Fuchs Endothelial Dystrophy 

Updated: May 04, 2018
Author: Vikas Mittal, MBBS, MS; Chief Editor: Hampton Roy, Sr, MD 

Overview

Background

Fuchs endothelial dystrophy (FED) is characterized by an asymmetrical, bilateral, slowly progressive edema of the cornea in elderly patients. When inherited, the transmission is autosomal dominant. Corneal endothelium is a monolayer of cells that acts as the major pump to deturgesce the cornea and ensures clarity. The normal attrition rate of endothelial cells is 0.6% per year; the rate is accelerated in Fuchs endothelial dystrophy. The root cause of the condition is a slowly progressive formation of guttate lesions between the corneal endothelium and the Descemet membrane. These wartlike, anvil-shaped or mushroom-shaped excrescences are said to be abnormal elaborations of basement membrane and fibrillar collagen by distressed or dystrophic endothelial cells. As the lesions enlarge, the covering endothelial cells initially become stretched, and they eventually fall off. Examples are shown in the images below.

Familial Fuchs endothelial dystrophy in a 65-year- Familial Fuchs endothelial dystrophy in a 65-year-old female. The other eye presented similarly. Her father and older brother were reported to have the same malady.
The left eye of a 75-year-old man showing fully de The left eye of a 75-year-old man showing fully developed Fuchs endothelial dystrophy. The optical section shows marked thickening of the central part of the cornea and lifting up of the epithelium. Bullae formation is seen on the nasal side. The epithelium is thickened.

Growth of cornea guttata progresses from the center of the cornea to the periphery. As the endothelial cells fall, the remaining cells enlarge to cover the gap. With the reduced number of endothelial cells, the pump function suffers. Endothelial cell attrition rises with increasing number and size of the guttate lesions. Cornea guttata may be discovered accidentally or when specular endothelial microscopy is performed to find out the cause of the visual disturbance.[1] Studies have indicated the possibility of associated anterior stromal changes in the form of keratocyte depletion in this condition.[2]

Fuchs endothelial dystrophy passes through 4 clinical stages. These stages evolve over a period of 2 or 3 decades. The changes are bilateral but usually asymmetric.

Stage 1

This stage is cornea guttata. It occurs in the fourth or fifth decade of life. Slit lamp examination by specular reflection may show cornea guttata in the central part of the corneal endothelium. Examples are shown in the images below.

Severe cornea guttata in a 61-year-old woman. The Severe cornea guttata in a 61-year-old woman. The endothelium is speckled with pigment. This patient had complained of mistiness in her otherwise excellent vision.
Specular endothelial microscopy in a case of sever Specular endothelial microscopy in a case of severe cornea guttata with transparent cornea. The guttata lesions have affected many individual cells and groups of cells.

Some pigment dusting also may be seen. The excrescences of corneal guttata increase in number and may become confluent, resulting in a beaten metal appearance of the endothelial surface. The condition spreads from the center toward the periphery.

The patient usually has no complaints at this stage. Some very observant patients notice that the quality of their 20/20 vision is not the same as before. A slit lamp examination of the endothelium leads to the diagnosis.

Stage 2

This stage is characterized by increasing visual and other problems, caused by incipient edema of the corneal stroma initially and later the epithelium. The patient sees halos around lights and also experiences blurred vision and glare. Tiny droplets of corneal epithelial edema (bedewing) are best seen using retroillumination. The epithelial microcysts later coalesce and form bullae; hence, the name bullous keratopathy. The bullae rupture and expose the cornea to the danger of infectious keratitis. The patient experiences foreign body sensation and pain. Corneal sensitivity is reduced by the destruction of the epithelial nerve endings.

Slit lamp examination shows typical changes quite early. The posterior corneal lamellae are first to become edematous. They cause wrinkling in the Descemet membrane, termed striae. Epithelial edema is seen later.

Stage 3

In this stage, subepithelial connective tissue and pannus formation along the epithelial basement membrane are present. The periphery of the cornea becomes vascularized. A reduction of bullae formation occurs. The epithelial edema is reduced, so that the patient is more comfortable. However, the stromal edema remains. The epithelial layer is strengthened by the underlying pannus and fibrous tissue.

No medical treatment is known to prevent or stop the formation of cornea guttata. Hyperosmotic drops and ointment and bandage contact lenses may help for a time. Once the vision becomes adversely affected, a penetrating graft is advised at the convenience and the need of the patient. A deep lamellar endothelial graft is new, potentially effective alternate technique. The results of surgery in Fuchs endothelial dystrophy are excellent in most cases.

Stage 4

The chronicity of the disease leads to fibrovascular proliferation, followed by end-stage subepithelial scarring. This decreases the vision further.

No known medical treatment prevents or stops the formation of cornea guttata. Hyperosmotic drops and ointment and bandage contact lenses may help temporarily. Once the vision becomes adversely affected, an endothelial graft is advised. Descemet membrane endothelial keratoplasty (DMEK) is the latest surgical technique for Fuchs endothelial dystrophy, and the results of this surgery are excellent in most cases.

