Descemet Membrane and Endothelial Dystrophies

Introduction

Posterior polymorphous corneal dystrophy (PPCD), initially called keratitis bullosa interna, was described by Koeppe in 1916 ( Table 72.1 ). The clinical expression of this disorder varies considerably, even within the same family. One family member may be asymptomatic with only a single endothelial lesion while a sibling might have corneal decompensation, broad peripheral synechiae, and advanced glaucoma. While the dystrophy is typically autosomal dominant and bilateral, unilateral cases without heredity have been described. Subtypes of PPCD have been described.

The 2015 the International Committee for Classification of Corneal Dystrophies (IC3D) guidelines have reclassified autosomal dominant congenital hereditary endothelial dystrophy (CHED), formerly known as CHED1, as PPCD. Careful review of the findings from each of the five published affected families suggested that CHED1 is actually indistinct from PPCD1. In the first family, while initially inheritance pattern was unclear, consanguinity was subsequently discovered with recessive inheritance. The second family likely had a stromal dystrophy, with stromal flake- and spot-like corneal opacification without endothelial dysfunction. On histopathology, stromal amorphous substance stained with Masson trichrome. The third family had clinical features that were similar to PPCD; however, the need for corneal transplantation, which had not been frequently required in PPCD, suggests it was a distinct entity. ^, When electron microscopy (EM) findings were initially studied in those affected, EM description of PPCD had yet to be published. Subsequently it was demonstrated that EM findings of the corneas in PPCD and from family 3 were indistinguishable. Chromosomal analysis eventually done on that same family demonstrated a linkage to a region within chromosome 20 at the original PPCD1 locus and additional mapping studies demonstrated the PPCD1 and CHED1 intervals were nearly identical. The fourth family thought to have CHED1 ^, showed atypical clinical features, such as peripheral endothelial changes with overlying stromal edema, though nearly all cases were asymptomatic. EM subsequently demonstrated similar findings to PPCD. The fifth family demonstrated findings of PPCD such as endothelial vesicles, layering of endothelial cells, and bands traversing the central cornea. Although the authors recognized the findings as consistent with PPCD, they decided to classify this as a distinct entity because of one case with a congenital diagnosis and the absence of posterior stroma involvement in asymptomatic individuals. It is now thought that both families 4 and 5 had PPCD based on their findings. ^, Further genetic studies will likely determine whether PPCD and CHED1 are indeed identical entities.

Molecular Genetics

PPCD is a genetically heterogeneous disease with four distinct genetic loci identified. PPCD1 links to locus 20p11.2-q11.2. without identification of specific gene. PPCD2 links to locus 1p34.3-p32.3, the location of the α helix of collagen type VIII ( COL8A2 ). Although this group reported a missense mutation, others did not find a mutation with additional screening of affected individuals. ^{, ,} PPCD3 links to locus 10p11.2 with discovery of four different nonsense and frameshift mutations in the gene that encodes the two-handed zinc-finger homeodomain transcription factor TCF8 . TCF8 is involved in the repression of the epithelial cell phenotype. Two unusual features of this family were the presence of guttata in many of the unaffected and affected members of the pedigree as well as the aggressive growth of a retrocorneal membrane after surgical intervention. Four novel pathogenic mutations within the ZEB1 gene are located at the same loci (10p11.2) and five frame shift mutations have been found. Another novel mutation has been described in a 3-year-old child with PPCD. Additional screening for the TCF8 gene identified eight different pathogenic mutations in eight probands, demonstrated that TCF8 mutations were found in 25% of affected families and were also associated with abdominal and inguinal hernias. PPCD4 links to locus 8q22.3-q24.12, with mutations in the GRLH2 gene found to be causative of the autosomal dominant disease.

Both vesicles and patches of dysmorphic endothelium similar to those in PPCD have been described in Alport syndrome. Examination of families with PPCD has revealed individuals with Alport-like renal abnormalities, hematuria, and sensorineural hearing loss. PPCD and Alport syndrome have been found to coexist in one case. Interestingly, classic Alport syndrome can result from mutations in the α5 chain of collagen IV, one of the collagen IV α-chains with restricted distribution to the eye, ear, and kidney. In addition, there is a shared molecular component between PPCD3 and Alport syndrome . A binding site for TCF8 is present in the promotor of the Alport syndrome gene COL4A3 , and this gene was reported in the corneal endothelium in one case of PPCD3.

