4 Clinicopathology of Corneal Endothelial Diseases Endothelial keratoplasty has been specifically devised solely to replace a defective corneal endothelial cell population in the concomitant presence of sufficient stromal optical clarity and topographic plus tectonic stability, to thereby support visual recovery. As such, the most appropriate cases for endothelial keratoplasty comprise those several intrinsic or acquired endothelial disorders that do not adversely affect stromal clarity or ocular surface integrity. Here we survey the clinical and pathological features of such primary and secondary corneal endothelial disorders, arranged in accordance with their primary or secondary endothelial dysfunctions as follows: a) Fuchs endothelial dystrophy (FED) b) Posterior polymorphous corneal dystrophy (PPCD) c) Congenital hereditary endothelial dystrophy (CHED) d) X-linked endothelial corneal dystrophy e) Iridocorneal endothelial (ICE) syndrome a) Postsurgical b) Trauma c) Postinflammatory and postinfectious: uveitis, keratitis, endotheliitis (herpes zoster ophthalmicus [HZO], herpes simplex virus [HSV], cytomegalovirus [CMV]) According to the recent report of the International Committee for the Classification of the Corneal Dystrophies (IC3D),1 the endothelial dystrophies comprise Fuchs endothelial dystrophy (FED), posterior polymorphous corneal dystrophy (PPCD), congenital hereditary endothelial corneal dystrophy (CHED), and X-linked endothelial corneal dystrophy (XECD). Primary and often inherited abnormalities of the corneal endothelium and Descemet membrane are the common characteristic of this group. The most prevalent corneal dystrophy in the United States, FED affects approximately 4% of the population over the age of 40 years2 and is more frequent and severe in women (3:1). Also common in European populations, it is rare among Asians. Exhibiting a strong inherited predisposition with more than one genetic cause, it is reported that two alleles present in the transcription factor 4 (TCF4) gene encoding the E2–2 protein increase the FED risk in homozygotes by up to 30 times.2 In particular, the TGC trinucleotide repeat expansion in TCF4 is strongly associated with FED, and a repeat length > 50 is highly specific and predictive for the disease and a predictor of disease risk.3,4 There is also evidence of significant allelic heterogeneity, with two mutations described in the collagen, type VIII, alpha 2 gene (COL8A2). Hence abnormality of solute carrier family 4, sodium borate transporter, member 11 (SLC4A11)—a sodium-coupled borate transporter of the human plasma membrane that is also linked with congenital hereditary endothelial dystrophy type 2—is implicated.5 FED is a bilateral but unpredictably progressive corneal disorder, usually appearing by the fifth or sixth decade of life but sometimes earlier. The hallmark clinical findings are minute focal excrescences (guttae) on a thickened Descemet membrane, progressing to generalized stromal and eventually epithelial edema with concomitant decreased visual acuity. With slit lamp biomicroscopy, guttata appear as a glittering golden brown excrescence of the Descemet membrane, and by retroillumination, as minute dewdrops. Because the advent of guttata precedes the development of visual symptoms by many years, serial examination by endothelial specular microscopy and corneal pachymetry is an important means to monitor disease progression. The dystrophy is classified into four stages: (1) cornea guttata initially central and subsequently diffusely; (2) endothelial decompensation and progressive stromal edema; (3) stromal edema progressing to cause intraepithelial and interepithelial edema, manifest as microcytic and/or bullous keratopathy; and (4) subepithelial fibrosis, scarring, and peripheral superficial vascularization consequent to long-standing chronic edema. Such surface and stromal alterations render stage 4 cases potentially inappropriate for endothelial keratoplasty. ► Fig. 4.1, ► Fig. 4.2, ► Fig. 4.3, ► Fig. 4.4, and ► Fig. 4.5 show the clinical aspects of different stages of Fuchs dystrophy. Confocal microscopy as well as specular microscopy provides relevant information at different FED stages. There is reduction of anterior and eventually stromal cell density.6 Most critically, endothelial cell population density and uniformity are diminished and guttata increase in frequency depending on disease severity and area of analysis. Corneal innervation can also be altered as total nerve length, total nerve number, and number of main nerve trunks and branches decrease with disease progression.7 Both light and electron microscopy disclose dramatic diffuse Descemet membrane thickening with superimposed focal guttate excrescences plus the progressive distortion and attrition of the endothelial cells. ► Fig. 4.5 and ► Fig. 4.6 show the pathological aspects of the disease. Much less common than FED, PPCD is an autosomal dominant disorder. The genetic locus is heterogenic as the pericentromeric region of chromosome 20 (PPCD1 locus), associated with mutations in COL8A2 on chromosome 1 (PPCM2 locus) and related to nonsense mutations in the zinc finger E-box binding homeobox 1 gene (ZEB1 or TCF8) on chromosome 10 have been identified.8,9 Small aggregates of vesicles bordered by a gray haze, and gray geographic areas arise at the level of the Descemet membrane and contain round or elliptical vesicular zones, creating a pattern resembling Swiss cheese. Adhesions fusing the iris with the