Pathophysiology

The cornea is a highly specialized tissue with unique physiological functions of the various constituents that help to keep it transparent. The endothelium plays a major role in maintaining corneal transparency. Oxygen from the anterior chamber serves the needs of the endothelium and the posterior layers of the cornea. The essential nutrients (eg, glucose, amino acids) pass through it to provide for the cellular elements of all the layers of the cornea. The endothelial monolayer is responsible for relative deturgescence. This is completed in 2 ways: (1) by acting as a barrier to the movement of salt and metabolites into the stroma, and (2) by actively pumping bicarbonate ions out of the stroma and back to the aqueous humor.

In Fuchs dystrophy, the basic lesion appears to be cornea guttata. Upon ultrastructural examination, this newly deposited abnormal portion of Descemet membrane consists of bundles and sheets of widely spaced, banded collagen and multiple laminations of basement membrane material. Endothelial cells may produce these wartlike, mushroom-shaped or anvil-shaped excrescences. Guttate excrescences in the peripheral cornea are of no consequence. However, their strong presence in the center of the cornea foreshadows trouble in the coming years. The increasing cornea guttata thins and progressively destroys the endothelial cells. The remaining cells enlarge and cover the gaps.

A stage comes, when because of the reduced number of functioning endothelial cells, the barrier and pump functions fail to maintain the delicate balance, and excessive hydration of the cornea starts (decompensation). The edema fluid separates the corneal lamellae and forms "fluid lakes." The separation of collagen fibrils leads to clouding of the cornea. As the disease progresses, the edema fluid enters the epithelium, resulting in an irregular epithelial surface. The retinal image becomes increasingly blurred. The edema varies from slight bedewing to frank bullae formation. Mild-to-moderate cornea guttata can remain as such for years without affecting vision. Only when stromal, and especially epithelial, edema manifest is the condition called Fuchs endothelial dystrophy. As the disease advances, vascular connective tissue is formed under and in the epithelium. This condition is followed by secondary complications (eg, epithelial erosions, microbial ulceration, corneal vascularization).

Epidemiology

Frequency

United States

Exact incidence of Fuchs endothelial dystrophy is not known. It begins with the formation of guttate excrescences. Cornea guttata is seen quite often. Frequency of cornea guttata increases with age. After age 40 years, 70% of patients have cornea guttata. Only 0.1% of these patients have epithelial edema and bullae formation.

International

A cross-sectional study in Japan found the prevalence of cornea guttata to be 4.1% among residents aged 40 years or older using only specular microscopic criteria.[3] Older age, female sex, and a thinner cornea were independently associated with a higher risk of cornea guttata.

Mortality/Morbidity

Once corneal decompensation starts, the course is relentless. In a matter of months or years, the vision is progressively disturbed. Finally, the patient is visually crippled. In addition, problems caused by repeated bullae formation, ulceration, scarring, and vascularization occur. If left untreated, the condition ends in near blindness, which may be painful.

Race

No race is immune from this condition.

Sex

Females are affected more than males (3:1).

Age

Fuchs endothelial dystrophy can be differentiated into early-onset (manifesting in the third decade of life) and late-onset (manifesting in the sixth decade of life, on average). However, the root of the condition is evident 1 or 2 decades earlier in the form of profuse cornea guttata in the central part of the cornea.

Prognosis

As a result of a successful corneal graft, patients experience complete freedom from bullae formation, pain, and irritation.

A high percentage of patients will have excellent transparency of the graft.

If the host cornea is not vascularized, the chances of graft rejection are minimized.

If the crystalline lens is transparent and the macular function is good, the chance of the patient regaining excellent vision is great.

Secondary procedures may be necessary to minimize astigmatism and any gross refractive error.

If the cornea has been vascularized as a result of repeated erosions and ulcer formation, the long-term results are less predictable.

Patient Education

As long as the vision is good for practical purposes, with or without local medication, surgery is not needed.

If a patient develops a cataract, that patient will need cataract surgery with or without keratoplasty. The surgeon in consultation with the patient will make the final decision.

This corneal condition needs a long-term, close interaction between the patient and the ophthalmologist.

The less affected eye needs as much attention as the affected eye.

Since the condition can be familial, other members of the family should have an eye examination.

A regular balanced diet and exercise are as useful to the body as they are to the eye.

Genetics and Inheritance

Proteomic and gene expression analyses may aid in clarifying the underlying mechanism and etiology of Fuchs endothelial dystrophy. Several gene expression profiles have been investigated and were found to differ in Fuchs endothelial dystrophy corneas as compared to normal corneas. Based on these analyses, there is increasing evidence that interaction between genetic and environmental factors contribute to the complex alterations in the proteome and genome of the diseased endothelial cells and that addressing such interactions will enable better characterization of the pathogenic mechanisms involved.[4] In addition to decreased antioxidant defense, distinct oxidative DNA damage has been identified, indicating that mitochondria are the primary targets of oxidative damage in Fuchs endothelial dystrophy. One of the first genetic defects identified in Fuchs endothelial dystrophy was mutations in the COL8A2 gene, which are associated with early-onset Fuchs endothelial dystrophy.[5]

A new IC3D classification system for corneal dystrophies consists of four categories that reflect the known genetic and pathologic evidence for a given dystrophy. Fuchs endothelial dystrophy falls into categories 1-3; category 4 is reserved for suspected new corneal dystrophies and does not fit the profile of Fuchs endothelial dystrophy. Some of the inherited cases of Fuchs endothelial dystrophy are autosomal dominant.[6]

Category 1 indicates a well-defined corneal dystrophy in which the gene has been identified and a specific mutation is known. Early-onset Fuchs endothelial dystrophy, mapped to COL8A2 (FECD C1), fits into this category. Early-onset Fuchs endothelial dystrophy usually begins in the first decade of life and becomes clinically detectable in the second and third decades.

