A Review of the Management of Fuchs Endothelial Corneal Dystrophy

A Review of the Management of Fuchs Endothelial Corneal Dystrophy
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ABSTRACT

BACKGROUND

This case report presents a patient with bullous keratopathy due to Fuchs Endothelial Corneal Dystrophy (FECD). Management considerations and current treatment options for FECD will be reviewed.

 

CASE REPORT

A 76-year-old white male presented with acute pain in his left eye. The patient was diagnosed with bullous keratopathy due to FECD. Following acute management of the epithelial defect, the patient was referred for an evaluation to consider surgical management with a corneal endothelial transplant.

 

CONCLUSION

Fuchs Endothelial Corneal Dystrophy leads to progressive visual deterioration that may cause acutely painful episodes. Medical management  has been limited to prescribing hyperosmotic agents. The advancement in therapeutic and surgical management has led to earlier intervention, better visual prognosis, and improved quality of life for patients affected by FECD. Optometrists play a role in the management of this condition’s diagnosis, treatment, and postsurgical care.

Keywords: Fuchs endothelial corneal dystrophy, corneal edema, endothelial transplant

 

INTRODUCTION

Fuchs Endothelial Corneal Dystrophy (FECD) is a progressive disease caused by corneal endothelial cell dysfunction, which ultimately leads to corneal edema and visual impairment. FECD, first described by Ernst Fuchs in 1910, is the most common posterior corneal dystrophy and the most common indication for corneal transplant in the US.1.2 Although much has been discovered about its pathophysiology, the etiology of FECD remains  uncertain with a likely autosomal dominant inheritance pattern.1,2 As a result of corneal endothelial cell dysfunction, loss of corneal deturgescence occurs.2 Historically, there has been no medical treatment available to alter the course of disease.3 Medical treatments provide only temporary symptom relief.3 Newer surgical advancements have decreased the need for penetrating keratoplasty (PKP) and include Descemet stripping endothelial keratoplasty (DSEK) and Descemet membrane endothelial keratoplasty (DMEK).1 Exciting emerging treatments include Rho kinase inhibitors, Descemet stripping only (DSO), and cultured corneal endothelial cell transplant.1

The function of the corneal endothelium is to maintain corneal dehydration essential for corneal transparency.3 Fluid and electrolyte balance within the stroma are also necessary for corneal transparency.3 Optimal corneal hydration is maintained by cellular pumps located in both the epithelial and endothelial layers.3 These pumps transport fluid and ions to draw fluid out of the cornea and  edema results if these critical cellular functions fail.3  A minimum number of cells is required for optimal endothelial function.4 As FECD progresses, the endothelial cell density falls below this critical threshold.3 FECD is considered a primary endothelial cell failure as opposed to a secondary endothelial cell failure caused by conditions such as trauma (including iatrogenic injury), inflammation, chronically elevated intraocular pressure (IOP), chemical exposure, or hypoxia.3

 

CASE REPORT

A 76-year-old white male presented with a complaint of mild pain in his left eye for four days. The onset was abrupt and described as a sharp pain and foreign body sensation. His symptoms had slowly improved since the onset. Additionally, the patient noticed tearing, mild redness, and blurred vision. Ocular history included uncomplicated phacoemulsification with posterior intraocular lens implantation OU in 2016 and FECD OU diagnosed more than ten years prior to cataract surgery. He was previously prescribed sodium chloride hypertonicity 5.0% ophthalmic solution (Muro 128) QID OU. The patient stated he discontinued Muro 128 a month ago but restarted once the left eye became painful. The patient denied a history of trauma or previous episodes of symptoms. His medical history was significant for hyperlipidemia and hypothyroidism for which he was treated with levothyroxine 25 mcg and simvastatin 20 mg daily. The patient denied drug or environmental allergies. His social and family ocular history were unremarkable. He reported using +2.50 readers. The patient’s recent manifest refraction was +0.75-0.75×170 20/40 OD, +0.50-1.00×177 20/40 OS, and prior ultrasound pachymetry measured 689 OD, 680 OS.

