|Year : 1979 | Volume
| Issue : 1 | Page : 1-14
Corneal blindness-A review
Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, India
A L Aurora
Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Aurora A L. Corneal blindness-A review. Indian J Ophthalmol 1979;27:1-14
Corneal blindness constitutes the major cause of visual impairment among the developing nations of the world. Before keratoplasty corneal opacfication, was by and large untreatable.
It is estimated that there may be as many as sixteen million blind people in the world today. and of these ten million cases could have been prevented or could be cured. Infectious diseases, with or without concomitant nutritional deficiency constitute the major cause of blindness in Asian countries except Japan. Trachoma and xerophthalmia are still the major causes of blindness in these povertystricken nations. The tragedy is that it is often the young population that is afflicted by these diseases and they become a heavy burden on an already poor society. It is not generally realized that in the long run, prevention will cost the nation much less than the treatment of these cases.
The pathogenesis of corneal blindness will be dealt with in this review by first dwelling on the histology and functional importance of each laver of the cornea. followed by the alterations ,produced by various disease processes.
The normal cornea ,,
The five layers of the cornea consist from anterior to posterior-the epithelium and its basement membrane, Bowman's zone (or layer), substantia propria, descemet's membrane, and endothelium. The epithelial surface is protected by the constantly renewed tear film composed of mucoid, watery and oily layers, the last being the outermost. These components are derived from the conjunctival goblet cells, major and accessory lacrimal glands, and the meibomian glands respectively. In a wide variety of ocular and systemic disorders, the tear film is adversely affected and the eye becomes dry favouring damage to the cornea. The causes of dry eye syndrome include avitaminosis A, trachoma, poor approximation of the eyelids to the globe, chemical burns, Sjogren's syndrome and some of the collagen diseases like systemic lupus erythematosus, scleroderma, polyarteritis nodosa and rheumatoid arthritis. Experimentally, keratinization of the corneal epithelium have been induced in rats by the extirpation of the lacrimal glands and by avitaminosis A. There remain some cases which are "idiopathic" and are often treated by the preparations containing benzalkonium chloride, a commonly used preservative in several eye drop preparations. It is not realized by many that benzalkonium chloride has harmful drying effects on the corneal tearfilm. It has been shown by Wilson et al that benzalkonium in a concentration of 0.01 precent (the concentration usually employed as a preservative) shortened the time required for the appearance of dry spots on the corneal surface of rabbit by a factor of about four and in man by a factor of about two.
The non-keratinizing stratified squamous epithelium constitutes about 10 percent of the total thickness of cornea. It is composed of five layers of cells. The deepest layer, consisting of basal cells possess hemidesmosomes which anchor the posterior cell membrane to the delicate basement membrane. Superficial to this layer are three layers of large squamous epithelial cells designated as winged cells. Next to this layer are the most superficial layer of thin, rather flattened cells, having numerous microplicae and microvilli as shown by scanning transmission electron microscopes.
The corneal epithelium, especially its surface cell layer, is rich in glycogen as documented by electron microscopy. Several serum protiens such as 1gA, IgD, IgE, IgG and albumin have been identified in the corneal ephithelium by immunofluorescent techniques. In the chick, corneal epithelium has been shown to synthesize collagen.
A variety of materials can be identified in corneal epithelial cells in pathologic states. Glycogen accumulation increases in the regenerating corneal epithelium. In mucopolysaccharidoses, Type I-H (Hurler Syndrome) and Type VI (Maroteaux-Lamy Syndrome), fibrillogranular material has been identified within the epithelial cells with the aid of electron microscope. In Fabry's disease sphingolipid is contained in laminated intracellular bodies in the corneal epithelium. Weingeist and Blodi have given detailed light and ultrastructural finding in the eye in Fabry's disease. Numerous intracellular vesicles have also been seen in the corneal epithelium and in subepithelial, "histiocytes" is GMI-gangliosidosis Type 1. Multiple needle-like crystals of calcium have been observed within the cytoplasm and nuclei of corneal epithelium in patients with hyperparathyroidism. Iron in sufficient quantities have been detected in Hudson-Stahli line in the aged, and in Fleischer's ring in keratoconus due to accumulation of ferritin-like pacrticles. Iron-containing pigment also occurs in the corneal epithelium in Stocker's line (ahead of pterygium) and in Ferry's line (in front of filtring bleb in glaucoma).