Category 2 indicates a well-defined corneal dystrophy that has been mapped to one or more specific chromosomal loci, but the gene or genes have not been identified. Familial Fuchs endothelial dystrophy is included in this category (FECD C2), in which multiple chromosomal loci have been mapped. Familial Fuchs endothelial dystrophy is described in the literature as a primarily autosomal dominant condition.[6, 7]

Category 3 indicates a well-defined corneal dystrophy in which the chromosomal locus has not been identified and accounts for a large percentage of familial Fuchs endothelial dystrophy cases. The IC3D classification applies only to hereditary cases of Fuchs endothelial dystrophy and does not apply if no evidence of inheritance has been established. Moreover, some authors argue that most Fuchs endothelial dystrophy cases are more like a degeneration than a dystrophy because of late onset, lack of family history of the disease, and occasional asymmetric pattern, commonly associated with degeneration.[8]

Results of a genomewide association study and replication studies showed that E2-2 protein was associated with Fuchs corneal dystrophy (FCD). The association of alleles in the transcription factor 4 gene (TCF4), which encodes an E2-2 protein, increased the odds of FCD by 30 for homozygotes. This type of genetic testing may be useful in the future.[9]

It was also shown that approximately 5% of Fuchs endothelial dystrophy cases in Chinese patients and 4% of cases in Indian patients can be attributed to mutations in the SLC4A11 gene.[10]

The first genetic locus for late-onset Fuchs endothelial dystrophy (called FCD1) that was mapped to the 13pTel-13q12.13 interval followed a typical autosomal dominant inheritance pattern.[11] A second locus for late-onset Fuchs endothelial dystrophy (FCD2) was mapped to 18q21.2-q21.32.[12] More recently, the FCD3 locus was identified in a single large family at the 5q33.1-q35.2 interval.[13]

 

Presentation

History

Fuchs endothelial dystrophy is a bilateral, slowly progressive degeneration of the cornea. It affects women 2-4 times more often than men. Patients often volunteer information about affected sisters and brothers.

The condition may be detected by chance, on slit lamp examination, or during a routine checkup.

A patient may complain of less than satisfactory 20/20 vision. Early morning vision may be reported as misty. As the day progresses, the mist clears. An observant patient may make this complaint. Mistiness may remain much longer than merely in the morning. It may persist the whole day. In the early stages, it is improved by use of hypertonic drops and ointment.

Patients may have difficulty performing visual tasks, which require attention to fine letters or figures.

Patients may see halos around the sources of light.

Patients may feel a gritty or foreign body sensation during part of or during the whole day.

Progressive fall in the corrected visual acuity occurs over previous months or years.

Attacks of redness, pain, and watering, lasting for hours or days occurs.

Constant redness, pain, watering, and poor vision may be present.

Rapid onset of symptoms of fading vision and irritation after an intraocular operation, especially for cataract, may occur.

A slow and poor recovery of vision may occur after a cataract operation.

Increasing visual deterioration may develop, sometimes weeks or months after a successful Nd:YAG laser surgery for secondary cataract.

Physical

Lids: Lids are normal in early cases. They may appear red and congested in advanced cases.

Conjunctiva: Conjunctiva is normal in early cases. It may be highly congested, especially around the limbus, when epithelial erosion, bullae formation, or infected ulceration is present.

Corneal epithelium: The corneal epithelium is normal and transparent in early cases. Bedewing of the epithelium occurs because of epithelial edema. Epithelial bullae may be present. Pannus formation occurs. Ulceration with or without infection may be present. The corneal epithelium may be thick and opaque.

Slit-lamp photograph of a 58-year-old man with epi Slit-lamp photograph of a 58-year-old man with epithelial bedewing and stromal and endothelial edema due to Fuchs endothelial dystrophy.

Corneal stroma: The corneal stroma has a normal transparency in early cases. Appearance of striae in the deeper layers is observed due to folds in the Descemet membrane. Edema of the corneal stroma occurs, first posteriorly and later anteriorly. Vascularization is present.

Corneal endothelium: Presence of cornea guttata in the central area occurs, as seen on slit lamp examination under high magnification or on specular reflection.

Beaten metal appearance may be seen in specular reflection. A similar appearance may be visible at the edge of the central corneal on retroillumination.

Anterior chamber: Anterior chamber is normal unless it is involved in some complication of the cornea.

Iris, lens, vitreous, and retina: Not involved in the process.

Intraocular pressure: Intraocular pressure (IOP) is within the reference range. IOP may be raised independent of the disease.

Vision: Vision is normal in the initial stages. Vision may be reduced to a varying degree later because of a corneal irregularity or opacification or corneal complication.

Causes

Several studies have proposed an autosomal dominant inheritance with high degree of penetrance for Fuchs endothelial dystrophy.[4] It affects females 2-4 times more than males. Females are more severely affected than males.

Another hypothesis suggests that dysfunction of the endothelial mitochondria, potentially resulting from abnormalities of the mitochondrial genome, may underlie the endothelial cell failure that characterizes Fuchs endothelial dystrophy.

