished.

Rare Stromal Dystrophies

Gelatinous drop-like dystrophy

Presenting in the first decade of life with photophobia, foreign body sensation and decreased vision, this autosomal recessive dystrophy, also known as familial subepithelial amyloidosis, resembles band keratopathy. The opacities are subepithelial and anterior stromal, and may, over time, assume a mulberry-like gelatinous appearance. Keratectomy and keratoplasty may be performed with variable success due to recurrence.

This dystrophy is linked to mutations in the M1S1 gene on chromosome 1p31. These defects lead to the accumulation of amyloid from a truncated surface glycoprotein.

Schnyder’s crystalline dystrophy

Also known as Scandinavian dystrophy due to a reported cohort of patients in central Massachussets of Scandinavian origin, this autosomal dominant dystrophy occurs within the first year of life as central, crystalline, anterior stromal lesions that are either discoid, ring-like, or geographic in distribution. A significant minority may have a noncrystalline form which occurs later in life. As the lesions progress, they involve more posterior stroma. By the third decade a prominent arcus lipoides is seen, and by age 40 most patients have full thickness corneal opacities. While there is no correlation between this disease and elevated serum cholesterol, patients’ lipid and cholesterol levels should be checked as early arcus, before age 50, and can be an indicator of hyperlipidemia. Important diseases in the differential diagnosis of central crystalline corneal deposits should also be ruled out and these include Bietti’s corneoretinal dystrophy, cystinosis, and dysproteinemias such as multiple myeloma.

Pain is infrequent because many of these patients develop decreased corneal sensation. Vision loss is the most common presentation and may be treated with lamellar or penetrating keratoplasty. Histologic examination of the corneal buttons reveal that the crystals are composed of cholesterol and lipid and the pathogenesis is believed to involve a defect in local lipid metabolism or transport. The genetic defect has been linked to chromosome 1p.

Central cloudy dystrophy

First described by Francois, this autosomal dominant or, rarely, sporadic dystrophy appears as bilaterally symmetric central and deep stromal cloudy, gray–white, illdefined, snowflake-like lesions. The appearance is similar to posterior crocodile shagreen, and, similarly, is rarely symptomatic.

Congenital hereditary stromal dystrophy

This dystrophy, which is often static or slowly progressive, has been described in several families and occurs at birth as a diffusely hazy cornea of normal thickness. The lesions are diffuse, bilateral, small, and located primarily in the anterior stroma. This generalized opacification may lead to profound vision loss and early penetrating keratoplasty may be warranted to prevent amblyopia.

The pathogenesis involves disorganization of corneal lamellae with randomly arranged collagen fibrils and loss of corneal transparency. The inheritance pattern is autosomal dominant and a defect has been identified in the decorin gene that encodes a dermatan sulfate proteoglycan.

Posterior amorphous dystrophy

Remarkable for central stromal thinning without ectasia or astigmatism, this autosomal dominant dystrophy begins in childhood and slowly progresses. It is characterized by bilateral gray sheets in the deep stroma extending to the limbus. The stroma may thin to about 300mm, but vision is only mildly affected.

In addition to stromal thinning, histologic examination demonstrates a thick collagenous layer posterior to Descemet’s membrane as well as relative absence of stromal keratocytes. The endothelium is unaffected.

Fleck dystrophy

Fleck dystrophy is usually discovered as an incidental finding, because it is asymptomatic in the majority of patients (recurrent erosions can rarely occur). It is autosomal dominant, may be present at birth or arise in infancy, and is rarely progressive. On slit-lamp examination, small white flecks can be seen in all stromal layers and represent swollen keratocytes with cytoplasmic vesicles due to membrane-bound vacuoles of lipid and mucopolysaccharide. On electron microscopy, flecks stain with oil-red O.

A causative mutation on chromosme 2q35 in the PIP5K3 gene has been identified. This gene codes for an enzyme involved in post-Golgi vesicle processing of protein and lipids.

Posterior Dystrophies

Fuchs’ Endothelial

By far the most common corneal dystrophy to lead to corneal transplantation, Fuchs’ is an autosomal dominant

dystrophy that directly involves Descemet’s membrane and the endothelium, and may indirectly impact all layers of the cornea. The classic lesion of Fuchs’ is the central guttae, but a controversial nonguttate form has been described. Over time, the guttata spread peripherally and coalesce. Descemet’s may assume a thickened, grayish, irregular appearance, and this may eventually mask the guttata. If corneal edema develops, it begins posteriorly as evidenced by Descemet’s and deep-stromal wrinkles. As the corneal edema progresses, the stroma thickens and microcystic epithelial edema can usually be appreciated by the time the cornea thickness has increased by 100 mm. Later in the course of the disease, the cornea takes on a ground-glass appearance (Figure 4).