The corneal epithelium may be damaged by minor trauma of trichiasis and ill-fitting contact lenses or may exfoliate due to a wide variety of more serious insults like those of infectious processes, chemical burns and traumatic abrasions. Electron microscopy has permitted the identification of infectious agents which could not be observed by light microscopy. In this regard the viral particles of herpetic keratitis have been identified within human corneal epithelial cells.
Two antigenically distinct subtypes of herpes simplex distinguished in man are type 1 and type 2. Type 2 is clinically associated with genital disease, whereas type 1 is usually responsible for facial oral and ocular lesions. The initial infection is generally asymptomatic, although a small proportion develop the syndrome called "Primary herpes". Primary ocular herpes presents with vesicular lesions of eyelids, pseudomembranous conjunctivitis, regional lymphadenopathy and punctate corneal disease in two-third of the cases. This can further lead to dendritic or stromal lesions as well as uveitis with or without keratitis.
In dendritic lesions, which constitute the most typical form of herpetic keratitis, the virus replicates in epithelial cells. Clinically the lesions begin as fine epithelial opacities, which become vesicular, coalesce in branching linear pattern and lead to typical dendritic ulcers due to degeneration of the affected epithelial cells. If the process of virus multiplication continues, the dendritic lesions may widen to give rise to geographic, maplike or amoeboid ulcers. However, the edges of these lesions have branchings suggestive of dendrites. These ulcers can progress to stromal ulcers. The stromal forms of herpetic keratitis have been categorized by Sugar and Kauffman into disciform keratitis, stromal necrosis and diffuse bullous keratopathy. After damage to the corneal epithelium, the basement membrane may be damaged. This will jeopardise the healing processes, as firm adhesions of healing epithelium by hemidesmosomes is prevented. Although, clinically, herpetic manifestations may disappear, the virus may persist in the corneal stromal cells or/and trigeminal ganglion, and get reactivated by stimuli like emotional upset, corticosteroid therapy, and ultraviolet light, to cause recurrent herpes. Herpes simplex virus has been identified in chronic ulcerative keratitis, quiescent failed grafts and retrocorneal membrane and has been cultured from the vitreous.
In conditions characterized by defective epithelial adherence, there is apparent loss of hemidesmosomes in the basal epithelial cell, or/ and damage to the basement membrane. Smelser (Quoted by Polack) pointed out that basement membrane and hemidesmosomes take several weeks or months to regenerate, and possibly it takes longer in diseased corneas. The beneficial effects of soft contact lenses left in place for several weeks in cases of recurrent corneal erosions supports this contention.
Corneal epithelium may become abnormally thickened and may manifest acanthosis and in dividual cell keratinization as in old healed corneal ulcers. In Meesmann's corneal dystrophy, the corneal epithelium has been reported twice as thick as normal. The cells were found to be irregular in size and arrangement except the basal cells.
The corneal epithelium, like other epithelial rests on a periodic-acid Schiff stain (PAS) positive basement membrane. Ultrastructurally it has fine filamentous or granular- appearance. It has an external layer formed by lipids and a deeper one formed by fine filaments that blend with Bowman's layer. In cases of chemical burns and in chronic herpetic infection, abnormality in basement membrane or its lack are suspected as responsible for recurrent corneal erosions. In corneal edema, again, there may be lack of formation of basement membrane.