Results of a genomewide association study and replication studies showed that E2-2 protein was associated with Fuchs corneal dystrophy (FCD). The association of alleles in the transcription factor 4 gene (TCF4), which encodes an E2-2 protein, increased the odds of FCD by 30 for homozygotes. This type of genetic testing may be useful in the future.[5]

Associated factors include the following:

  • Cataract
  • Age-related macular degeneration
  • Cardiovascular disease
  • Axial hypermetropia
  • Female hormones
  • Inflammation (pseudo-Fuchs endothelial dystrophy)
  • Acute angle-closure glaucoma: This may complicate the course of Fuchs endothelial dystrophy, presumably because the thick peripheral cornea further compromises the already narrow angle, including acute angle closure form.
 

DDx

Differential Diagnoses

 

Workup

Other Tests

Perform specular endothelial microscopy examinations of all siblings of patients with Fuchs endothelial dystrophy. The photographs of the affected corneas may be kept for future reference. Endothelial cell density, hexagonality, and polymegethism may be recorded. The following 5 stages may be seen, as described by Laing et al:[6]

  • Stage 1: The guttate excrescences are in the form of dark structures with sharply defined single bright spots at their center. The structures are considerably smaller in size than a single endothelial cell. Such an excrescence does not lie near the boundary wall of the cell.
  • Stage 2: The excrescence is almost the size of the endothelial cell. The surrounding cells have a stretched appearance.
  • Stage 3: The excrescence is considerably larger, and many cells are involved in one lesion. The dark structure is 5-10 times the size of an endothelial cell. The adjacent cells are abnormal and have missing boundaries. Many lesions are seen close to each other, but they do not coalesce. The excrescences are of 2 types, a smooth round shape or a rough excrescence.
  • Stage 4: The individual excrescences have coalesced. The net result is multilobed, rather than a round outline. The dark areas have many bright spots. The multilobulated structures cover considerable area. The cells between the excrescence masses tend to become abnormal. Coalesced areas contain both the smooth and the rough variety of excrescences.
  • Stage 5: An organized mosaic of endothelial cells is difficult to see. Many stages may be observed in the different areas of the same eye.

Pachymetry is a good way of gauging the increase in corneal edema. The thickness can be compared with the new readings on subsequent visits. Increasing thickness of the cornea means increasing corneal endothelial decompensation. Presence of Descemet folds, epithelial bedewing, and corneal thickness of greater than 0.62 mm indicates potential decompensation. This also affects clinical decisions regarding surgery.

Confocal microscopy can aid in demonstrating corneal endothelial cell polymorphism and pleomorphism, as well as in measuring endothelial cell density in significant stromal edema setting to a certain extent.

Histologic Findings

In the early stages, the focal thickening of the Descemet membrane is similar to those seen in the Hassall-Henle warts of the peripheral cornea. The corneal endothelium appears stretched and thinned over the dome of the excrescences.

In advanced cases, a generalized thickening of the Descemet membrane is observed. This thickening appears to bury the cornea guttata that formed in the earlier stages.

In normal corneas, histologic preparations show lamellar separation as an artifact. In the cases of corneal edema, the artifactitious lamellar separation of the lamellae is reduced. Subepithelial bullae formation is seen at the anterior corneal surface. In the periphery of the cornea, subepithelial fibrous tissue is usually seen. Intraepithelial cysts filled with cellular debris are also seen. Intraepithelial basement membrane formation may occur due to the misdirection of the epithelial cells. The Bowman membrane is normal, unless it has been involved in ulcer formation and keratitis, after the rupture of a bulla.

 

Treatment

Medical Care

Patients who have Fuchs endothelial dystrophy and clear corneas need no treatment. It is only when the corneal decompensation starts that medical treatment becomes necessary. This treatment is necessary until it is not possible to preserve good vision; at that point, keratoplasty is necessary.

Dehydrating agents

Sodium chloride 5% eye drops are instilled 4-6 times during the day, especially in the early hours of the day and less frequently in the evening. Sodium chloride ointment is used at bedtime.

Glycerine can be used for diagnostic purposes. It causes rapid dehydration of the cornea and clears the vision. Certain patients are able to use it for therapeutic purposes, but it is rather uncomfortable. It is instilled many times a day, as needed.

Use of warm dry air (evaporation)

A hair dryer, kept at arm's distance, can be used to blow warm air over the cornea for 5-10 minutes upon awakening. Drying of the cornea may improve the vision of the patient for some time.

Lowering the intraocular pressure (IOP) 

Lowering the intraocular pressure (IOP) is useful when it is even mildly raised. It occasionally helps even when the pressure is normal, especially in borderline cases of corneal decompensation. Topical carbonic anhydrase inhibitors should be avoided as it hinders the activity of endothelial pump.

Topical nonsteroidal anti-inflammatory drug (NSAID)

Diclofenac 0.1% and ketorolac 0.5% drops may help to alleviate symptoms (eg, itching, burning, gritty sensation) but may increase the risk of poor epithelial healing and subsequent corneal melting.

Supportive treatment for ruptured bullae

Anterior stromal punctures may be indicated.

Multiple ablation pits with Fugo blade can be used.

Soft contact lenses can be useful in cases of bullae formation.

Cycloplegics, local antibiotics, and pad and bandage treat the eye for a couple of days.

Excimer laser phototherapeutic keratectomy, amniotic membrane graft, or a conjunctival flap can also be considered.