His entering uncorrected visual acuities were 20/50, pinhole 20/40 OD, and 20/200, pinhole 20/150 OS. Pupils were equal, round, and reactive to light without relative afferent pupillary defect. Confrontation visual fields and extraocular movements were normal. Slit-lamp examination showed normal lids and lashes in each eye. The conjunctiva in the right eye was white and quiet while the conjunctiva in the left eye was mildly hyperemic. Dense central guttae, moderate stromal edema with haze, Descemet folds, and mild central subepithelial haze were evident OU. The left cornea had a 1mm punctate central epithelial defect without infiltrate and small, adjacent epithelial bullae. Neither cells nor flare were present in the anterior chamber, the iris was normal, and a clear posterior chamber intraocular lens was noted OU. Fluorescein staining demonstrated an intact epithelium right eye, while the small epithelial defect was present in the left eye. Goldmann applanation tonometry measured 11 mmHg in the OD, 9 mmHg OS using topical fluorescein and benoxinate ophthalmic solution in each eye. The fundus exam showed no pathology in either eye.

The patient was diagnosed with bullous keratopathy secondary to FECD OS. He was treated with ofloxacin 0.3% QID, preservative-free artificial tears every two hours, and bacitracin zinc/polymyxin B sulfate ointment at bedtime OS and was directed to use Muro 128 QID solution OD only. He was seen one day after this visit and then four days after. At the four day follow up appointment, the patient noted complete resolution of foreign body sensation. He reported that his vision was “back to normal” with diurnal fluctuation noted with ocular medication compliance. Uncorrected visual acuities improved to 20/40, pinhole 20/30 OD, and 20/50, pinhole 20/40 OS. Entrance testing remained normal. Slit-lamp exam showed complete resolution of previous epithelial defect. The patient was advised to stop ofloxacin 0.3% QID and bacitracin zinc/polymyxin B sulfate ointment OS, but to resume the use of Muro 128 solution QID OU and preservative-free artificial tears BID OU.

At future follow up visits, the patient remained pain-free and the vision and pachymetry remained stable. The patient was referred to the cornea service and DMEK surgery was planned for both eyes. At the time of this case presentation, the innovative use of the rho-kinase inhibitors was not available but would have been considered in this case.

 

DISCUSSION

There are two types of FECD, early-onset and late-onset.2 The less common early-onset FECD presents in the first decade, and affects females and males equally.2 The classic and more common late-onset FECD presents in the fourth decade or later and has a female to male ratio of 3:1.2 The course of progression is similar between both types reaching end-stage disease within two to three decades of onset.1

 

ANATOMY

Corneal endothelial cells form a side-by-side monolayer of mostly hexagonal-shaped cells.4 The average cell is 18-20 µm in width and 4-9 µm in thickness.4 Normally, corneal endothelial cell mitosis or regeneration does not occur, and loss occurs at 0.6% per year.5 Endothelial cell density is approximately 3000-3500 cells/mm2 in childhood.5 By the age of 85 cell density reaches an average of 2300 cells/mm2.5 The minimum amount of corneal endothelial cell density required to maintain corneal transparency is 400-700 cells/mm2.4 When apoptosis occurs, the remaining cells enlarge to compensate.1,4 This results in polymegethism, variation in cell size, pleomorphism and abnormality in cell shape.1

 

PHYSIOLOGY

The corneal endothelial cells maintain stromal dehydration through active transport and passive barrier functions. Both hydrostatic pressure from the aqueous humor and oncotic pressure of the corneal stroma passively force fluid into the corneal stroma. The metabolically active enzyme pumps, located on the endothelial cell borders, actively counteract the influx by creating an osmotic gradient of fluid flow into the anterior chamber.Oxygen required for endothelial cell metabolism diffuses from the atmosphere through the cornea.4 During sleep, when the closed eye limits the amount of available oxygen, anaerobic metabolism occurs and results in lactic acid production.4 Stromal lactic acid causes an increase in stromal oncotic pressure, drawing fluid into the cornea.4 A normal corneal endothelium will compensate for this imbalance and prevent overhydration of the cornea.4 When reduced corneal endothelial cell counts exist, approximated at 700 cells/mm2, symptomatic corneal edema upon awakening will occur.4

 

