What is the most common cause of copper-punched lesions of the corneal endothelium?

Fuchs Endothelial Corneal Dystrophy is the Most Common Cause of Copper-Punched Lesions of Corneal Endothelium

Fuchs endothelial corneal dystrophy (FECD) is definitively the most common cause of copper-punched lesions (guttae) of the corneal endothelium, leading to progressive endothelial dysfunction and potential corneal edema. 1

Pathophysiology of Copper-Punched Lesions

Copper-punched lesions, clinically known as guttae, are characteristic "drop-like deposits" that form on Descemet's membrane (the basement membrane of the corneal endothelium). These lesions:

• Represent focal thickening of Descemet's membrane
• Disrupt the normal corneal endothelial cell monolayer
• Progressively accumulate in FECD, causing endothelial cell dysfunction
• Lead to corneal edema when endothelial cell density falls below critical threshold

The formation of these guttae is central to the diagnosis of FECD, which affects approximately 5% of middle-aged Caucasians in the United States 2.

Clinical Presentation and Progression

The development of copper-punched lesions follows a predictable pattern:

1. Early stage: Asymptomatic central guttae visible on slit lamp examination
2. Intermediate stage: Increasing density of guttae with early endothelial dysfunction
3. Advanced stage: Confluent guttae with significant endothelial cell loss leading to:
   • Corneal edema (initially worse upon waking)
   • Blurred or variable vision with diurnal character
   • Photophobia and foreign-body sensation
   • Progressive visual impairment 1

Diagnostic Evaluation

When copper-punched lesions are observed:

• Slit lamp examination: Reveals characteristic guttae appearance
• Specular microscopy: Shows decreased endothelial cell density and polymegathism
• Pachymetry: Measures increased corneal thickness in advanced cases
• Confocal microscopy: Can detect early guttae before they are clinically apparent

Genetic Basis

FECD has strong genetic associations:

• The strongest association is with an intronic (CTG·CAG)n trinucleotide repeat expansion in the TCF4 gene, found in the majority of affected patients 2
• Similar to myotonic dystrophy type 1, poly(CUG)n RNA foci form in corneal endothelial cells
• These foci sequester the mRNA-splicing factor MBNL1, leading to missplicing of essential mRNAs

Treatment Options

Treatment depends on disease severity:

1. Early disease:

   • Hypertonic saline drops to reduce epithelial edema
   • Management of contributing factors (e.g., elevated IOP)

2. Advanced disease with corneal decompensation:

   • Endothelial keratoplasty (EK): The preferred surgical approach
     • DSAEK (Descemet's stripping automated endothelial keratoplasty)
     • DMEK (Descemet's membrane endothelial keratoplasty)
   • Penetrating keratoplasty (PK): Full-thickness transplant, less commonly performed now

DMEK shows significantly decreased rejection rates (0-6% at 1 year) compared to DSAEK (2-9%) and PK (17%) 1.

Clinical Pearls and Pitfalls

• Pearl: Visual acuity may be significantly affected even with mild edema due to higher-order aberrations and glare
• Pitfall: Delaying treatment can lead to chronic corneal edema and irreversible stromal scarring
• Pearl: DMEK provides better visual outcomes with lower rejection rates than DSAEK or PK
• Pitfall: Graft dislocation is a unique complication of endothelial keratoplasty, occurring in 5.9-27.4% of DMEK cases and 14.5-15% of DSAEK cases 1
• Pearl: Endothelial decompensation, with or without prior rejection, is the leading cause of graft failure for both PK and EK

Emerging Therapies

Research is exploring cell-based therapies:

• Cultured human corneal endothelial cell injection following descemetorhexis shows promise in experimental models 3
• This approach could potentially treat both the endothelial dysfunction and remove the pathological Descemet's membrane with guttae

By understanding the pathophysiology and clinical presentation of copper-punched lesions in the corneal endothelium, clinicians can provide early diagnosis and appropriate management of FECD, potentially preserving visual function and quality of life.