Surgical Care

Failing vision or pain in the presence of epithelial edema and stromal haze, which cannot be treated by the instillation of 5% sodium chloride drops and ointment, necessitates recourse to surgery.

Despite the lack of an accurate estimate of the prevalence of Fuchs endothelial dystrophy, it remains one of the most common indications for corneal transplantation, accounting for up to 29% of cases.[8]

A selection has to be made between the following 2 options: (1) keratoplasty alone, when no cataract is present, or (2) if a cataract is present and adds significantly to visual disability and specular endothelial microscopy results suggest the need for a corneal graft, then a combined corneal transplant, cataract extraction, and lens implant procedure should be performed.

Penetrating keratoplasty (PK) with or without cataract surgery had been the standard treatment for Fuchs endothelial dystrophy since the past 100 years. PK involves replacement of whole cornea, although only endothelial layer is defective. In last few years, major advances in this field have made replacement of endothelial layer possible without disturbing normal anterior structures of cornea using endothelial keratoplasty. Descemet stripping endothelial keratoplasty (DSEK) involves transplant of healthy endothelial layer along with minimal posterior corneal stroma. When automated stripping of Descemet membrane is performed, the procedure is termed Descemet stripping automated endothelial keratoplasty (DSAEK). Descemet membrane endothelial keratoplasty (DMEK) is the transplant of endothelial cells along with the Descemet membrane only.[14]

Patients who undergo DSEK regain early and more superior visual acuity than patients who undergo PK due to lack of surface sutures.[15, 16] These eyes are structurally stronger and more resistant to postoperative traumatic injury, and no suture-related graft infection or graft rejection occurs. There is no risk of expulsive hemorrhage, as this is a closed chamber surgery. Endothelial keratoplasty gives more predictable refractive outcomes than PK.[17]

Ocular coherence tomography (OCT) image of a patie Ocular coherence tomography (OCT) image of a patient with Fuchs endothelial dystrophy showing gross corneal edema of 850 microns and epithelial bullae formation.
Ocular coherence tomography (OCT) image of the sam Ocular coherence tomography (OCT) image of the same patient as above with Fuchs endothelial dystrophy after undergoing Descemet membrane endothelial keratoplasty (DMEK) and showing overall compact cornea with a thickness of 450 microns and thin attached DMEK graft.

A study by van der Meulen et al found that straylight pre-DSEK can be a useful clinical metric to predict postoperative improvement, especially in cases where the preoperative visual acuity is near 20/20. Straylight also improved more in younger eyes than in older eyes after the procedure.[18]

Frequent visits are no longer required, as is the case in patients who undergo PK. DSEK can be combined with cataract surgery (ie, phacoemulsification or manual small incision cataract surgery) in patients with associated cataracts. In patients with associated corneal stromal scaring, PK is still the treatment of choice.

Some researchers feel that repopulation of the central corneal endothelium with corneal deturgescence can occur after deliberate central Descemet stripping in patients with Fuchs endothelial dystrophy who have undergone cataract removal. This may offer a novel treatment for patients with Fuchs endothelial dystrophy that could reduce the need for endothelial transplantation.[19] However, further studies are needed to validate this.

Descemet stripping endothelial keratoplasty (DSEK)

Preoperative assessment is required mainly to rule out glaucoma and posterior segment abnormality. Careful slit lamp examination is required to check anterior chamber depth and rule out any associated angle anomalies and peripheral anterior synechiae. Anterior segment optical coherence tomography (OCT) and ultrasound biomicroscopy (UBM) can be helpful in patients having very hazy view. Appropriate methods should be used to check IOP. Ultrasound B-scan is helpful in ruling out gross posterior segment abnormality and disc excavation.

Preparation of donor tissue 

The target is to prepare a donor disc of the required diameter with a posterior one third stroma and Descemet membrane with healthy endothelial cells. Preparation can be manual or automated (Microkeratome); the latter is DSAEK. A femtosecond laser can also be used to prepare donor lenticule (FS-DSEK). With the present data, all methods seem comparable in terms of clinical outcome, although this has yet to be clearly established. Manual dissection is most cost effective and is performed using artificial anterior chamber and blunt dissectors.

Steps of manual preparation of donor disc include the following:

  • Donor tissue is mounted on artificial anterior chamber, and the epithelium is removed to improve the view.
  • Manual lamellar dissection is performed at approximately more than two thirds depth with 2 blunt dissectors (straight and curved).
  • Donor tissue is removed from artificial anterior chamber, and the desired diameter is punched.

Preparation of the recipient bed

Surgery is performed under conventional peribulbar anesthesia, although it can be done under topical anesthesia as well.

Preoperatively, pilocarpine 2% is used to constrict the pupil when only DSEK is planned and the pupil is dilated if cataract surgery is also planned.

The superficial epithelium is scraped off. Three 1-mm side-ports are made at 6-o'clock, 10-o'clock, and 2-o'clock positions. The 10-o'clock and 2-o’clock incisions are for Descemet membrane stripping and to manipulate and unfold the donor lenticule. The 6-o’clock incision is used for anterior chamber maintainer (ACM). Avoiding any kind of viscoelastic substance is desirable, and, if required, use only cohesive viscoelastic agent.