Fuchs’ guttata are 2.5 times more likely to develop in women than men, and women are nearly 6 times more likely to develop Fuchs’ corneal edema. Symptoms of blurring are often first seen in during the morning hours because the cornea swells overnight due to decreased evaporation and the increased hypotonicity of the tear film. Some patients find relief from hypertonic solutions, decreasing intraocular pressure, or by facilitating tear evaporation with external devices such as blow dryers. Recurrent erosions often occur in advanced cases due to edema-induced anterior basement membrane-like lesions and ruptured epithelial bullae. Repeat epithelial defects may lead to fibrous scarring and neovascularization. These epithelial lesions may be managed with bandage contact lenses. As mentioned previously, many patients require management with penetrating or endothelial keratoplasty, especially after other intraocular surgeries which may lead to further loss of endothelial cell viability.

The pathology of Fuchs’ is well characterized and primarily consists of changes in endothelial cell architecture and number, and abnormalities of posterior Descemet’s membrane. The number of endothelial cells decreases while the remaining cells show an increase in size, a less hexagonal and more irregular shape, and an

Figure 4 Slit-lamp photograph of Fuch’s dystrophy.

eccentricity of cellular nuclei. This can be seen in vivo with specular microscopy as a decreased endothelial cell density, polymegathism, and cellular polymorphism. On electron microscopy the cells look more fibroblastic with an increase in rough endoplasmic reticulum, lysosomes, vacuoles, and cytoplasmic filaments. The posterior nonbanded zone of Descemet’s membrane is thinner than normal, on an average less than 2 mm compared to 8 mm in a normal adult population. An abnormal PAS-positive posterior collagenous layer significantly increases the overall thickness of Descemet’s to 2–3 times that of normal corneas, and this layer is contiguous with guttae that jut out posteriorly, thinning the overlying endothelial cells and pushing their nuclei aside into the intervening valleys. With corneal edema, the corneal lamellae thicken, and histologically this is evidenced by a decrease in artifactual clefting.

The genetic defects leading to Fuchs’ are numerous and the identified mutations have been linked to chromosome 1p32-1p34, as well as chromosomes 7, 15, 17, and X.

Posterior Polymorphous Membrane

Typically beginning in the second or third decade of life, this autosomal dominant dystrophy of Descemet’s and the endothelium is named for the diversity of clinical findings seen on slit-lamp examination. The hallmark lesions are posterior vesicles, and these may be accompanied by bands or by diffuse opacities in 50% and 10% of the cases, respectively. The vesicles, misleadingly, look like transparent cysts of Descemet’s membrane. The bands, if present, are usually horizontal, have scalloped edges, and most commonly occur along the inferior paracentral cornea. The bands can be distinguished from tears or folds of Descemet’s because they lack tapered edges. Diffuse opacities range in size from 500 to 2000 mM, have a peau d’orange texture and are associated with adjacent posterior stromal haziness. As in Fuchs’, guttata may be seen and corneal edema can develop. Rarely, this dystrophy is associated with corneal steepening or ectasia.

For the majority of patients the dystrophy causes no symptoms, is nonprogressive and may be picked up incidentally in the second or third decade of life. However, there is a wide spectrum of disease severity and some cases are vision threatening. In fact, severe corneal edema and clouding may be present at birth or early childhood, and this dystrophy needs to be considered in the differential diagnosis of congenital corneal clouding. While most cases are bilateral, there may be a marked degree of asymmetry in its presentation. In addition to corneal symptoms, patients may develop high intraocular pressure as a result of the peripheral anterior synechiae.

For patients with corneal decompensation, penetrating keratoplasty has been the treatment of choice. The success

rate of keratoplasty is much higher for patients without significant broad preoperative synechiae or high pressure, and may be extremely low for patients with these problems. Recurrence after keratoplasty may occur in the form of a retrocorneal membrane. The pressure elevations associated with this dystrophy are difficult to manage medically or surgically.

The pathologic findings demonstrate layered-endothelial cells that have assumed epithelial characteristics such as microvilli and rapid growth in culture, and stain with epithelial cell markers such as cytokeratin (CK), pancytokeratin, and CK7 (a glandular epithelial marker). Descemet’s membane is irregular with a typically normal anterior-banded zone but an absent or markedly abnormal posterior nonbanded zone. Much of the posterior zone is replaced by heterogenous collagenous components that comprise a 15–25-mM-thick posterior collagenous layer. Posterior synechiae may be found in up to a quarter of patients, and may be accompanied by iris defects including atrophy and corectopia.

On specular microscopy, the various posterior polymorphous lesions can be further examined. The vesicles appear as well-demarcated dark round areas with lighter ridges and dots. The bands have shallow hills and valleys composed of confluent vesicles, and the diffuse lesions are well-demarcated reflective areas with enlarged, pleomorphic, indistinct endothelial cells that are surrounded by more normal appearing endothelial cells.