PATHOPHYSIOLOGY

Numerous mechanisms associated with various gene mutations have been identified in the pathophysiology of FECD.1 Early-onset FECD is associated with a defect in COL8A2 gene, which is responsible for forming the alpha 2 chain of collagen VIII component of Descemet membrane.1,2 Late-onset FECD is associated with defects in multiple genes including SLC4A11, LOHXD1, AGBL1, TCF4, and TCF8.2 The genetics of late-onset FECD cases demonstrate variable penetrance and expressivity.1 FECD is historically considered an autosomal dominant disorder, but the majority of patients with FECD have no known family history of the condition.1 Most cases ultimately do not have an identifiable gene mutation.1,2 Mitochondrial dysfunction, oxidative stress, apoptosis, altered protein response, and epithelial-to-mesenchymal transition are all involved in the pathophysiology of FECD.1 These diffuse mutations and pathological pathways appear phenotypically identical, resulting in the appearance of the guttae excrescences on Descemet’s membrane projecting towards the anterior chamber, a reduction of corneal endothelial cells resulting in pleomorphism and polymegethism, increased corneal thickness, and resultant loss of corneal transparency.2

 

PRESENTATION

FECD consists of four stages. The first stage manifests as central corneal guttae. Symptoms at this stage are usually absent.2 Some patients with central guttae without edema may experience glare and a reduced quality of vision due to scattering of light.1,2 Importantly, guttae are found in 4% of the US population, although only a fraction will develop FECD.1 The percentage of patients with central guttae who progress to visually significant corneal edema is unknown.1,2 In the second stage, guttae spread to involve the peripheral endothelium resulting in a beaten metal appearance.2 Endothelial decompensation with resultant corneal edema is present in this stage.2 In early corneal edema, the epithelium will lack luster and develop a gray hue.3 The stroma, which may be optically clear in mild corneal edema, will show increased thickness.3 Patients are symptomatic at this stage with symptoms greatest upon awakening due to reduced oxygen availability.1 With advanced edema, Descemet folds, a ground glass appearance, epithelial microcysts, and progressed visual impairment occur.3 Stage 3 is marked by the development of epithelial bullae, known as bullous keratopathy.2 Bullae develop as microcysts coalesce.2,3 Ruptured bullae can cause severe pain at this stage.2 Stage 4 is reached when scarring in the form of avascular subepithelial fibrosis is present.2

 

DIAGNOSIS

FECD is diagnosed via clinical exam and diagnostic testing. Measurement of corneal thickness with pachymetry, either ultrasound, optical coherence tomography (OCT), or optical methods, is readily available and allows for monitoring disease progression. When corneal transparency is reduced, ultrasound and OCT pachymetry measurements are more reliable than optical means.3 Specular microscopy shows the density and morphology of endothelial cells.4 Various software programs are available to analyze the images and provide clinically useful indices: the cell density (CD) is measured in cells/mm,2 pleomorphism is measured by the hexagonal percentage (HEX), and polymegethism is measured by the coefficient of variation (CV).4 In advanced FECD, when the endothelial view is compromised by edema, in vivo confocal microscopy may be utilized.2 As FECD progresses, corneal thickness, polymegethism, and pleomorphism all increase.

The differential diagnoses for FECD include any condition associated with guttae, corneal edema, or pseudoguttae.2 Macular dystrophy and posterior polymorphous dystrophy are associated with guttae.2 Pseudoguttae are transient and may be a result of trauma, inflammation, toxin exposure, or infection.2 Other conditions associated with corneal edema, such as iridocorneal endothelial dystrophies, pseudophakic bullous keratopathy, or herpetic keratitis can be eliminated as differentials based on their associated clinical features and largely unilateral presentations.

 

TREATMENT

No current medical treatment can arrest the progression of FECD.Early FECD is often managed with hypertonic sodium chloride 5% solution or ointment, which may offer temporary relief by dehydrating the cornea.2 However, a recent study evaluated the effect of hyperosmotic eye drops in patients with FECD and concluded there is no benefit to the use of hyperosmolar solution for the treatment of diurnal corneal edema fluctuations.5

Surgical decisions are based on signs and symptoms. Patients with dense central guttae without the presence of corneal edema may be symptomatic for glare and fluctuating vision. Reduced visual acuity and the presence of corneal edema indicate corneal endothelial decompensation warrant surgical intervention. Traditionally, the only surgical option to treat FECD was PKP. Due to a high risk-to-benefit ratio with PKP, surgery was postponed until the advanced stage of disease.1As a result of innovations in endothelial keratoplasty (EK) over the last 20 years, EK has replaced PKP as the preferred treatment. Hence, surgical intervention is now recommended earlier in the disease course.1 Because EK leaves the majority of the stroma in place, dense stromal scarring is a contraindication of the procedure. Therefore, surgery should be considered earlier in the disease course, prior to the development of epithelia bullae and dense anterior stromal scarring. Compared to PKP, endothelial keratoplasty eliminates the risks of permanently reduced tectonic strength of the cornea, intraoperative “open-sky” complications, and suture-related infections.1 Additionally, endothelial keratoplasty yields a faster visual recovery, improved refractive outcome, and a lower rate of rejection as compared to PKP.6