In a variety of lesions, the basement membrane may be thick and multilaminer as in Fabry's disease. The aberrant basement membrane in some conditions may extend between epithelial cells producing clinically the "dot", ":fingerprint", "map-like" and microcystic dystrophy. Cogan et al brought forward histological evidence that an aberrant basement membrane in the midepithelial layer blocked the forward migration of the newly formed cells. These entrapped cells formed pseudocysts posterior to the unusual basement membrane resulting in the microcystic dystrophy of the cornea. Some of these cysts eventually ruptured anteriorly through breaks in the basement membrane while others needed surgical intervention. Because of the spontaneous rupture of these cysts, clinically the opacities tended to come and go at different sites of the cornea. The clinicopathological studies of dot, map (geographic), fingerprint, and microcystic corneal dystrophies by Rodrigues et al suggest a spectrum of epithelial changes. In the microcystic variety, an inverted basal cell layer continues to proliferate, and the flattened cells desquamate into an intraepithelial pocket. In Meesman's corneal dystrophy the basement membrane has been reported as irregularly arranged. In the very early stages of keratoconus, the basement membrane usually exhibits no change until the cell walls of the degenerated basal epithelial cells breakdown and the disintegrated cytoplasm comes into contact with the basement membrane. The basement membrane then shows disintegration of its reticular framework which normally supports the lipid layer. The damaged basement membrane gradually breaks down at places, allowing irregular aggregations of the lipid particles to seep between the collagen fibres of Bowman's zone and anterior stroma. The collagen fibres of Bowman's zone and stroma reveal degenerative changes in the later stages. The process can be arrested only if a new basement membrane forms with a good lipid layer.
Subepithelial connective tissue accompained by blood vessels and leucocytes is seen between the corneal epithelium and the Bowman's zone in inflammatory conditions like trachoma. It is also seen with only occasional leucocyte in glaucoma and chronic corneal edema due to any cause.
Bowman's zone (layer)
This 10 to 16 um thick acellular modified zone of stroma lies beaaeath the epithelial basement membrane. Abnormalities of this zone, which once damaged cannot be reformed, are seen in many corneal diseases and lead to corneal opacification.
The damage to Bowman's zone in corneal ulceration and trachoma is well known. Fragmentation of this layer in keratoconus has been already mentioned above. In Reis-Bucklers' dystrophy, the opacities are located at the level of basement membrane and Bowman's zone which are replaced by fibrous tissue. There is also hyperactivity of keratocytes in the anterior stroma. At times, Bowman's layer may be damaged to the exclusion of basement membrane. The fibrillary material which replaces Bowman's layer in this condition shows 200-250A° thick fibrils as well as some in the range of 80 to 100A°. However, changes in the basal epithelial layer have been observed by Babel et al (Quoted by Polack) in a corneal graft done thirty years previously for Reis-Bucklers, suggesting the epithelial origin of the disease. PAS positive material seen between degenerated epithelial cells, but with normal Bowman's layer, is believed to represent the electron microscopic change of Grayson-Wildbrandt dystrophy, possibly a variation of Reis-Bucklers.
In Salzman's nodular degeneration related to previous corneal inflammation (mostly viral), the nodular hyaline formations replace the Bowman's layer and occupy the superficial corneal stroma.
In band keratopathy, calcium in the form of hydroxyapatite, is deposited as small clumps in the Bowman's layer. Later they coalesce and destroy this layer. Band keratopathy is a common finding in phthisical eye balls.
In bleb dystrophy of the cornea, friable neutral mucopolysaccharide-protein complex is deposited as a continuous layer between the basement membrane and Bowman's layer. This material though homogenous in appearance under the light microscope, has a fine granular ultrastructures. Shearing of this friable layer possibly favours recurrent epithelial erosions as the basement me mbrane/hemidesmosome system is apparently normal.
