H18.51 Endothelial Corneal Dystrophy

Corneal guttata seen during biomicroscopy

ICD-10 Diagnosis Code

H18.51–Endothelial corneal dystrophy

Title
Endothelial Corneal Dystrophy

Category
Corneal Opacity And Other Disorders Of Cornea

Description
Endothelial corneal dystrophy is characterized by corneal guttata and other morphologic abnormalities of the endothelium.

DEFINITION

Endothelial corneal dystrophy is a broad term used to describe several diseases and conditions that affect the structure and function of the corneal endothelium. The conditions are known as corneal endotheliopathies and the ICD-9-CM coding system groups most of them under the 371.57 diagnosis code.

Corneal Endotheliopathies Corneal guttata Endothelial corneal dystrophy Fuchs’ endothelial dystrophy Although biomicroscopic examination will reveal the clinical signs of most corneal diseases, specular endothelial microscopy is the most accurate method of examining the corneal endothelium. Specular endothelial microscopy provides information on the endothelium that is difficult or impossible to derive from the clinical examination alone.

Specular Endothelial Microscopy Non-invasive photographic technique Computer-assisted morphometry of the endothelium Morphologic analysis reveals information about the size, shape and population of endothelial cells Structural analysis measures corneal thickness Instrument captures a reflected image of the endothelium called a specular photomicrograph An interpretation of photomicrograph allows for both a qualitative and quantitative analysis of the corneal endothelium

		Specular Endothelial Microscopy Normal corneal endothelium appears as a somewhat-regular array of cells known as the endothelial mosaic Qualitative analysis identifies abnormal endothelial structures and grades the endothelium on the basis of an overall visual assessment of endothelial appearance Quantitative analysis assigns a number or set of numbers to specific morphologic parameters of the corneal endothelium Specular Photomicrograph Interpretation Normal endothelial cell density Normal rate of polymegethism Normal percentage of hexagonally-shaped cells Normal corneal thickness No corneal guttata

NATURAL HISTORY

The cornea is the main refracting surface of the eye. To refract light properly, the anterior surface of the cornea must maintain a regular shape and the entire structure must have some degree of optical transparency. To achieve structural stability and optical transparency, the anatomy of the cornea is highly specialized.

Corneal Anatomy

The layers of the cornea are optically transparent so that the entire structure can transmit visible light. When viewed in cross-section, the cornea is a basic structure of two covering layers with a central collagen stroma. This three-layer model of corneal anatomy is based on structural and biochemical differences between the layers.

The outer covering layer is called the anterior cornea. This layer is composed of the corneal epithelium and a basement membrane called Bowman’s membrane. The anterior cornea functions as a semi-permeable membrane that keeps pathogens out of the eye but allows nutrients from the pre-ocular tear film to nourish the anterior cornea.

The middle layer of the cornea is called the stroma. This layer comprises over 90% of the cornea’s thickness and is composed of tightly packed collagen fibrils in an orderly lamellar arrangement. The spacing and arrangement of the fibrils makes the stroma optically transparent.

To maintain optical transparency, the stroma must be maintained in a state of relative deturgescence and the normal level of stromal hydration is 78% water. The inability to maintain stromal deturgescenece can result in corneal edema and a loss of stromal transparency.

The inner covering layer is called the posterior cornea. This layer is composed of the corneal endothelium and Descemet’s membrane. The endothelium fuctions as a semi-permeable membrane that controls fluid and solute transport across the posterior surface of the cornea while Descememt’s membrane serves as a barrier against injury.

The geographic regions of the cornea differ anatomically, physiologically, immunologically and pathologically. The central region is about six millimeters in diameter while the surrounding peripheral region is approximately twelve millimeters in diameter.