Clinical Presentation and Course

PPCD is usually a bilateral disease, though it can be asymmetric, with typical onset in childhood. In the vast majority of cases, it is asymptomatic and stable, diagnosed incidentally on routine examination. Less commonly, it can be progressive with visual loss.

The underlying corneal abnormality occurs in the Descemet membrane and the endothelium, with vesicle-like lesions, band lesions, and/or diffuse opacities. ^, The vesicular lesion, a hallmark of PPCD, occurs in almost all patients with the disorder, occurring as a sole finding in 42% of cases.

On slit lamp examination, the vesicular lesion appears as a transparent cyst surrounded by a gray halo at the level of the Descemet membrane and endothelium ( Fig. 72.1 ). The vesicles can be found anywhere on the posterior cornea and may appear as isolated lesions or in lines, clusters, or confluent groups. ^, Specular microscopy demonstrates sharply demarcated round areas that contain lighter thick ridges, cell aggregates ( Fig. 72.2 ) or black spots that interrupt the endothelial mosaic ( Fig. 72.3 ) with a lesion diameter of 0.10–1.00 mm. With relief mode, specular microscopy vesicles appear as pits or excavations on posterior Descemet membrane, filled with fibrillar or collagenous material. Enlarged and pleomorphic endothelium may line the vesicles, and intervening endothelial cells between lesions can be normal-sized with a mosaic pattern, crowded and smaller than normal, or enlarged and pleomorphic. ^{, ,}

Band lesions are typically horizontal, have parallel scalloped edges, and do not taper toward the ends ( Fig. 72.4 ). ^, Although band lesions may be seen anywhere on the posterior cornea, they are most frequently noted just inferior to the central cornea and are easily differentiated from the tapered smooth-edged tears seen in congenital glaucoma, trauma, and hydrops. Specular microscopy demonstrates shallow trenches and ridges arising from a large number of confluent vesicles ( Fig. 72.5 ). ^, The endothelial cells that line the bands appear enlarged and pleomorphic.

Diffuse opacities are either small, macular, gray-white lesions or larger sinuous geographic lesions at the level of the Descemet membrane ( Fig. 72.6 ). With direct illumination, there is a haze in the posterior stroma adjacent to the lesions. In retroillumination, the opacities have a peau d’orange texture ranging in size from 0.5 to 2.0 mm in diameter. Specular microscopy reveals well-demarcated areas of enlarged and pleomorphic cells with indistinct opacity borders having multiple reflective highlights surrounded by normal or small endothelial cells ( Fig. 72.7 ). Endothelial guttae can also be seen in PPCD. ^, Although the guttae are similar to those in macular corneal dystrophy, interstitial keratitis, and Fuchs dystrophy, the accompanying signs can distinguish the three conditions.

Though corneal edema infrequently occurs, it can appear at any age, may be stable or progressive, and range from minimal stromal thickening to bullous keratopathy. ^,

Advanced stromal edema may be associated with stromal lipid deposition or superficial band keratopathy.

Peripheral anterior synechiae (PAS) are present in 25% of eyes with PPCD. They can range from fine adhesions, visible only by gonioscopy, to large, broad-based membranes with a glassy surface seen with slit lamp biomicroscopy ( Fig. 72.8 ). The iris may be normal or show broad areas of atrophy, with or without corectopia. Elevated intraocular pressure (IOP) has been reported in 15% of patients and can present with either closed or open angles. ^, Angle closure is thought to result from synechiae formed by endothelial cell migration across the trabecular meshwork onto the iris. Open angle glaucoma is likely secondary to high iris insertion, leading to compression of the trabecular meshwork.

Corneal steepening with or without features of keratoconus has also been described. Most patients with PPCD3 have corneal curvatures greater than 48.0 D.