Ghosh and McCulloch have reported the presence of vacuoles in Bowman's layer and anterior stroma in crystalline dystrophy of the cornea. The vacuoles contained a black osmpphilic substance, which was confirmed by regular histological studies as fat. Macrophages laden with fat were seen migrating through the epithelium to extrude the material. Cells with large vacuolar inclusions have been observed within Bowman's zone in mucopolysaccharidosis type IV. Bowman's layer is involved in some of the disease states primarily affecting the stroma, such as lipid keratopathy and Schynder's dystrophy.,,
This layer of the cornea measures approximately 500um in thickness and it constitutes nine tenths of the thickness of the entire cornea in man. It is composed of constituents which have nearly the same refractive index and include the collagen, proteoglycans and structural glycoproteins. These three constituents together account for most of the dry weight of the corneal stroma, and are synthesized by the corneal fibroblasts (Keratocytes). The structural glycoprotein is highly antigenic and may play an important role in corneal graft rejection. Serum proteins are present in the cornea. Glycosaminoglycans constitute 4.5 percent of the dry weight of the human cornea. These are normally hound covalently to core protein as proteoglycan macromolecule. The glycosaminoglycans identified in the cornea include chondroitin sulphate (chondroitin-6-sulphate in man), keratan sulphate and chondroitin. Biochernically corneal keratan sulphate (keratan sulphate I) differs from cartilagenous Keratan sulphate (Keratan sulphate II) in several respects. The mutual repulsion of the glycosaminoglycan molecules with collagen fibrils is believed to contribute to the maintenance of the regular spacing of the collagen fibrils of the cornea. The glycosaminoglycans are important in the hydration of the cornea and hence for the degree of its transparency. The glycosaminoglycan of the cornea increase in quantity during embryonic development. The newborn corneal glycosaminoglycans have less sulphate content than in the adult. The biosynthesis of corneal glycosaminoglycans are affected by several factors. The uptake of sulphate in the cornea is inhibited by iodacetate, salicylates and the anti-inflammatory steroids.
The cornea contains collagen fibrils arranged in alternating lamellae. The lamellae are tape-like bands. The constituent fibrils of each band are closely united to each other and with those of the neighbouring bands so that it is impossible to separate the cornea into lamellae or bands without much tearing taking place. The bands of each lamella are parallel to each other but those of alternate layers make a right angle or nearly so with each other. Most of the corneal fibres are parallel to the surface but some oblique ones are present especially near the Bowman's zone. Between the lamellae are found the fixed cells (Keratocytes) and the wandering cells, the latter derived from the marginal loops of the corneal blood vessels. The wandering cells are normally few, but play an important role in inflammation. The keratocytes lie within and not between the collagen lamellae. Schwann cells are seen around the corneal nerves. Four different molecular species of collagen (Type I through IV) have been recognised in vertebrate tissues on the basis of their component polypeptide chains. Type I collagen has been identified in the corneal stroma of man. The tissue culture studies of human corneal fibroblasts have shown a heterogeneous procollagen molecule ranging in molecular weight from 200,000 to 120,000 daltons along with a 1 and a 2 collagen chains. The collagen fibrils change in size with aging.
Corneal opacification is a significant feature in a variety of disease processes including keratoconus, systemic mucopolysaccharidoses, keratomalacia, labrador keratopathy, lipid keratopathy, macular corneal dystrophy, granular dystrophy, lattice dystrophies, sclerocornea, Peters anomaly, trachoma, healed corneal ulcers and stromal oedema.
Many of the conditions responsible for corneal opacification in the populace of developing countries are either preventable or atleast can be controlled at their initial stages, provided a timely and proper medical and surgical care is instituted. Of the 200 corneas examined by Aurora et al. 70.5 percent cases of opacification were due to corneal ulcers, 18.5 percent due to injuries, and 11 percent due to degenerative and dystrophic conditions. In the entire study of 200 corneas, 10 corneas revealed changes of keratinoid degeneration (Labrador Keratopathy). Keratoconus accounted for 7 of the 22 cases of degenerative conditions.
Corneal collagen is destroyed by enzymatic hydrolysis in a variety of conditions including Mooren's ulcer and alkali burns. Brown , has postulated that conjunctiva produces a collagenolytic enzyme and probably a proteoglycanolytic enzyme in cases of Mooren's ulcer. The removal of limbal conjunctiva adjacent to Mooren's ulcer considerably helped in the healing process. Corneal ulcers still constitute a major cause of corneal blindness in the developing countries, leading at times to serious complications of endophthalmitis and panophthalmitis. Several workers have reported clinical and/or microbiological features of such ulcers, ,,,,,,,,,. A correlative study between the type of organism isolated and histopathological features of corneal ulcers based on detailed examination of 167 corneal buttons and 4 eye balls has been reported by Aurora et al. 112 ulcers occurred spontaneously while 59 ulcers were a consequence of injury. Mycotic infection was observed more frequently in injury cases. Majority of the superficial ulcers were sterile. However, the viral etiology could not be completely ruled out in these cases.
