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Fuchs' corneal endothelial dystrophy.

Introduction

Fuchs' Corneal Endothelial Dystrophy (FCED) is a slowly progressive, hereditary disease first described by the Austrian ophthalmologist Ernst Fuchs in 1910. (1) He reported patients with corneal epithelial oedema but it wasn't until the 1920s that it was shown that the primary pathology was in the corneal endothelium. (2) Despite being one of the commonest genetic corneal pathologies, it is commonly misspelt with the apostrophe in the wrong position!

In his first series, Fuchs described the classical presentation of early morning blurring in one or both eyes of people in their fifth or sixth decade. An increasingly common presentation nowadays is as an asymptomatic co-pathology in patients who are diagnosed with cataract.

Known to be genetic, inheritance patterns and pathology vary significantly; (3) because of this, FCED should be looked on as a group of conditions with different genetic causes but which have common clinical findings and end-points. There is also some evidence for additional environmental causative factors in susceptible individuals. (4)

Inheritance

In families with classic mature onset FCED, associations with abnormalities at a number of specific chromosome loci and mutations in known genes have been identified. (5) It seems likely that disease presentation and severity may depend on the presence of two or more of these abnormalities in an individual. Some patients will have a family history, often fitting in with an autosomal dominant pattern. Others will have no apparent inherited link: these cases may represent the first clinically significant individual in a family of sub-clinical disease or the result of combined genotypes, one from each parent. Another possibility is that by the time a patient presents, perhaps in their seventies or eighties, their parents will be long deceased and all potential family history will have been lost. Early onset FCED is less common and forms a distinct disease sub-set. Not only are the genetic defects better defined, but also patient's corneas show specific histopathological patterns including greater Descemet's membrane thickening and types of guttae. Inherited in a clear autosomal dominant pattern without any sex-difference, patients often become symptomatic in their 20s or 30s.

Pathophysiology

Guttae (from the Latin gutta for 'drop') on the corneal endothelium are the characteristic first sign of FCED. In early cases, patients are asymptomatic and may remain so for many years. As they progress and become more confluent they give rise to the often-described 'beaten metal' appearance, but still may not have significant impact on vision (see Figure 1). Under the microscope, corneas with FCED have significant thickening of Descemet's membrane (see Figure 2). Guttae themselves are 'excrescences' or deposits of additional collagen on this already thickened layer beneath. Although classic in appearance, other corneal endothelial deposits such as keratic precipitates should be borne in mind when first diagnosing FCED. Guttae are usually bilateral and initially central; their interpalpebral location has meant that ultra-violet irradiation has been proposed as an additional causative factor.

Of course it is not guttae themselves but reduced endothelial cell density (ECD) and secondary loss of pump-function that is the primary cause for visual loss in FCED. It is not clear whether the reduction of corneal endothelial cell numbers and loss of function is secondary to the Descemet's membrane changes, occurs independently or is a mixture of both. The chromosomal and gene defects that have links to FCED encode for a variety of cell functions such as collagen synthesis and enzyme functions. (4) Normal adults have an ECD of between 2,000-3,000 cells per [mm.sup.2], those with FCED perhaps 1,000 or less. As the disease progresses, ECD drops further; to cover the remaining space between guttae, endothelial cells become larger, more spread out and no longer hexagonal in shape and are described as being 'pleomorphic' (see Figure 3 page 46). The cornea achieves optical clarity through its lamellar, repeated microscopic anatomy and relative dehydration. The latter is maintained by the endothelial cell pump and tear film evaporation. When cell number and function drop below a certain threshold, the loss of tear evaporation when the patient is asleep means the cornea starts to swell. Although this will initially clear soon after waking, as the disease progresses it will take longer and longer to do so until eventually the cornea remains cloudy all day.

Patients with FCED have abnormal types of collagen in their Descemet's membrane and endothelial cells also show changes in specific proteins and enzymes concerned with cell function and cell-death. Many of these specific cell abnormalities can be found in other cells of different layers of the cornea; some of these are secondary to oedema but others are known to be genetically determined.

In the advanced stages, the chronically oedematous stroma and epithelium will go on to develop bullae, scarring and neovascularisation (see Figures 4 and 5).

Cataract surgery results in inevitable progression of FCED. An already compromised endothelium is placed under stress during the operation by ultrasound from the phacoemulsification probe, fluid flow and physical trauma. This will at least result in delayed visual recovery but can leave a patient with permanent corneal oedema.

Clinical presentation

In the majority, bilateral guttae become clinically detectable in middle age, more frequently in women. They progress over the coming decades, but at differing rates between individuals. First symptoms include painless blurring of vision, photophobia, glare and haloes around lights. As previously noted, such symptoms are often, although not always, more severe in the morning.

When patients present with cataract and FCED, it is often difficult to ascertain how much of the symptoms are due to each pathology. In this situation, diurnal variation in vision is a useful indicator that the corneal pathology is at least contributing to symptoms.

As FCED progresses further, best-corrected vision will deteriorate such that it remains reduced all day. Slit lamp examination at this time will reveal corneal stromal oedema and thickening, and later opacification. More advanced disease results in corneal epithelial oedema and bullae, by which time the patient may be experiencing significant ocular surface pain.

In bilateral disease, the clinical presence of corneal guttae is diagnostic. Unilateral disease must be distinguished from other causes of corneal endothelial failure such as herpetic keratitis or congenital abnormalities.

Imaging

Fuchs' dystrophy is usually a clinical diagnosis that does not require confirmation with tests or imaging. Corneal pachymetry may confirm a thickened oedematous cornea, but in the inevitable absence of pre-disease measurements and the wide natural variation in corneal thickness, rarely provides useful information. Corneal endothelial specular microscopy (see Figure 3) or confocal microscopy can confirm reduced ECD and the presence of guttae, but such imaging is usually difficult in an already oedematous cornea. Imaging may be useful in the differential diagnosis of apparently uniocular disease or in screening prior to surgery in those with a family history.