Regional characteristics of the central cornea include the following:

Decreased thickness
More uniformity in the arrangement of the collagen fibers in the stroma
Higher concentration of nerve endings
Higher dependence on the pre-ocular tear film for nutrition
Higher sensitivity to the effects of corneal edema secondary to corneal hypoxia

Regional characteristics of the peripheral cornea include the following:

Increased thickness
Loose ordering of the collagen fibers in the stroma
Lower concentration of nerve endings
Higher dependence on the capillaries at the limbus for nutrition
Higher sensitivity to immune system responses

Corneal Endothelial Physiology

The corneal endothelium is a monolayer of 350,000 to 500,000 specialized cells that cover the posterior surface of the cornea. One of the endothelium’s physiological functions is to secrete a collagen matrix that forms Descemet’s membrane. At birth, Descemet’s membrane is approximately 3um thick. Throughout life, endothelial cells continue to synthesize and deposit additional collagen matrix. Over time, Descemets’s membrane grows thicker and thicker and by age 70 years, the average Descemet’s membrane is 13 um thick.

Corneal Hydration

Corneal hydration is one of the biomechanical properties of the anterior segment, and it is affected by several interdependent factors. To control corneal hydration, the endothelium forms an anatomical and physiological barrier to the aqueous that makes the structure semi-permeable. The ability to be semi-permeable is required because the endothelium must allow movement of nutrients into the cornea from the aqueous but maintain resistance to the effects of intraocular pressure.

Fluid Barrier Function

Endothelial permeability is controlled by tight junctions that are formed between endothelial cells. These connections between cells are found at the apex of the lateral cell membrane and serve to restrict the amount of fluid entering the corneal stroma. There are several tight junctions between individual endothelial cells and these spaces are collectively referred to as junctional complexes.

Metabolic Pump Function

In addition to its fluid barrier function, the endothelium also maintains stromal deturgescence by pumping fluid out of the stroma through an active transport mechanism. The site of the metabolic pump is also within the lateral cell membrane, and it is a part of a completely formed junctional complex between the endothelial cells. The active transport pumping mechanism uses enzymes to translocate bicarbonate ions across the endothelial cell membrane, which passively permits water to follow the ions into the anterior chamber.

Endothelial Cell Density

Complete coverage of the posterior corneal surface by endothelial cells is required to maintain corneal hydration
The minimum number of endothelial cells needed to maintain corneal hydration is the critical cell density and it averages between 300-500 cells/mm2
A clinical estimation of endothelial cell density is called determining a cell count
Endothelial cell density is represented by the CD value on the specular photomicrograph (CD = 2959 cells/mm2)
Advanced age, disease and injury may produce abnormal reductions in endothelial cell density
Asymmetry in cell density of more than 280 cells/mm2 between the eyes may be clinically significant
Although some reduction in cell density occurs with age, most patients should have CD values that follow the ranges in the age-matched normative data table listed below

Age-Matched Normal Endothelial Cell Density

Endothelial Cell Density

Age 10-192,900 – 3,200 cells/mm2
Age 20-202,600 – 3,200 cells/mm2
Age 30-29 2,400 – 3,200 cells/mm2
Age 40-492,300 – 3,100 cells/mm2
Age 50-592,100 – 2,900 cells/mm2
Age 60-692,000 – 2,800 cells/mm2
Age 70-791,800 – 2,600 cells/mm2
Age 80-891,500 – 2,300 cells/mm2

The central corneal endothelium changes as a person ages
Endothelial cell density decreases from birth to death
The central corneal endothelium loses 100 to 500 cells per year (0.5%)
Endothelial cells no not undergo mitosis for cellular replacement
Dead or damaged cells slough off the endothelium
Sloughed cells create a defect in the endothelial mosaic
The defect compromises the endothelium’s ability to control hydration
To repair the defect, the endothelium relies on cell movement

Polymegethism: The Wound Repair Mechanism

The normal wound repair mechanism involves cell movement to repair defects in the endothelail mosaic
Endothelial cells adjacent to a defect move to fill in the space created by the sloughed endothelial cell
The cells move by stretching, sliding or fusing together
Movement of cells as they repair defects creates the variations in cell size that characterizes polymegethism
Rate of polymegethism is represented by the coefficient of variation (CV) on the specular photomicrograph
The average CV value is 27
CV values above 40 are abnormal and indicate an overactive endothelial wound repair mechanism
Recent studies indicate than an elevated rate of polymegethism is the first morphologic abnormality in most corneal endotheliopathies