Pathological corneas reveal a variety of morphological abnormalities of collagen. In corneal scars. the diameter of collagen fibres varies considerably. In sclerocornea, the individual collagen fibres vary in diameter with some being thicker than normal. In corneal edema, the stroma thickens, the corneal lamellae disunite from each other and the fibres are in disarray accounting for loss of corneal transparency.
Keratoconus is an important cause of corneal opacification. It is a bilateral disease of unknown cause and usually manifests at puberty first in one eye and then in the other. The hereditary factors involved are not clear. According to Gasset, the condition can be suspected during retinoscopy and the diognosis can be confirmed with the help of ophthalmoscope, placidosdisc, keratometer and by photographic methods. In this condition, according to Teng, the basal cells of the surface epithelium show the earliest change of disorganisation of the organelles followed by fragmentation of the basement membrane, fibrillation and breaks in Bowman's layer and similar changes in the anterior stroma. The process may extend into the deeper layers of the stroma all the way to Descemet's membrane. However, this view is not generally accepted. Some of the earliest and most prominent changes occur in Bowman's layer. The collagen fibres in keratoconus are decreased in number but appear morphologically normal. Robert et al (quoted by Klint-worth) have found relative decrease in hydroxylation of lysine and glycosylation of hydroxylysine, decreased total collagen and relatively increased structural glycoprotein. However, keratoconus was not observed in a hydroxylysine deficient collagen disease. Cannon and Foster suggest a change in the hydroxylation of selected lysyl residues of normal collagen or the synthesis of abnormal collagen, perhaps of an unusual type. They further suggest that etiology of keratoconus may be complex and variable.
There are several reports of "fragilitis oculi" or the Ehlers-Danlos syndrome type VI characterized by blue sclera, keratoglobus or keratoconus and rupture of the globe particularly the cornea, following minor trauma. These cases also have scoliosis, dolichostenomelia, hyperextensible joints, hearing defects, hernias, retinal detachment, myopia and fragilitas ossium. In this syndrome, the patients lack lysyl hydroxylase, an enzyme that catalyzes the hydroxylation of lysine to hydroxylysine. Hydroxylysine is an important source of cross-links in collagen. However, Judisch et al have described two brothers affected with Ehlers-Danlos syndrome type VI in whom the skin fibroblast cultures yielded normal activity of lysyl hydroxylase. These authors suggested that there may be two variants of the same disease.
Corneal opacification is significant in Type I-H (Hurler's syndrome) and Type I-S (Scheie syndrome) mucopolysaccharidoses. Stromal keratocytes contain numerous membrane bound vacuoles so,uetimes enclosing fibrillogranular material. Macular corneal dystrophy, is considered a localized mucopolysaccharidosis. Teng has described in detail the light microscopic and uitrastructural changes in macular dystrophy of the cornea.
Keratomalacia seen in Vitamin A and protein deficient children (Raghuveer et al, to be published) is a preventable nutritional disorder.
Labrador keratopathy has been given a multitude of names including chronic actinic keratopathy, keratinoid degeneration, chronic climatic keratopathy, climatic droplet keratopathy, noncalcific band keratopathy and Bietti's nodular dystrophy to name a few. In this condition opacification of cornea occurs in interpalpebral region of both eyes and increases with age. Histological studies of the corneas carried out by several workers have shown it to consist of variably stainable droplet to globoid material in the superficial stroma, at times pushing the overlying epithelium to extreme thinness or complete loss. This material did not contain elastic fibres, arnyloid, calcium or lipid. Garner et al consider the material to be keratin precursor or its variant. In 9 of the 10 cases reported by Aurora et al this change was considered secondary to an associated ocular pathology. The globular deposits appear to originate from stroma and Bowman's layer. Ultraviolet light is considered a probable causative factor in primary cases and association with pinguecula and pterygia have been reported by Klintworth, and Young and Finlay. Fraunfelder and Hanna have described three types of the same lesion as spheroidal degeneration. Only the third type was associated with pinguecula. Though this condition usually occurs in older age groups, Ahmad et al have described it in a 16-year old boy. Brownstein et al consider their cases of elastotic hyaline corneal deposits as similar to labrador keratopathy.