The two methods of EK utilized are DSEK and DMEK. Both techniques involve a descemetorhexis, which selectively removes the patient’s Descemet membrane and endothelial layers.6 DSEK uses a donor graft consisting of donor stroma in addition to Descemet membrane, and endothelium.6 DMEK donor grafts consist of Descemet membrane and endothelium only.6 Disadvantages of DSEK include hyperopic shifts due to additional central stromal thickness and graft folds.6 DMEK grafts produce improved visual outcomes and have a lower risk of rejection, therefore requiring less steroidal therapy, compared to DSEK.1, 6

 Future therapies of endothelial replacement are underway. Despite the success of EK, limited availability of donor specimens and surgical expertise, along with the need for long term immunosuppression can limit its application.6 Newer treatments focus on cell-based therapy and regenerative medicine.6

Cell-based therapy involves the cultivation of corneal endothelial cells from donor corneas or alternative pluripotent stem cell sources.6 In 2018, in vitro propagated cadaver endothelial cells were successfully transplanted in patients with FECD.6 Animal models of FECD have shown success using endothelial cells derived from non-ocular precursor cells, including skin-derived cells.6

Regenerative therapies are based on research and case reports indicating corneal endothelial cells in FECD can self-regenerate if the abnormal Descemet membrane and dysfunctional central endothelium is removed.1,8 The newest surgical procedures involving regenerative techniques are Descemetorhexis without endothelial keratoplasty (DWEK), also called Descemet stripping only (DSO), and Descemet membrane transplantation.6 In DWEK/DSO, abnormal central endothelium and Descemet membrane are removed. Peripheral, healthy cells migrate centrally to restore normal endothelial functioning.6 For more advanced cases requiring a larger Descemetorhexis, a DMT provides a scaffold to improve repopulation from the remaining peripheral cells.6

Rho-associated kinase (ROCK) inhibitors represent a new pharmaceutical therapy for FCED.7 Studies involving ROCK inhibitors in FECD have demonstrated the ability to reduce corneal edema and improve vision by promoting endothelial cell proliferation and adhesion while reducing endothelial cell apoptosis.1,8 Okura first reported on the utilization of a ROCK inhibitor in FECD in 2013.9 In 2021 and 2022, two trials evaluated the efficacy of netarsudil 0.02% ophthalmic solution, a ROCK inhibitor, in FECD treatment.7,10 The trials demonstrated that netarsudil 0.02%  daily significantly improved vision and reduced corneal thickness in patients with FECD.10,11 There was no additional benefit with BID dosing.11 Improved corneal edema and acuity are seen within one to three months of treatment.7 It has yet to be determine when to initiate treatment with ROCK inhibitors in FECD.11  Adverse reactions associated with netarsudil include conjunctival hyperemia, corneal verticillata, pain, subconjunctival hemorrhage, and reticular bullous epithelial edema.12  Awareness of this corneal side effect of netarsudil 0.02% is particularly important in the management of FECD because a history of corneal edema increases its risk, and the drug-induced corneal edema may be mistaken for progression of the corneal disease.12 The use of ROCK inhibitors for endothelial dysfunction is currently off label in the United States.

An additional management consideration is the common presentation of the patient with both cataract and FECD. Cataract and early FECD present with similar symptoms of relatively preserved Snellen acuity in the presence of glare with bright lights and oncoming headlights while driving. When considering cataract surgery in a patient with FECD, it is important to discuss with the patient the increased risk of pseudophakic bullous keratopathy. A minimum of 1000 cells/mm2 and corneal thickness of less than 640 μm is protective against pseudophakic bullous keratopathy.13 When considering surgery in a FECD patient, it is often preferable to perform cataract surgery first, followed by endothelial keratoplasty if necessary.10

 

CONCLUSION

FECD causes progressive visual deterioration that may develop into acutely painful episodes. For decades, topical medical treatment was limited to hyperosmotic agents. Significant therapeutic and surgical advancements have been introduced which can help to offer earlier intervention, improve quality of life, and improve visual outcomes.