DIAGNOSTIC EVALUATION

The main goal of the diagnostic evaluation in a patient with endothelial corneal dystrophy is to accomplish the following:

Determine the presence or absence of a corneal endotheliopathy
Classify the corneal endotheliopathy as either primary or secondary
Identify and exclude differential diagnoses
Determine if the corneal endotheliopathy is clinically significant
Prescribe a treatment program

Patient History

Patients with endothelial corneal dystrophy may present with any of the following clinical symptoms:

None
Reduced visual acuity
Fluctuating visual acuity
Glare
Photophobia
Halos around lights
Foreign body sensations
Contact lens intolerance

Clinical Appearance of the Cornea 54-year-old female with complaints of decreased vision 20/25 best corrected visual acuity Mild loss of stromal transparency visible on biomicroscopy with direct illumination Corneal guttata visible on biomicroscopy wih specular reflection illumination technique

		Clinical Appearance of the Cornea Corneal guttata visible on biomicroscopy – 40x magnification with specular reflection illumination technique Corneal guttae nodules appear as darkened areas that resemble holes in the endothelial mosaic Endothelial cells under physiological stress secrete an altered basement membrane material that forms the corneal guttae nodules Individual nodules are called corneal guttae while multiple lesions are referred to as corneal guttata The presence of corneal guttata indicates physiological stress to the endothelium

Clinical Appearance with Specular Microscopy Confluent corneal guttata – 400x magnification Abnormal reduction in endothelial cell density (CD = 1481) Abnormal rate of polymegethism (CV = 54) Increased corneal thickness (pachymetry = 628 um) Physical Diagnosis Fuchs’ endothelial dystrophy – Stage 2

CLASSIFICATION

Corneal endotheliopathies are classified as either primary or secondary. In primary corneal endotheliopathies, the damage to the corneal endothelium is not associated with any other ocular or systemic disorder. In secondary corneal endotheliopathies, there is a recognizable ocular or systemic disorder which contributes to the damage of the corneal endothelium.

Primary Corneal Endothelipathies	Seconday Corneal Endotheliopathies
Corneal guttata	Contact lens-induced endotheliopathy
Fuchs’ endothelial dystrophy	Iatrogenic endotheliopathy
Age-related endotheliopathy	Inflammation-induced endothliopathy

Corneal Guttata — Classification

Corneal guttata is the most common primary corneal endotheliopathy and they are present in 70% of the population over 40 years old.

Corneal guttata are secretions of collagen from the endothelial cells that form a nodularity on the posterior surface of Descemet’s membrane. These nodules are created when endothelial cells under physiological stress secrete an altered basement membrane material that accumulates under the cells. The deposits of abnormal collagen eventually form a nodular-shaped lesion called a corneal gutta and the nodules are collectively referred to as corneal guttata.

The clinical finding of corneal guttata is not specific; they may occur as part of the normal aging process, in corneal endothelial dystrophies, or secondary to ocular inflammation and trauma. Corneal guttata mainly affect the central region of the cornea and, when they are mild or moderate in their presentation, they usually have no effect on visual acuity.

Posterior Cornea

Transmission Electron Photomicrograph of the Posterior Cornea

Normal endothelial cells on opposing sides of corneal gutta
Corneal gutta protrudes towards the anterior chamber
Abnormal endothelial cell overlies the corneal gutta nodule
Abnormal cell is continuous with normal endothelial cells

Corneal Gutta

Isolated corneal gutta appears as a darkened area on specular photomicrograph
Darkened area resembles a hole in the endothelial mosaic
Darkened area is created on specular microscopy because the apex of the corneal gutta nodule is above the specular reflection’s plane of focus
The appearance, enlargement or coalescence of corneal guttata is a clinical sign of endothelial corneal dystrophy

Corneal guttata formations usually do not change quickly. Studies of patients with Fuchs’ endothelial dystrophy found that few corneal guttata disappeared and few new guttata formations appeared within a 2-year period. Despite this slow rate of development and progression, corneal guttata may appear where none were previously present, may enlarge in number or size, or the may fuse together. When the corneal guttata are large and/or confluent, the endothelium may not function normally and visual acuity may be impaired.