At least two different loci are associated with posterior polymorphous dystrophy and they are found on chromosomes 20q11 and 1p34.3–p32. The resultant defects may affect the production of type VIII collagen, the predominant component of the anterior-banded zone.

Congenital Hereditary Endothelial Dystrophy

Present at birth or in the early postnatal period, this dystrophy is bilateral, symmetric, and diffuse, with corneal haze spanning from limbus to limbus. The cornea is very thick – 2–3 times normal – and there are no other associated anterior segment defects. Rarely, this corneal edema begins later in infancy or early childhood. Treatment consists of early keratoplasty.

Examination of the excised corneal buttons reveals reduction, absence, or degeneration of endothelial cells and diffuse corneal edema. As in all posterior dystrophies, there is an abnormal posterior nonbanded zone which merges into a posterior collagenous layer.

Inheritance is most often autosomal recessive and linked to chromsome 20p13, but rarely may be inherited as a dominant trait on chromosome 20p11.2–q11.2.

See also: Corneal Endothelium: Overview; Corneal Epithelium: Cell Biology and Basic Science; Corneal

Epithelium: Transport and Permeability; Corneal Epithelium: Wound Healing Junctions, Attachment to Stroma Receptors, Matrix Metalloproteinases, Intracellular Communications; Corneal Imaging: Clinical; Corneal Scars; The Corneal Stroma; Cornea Overview; Imaging of the Cornea; Regulation of Corneal Endothelial Cell Proliferation; Regulation of Corneal Endothelial Function.

Further Reading

Afshari, N. A., Mullally, J. E., Afshari, M. A., et al. (2001). Survey of patients with granular, lattice, avellino, and Reis-Bu¨cklers corneal dystrophies for mutations in the BIGH3 and gelsolin genes. Archives of Ophthalmology 119: 16–22.

Afshari, N. A., Li, Y. J., Pericak-Vance, M. A., et al. (2009). Genome wide linkage scan in Fuchs endothelial corneal dystrophy. Investigative Ophthalmology and Visual Science 50: 1093–1097.

Bron, A. J. (2000). Genetics of the corneal dystrophies: What we have learned in the past twenty-five years. Cornea 19: 699–711.

Dinh, R., Rapuano, C. J., Cohen, E. J., et al. (1999). Recurrence of corneal dystrophy after excimer laser phototherapeutic keratectomy. Ophthalmology 106: 1490–1497.

Holland, E. J., Daya, S. M., Stone, E. M., et al. (1992). Avellino corneal dystrophy: Clinical manifestations and natural history.

Ophthalmology 99: 1564–1568.

Kang, P. C., Klintworth, G. K., Kim, T., et al. (2005). Trends in the indications for penetrating keratoplasty, 1980–2001. Cornea 24: 801–803.

Krachmer, J. H., Mannis, M. J., and Holland, E. J. (2005). Cornea, 2nd edn. Philadelphia, PA: Elselvier Mosby.

Kanski, J. J. (2003). Clinical Ophthalmology: A Systematic Approach, 5th edn. Edinburgh: Butterworth Heinemannn.

Stone, E. M., Mathers, W. D., Rosenwasser, G. O., et al. (1994). Three autosomal dominant corneal dystrophies map to chromosome 5q.

Nature Genetics 6: 46–51.

Vasilliki, P. and Colby, K. (2008). Genetics of anterior and stromal corneal dystrophies. Seminars in Ophthalmomlogy 23: 9–17.

Yanofff, M. and Duker, J. S. (2004). Ophthalmology, 2nd edn. St. Louis, MO: Mosby.

Relevant Websites

http://www.emedicine.com – eMedicine: Ophthalmology Article. http://www.nei.nih.gov – Facts about the Cornea and Corneal Disease

(NEI Health Information). http://www.cornealdystrophyfoundation.org – The Corneal Dystrophy

Foundation.

Glossary

Confocal – Noncontact imaging modality based on the principle that light passed through an aperture and focused by an objective lens onto an area of interest.

Optical coherence tomography (OCT) –

Noncontact imaging modality in which back-reflected light or backscattered infrared light from internal tissue microstructure is analyzed to achieve two or three-dimensional cross-sectional tomographic images of optical reflectivity.

Phototherapeutic keratectomy (PTK) – Surgery using a laser to treat various ocular disorders by removing tissue from the cornea.

Introduction

Assessment of anterior segment structures is an integral part of the ophthalmic evaluation. Clinical techniques for examining the human cornea in vivo have greatly expanded over the last several decades. The clinician’s armamentarium includes slit lamp biomicroscopy, specular microscopy of the endothelium, computed corneal topography, high-frequency ultrasound, anterior segment optical coherence topography (OCT), and confocal microscopy. Advanced anterior segment imaging is a routine part of the anterior segment physicians’ practice. Confocal microscopic evaluation of the cornea in vivo began in the late 1980s. The invention of OCT in the early 1990s initially centered on retinal imaging and was subsequently modified for anterior segment applications.

