Posterior Polymorphous Corneal Dystrophy

Etiology

Posterior polymorphous corneal dystrophy (PPCD) is genetically heterogeneous with variable expression.

Several genetic mutations are implicated in the genesis of PPCD 1-4.

• PPCD1 (122000) is due to a heterozygous mutation in the promoter of the OVOL2 gene (616441), cytogenic location 20p11.22.
• PPCD2 (609140) is due to a mutation in the COL8A2 gene (120252), cytogenic location 1p34.2-p32.3.
• PPCD3 (609141) is due to a mutation in the ZEB1 gene (189909), cytogenic location 10p11.22.
• PPCD4 (618031) is due to a mutation in the GRHL2 gene (608576), cytogenic location 8q22.

Epidemiology

Posterior polymorphous dystrophy (PPCD) is considered very rare.

As many patients are asymptomatic the exact incidence of PPCD is unknown. PPCD affects males and females equally.

Reports estimate higher than normal prevalence in the Czech Republic (estimated 1:100,000) [8].

Pathophysiology

The symptoms in this condition range remarkably from asymptomatic to aggressive, vision-threatening. Posterior polymorphous corneal dystrophy (PPCD) can be evident at birth but is most often detected later in life. Abnormal developmental differentiation of endothelial cells leads to secondary alterations of the Descemet membrane. This results in multiple laters of epithelium-like cells within the corneal epithelium. These aberrant cells migrate secreting atypical basement membrane resulting in thickening of the Descemet membrane. Groupings of polymorphic irregularities are evident at the Descemet membrane. These are associated with varying levels of corneal opacification and endothelial degradation. In mild disease with sparse tissue irregularities limited only to the posterior cornea patients may report blurred vision, glare symptoms and, infrequently, eye pain.

Compromises at the Descemet membrane in PPCD are associated with topographic changes in the cornea. Corneal steepening may manifest as regular astigmatism, irregular astigmatism or keratoconus. In patients with intact neurodevelopment of the visual system, visual function can be improved with glasses, standard or specialty contact lenses or certain refractive procedures. However, infants and toddlers have incomplete development of their abilities to process visual stimuli. Any significant asymmetry in refractive status during the critical or sensitive period, up to age 3 and age 9 respectively, may delay or limit the maturation of visual sensory development in one or both eyes [9]. In PPCD the manifestations of the dystrophy can be asymmetric. Similarly, the refractive disparity can occur, which if left untreated can result in anisometropic amblyopia [10], [11].

In severe cases of PPCD, the risk for permanent loss of vision is increased. Endothelial compromise affects corneal deturgescence. Significant endothelial compromise can lead to focal or diffuse corneal edema. As fluid accumulates in the corneal stroma, swelling and opacification occur. Corneal bullae may form migrating anteriorly resulting in sharp eye pains. Vision may be profoundly limited by dense central corneal edema. Further corneal decompensation will occur. Surgical intervention is necessary to restore endothelial function and regain some level of corneal clarity [12]. As is the case with refractive disparity induced by high astigmatism, there is potential for infants and toddlers to develop amblyopia [13]. Deprivation amblyopia occurs in the setting of visual obscuration by congenital or traumatic cataract, eyelid ptosis or media opacity such as corneal opacification. 

With PPCD the abnormal cells have several epithelium-like characteristics. The aberrant corneal endothelium is multilayered with keratin, numerous microvilli, and desmosomes. The thickened tissue has greater biomechanical resistance to an outside force. This can alter corneal hysteresis leading to an over-estimation of measured intraocular pressures which confounds the diagnosis of glaucoma.

Irregular basement membrane secretions bridging the anatomical angle can lead to elevated intraocular pressure and secondary glaucoma [14]. Peripheral anterior synechia or iridocorneal adhesions may be evident with gonioscopy. In advanced cases, iris atrophy and corectopia may present. 

Penetrating keratoplasty is required for 20-25% of patients with significant endothelial involvement and diffuse corneal edema [15], [16]. If the corneal stroma and epithelium are not edematous lamellar keratoplasty is preferred as this technique yields faster healing and improved visual outcomes [15]. Glaucoma filtering surgery may be necessary for a disease that is recalcitrant to topical therapy [17]. In each instance, the prognosis is guarded as irregular endothelial cells persist disrupting the grafted tissues or the drainage apparatus.

Histopathology

A healthy endothelium is arranged at the posterior cornea in a single layer with a predictable hexagonal cellular configuration. In posterior polymorphous corneal dystrophy (PPCD) the endothelial cells undergo an aberrant differentiation. There is a proliferation of metaplastic cells resulting in multiple layers of cells that manifest epithelium-like characteristics forming an anomalous collagenous layer. Scanning electron microscopy of corneal tissue demonstrates a transformation of the posterior corneal surface with degenerated endothelial cells, fibroblast-like cells, and stratified epithelial-like cells with numerous microvilli, keratin, and desmosomes. Like epithelium, these cells migrate across the Descemet membrane and, on occasion, across the trabecular meshwork and anterior iris surface. The thickened tissue has greater biomechanical resistance to outside force affecting corneal hysteresis [18][19].

History and Physical

Posterior polymorphous corneal dystrophy (PPCD) frequently is an asymptomatic condition that may be diagnosed at the time of a routine eye examination. 