Electron Photomicrograph of the Posterior Cornea

Endothelial cells under physiological stress show degenerative changes such as vacuoles and swollen organelles
Electron microscopy reveals that the endothelium is intact when corneal guttata are present
Darkened areas on specular microscopy consist of attenuated, dystrophic endothelial cells wrapped around and covering the corneal guttae

In patients with clinically significant endothelial disease, corneal guttata grow in size and number. The natural history of corneal guttata progression includes five specific stages of development, which can be discerned with specular microscopy.

Corneal Guttata – Stage 1

The corneal gutta nodule appears as a small dark structure in the center of an endothelial cell

Stage 1 corneal guttata in a 16-year-old female



Corneal Guttata – Stage 2 The corneal gutta nodule is almost the same size as an endothelial cell Endothelial cells surrounding the gutta nodule have a stretched appearance

		Corneal Guttata -Stage 3 The corneal gutta is large Many endothothelial cells are involved with one nodule Endothelial cells adjacent to the large gutta have missing cell boundaries Multiple guttae may be present

Corneal Guttata – Stage 3 The corneal gutta is very large Many endothelial cells are involved with one nodule Endothelial cells adjacent to the very large gutta have missing cell boundries Multiple corneal guttae nodules are present Corneal guttae nodules may be close together, but they do not coalesce

		Corneal Guttata – Stage 4 The individual corneal guttae nodules have coalesced Endothelial cells between the corneal guttae become abnormal

Cornal Guttata – Stage 4 The individual corneal guttae nodules have coalesced Endothelial cells between the corneal guttae become abnormal Coalescence of multiple guttae nodules produces confluent corneal guttata

		Corneal Guttata – Stage 5 Progressive coalescence of corneal guttae nodules continues Normal tessellation of endothelial mosaic is difficult or impossible to visualize In this advanced stage of the disease, the specular microscope is unable to perform a quantitative morphologic analysis of the corneal endothelium

		Corneal Guttata – Stage 5 Progressive coalescence of the corneal guttae nodules continues Normal tessellation of the endothelial mosaic is impossible to visualize Collagenous material deposited on Descemet’s membrane appear as bright structures on specular microscopy

Corneal Guttata – Stage 5 Anterior segment OCT imaging Highly reflective areas in the posterior cornea Corneal guttae nodules protrude into the anterior chamber Corneal guttata are mainly located in the central corneal region

Fuchs’ Endothelial Dystrophy — Classification

When confluent corneal guttata are present with clinically significant corneal edema, the condition is called Fuchs’ endothelial dystrophy. The disease is one of a group of opacifying disorders which develop in the absence of inflammation and it is characterized by a progressive loss of endothelial cell structure and function. Fuchs’ endothelial dystrophy affects 4% of the population over 40 years old.

Fuchs’ endothelial dystrophy is classified into three stages.

Stage 1 – The patient is usually asymptomatic. The identifying clinical characteristics include the following:

The presence of corneal guttata at an early age
An abnormal rate of polymegethism
The presence of pleomorphism at an early age
Endothelial pigment dusting

Stage 2 – The patient may have visual symptoms. The identifying clinical characteristics include the following:

Corneal guttata formation increases
Possible glare and decreased visual acuity, particularly upon awakening
Stromal edema may develop secondary to the coalescence of corneal guttata
Epithelial edema and folds in Descement’s membrane may develop after prolonged stromal edema

Stage 3 – The patient is usually symptomatic. The identifying clinical characteristics include the following:

The loss of endothelial function results in persistent stromal edema
Advanced disease produces epithelial edema that is characterized by epithelial bullae, subepithelial bullae, and epithelial blisters (bullous keratopathy)
Pain and photophobia occur secondary to corneal nerve damage

DIFFERENTIAL DIAGNOSES

		Anterior Basement Membrane Dystrophy Basement membrane dystrophy is characterized by abnormal quantities of basement membrane and cytoplasmic debris that are misdirected into the corneal epithelium. Clinically, the abnormal deposits appear as dot-like opacities, map-like patterns, or whorled fingerprint-like lines in the corneal epithelium. In many patients, the epithelial lesions change in appearance, location and number over time