Astigmatic anisometropic amblyopia has been reported in unilateral PPCD, clinicians should be vigilant in the diagnosis and treatment of refractive errors in children with early onset PPMD.

Differential Diagnosis

PPCD and the iridocorneal endothelial (ICE) syndromes can be confused as both may demonstrate PAS, glassy membranes over the angle and anterior surface of the iris, iris atrophy, corectopia, increased IOP, and corneal edema. ^, While PPCD is typically bilateral and inherited, ICE syndrome is unilateral and sporadic. Exceptions occur, however, as PPCD can be nonfamilial and unilateral and ICE syndrome can be bilateral. ^, In one report, a patient had clinical features of both the ICE syndrome and PPCD. Specular microscopy may assist in distinguishing the two diseases. The involved cells in the ICE syndrome classically appear as dark areas with a central highlight and light peripheral borders. PPCD and ICE syndrome can be differentiated based on specular microscopy alone.

The term posterior corneal vesicle syndrome has been coined to describe patients who have unilateral vesicular or band lesions similar to PPCD without similar findings in other family members. These patients typically have the onset at a younger age than PPCD, with good vision, no progression, and the absence of other ocular abnormalities. Specular microscopy reveals changes similar to those seen in PPCD.

PPCD may present with a cloudy cornea at birth, ^, so must be included in the differential diagnosis of congenital corneal opacification along with metabolic disorders, CHED, congenital hereditary stromal dystrophy (CHSD), congenital glaucoma, sclerocornea, congenital infections, and X-linked endothelial corneal dystrophy (XECD).

Prognosis and Management

PPCD is stable and asymptomatic in most patients. Less commonly, the dystrophy may be very extensive and progressive, necessitating surgical intervention. In the largest series of PPCD cases reported, comprised of eight families with 120 individuals, only 13 patients required penetrating keratoplasty (PKP). PAS and elevated IOP were risk factors for severe disease. While only 27% of the patients had PAS, a little more than half of with iridocorneal adhesions did require PKP. Similarly, only 14% of patients in this series had increased IOP, but more than half of those individuals also required PKP.

Surgical prognosis was correlated with the presence of PAS and elevated IOP. Of patients undergoing transplantation, 50% attained 20/40 vision postoperatively and 55% of patients maintained clear grafts in this study. However, in the patients with PAS visible on slit lamp examination, 80% had postoperative vision worse than 20/400. In contrast, 91% of patients with PAS visible only by gonioscopy, or with no synechiae, maintained a clear graft, and 82% attained 20/40 vision postoperatively.

In this same study, all patients with elevated preoperative IOP had difficulty with postoperative IOP control. Aggressive medical management or surgical intervention with filtering procedures or cryotherapy had limited success. In addition, most patients with elevated IOP had postoperative vision less than 20/400. Consequently, PAS visible without gonioscopy and increased IOP are relative contraindications to corneal transplantation in PPCD.

PPCD can recur after transplantation. In a series with 22 corneal transplants, four corneas developed retrocorneal membranes, three of which led to opacified grafts. Histologic examination on only one cornea demonstrated a retrocorneal epithelial-like endothelial membrane.

Light Microscopy

Light microscopy of corneal buttons after PKP for PPCD reveals evidence of chronic edema, subepithelial fibrosis, and/or band keratopathy ( Table 72.2 ). Findings varied from generalized thickening of the Descemet membrane with foci of bilayered large endothelial cells ( Fig. 72.9A ) to an irregular Descemet membrane with focal absences and three to four layered broad patches of flattened endothelial cells ( Fig. 72.9B ). The vesicles so typical of PPCD are actually not fluid-filled at all but are excavations filled with fibrillar or collagenous material.