posterior surface of the peripheral cornea can progress to secondary glaucoma. PPCD is bilateral but extremely asymmetrical such that only one cornea appears clinically affected.1,10 Most patients remain asymptomatic, and corneal edema is usually absent or clinically insignificant because the corneal endothelium remains functionally adequate. In cases where endothelial dysfunction is progressive, stromal edema and calcific band keratopathy can develop and are indications for surgical intervention. ► Fig. 4.7 and ► Fig. 4.8 represent some clinical aspects of PPCD. Fig. 4.1 Fuchs endothelial dystrophy. (a) Slit lamp biomicroscopy discloses stromal edema involving the visual axis. (b) In early-stage dystrophy, endothelial specular microscopy clearly resolves relatively normal endothelial cell mosaic of polygonal cells with sporadic guttae evident as focal dark opacities. (c) In an advanced case requiring keratoplasty, scanning electron microscopy of the keratoplasty disc shows multiple guttae as mushroomlike excrescences projecting posteriorly from the exposed surface of the Descemet membrane, which itself has become increasingly fibrotic. No intact endothelial cells are apparent. (× 1000) Fig. 4.2 Fuchs endothelial dystrophy. (a–c) Slit lamp biomicroscopy displays various stages of corneal edema as well as cataract. (d) High magnification retroillumination biomicroscopy highlights guttae as glittering golden-brown excrescences of the Descemet membrane having a beaten metal appearance. Fig. 4.3 Fuchs endothelial dystrophy. Slit lamp biomicroscopy with high magnification and retroillumination highlights guttae as a glittering golden-brown excrescence of the Descemet membrane. (Courtesy of Gustavo A. Novais, MD, PhD.) Fig. 4.4 Fuchs endothelial dystrophy. (a) Biomicroscopy with fluorescein staining of tear film reveals fine microcytic epithelial edema. (b) Light microscopy of anterior cornea exhibits intra- and interepithelial edema, although the Bowman layer and stroma remain intact. (Hematoxylineosin, × 400) Cornea endothelial vesicular lesions are characterized by rounded dark areas (doughnut-like) with cellular detail centrally. Vesicles may also coalesce and form well-demarcated curvilinear bands appearing to protrude into the anterior chamber, some with central posterior concavity. Endothelial pleomorphism and polymegathism can also be notable, and, in particular, focal epithelioid mosaicism is evident.11,12 ► Fig. 4.9, ► Fig. 4.10, and ► Fig. 4.11 show some of the pathological characteristics of PPCD. Although long thought to have both dominant and recessive forms, congenital hereditary endothelial dystrophy (CHED) is now considered solely as a congenital autosomal recessive disorder1 with mutation of the gene SLC4A11 in the 20p13 locus.13 Fig. 4.6 Fuchs endothelial dystrophy. Slit lamp photos (a) with and (b) without fluorescein highlight epithelial macrobullous edema as well as diffuse stromal swelling and haze plus superficial neovascularization. (c) Light microscopy of keratoplasty specimen displays microbullous separation of epithelium from Bowman layer and stroma, consequent to profound epithelial and stromal edema (Hematoxylin-eosin, x300). Corneal abnormalities are bilateral but often asymmetric, as profound stromal edema (two to three times normal thickness) varies from diffuse haze to complete opacity with occasional gray spots. The endothelial cell population density is extremely low. Importantly, intraocular pressure (IOP) is not elevated. ► Fig. 4.12 shows the clinical and pathological characteristics of CHED. Descemet membrane is often diffusely thickened in the posterior nonbanded zone, and focal guttae are never evident. The endothelium is extremely attenuated or altogether absent. This rare X-chromosomal dominant dystrophy is consequent to mutation at locus at Xq25. Fig. 4.8 Posterior polymorphous dystrophy. (a) Thin slit beam resolves Descemet membrane thickening. (b) By retroillumination, multiple focal vesicular alterations of the Descemet membrane become apparent. Due to the mode of inheritance, males are more severely affected. Females are asymptomatic but evidence endothelial changes reminiscent of moon craters. In males, the abnormalities are similar to those evident in CHED. Advanced cases can also develop band keratopathy. The ICE syndrome comprises a group of related disorders, all characterized by an abnormal corneal endothelium. It almost always appears unilateral (although with minimal fellow-eye abnormality), manifests in young adulthood, and is more prevalent in women. The etiology remains unknown, although some studies have related the endothelial cell metaplasia to viral infections (herpes simplex and Epstein–Barr viruses).14,15 Additional clarification remains required.16 Mechanistically, the abnormal metaplastic endothelial cell layer grows across the anterior chamber angle, and the contraction of this tissue results in angle closure as well as full-thickness iris tissue distortions and defects. In the early stages of the disease, the affected individuals are usually asymptomatic, but with progression, blurred vision, elevated IOP, and/or iris changes become evident. Depending on the relative contributions of corneal, angle, and iris changes, three syndromes are commonly recognized: 1. Essential iris atrophy: significant iris traction, thinning, and holes with irregular displaced pupil (► Fig. 4.13) 2. Chandler syndrome: corneal edema with relatively mild iris changes 3. Cogan–Reese iris nevus syndrome: pigmented iris surface nodules, iris atrophy Specular microscopy reveals a population of abnormal endothelial cells, so-called ICE-cells,17 which are uniquely enlarged, pleomorphic, and epithelial-like and show a light–dark reversal with light cell borders, dark cell interiors, and hyperreflective nuclei.18 They appear progressively irregular and seemingly relate to the disease stage.19,20 Abnormally grouped keratocytic clusters may appear in the posterior stroma.20 Scanning microscopy of a keratoplasty specimen with ICE syndrome is shown in ► Fig. 4.14. Irreversible corneal endothelial dysfunction resulting in clinically significant bullous keratopathy may occur in approximately 1 to 2% of patients undergoing cataract surgery, thereby representing annually about 2 to 4 million cases worldwide.21 The primary cause is the loss of endothelial cells secondary to surgical trauma, in most situations involving older patients with more densely mature cataracts and/or with preexisting corneal endothelial compromise, such as Fuchs endothelial dystrophy. ► Fig. 4.15 shows the clinical characteristics of a patient with endothelial dysfunction after cataract surgery. Corneal edema also occurs after multiple surgeries for glaucoma, particularly those involving tube shunts, and intraocular lens (IOL) secondary placement or exchange by either anterior chamber or scleral-fixated posterior chamber IOL. Following intraocular surgery, reduction in the population of Na +, K + adenosine triphosphatase (-ATPase) pumps, predominantly in the corneal endothelium but also in the epithelium, contribute to the development of bullous keratopathy.21 ► Fig. 4.16, ► Fig. 4.17, and ► Fig. 4.18 describe the pathological aspects of the disease. The toxic anterior segment syndrome (TASS) is an acute and intense sterile inflammation of the anterior segment of the eye following cataract and other anterior segment surgical procedures.22 Typically developing within 24 hours after surgery, TASS is characterized by corneal edema and anterior chamber hypopyon (► Fig. 4.19). Often occurring as a cluster of cases, TASS is distinguished from infectious endophthalmitis by its immediate postoperative onset. A recent study reported an incidence of 0.22%.23 Several causes of TASS have been proposed, including intraocular solutions with inappropriate chemical composition, concentration, pH, or osmolality; preservatives; denatured ophthalmic viscosurgical devices; enzymatic detergents; bacterial endotoxin; oxidized metal deposits and residues; and factors related to IOLs, such as residues from polishing or sterilizing compounds.22 Problems with the instrument-cleaning process, especially inadequate flushing of ophthalmic instruments and handpieces, enzymatic detergents, and ultrasound baths, remain the most common associations.24 Patients experience often extremely reduced vision, but pain is relatively infrequent. Pancorneal edema and marked anterior segment inflammatory response, frequently with hypopyon and fibrin reaction, are common. Other findings include iris damage with a dilated, irregular, and tonic pupil as well as trabecular meshwork involvement with possible secondary glaucoma. Following resolution of the acute inflammatory reaction, specular microscopy discloses a major reduction in the endothelial cell population with pleomorphism.25 If collateral anterior segment damage is otherwise modest, such eyes are appropriate for endothelial keratoplasty, often in conjunction with iridoplasty. Following penetrating or endothelial keratoplasty, the long-term loss of corneal clarity due to endothelial cell attrition and subsequent endothelial dysfunction, is an important cause of non-rejection-associated graft failure. Endothelial failure accounts for 15% of all causes of graft failure, against 5 to 18% due to rejection. For favorable prognostic indications, survival of first-time penetrating keratoplasty (PK) is 90% at 5 years and 82% at 10 years. A combination of factors can lead to postkeratoplasty endothelial failure. Donor factors, tissue storage, and preparation techniques, as well as surgical and postoperative host factors, collectively contribute to endothelial cell damage and attrition. In the extremes, primary donor failure comprises immediate postoperative irreversible edema of the graft, whereas chronic endothelial failure progressively occurs several years after keratoplasty. A recent large study detected a significant effect of donor age, and preoperative donor endothelial cell population density (ECD) (favorable if > 2200 cells/mm2), on endothelial failure at 5 years following PK.26 However, other long-term studies have failed to demonstrate an adverse effect of donor age on PK survival.27
4.1 Introduction
4.1.1 Primary/Intrinsic Endothelial Disorders
Fuchs Endothelial Dystrophy
Etiology
Clinical Features
Imaging and Pathology
Posterior Polymorphous Corneal Dystrophy
Etiology
Clinical Features
Imaging and Pathology
Congenital Hereditary Endothelial Dystrophy
Etiology
Clinical Features
Imaging and Pathology
X-Linked Endothelial Corneal Dystrophy
Etiology
Clinical Features
Iridocorneal Endothelial (ICE) Syndrome: Chandler, Essential Iris Atrophy, Cogan–Reese
Etiology
Imaging and Pathology
4.1.2 Secondary/Acquired Endothelial Disorders
Postsurgical
Cataract: Aphakic and Pseudophakic Corneal Edema
Toxic Anterior Segment Syndrome
Keratoplasty: Immunologic Rejection and Endothelial Attrition/Decompensation
Etiology
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