Trypan blue (0.06%) solution is used to stain the diseased endothelium. Circular scoring of the Descemet membrane is performed with a reverse Sinskey hook corresponding to epithelial template mark. Scoring (touching the membrane with optimal pressure) can be performed in a complete circle form (Descemetorrhexis) or in a "can opener" form. Scoring makes a cut in the Descemet membrane, which can later be completely stripped off with the help of the hook. Any remnant strands of Descemet membrane can be manually removed, as they will be seen as bluish-stained residual fragments.

A 5-mm to 5.5-mm sclerocorneal tunnel is prepared similar to making a tunnel in manual small incision cataract surgery. Making the tunnel temporal is desirable, so as to induce minimal astigmatism.

If required, cataract surgery with intraocular lens implantation (phacoemulsification or manual small incision cataract surgery) is performed at this stage because the view is comparatively better after removing the Descemet membrane and epithelium.

If viscoelastic agent is used, it is thoroughly and carefully washed out with balanced salt solution (BSS) using an irrigation/aspiration cannula, and an AC is then well formed with BSS.

Transplantation of the donor lenticule 

DSAEK insertion devices can be categorized into 3 groups based on their mechanism of action: the folding technique (ie, taco-folding); glides such as Sheet’s, Busin, or Tan endo-glide; and push-in designs (injectors). Folding and grasping the donor tissue with forceps or the pull-through technique using glides to enable graft insertion through a small incision can be traumatic to endothelium in shallower anterior chambers. The standard Busin glide-assisted graft insertion technique is described below.

The graft is delivered to the patient’s eye using the pull-through technique by Busin.[20] The graft is placed on the plate and pulled into the funnel-shaped part of the Busin glide using a microincision forceps. The Busin glide is then inverted and positioned at the nasal clear cornea tunnel. On the temporal side, a microincision forceps is inserted to pull the graft into the anterior chamber, allowing it to unfold spontaneously. Air is injected underneath the graft until the anterior chamber is completely filled with air, which is left in place for 60 minutes.

Intraoperative OCT can be used to demonstrate the attachment of the donor lenticule with proper orientation to the posterior host stroma. Upon completion of the surgery, air is reduced to about 50% of the anterior chamber volume and is replaced with saline. A bandage contact lens is given in all cases. The eye is patched and the patient is instructed to lie supine for at least 12 hours.

Discharge and steroid therapy

Patients can be discharged after 48 hours. Postoperative medications include topical steroids (prednisolone acetate 1%) in tapering doses, starting from 8 times per day to 1 time per day over 6 months before finally administering topical loteprednol 1 time per day indefinitely. Few surgeons consider completely discontinuing topical steroids.

Descemet membrane endothelial keratoplasty (DMEK)

In contrast to DSEK, which includes posterior donor stroma, DMEK consists of donor endothelium and Descemet membrane without creation of a stromal interface (stromal irregularities or macrofolding or microfolding of donor stromal tissue), inducing significantly less posterior surface aberrations, improving refractive predictability, and resulting in better vision and quicker visual recovery. Compared with DSAEK, DMEK yielded a significantly higher rate of 20/20 and 20/25 vision.

Slit lamp photograph of a 62-year-old man with Fuc Slit lamp photograph of a 62-year-old man with Fuchs endothelial dystrophy showing corneal stromal edema and Descemet folds.
Slit lamp photograph of the same patient as above Slit lamp photograph of the same patient as above who underwent DMEK and showed symptomatic amelioration. Her vision improved to 20/40.

In addition, because less tissue is injected into the recipient’s eye, the overall rejection rate associated with DMEK is shown to be 15 times less than that associated with DSEK.[14]

DMEK and DSAEK yielded similar endothelial survival within a follow-up of 6 months.[21]

DMEK restored physiologic pachymetry, but donor preparation, unfolding, and attachment are currently more challenging with DMEK than with DSAEK.[17] DSAEK allows for easier preparation and implantation, provides the opportunity to use precut donor tissue, and has a lower rebubbling rate.

Graft preparation

The basic aim is to separate the Descemet endothelial complex from corneal stroma.

The corneoscleral button is placed “endothelial side up” on a Teflon block, and a few drops of corneal preservation medium (Optisol) are placed over it such that the liquid reaches the edge of corneoscleral rim. Attempt to keep the tissue-Teflon interface free of fluid to minimize tissue movement during donor harvesting.

An 8.5-mm (the diameter can vary according to the corneal diameters) corneal trephine stained with gentian violet at the edge is then used to make an initial central partial-thickness groove in the corneoscleral button by gentle tapping. The aim is to get a starting point to separate the Descemet membrane from posterior stroma.

The tip of a Sinskey hook is then used to delineate the cleft between the Descemet membrane and underlying stroma all around. At least 2-3 mm of Descemet membrane lift is ensured to help in holding for further separation.

Subsequently, the edge of the Descemet membrane is held with one or two blunt suture-tying forceps and gently pulled in a direction parallel to endothelium and toward the opposite edge.

In one attempt, 20%-30% of the Descemet membrane can be separated. This is performed in each quadrant until all of the Descemet membrane is separated from stroma. Four to five rotations are required to separate the whole of the Descemet membrane.