Electron Microscopy

Focal areas of endothelium contain large squamous epithelial cells like those seen in epithelial downgrowth after penetrating injury with large numbers of 8–10 nm intermediate filaments (tonofilaments), some in bundles and attached to prominent desmosomal intercellular junctions, which are commonly seen in epithelial cells. Cells do not have the tight junctions characteristic of endothelium ( Fig. 72.10 ). Apical cell surfaces are densely covered by microvilli ( Fig. 72.11 ). Attenuated and degenerated endothelial cells are always present, showing a contracted appearance with blebs or hole-like pits on their surface. However, normal endothelial cells with minimal or no microvilli over their free surfaces as well as fibroblast-like cells with prominent endoplasmic reticulum (ER) are present,

The presence of the unusual epithelial-like cell type described in PPCD has been confirmed by transmission and scanning EM. The epithelial-like nature of the cell is strongly supported by the presence of intermediate filaments staining positively with antibodies to human epidermal cytokeratins (CKs). These areas alternate with nonstaining patches appearing to represent normal endothelium. In tissue culture, the epithelial-like cells act like epithelium in their more rapid growth rate. In primary cultures, the epithelial-like and normal endothelium grow out as two cell lines, with CK positivity limited to the epithelial-like cells. A few fibroblast-like spindle cells are also present.

Despite their similarity to epithelial cells, the epithelial-like endothelial cells in PPCD do not represent a simple change from endothelium to surface epithelium. In both PPCD and control corneas surface epithelium stains positive for CKs typically found in the cytoplasmic filaments of squamous epithelium, such as pancytokeratin (panCK), AE1, and AE3. Endothelium in normal corneas does not stain positive for any of those CKs, but the endothelium in PPCD reacts strongly with panCK antibodies and less consistently with AE1 and AE3. The endothelium in PPCD also stains strongly for cytokeratin 7 (CK7), normally found in glandular epithelium, but not in stratified squamous epithelium or endothelium.

The Descemet membrane in most cases of PPCD has a normal anterior banded zone (ABZ) approximately 3 μm in thickness. The normal banding (110–120 nm) in this zone is formed primarily by collagen type VIII, a collagen commonly found in the fetus, especially around blood vessels. The ABZ collagen is secreted by endothelial cells between the fourth month of fetal life and birth. Therefore a normal ABZ suggests that the endothelial cells were functioning normally prior to birth. In the few PPCD patients who have cloudy and edematous corneas at birth, the ABZ of Descemet membrane in focal areas is partially or completely absent, thinned, or demonstrates nonhomogeneous banding. ^, Thus in those individuals endothelial dysfunction occurs before or around the time of the fourth month of gestation.

The next layer of Descemet membrane, the posterior nonbanded zone (PNBZ), is slowly synthesized throughout postnatal life as a homogeneous basement membrane. In PPCD there is little or no traditional PNBZ, but rather an abnormal mixture of collagenous components, often appearing multilaminated (see Fig. 72.10 ). These laminae contain aggregates of small collagen fibrils, 100 nm banded material resembling the ABZ, and large bundles of 50 and 100 nm banded collagen. Relatively normal, homogeneous type IV collagenous basement membrane may be admixed in deeper portions of this posterior collagenous layer (PCL), sometimes giving the appearance of a second thin Descemet membrane (see Fig. 72.10 ).

The vesicles so characteristic of PPCD clinically have not had a completely satisfactory explanation pathologically. Some studies suggest they represent vacuolar degeneration within or between dying endothelial cells, often covered by a layer of epithelial-like cells. Others infer that the multilayered epithelial-like cell clumps are themselves responsible. Fusiform protuberances from the Descemet membrane that might appear vesicular were found to be dense plaques between two laminae of Descemet membrane, or gutta-like aggregates in the PCL. ^,

The multilayered epithelial-like cells can migrate onto the trabecula and iris, causing extensive PAS and glaucoma ( Fig. 72.12 ). The thick membrane over the trabecula resembles the abnormal Descemet membrane PCL. On the iris, there is less basement membrane and a matrix of looser collagen fibrils, granular material, and tubular bundles suggestive of elastic system microfibrils ( Fig. 72.13 ). The epithelial-like membrane is multilayered with prominent desmosomes, unlike the monolayer of endothelial cells in the migrating cells of the ICE syndrome that is connected by normal junctional complexes with a thinner basement membrane.

Introduction

In 1910, Fuchs described bilateral corneal stromal and epithelial edema in elderly patients prior to the invention of slit lamp microscopy (see Table 72.1 ). The disease subsequently became known as Fuchs endothelial corneal dystrophy (FECD).