 

REFERENCES

  1. Sarnicola C, Farooq AV, Colby K. Fuchs Endothelial Corneal Dystrophy: Update on Pathogenesis and Future Directions. Eye Contact Lens. 2019;45(1):1-10. doi: 10.1097/icl.0000000000000469. PubMed PMID: 30005051.
  2. Weinstein, J. Descemet Membrane and Endothelial Dystrophies. In Mannis, M, Holland, E, editors. Cornea. Amsterdam: Elsevier Cornea;
  3. Shapiro, B. Corneal Edema. In Mannis, M, Holland, E, editors. Cornea. Amsterdam: Elsevier Cornea;
  4. Abib F, RY RH, Santos Rd. Corneal Endothelium: Histology, Physiology and In-vivo Examination with Specular Microscope. JSM Ophthalmology. 2017;25(1063).
  5. Zander DB, Bahringer D, Fritz M, Grewing V, Maier PC, Lapp T, et al. Hyperosmolar Eye Drops for Diurnal Corneal Edema in Fuchs’ Endothelial Dystrophy: A Double-Masked, Randomized Controlled Trial. Ophthalmology. 2021;128(11):1527-33. Epub 20210420. doi: 10.1016/j.ophtha.2021.04.015. PubMed PMID: 33892048.
  6. Ong HS, Ang M, Mehta JS. Evolution of therapies for the corneal endothelium: past, present and future approaches. Br J Ophthalmol. 2021;105(4):454-67. Epub 20200724. doi: 10.1136/bjophthalmol-2020-316149. PubMed PMID: 32709756; PubMed Central PMCID: PMC8005807.
  7. Blitzer AL, Colby KA. Update on the Surgical Management of Fuchs Endothelial Corneal Dystrophy. Ophthalmol Ther. 2020;9(4):757-65. Epub 20200825. doi: 10.1007/s40123-020-00293-3. PubMed PMID: 32840804; PubMed Central PMCID: PMC7708572.
  8. Macsai MS, Shiloach M. Use of Topical Rho Kinase Inhibitors in the Treatment of Fuchs Dystrophy After Descemet Stripping Only. Cornea. 2019;38(5):529-34. doi: 10.1097/ico.0000000000001883. PubMed PMID: 30720541.
  9. Okumura N, Koizumi N, Kay EP, Ueno M, Sakamoto Y, Nakamura S, et al. The ROCK inhibitor eye drop accelerates corneal endothelium wound healing. Invest Ophthalmol Vis Sci. 2013;54(4):2493-502. Epub 20130403. doi: 10.1167/iovs.12-11320. PubMed PMID: 23462749.
  10. Price MO, Price FW, Jr. Randomized, Double-Masked, Pilot Study of Netarsudil 0.02% Ophthalmic Solution for Treatment of Corneal Edema in Fuchs Dystrophy. Am J Ophthalmol. 2021;227:100-5. Epub 20210315. doi: 10.1016/j.ajo.2021.03.006. PubMed PMID: 33737034.
  11. Lindstrom RL, Lewis AE, Holland EJ, Sheppard JD, Hovanesian JA, Senchyna M, et al. Phase 2, Randomized, Open-Label Parallel-Group Study of Two Dosing Regimens of Netarsudil for the Treatment of Corneal Edema Due to Fuchs Corneal Dystrophy. J Ocul Pharmacol Ther. 2022;38(10):657-63. Epub 20221103. doi: 10.1089/jop.2022.0069. PubMed PMID: 36327101; PubMed Central PMCID: PMC9784611.
  12. Syed ZA, Rapuano CJ. Rho kinase (ROCK) inhibitors in the management of corneal endothelial disease. Curr Opin Ophthalmol. 2021;32(3):268-74. doi: 10.1097/icu.0000000000000748. PubMed PMID: 33606407.
  13. Li, J. Indications and Decision-Making for Endothelial Keratoplasty. In Mannis, M, Holland, E, editors. Cornea. Amsterdam: Elsevier Cornea;
Adam Benjamin, Jr. Department of Veterans Affairs | Crown Point, IN

Jamie Hogan, OD, Dipl AAO, graduated from the Illinois College of Optometry and completed her Primary Care Optometry residency at the Dayton VA Medical Center. She currently practices at the Adam Benjamin Jr. VA Clinic and serves as an Adjunct Clinical Instructor of Optometry of the Illinois College of Optometry in the Department of Community Based Education. Dr. Hogan is a Diplomate in the Anterior Segment Section of the American Academy of Optometry.

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