Simultaneous and coordinated movements of both hands are used when the edge of the Descemet membrane is held with two forceps. In addition, the Descemet membrane is kept in corneal preservation medium at all times. When two thirds of the Descemet membrane is peeled from one side, a small skin biopsy punch (3 mm) is used to punch a hole in the stroma-epithelium complex. The Descemet membrane is reposited, and the entire corneal tissue is flipped and the underside of the DM marked with dye (the letter P or S or F) to identify the right side up in case the graft roll becomes reversed. The remaining dissection is then completed. A small tear in the Descemet membrane endothelial complex does not necessitate tissue replacement, and a good anatomical and visual outcome can be achieved in such cases.[22] After the Descemet membrane is completely peeled off, it tends to roll over, and it is kept afloat in corneal preservation medium until its injection into the eye.

Recipient preparation

The surgery is performed under peribulbar anesthesia.

Epithelium is removed to improve visibility. The sideports are made and the ACM attached. The Descemet membrane is stripped as performed during routine Descemet stripping endothelial keratoplasty.

However, a few researchers have advocated that this scoring is unnecessary in cases of Fuchs endothelial dystrophy.

A small peripheral iridotomy is performed at the 6-o’clock position using an automated vitrector. Finally, the ACM is removed and the paracentesis wound hydrated.

Donor injection

The harvested Descemet membrane endothelial complex is stained with trypan blue 0.06% to improve its visualization inside the eye.

Staining with trypan blue dye and its subsequent wash is performed by instilling the same drop by drop at the edge of the corneoscleral rim, avoiding direct instillation onto the endothelium.

The Descemet membrane–endothelium complex tends to roll up spontaneously with the endothelium at the outer side. This Descemet membrane roll is aspirated into a customized injector mounted on a 2-mL syringe.

The customized Descemet endothelial complex injector is prepared from a routine Akreos (Bausch and Lomb, USA) intraocular lens (IOL) injector. The injector is cut from the proximal end and attached to a silicon tube used for phacoemulsification. Hence, a “no-touch” technique is used for insertion into the eye.

Before injecting the Descemet endothelial complex into the eye, the anterior chamber is decompressed by tapping the posterior lip of the paracentesis wound.

The Descemet endothelial complex is injected into the anterior chamber with a single push.

Donor unfolding

The graft is oriented with the endothelial side down (donor Descemet membrane facing recipient posterior stroma) onto the recipient posterior stroma by careful indirect manipulation of the tissue with air and fluid.

Fluid waves from the side ports, intermittent decompression of side ports, and repeated tapping on the corneal surface help the Descemet endothelial complex unfold.

While unfolding, the edges of the Descemet membrane folds should face the corneal stroma instead of the iris.

Once the proper direction of unfolding is confirmed, a small air bubble is injected below the Descemet endothelial complex.

Surface strokes (not massage) are used to unfold it further.

Finally, a large air bubble is used to fill the anterior chamber completely with air.

An air-tight globe is achieved and maintained since an inferior peripheral iridotomy has already been performed.

Topical 5% povidone iodine, homatropine 2%, and prednisolone forte 1% eye drops are instilled, and the eye is patched.

Postoperative course

The patch is opened after 2 hours and slit-lamp examination performed to confirm an attached Descemet membrane.

Slit lamp photograph on postoperative day 1 of a p Slit lamp photograph on postoperative day 1 of a patient who underwent Descemet membrane endothelial keratoplasty (DMEK), showing an intact and well-adherent graft, compact cornea inferior peripheral iridectomy, and an air bubble.

The postoperative medications used are the same as used for DSEK.

If graft detachment is recognized, either clinically or on OCT, it can be managed via repeat air injection.

Cataract surgery in Fuchs endothelial dystrophy

Cataract surgery alone should be considered in patients with Fuchs endothelial dystrophy who have good endothelial cell density and corneal pachymetry less than 600-640 µm. If precautions are taken to protect the endothelium during surgery with endothelium coating viscoelastics and controlled phacoemulsification parameters, most cases of confluent guttata, without corneal symptoms, do well with cataract and lens implant surgery alone.

Inpatient & Outpatient Medications

Administer oral acetazolamide as needed to control intraocular pressure (IOP). Topical cycloplegics are necessary to avoid any papillary block due to the air bubble in the anterior chamber.

Prednisolone acetate 1% drops are instilled 8 times per day, tapering gradually to bid for 4-8 weeks and qd for several months. Afterward, loteprednol drops 0.25% are given daily for 1-2 years.

If an epithelial defect is present, topical antibiotic drops or ointment is used 4-6 times per day.

For patients with deficient tear secretion, use artificial tears 6-8 times per day.

Further Inpatient Care

If additional surgery is needed to treat various complications of Fuchs endothelial dystrophy that can arise, further inpatient care may be required.

Diet

No dietary restrictions are noted.

Activity

Advise the patient to avoid any kind of trauma to the eye. The eye may be cleaned with boiled and cooled wet cotton swabs. After a period of 2 weeks, the patient can take a brisk walk, watch television, and resume any visual task that the eye is capable of with or without refractive correction.

Complications

The following are potential complications:

  • Graft detachment
  • Graft rejection and failure
  • Tunnel wound gape and aqueous leakage and postoperative infection
  • Secondary glaucoma
  • Endophthalmitis
  • Cataract formation
  • Infective keratitis and, in some cases reactivation of HSV keratitis
  • Epithelial healing problems and ulceration
  • Vitreoretinal problems - Cystoid macular edema, choroidal detachment, and retinal detachment

Prevention

Eye protection measures include the following:

  • Patients should avoid rubbing and bumping the eye.
  • Patients should use a protective shield at night and protective glasses during the day for at least 3 months, and ideally longer, after surgery.
  • Patients should avoid splashing the eye with tap water when taking a bath.