• PPCD is a hereditary disease. A family history of corneal disease should be elucidated.
• Asymptomatic patients will have normal or near-normal visual acuity.
• Glare symptoms are frequently reported.
• With careful biomicroscopy, bilateral polymorphic irregularities are evident at the Descemet membrane and the endothelium.
• Although corneal dystrophies are a bilateral entity it is not uncommon to have asymmetric signs.
• The appearance of the lesions is highly variable. Clusters of blister-like vesicles are most commonly encountered.
• Another pathognomonic configuration has parallel linear bands with scalloped edges across or adjacent to the visual axis.
• Larger areas of diffuse opacities are rare but are more likely to diminish visual function. 
• The onset of signs or symptoms should be ascertained. Infants or toddlers within the critical or sensitive period are likely to develop amblyopia.
• Structural irregularities of the Descemet membrane can induce corneal steepening and high astigmatism [20].
• Significant asymmetry in refraction may contribute to the development of anisometropic amblyopia in susceptible children. 
• Rarely corneal edema due to compromised corneal endothelium is evident at birth. 
• Persistent central corneal opacity may contribute to the development of deprivation amblyopia in susceptible children.
• If endothelial findings are present gonioscopy should be performed to evaluate the anatomic angle.
• Peripheral anterior synechia (PAS) can found in isolation or as broad bands. Peripheral corneal edema may overly broad bands of PAS.
• If intraocular pressure is elevated a careful glaucoma workup should be initiated.
• If there are iris or pupillary distortions a glaucoma workup should be initiated.

Evaluation

Careful evaluation of the posterior corneal tissues with slit-lamp biomicroscope allows immediate, in-office visualization of the polymorphous lesions.

• Polymorphous lesions may be visualized at the biomicroscope with moderate to high magnification using direct or, preferentially, retro-illumination techniques.
• Specular microscopy enables high-resolution imaging of the characteristic findings associated with PPCD within Descemet membrane and endothelial layer.
• Endothelial cell count can be diminished. The remaining endothelium demonstrates structural pleomorphic irregularities. 
• Confocal microscopy is of value in definitively identifying features characteristic of PPCD.
• Careful intraocular pressure measurement is necessary to screen for glaucoma.
• Anterior segment optical coherence tomography (OCT) images any abnormalities associated with aberrant endothelium bridging the anatomic angle.
• As an autosomal dominant entity, examination of family members may be helpful in confirming the diagnosis.

Treatment / Management

Asymptomatic patients with limited findings should be educated regarding the presence and potential significance of posterior polymorphous corneal dystrophy (PPCD). 

• Initiate amblyopia therapy in young children with high or asymmetric refractive error.
• Initiate immediate referral to a pediatric ophthalmologist if non-clearing corneal edema is present.
• Initiate amblyopia therapy in young children that have a history of corneal edema affecting form perception.
• Long-term monitoring of the posterior corneal layers is required.
• If secondary epithelial erosions or bullous keratopathy are present a bandage soft contact lens should be considered.
• If endothelial findings are present, gonioscopy should be performed to evaluate the anatomic angle. 
• If intraocular pressure is elevated, a careful glaucoma workup should be initiated. 
• If findings substantiate a diagnosis of glaucoma, then initiate first-line topical glaucoma therapy.
  • Monotherapy with a prostaglandin analog will control intraocular pressure (IOP) in the majority of cases.
  • Changing class or adding a medication may be necessary to realize IOP control.
  • Laser peripheral iridotomy (LPI) is not recommended if epithelialization of the trabecular meshwork has been identified.
  • If unable to achieve or maintain rigid IOP control, glaucoma filtering surgery may be necessary.
    • Minimally invasive glaucoma surgery (MIGS) offers promise.
• If there are iris or pupillary distortions a glaucoma workup should be initiated.
• Penetrating Keratoplasty (PK) has historically been successful, but has slow and challenging recovery as well as variable visual outcomes.
• Descemet membrane endothelial keratoplasty (DMEK) if the corneal stroma and epithelium are unaffected.
• Descemet stripping automated endothelial keratoplasty (DSAEK) is preferred if the corneal stroma and epithelium are unaffected.
• If iridocorneal adhesions are present corneal grafting procedures are at risk for failure.

Differential Diagnosis

The differential diagnoses includes:

• ICE syndrome (Chandler syndrome).
• Congenital hereditary endothelial dystrophy. 
• Pre-Descemet corneal dystrophy.
• Fuchs endothelial dystrophy.
• Primary congenital glaucoma.
• Traumatic rupture of Descemet membrane.

Prognosis

The prognosis for posterior polymorphous dystrophy (PPCD) is dependent on the extent of the disease.

• In most cases, PPCD is a static or very slowly progressive disease.
• The frequency of follow-up required is dependant on the severity of the disease.
• Patients with mild disease that are identified in adulthood have a good prognosis and are not likely to require treatment.
• If significant refractive disparity is present in childhood anisometropic amblyopia may develop.
• Infants with corneal edema require timely intervention to reduce the potential for developing deprivation amblyopia.
• Those with iridocorneal adhesions should be monitored for glaucoma.
• Those with elevated intraocular pressure, visual field defects or glaucomatous optic nerve appearance should be treated for glaucoma.
• Penetrating keratoplasty should be considered if corneal opacities limit visual potential.
• If iridocorneal adhesions are present corneal grafting procedures are at risk for failure.

Complications

 Infants and toddlers are at risk for amblyopia if neurodevelopment of the visual system is disrupted.

• Intervention is imperative during the critical period (up to age 3). Strongly recommended during the sensitive period (ages 3 to 9).
• To reduce the risk of complications, patients prescribed bandage soft contact lens (BSCL) therapy must be proficient in the handling and care of the BSCL.
• Patients prescribed BSCL are at risk for infection, pain and vision loss if secondary corneal infection were to occur.
• Those with iridocorneal adhesions should be monitored for glaucoma.
• Those with elevated intraocular pressure, visual field defects or glaucomatous optic nerve appearance should be treated for glaucoma.
• Penetrating keratoplasty should be considered if corneal opacities limit visual potential.
• If iridocorneal adhesions are present corneal grafting procedures are at risk for failure.
• Posterior polymorphous corneal dystrophy can recur in corneal grafts.