Granular dystrophy of the cornea, a dominant condition, is the most common hereditary corneal dystrophy. It is characterized by superficial location of the lesions and histologically by the deposition of discrete aggregates of a granular hyaline material in the corneal stroma and basement membrane. The aggregates have sharp edges, stain red with Masson trichrome stain, but negatively with the PAS reaction, and with the stains for acid mucopolysaccharides. Ultrastructurally the granuales consist of fairly sharp edged fragments or needle-shaped structures of a homogeneous material. Regardless of their morphologic variations, they appear to be embedded within masses of delicate filaments. Brownstein et al have described recurrence of granular dystrophy in a donor graft. Stuart et al however emphasized almost complete sparing of donor stroma in recurrent cases.
Corneal amyloidosis in the primary form is seen in lattice dystrophies. Secondary localized amyloidosis involving the cornea has been observed in association with various ocular diseases like trachoma, retrolental fibroplasia and penetrating injuries etc., Lattice corneal dystrophies are inherited varieties of corneal amyloidosis. Two types described are the lattice corneal dystrophy Type I (Biber-MaabDimmer) and Type II (Meretoja). Lattice corneal dystrophy Type I has an autosomal dominant mode of inheritance and affects chiefly the central part of the corneal stroma as a network of delicate double-contoured interdigitating filamentous structures. The lattice pattern of the corneal deposits resembles corneal nerves on casual examination. Ultrastructural studies have failed to reveal nerves in affected areas. This type of lattice dystrophy may be unilateral, but usually begins clinically in both eyes at the end of first decade of life but sometimes not until middle life. The disease is slowly progressive causing marked visual impairment before the fifth or sixth decade. In 1969, Meretoja (quoted by Klintworth) described lattice corneal dystrophy type II which also has autosomal dominant mode of inheritence and is associated with systemic amyloidosis. This type is less severe than type I. The patients often have masklike facial expression with blepharochalasis, lobby ears and protruding lips. Cranial and peripheral nerve palsies develop. The skin is dry and itchy with lichen amyloidosis and cutis laxa. Besides lattice corneal dystrophy, another familial variety of corneal amyloidosis has been recognised in Japan and United States. Japanese workers have designated it as "gelatinous droplike dystrophy of the cornea." The condition is characterized by multiple subepithelial deposits of amyloid. It needs to be mentioned that in various forms of amyloidosis, the amyloid is similar at both light microscopic and ultrastructural levels.
In polymorphic stromal dystrophy, punctate irregular opacities have been observed mainly in the deepest layers of the corneas. The lesions are dense enough to distort the view of the fundus and break up the red reflex. Some of the densities may protrude posteriorly, giving the posterior corneal surface an irregular contour. Boruchoff and Kuwabara describe the ultrastructural features of a case of posterior polymorphous degeneration. The interesting feature of this case was the replacement of the endothelium by epithelium obviously due to metaplasia.
Descemet's membrane and endothelium
The endothelium forms the posteriormost layer of cornea and is attached firmly to its basement membrane, the Descemet's membrane. The endothelium has been studied in great detail with light microscope, as well as ultrastructurally both by transmission and scanning electron microscope. Recent studies by specular microscope have further added to our knowledge about this very important functionally dynamic layer of the cornea. The endothelium comprises a single layer of approximately 500,000 thin polygonal cells (mostly hexagonal) measuring 5um in height and 18 to 20 um in width.
The endothelial cells have limited mitotic activity as shown by autoradiographic studies. Mitosis occur in young endothelial cells but are extremely rare in adult cells. These cells decrease in number with age, and after damage in corneal graft failure, intraocular lens implants acute glaucoma and surgical procedures. In the adult eye, loss of endothelial cells in the central two-thirds of the cornea leads to replacement by thinning and spreading out of the surrounding cells rather than by division of adjacent cells. The height of the endothelial cells also decreases with age. As the endothelial cells heal by thinning and spreading and not by increase in their number, it can be assumed that the older corneas have less healing reserve. Similarly a younger cornea with less number of endothelial cells, due to previous corneal pathology, will also have less healing reserve, and therefore, presumably be prematurely aged. Any further insult to such endothelium will lead to endothelial decompensation and corneal edema. Endothelium is essential for the prevention of swelling of cornea and the formation of Descemet's membrane. The endothelium keeps the cornea clear and thin by actively pumping ions or fluid from the stroma to the anterior chamber by the sodium-dependent AT Pase system, and by acting as a physical barrier to the movement of fluid into the cornea. The normal state of deturgescence of the cornea is dependent on the delicate balance between fluid that leaks into the corneal stroma and the fluid which is actively pumped back into the aqueous.