Patients should observe the following cleanliness guidelines:

  • Avoid cleaning the eye with nonsterile products.
  • Avoid applying cosmetics on the lid margin.
  • Avoid smoke and dusty environment.
  • Avoid putting any drops, other than prescribed drops, in the eye.
  • Do not touch the nozzle of the eye drop bottle during use. Store the medicine bottle in a cool place, preferably inside a refrigerator.

Patients should beware of warning signs; seek urgent consultation if any of the following warning signs occur:

  • Feeling of heaviness and pain
  • Redness of the eye, especially around the cornea
  • Diminution of eyesight
  • Light sensitivity

Long-Term Monitoring

Perform routine checkups to assess vision, fundus, and intraocular tension.

Examine the condition of the graft on the first, seventh, and twenty-first postoperative day and then every 30 days afterward to evaluate for any signs of graft rejection.

Transfer

Because the surgery is performed on elderly patients who are sometimes frail and who may have multiple health problems (eg, cardiovascular, respiratory, renal, cerebral systems), be prepared at all times to transfer the patient to an appropriate institution, as and when the need arises.

Future Advances

Recent work demonstrating the ability to culture human corneal endothelial cells ex vivo on several substrates, including denuded Descemet membrane and amniotic membrane, indicates promising areas of future research.[23] Gene therapy–based approaches may invite therapy for Fuchs endothelial dystrophy as mutations in the COL8A2 gene have already been shown to play a role in etiology, and additional causal mutations in different genes will probably be identified. Genetic modification of corneal endothelial cells has already been accomplished, and Fuchs endothelial dystrophy mutations could theoretically be corrected in corneal endothelial cells as a potential treatment for this disease.[24] Future research and improvements in endothelial keratoplasty, endothelial cell engineering, and gene therapy represent promising new approaches for the management of this common corneal disorder.

 

Medication

Medication Summary

Patients undergoing keratoplasty may require carbonic anhydrase inhibitors before and after the surgery. They are highly effective in reducing the intraocular pressure (IOP) to desired levels.

Carbonic anhydrase inhibitors

Class Summary

Carbonic anhydrase (CA) is an enzyme found in many tissues of the body, including the eye. Catalyzes a reversible reaction where carbon dioxide becomes hydrated and carbonic acid dehydrated. By slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport, it may inhibit CA in the ciliary processes of the eye. This effect decreases aqueous humor secretion, reducing IOP.

Acetazolamide (Diamox)

Because of highly predictable effect on IOP. Reduces rate of aqueous humor formation by inhibiting enzyme carbonic anhydrase, which results in decreased IOP. Available in PO and parenteral forms.

Corticosteroids

Class Summary

These agents are most effective in treating inflammations and preventing and treating graft reactions following keratoplasty operation.

Prednisolone (AK-Pred, Econopred, Prelone)

Acting on the nucleus of the cell, the steroids produce certain proteins that are immunosuppressive and prevent the production of inflammatory mediators. By their action on the cell wall, they decrease the release of PG. The net result is suppression of inflammation and immune reaction. These effects are obtained through such diverse mechanisms of action as anti-inflammatory, antiallergenic, antiexudative, antiangiogenic, and antiproliferative. Although they have systemic effects, their main action is exerted at the site of inflammation. Therefore, topical application is useful to prevent immune reaction and inflammation.

Has a short biological life of 12-36 h, therefore, interferes less with physiological processes.

Ocular lubricants

Class Summary

Hypertonicity of sodium chloride is used to treat corneal edema.

Sodium chloride hypertonic, ophthalmic (Muro 128, Muroptic-5)

Sterile ophthalmic solution and ointment used to draw water out of cornea of the eye.

Nonsteroidal anti-inflammatory agents

Class Summary

The inhibition of prostaglandin synthesis, results in vasoconstriction, a decrease in vascular permeability, leukocytosis, and a decrease on IOP. However, these agents have no significant effect on IOP.

Diclofenac ophthalmic (Voltaren)

Diclofenac sodium is designated chemically as 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt, with an empirical formula of C14 H10 Cl2 NO2 NA. One of a series of phenylacetic acids that has demonstrated anti-inflammatory and analgesic properties in pharmacological studies. Believed to inhibit the enzyme cyclooxygenase, which is essential in the biosynthesis of prostaglandins.

Ketorolac tromethamine 0.5% (Acular)

Member of the pyrrolo-pyrrole group of NSAIDs. When administered systemically, has demonstrated analgesic, anti-inflammatory, and antipyretic activity. Mechanism of action is believed to be due, in part, to its ability to inhibit prostaglandin biosynthesis.

Cycloplegics/mydriatics

Class Summary

Instillation of a long-acting cycloplegic agent can relax any ciliary muscle spasm that can cause a deep aching pain and photophobia.

Cyclopentolate hydrochloride 1% (AK-Pentolate, Cyclogyl)

An anticholinergic prepared as a sterile, borate buffered solution for topical ocular use. Prevents muscle of ciliary body, and sphincter muscle of iris, from responding to cholinergic stimulation. Induces mydriasis in 30-60 min and cycloplegia in 25-75 min.

Use has been associated with psychotic reactions and behavior disturbances in pediatric patients.