Prevalence

The few studies that have screened for the presence of corneal guttae in general populations suggest relatively high prevalence of up to 5% in the over 60s age group. (5) Obviously, most of these patients are asymptomatic and will remain so. Late-onset FCED is more common in females and has a higher prevalence in Caucasians than other races. Cases severe enough to impair vision and require treatment is much less common. However, the number of patients undergoing corneal endothelial transplant may rise as techniques and outcomes improve and if the proportion of the older population undergoing cataract surgery increases.

Treatment

Some patients with early disease can be managed with medical treatments. Hypertonic 5% saline drops work by drawing water from the cornea by osmosis. They often sting on installation but can reduce the time taken for early morning blur symptoms to clear. Other patients find that judicious use of a warm air source, such as a hair dryer, can have a similar effect. Occasionally patients can reduce the impact of early morning blur by changing their daily routine, for example, waking up early enough for their vision to clear before they start their daily activities.

Reflective learning

Having completed this CET exam, consider whether you feel more confident in your clinical skills--how will you change the way you practice? How will you use this information to improve your work for patient benefit?

When medical treatments are no longer effective, the only option is to consider corneal transplant. Such treatment has been revolutionised over the last decade with the widespread switch to endothelial keratoplasty from a traditional full-thickness cornea transplant. (7) This technique continues to evolve, but has already become a common, local anaesthetic day-case procedure. The main advantage over penetrating keratoplasty is that it has virtually no effect on the corneal surface, thereby maintaining its natural shape and avoiding the potentially large refractive changes of corneal suturing (see Figure 6).

Endothelial keratoplasty currently involves preparation and insertion into the eye of a disc of deep corneal donor stroma with its attached endothelium. Such discs are prepared using an artificial anterior chamber, either manually with a special blade or with a LASIK microkeratotome. Prior to insertion, the host corneal endothelium is manually stripped. The donor disc is then inserted through a small incision using an injector, then opened up and opposed to the back of the host cornea with an air bubble. Such surgery is described as descemet's stripping (automated) endothelial keratoplasty (DSAEK, or sometimes just EK for short).

DSAEK is usually performed on eyes that are pseudophakic or combined with simultaneous cataract surgery. This is because it makes surgery technically easier, it eliminates risk to a graft of subsequent cataract extraction, and, in general, most patients are of the age where early lens opacity is inevitable. The exceptions to this are patients under 40 with familial early-onset FCED, where it may be justifiable to leave the subject's natural lens.

Visual recovery after DSAEK is usually fairly rapid. Patients require follow-up and the administration of topical steroid medication for a prolonged period of time after surgery. Complications include graft detachment in the short term and graft rejection in the longer term.

Cataract surgery in patients with Fuchs' dystrophy

If an older, phakic patient has clinically significant FCED, with stromal and epithelial oedema and/or significant diurnal variation in symptoms, the decision to undertake simultaneous or closely sequential phacoemulsification and DSAEK is easy. The more difficult decision is what to advise patients with less advanced FCED coming up to lens surgery because cataract surgery causes inevitable further reduction in ECD. (8) It is impossible to quantify the risk of corneal decompensation in these cases due to multiple variables such as endothelial cell health, density and nature of the cataract, surgeon skill, patient expectations and so on. In this situation it is clearly important to inform the patient of the risk to their cornea as a result of the surgery, their likely slow visual recovery and the possible need for subsequent DSAEK. It is also impossible to predict the rate of recovery of endothelial function in these patients; some may regain corneal clarity quickly, others take many weeks or months, and still others achieve early recovery but then delayed decompensation. Informed surgical consent must obviously cover these scenarios.

The future

The human corneal endothelium does not normally regenerate; the cell number is fixed at birth and only usually gradually reduces over time. In diseases such as FCED it would obviously be useful to 'switch on' cell reproduction to restore depleted ECD. Numerous research groups are currently investigating the potential of human cultured endothelial cells to restore the ECD in diseases such as FCED. (9) Animal models have already demonstrated that this may be possible, but its application to humans is still some way off.

Course code: C-38878 | Deadline: January 9, 2015

Learning objectives

To be able to explain to patients about Fuchs' corneal endothelial dystrophy (Group 1.2.4)

To be able to identify cases of Fuchs' corneal endothelial dystrophy using appropriate techniques (Group 3.1.2)

To be able to recognise cases of Fuchs' corneal endothelial dystrophy and manage appropriately (Group 6.1.5)

Learning objectives

To be able to explain to patients about Fuchs' corneal endothelial dystrophy (Group 1.2.4)

To understand the symptoms associated with Fuchs' corneal endothelial dystrophy (Group 8.1.2)

Learning objectives

To understand the natural progress of Fuchs' corneal endothelial dystrophy (Group 1.1.1)

To be able to recognise cases of Fuchs' corneal endothelial dystrophy and manage appropriately (Group 2.1.2)

Matthew Edwards MBChB, FRCOphth

Matthew Edwards is a consultant ophthalmic surgeon at the Royal Hallamshire Hospital specialising in corneal surgery and ocular surface disease and has been instrumental in establishing the Laser-Vision clinic at the Sheffield Vision Centre. He is an active member of the British Society of Refractive Surgery, a member of the Societies of Cataract and Refractive Surgery in both the United Kingdom and the US and an honorary senior lecturer at the University of Sheffield, publishing articles regularly in peer-reviewed journals.
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Title Annotation:1 CET POINT
Author:Edwards, Matthew
Publication:Optometry Today
Geographic Code:4EUUK
Date:Dec 12, 2014
Words:2138
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