In the clinical setting, confocal microscopy and anterior segment OCT are noninvasive devices that allows for examination of normal and diseased corneas and anterior segment structures such as the angle, iris, and lens, aiding in both routine patient care and in managing complex pathology.

Confocal Microscopy

Historical Overview

Marvin Minsky invented the confocal microscope in 1955. His novel invention imaged tissue parallel to its surface.

Traditionally, images of the tissue were oriented perpendicular to their surface. Minsky exploited the pinhole effect to accomplish his goal. He proposed that both the illumination (condenser) and observation (objective) systems could be focused on a single point (both have common focal points, and thus the name confocal). Using a pinhole eliminates unwanted optical artifacts from light reflected above and below the tissue of interest, improving image quality. However, this increased resolution comes at a cost of a small field of view. A full field of view is accomplished by scanning. In 1968, the first tandem scanning confocal microscope (TSCM) was developed. This improvement used a rotating Nipkow disk to simultaneously scan multiple points on a stationary specimen. In 1985, the confocal was first used to describe imaging of human corneas ex vivo and rabbit corneas in vivo. Around the same time of development of the TSCM, Svishchev introduced the scanning two-sided mirror confocal microscope. This was later modified by Thaer to enable real-time scanning, the precursor to the modern slit scanning confocal microscope (SSCM).

Current commercially available confocal microscopes include the Confoscan 4 (Nidek Technologies, Gamagori, Japan), Confoscan P4 (Tomey Corporation, Cambridge, MA, USA), Microphthal (Helmut Hund, Wetzlar, Germany), and the Heidelberg Retina Tomograpy II Rostock Cornea Module (Heidelberg Engineering, GmBH, Germany).

How it Works

Confocal microscopy is based on the principle that light passed through an aperture and focused by an objective lens onto an area of interest. The reflected light is then focused by a second objective lens through a second aperture to eliminate out of focus light. The ability of the system to discriminate light that is outside the focal plane results in images of higher X-, Y-, and Z-axis resolutions. The drawback is a small field of view (Figure 1). Moving the confocal system (scanning) over the stationary specimen allows for larger fields of view. The Z-axis resolution of the confocal microscope permits the dynamic scanning capability of the instrument, allowing in vivo corneal imaging without the need for stains or dyes. With computerized three-dimensional reconstruction, this technology has improved lateral and axial resolution to 1–6 and 4 –15 mm, respectively, and increased magnification up to 600 . Image quality is affected by image contrast, the light source, the scanning method, the path of light in the cornea, and the optics of the objective.

Out of

focus

Observer or camera

Figure 1 Schematic of the optical principles of confocal microscopy. White light that passes through the first pinhole is focused on the focal plane in the cornea by the condensing lens. Returning light is diverted through the objective lens and a conjugate exit pinhole and reaches the observer or camera. Scattered out of focus light from below or above the focal plane (broken lines) is greatly limited by the pinholes and does not reach the observation system. Reprinted with permission

from BJO.

Image separation (depth) is recorded by the movement of the objective between images. Water immersion objective lenses of high numerical apertures are typically used, as they eliminate surface reflections and provide good depth resolution. This requires a short working distance. In clinical practice, subject preparation for the scan is of great importance. Topical anesthesia, patient counseling of the short working distance, bright illumination, and use of coupling agents all aid in capturing useful images. Maintaining a perpendicular orientation to the corneal surface is necessary to avoid oblique sectioning.

Clinical Applications

The normal cornea

The normal human cornea consists of five layers: epithelium, Bowman’s layer, stroma, Descemet’s membrane, and endothelium. All of these layers, with the exception of Descemet’s membrane, can be imaged by confocal microscopy. It is important to note that the more a cellular component reflects light, the brighter the image will appear on a confocal scan.

From front to back, the corneal epithelium is composed of superficial, wing, and basal cells, with a normal thickness of approximately 50 mm. In the superficial layers, cells appear flat and polygonal with hyperreflective nuclei. Wing cells appear uniform in shape and size with dark nuclei. These cells are generally larger than basal cells, but smaller than superficial cells. The basal cells are smaller, more uniform in size, and have bright borders and highly reflective cell nuclei (Figures 2 and 3).

Between the basal epithelium and Bowman’s layer are corneal nerves that appear as beaded, well-defined linear

Figure 2 Superficial epithelium.

Figure 3 Basal epithelium.

Figure 4 Basal nerve plexus.

branching structures with homogeneous reflectivity (Figure 4).

Bowman’s layer appears as an amorphous homogenous layer in the normal cornea. It is acellular, with randomly