The endothelial cells produce Descemet's membrane throughout life, so that the membrane continues to gain slightly in thickness., Descemet's membrane is PAS positive just like other basement membranes. It can be separated from the endothelium as well as from the stroma. If incised, the cut edges tend to curl backward into the anterior chamber. During fetal life Descemet's membrane is thinner than the endothelial cells, but after birth it attains thickness comparable to the endothelial cells. At birth it is 3 to 4 um- thick and by adult life it measures 10 to 12 um in thickness. At the periphery of the cornea, - the membrane frays out into the trabecular sheets. Ultrastructurally, the Descemet's membrane is formed of a number of very regularly arranged stratified layers. The anterior third of Descemet's membrane is 4 uni thick and displays a vertically banded pattern. The posterior twothirds, which is 5 to 15 um thick, appears amorphous and granular. In the anterior third, collagen fibrils have a compact lamellar arrangement and form small nodules at the site of crossing of these fibrils. The nodules are joined by fine collagen filaments which are aligned vertically to give this part of the membrane a vertically banded appearance with a periodicity of 100 nm. The posterior granular-appearing twothirds of Descemet's membrane contain smaller, less regularly arranged fibrils. The transition between anterior one-third and posterior two-thirds is indistinct.
The Descemet's membrane regularly shows, just inside its periphery, periodic thickenings bulging into the anterior chamber, in persons over the age of 20 years. These bulgings known as Hassall-Henle warts are dome-shaped thickenings of the Descemet's membrane. The warts contain many fissures and channels filled with cellular debris derived from endothelial cells. The endothelial cells covering the warts are attenuated.
The endothelial dystrophies of the cornea affect the endothelium and its basement membrane, the Descemet's membrane. Hogan el al have classified these dystrophies into primary and secondary, the latter being secondary to ocular trauma and due to ocular diseases like uveitis, glaucoma and keratitis. The primary dystrophies have been further classified into congenital, acquired and those associated with corneal stromal dystrophies.
Among the congenital corneal dystrophies one form is developmental and is characterized by an absence of portion of Descemet's membrane and endothelium. A much rarer type is associated with cornea guttata. The cases with central defect in the Descemet's membrane variously designated as Peters anomaly, congenital central corneal leukoma and congenital corneal leucomas fall into three distinct groups (Townsend et al).
1. Central defect in Descemet's membrane alone without keratolenticular contact or cataract.
2. Central defect in Descemet's membrane with keratolenticular contact or cataract.
3. Central defect in Descemet's membrane with Rieger's mesodermal dysgenesis.
The defects in the Descemet's membrane may not be strictly central. These cases may be referred to as congenital corneal leukomas with noncentral defect in the Descemet's membrane.
In the three cases of central defect in Descemet's membrane alone reported by Townsend et al. loss of retinal ganglion cells was also noted in one case. The ten cases of keratolenticular contact or cataract were found to have a variety of intraocular malformations including retinal dysplasia in six cases and optic atrophy in three cases. There was only one case in this series of central defect of Descemet's membrane in association with Rieger's mesodermal dysgenesis. Townsend et al consider that the defect in the Descemet's membrane could be due to mechanical pressure of the forwardly displaced lens or of pupillary membrane at a time when the Descemet's membrane was absent or still a delicate thin structure. It needs to be mentioned that lenticular contact with the cornea may be present without corneal leukoma as reported by Jayanthi and Aurora in their histopathological studies. In none of the four cases which showed lens in contact with the cornea, corneal opacification or defect in the Descemet's membrane was observed. Nakanishi and Brown describe absence of Bowman's layer in central area in two corneas of Peters anomaly studied by them.