		Iatrogenic Corneal Endotheliopathy Endothelial damage caused by cataract surgery Surgical trauma generally results in a 4-10% loss of cells Risk factors for a higher percentage of postoperative cell loss include preexisting endothelial disease, diabetes, glaucoma, shallow anterior chamber and previous ocular surgery

		Fuchs’ Endothelial Dystrophy 52-year-old white female 20/25 best corrected visual acuity Stage 4 corneal guttata

		Inflammation-Induced Corneal Endotheliopathy 47-year-old black female Chronic uveitis (2-month duration) 20/40 best corrected visual acuity Posterior synechiae visible with pupilary dilation

TREATMENT OPTIONS

The treatment of patients with Fuchs’ endothelial dystrophy varies depending on the severity of the disease.

STAGE 1 DISEASE

Pharmocologic Treatment

Hyperosmotics

The goal of treatment is to improve visual acuity by deturgescence of the stroma or epithelium. Compliance with topical hyperosmotic solutions can be challenging due to the burning sensations they often produce. Nighttime application of hyperosmotic ointment is an excellent if not preferred treatment.

Artificial Tears (FreshKote Ophthalmic Solution)

The goal of treatment is to remove excess water from the epithelium by utilizing the high oncotic pressure of the solution

STAGE 2 DISEASE

Pharmocologic Treatment

Hyperosmotics

The goal of treatment is to improve visual acuity by deturgescence of the stroma or epithelium. Compliance with topical hyperosmotic solutions can be challenging due to the burning sensations they often produce. Nighttime application of hyperosmotic ointment is an excellent if not preferred treatment.

Artificial Tears (FreshKote Ophthalmic Solution)

The goal of treatment is to remove excess water from the epithelium by utilizing the high oncotic pressure of the solution

STAGE 3 DISEASE

Pharmocologic Treatment

Topical Ocular Hypotensives

In addition to hyperosmotics and FreshKote artificial tears, ocular hypotensive medications may be used to decrease intraocular pressure and corneal edema. These drugs reduce the fluid volume in the anterior chamber, thereby reducing stress on the endothelial pump mechanisms. These medications may be used even if the patient’s intraocular pressure is within a statistically normal range.

Beta-blockers
Adrenergic agonists
Propagandists
Docosanoids
Cholinergic Agonists

Topical Non-Steroidal Anti-Inflammatory (NSAID)

Although these medications have no therapeutic effect on Fuchs’ dystrophy, they may be helpful in treating the pain associated with epithelial bullae and blisters. Because corneal melts have been associated with older NSAIDs, these medications should be avoided for long-term use.

Ketorolac (e.g., Acuvail)
Bromfenac (e.g., Prolensa)
Nepafenac (e.g., Ilevro)

Topical steroids have not been shown to be of significant therapeutic benefit in Fuchs’ endothelial dystorphy and are not the best medication to relieve pain in this condition.

Mechanical Treatment

Bandage contact lenses – (in patients with Fuchs’ endothelial dystrophy, overnight wear of soft contact lens can be used to decrease pain and improve visual acuity)
Amniotic membrane insert

Surgical Treatment

Deep lamellar keratoplasty or one of its variations.

DMEK — Descemet’s membrane endothelial keratoplasty
DSEK — Descemet’s stripping endothelial keratoplasty
DSAEK — Descemet’s stripping automated endothelial keratoplasty

DSEK is the most common surgical technique performed today. In this procedure, the surgeon peels away the posterior cornea (e.g., endothelium and Descemet’s membrane) and approximately 25% of the posterior stroma. A donor button of posterior stroma and posterior cornea are then implanted.

Amniotic Membrane Inserts:


		ProKera Amniotic Membrane Insert Cryopreserved amniotic membrane graft fastened to a thermoplastic symblepharon ring The device acts as a self-retaining biological bandage Promotes reepithelialization

BioDOptix Amniotic Membrane Insert Dehydrated amniotic membrane graft

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