Townsend et al have subdivided their cases of congenital corneal leukomas with noncentral defect in Descemet's membrane into three groups viz: paracentral defects (2 patients, 2 eyes), sector defects (2 patients, four eyes) and diffuse defects (7 patients, 7 eyes) depending on the location of the corneal opacification. A variety of other associated ocular abnormalities were present in all these cases.
Some dystrophies that affect the deep corneal tissues often show the changes in the endothelium and Descemet's membrane, usually seen in cornea guttata. Primary correa guttata found nearly three time more frequently in females than in males, affects persons usually beyond the age of 50 years. Goar (quoted by Hogan et al reported the presence of this lesion in 6.62 percent of his 800 patients in routine practice. In 595 patients under 50 years of age, only 5 percent had cornea guttata as against 11 percent of the remaining 205 patients over the age of 50 years. In many cases of cornea guttata, there are no symptoms. However, if the Descemet's membrane becomes thickened or there are dense warts, or the corneal endothelium decompensates leading to stromal and epithelial edema, vision gets blurred. In the typical early case, the Descemet's membrane may or may not be thickened but the endothelial cells contain clumps of phagocytosed pigment which can be detected by slit lamp examination. As the disease progresses, central warts appear on the Descemet's membrane and protrude into the anterior chamber. The warts vary in size and are scattered or grouped closely. The older central warts are larger than those located peripherally. The lesions slowly spread peripherally, but the outer cornea is rarely affected. Some cases show thickening of the membrane and no warts. The endothelial cells covering the warts are attenuated and cytoplasmic remnants of endothelial cells may be seen between the warts. With further thickening of the Descemet's membrane, the warts get completely surrounded by layers of fibrils of newly formed membrane, separating the warts from the endothelium. These warts are then designated as "buried warts". At times a wart may be deeply buried within the Descemet's membrane and a duplicate wart forms under the endothelium. The ultrastructural studies have shown that the normal anterior portion of the Descemet's membrane is continuous with an identical posterior portion comprising the warts. Even in cases of specimen with buried warts, the structure of warts was the same as the structure of Descemet's membrane. The warts contain regularly arranged long spacing and regular collagen. The endothelial cells gradually get markedly attenuated, lose intercellular junctions and fail in their function of deturgescence of the cornea. The cytoplasm of the degenerating cells contain large vacuoles and swollen organelles with often disrupted membranes, Polack studied 12 corneal buttons of Fuch's dystrophy with bullous keratopathy. The specimens were examined by light microscopy and also processed for scanning and transmission electron microscopy. The specimens could be separated into three groups viz: (i) Corneas with abnormal or absent endothelium, few small warts and presence posteriorly of fibroblast-like cells as well as long filaments over Descemet's membrane. (ii) Endothelial cells were present for the most part but were abnormal in size and shape. No warts or filaments were seen. Fibroblastic cells were present over or between the endothelial cells. (iii) Absent or abnormal endothelial cells and presence of large number of warts of different sizes.
In congenital hereditary endothelial dystrophy, Descemet's membrane may be as thick as 40 um. In this condition, the anterior banded zone of the Descemet's membrane is normal, but the non-banded posterior portion is replaced by a mixture of long-spacing and regular collagen.
The human cornea is markedly hydrophilic and swells in vitro. Its deturgescent state is dependent on multitude of factors which include, the chemical constituents of the cornea, intraocular pressure, the functional status of epithelium and endothelium. The epithelium forms a barrier and endothelium acts as an effective pump to maintain the deturgescent state of the cornea. The association of corneal edema with epithelial lesions and ulceration and in a variety of endothelial lesions is well known. In addition to these factors the permeability of the Timbal vascular plexus needs to be kept in mind. Permanent corneal edema and opacification has been reported after ultrasonic cataract surgery.
Several models of experimental corneal vascularization utilizing chemicals, microbiological agents, physical injuries and deficiency states have been used to understand its genesis. It has been noted by Campbell and Michaelson that the induction of corneal vascularization depended on the proximity of the lesion to the corneoscleral limbus. Gimbrone et al in their experimental work in rabbits, emphasized that when tumors were implanted in the corneal stroma, the distance between the tumor and the limbus determined the time required for vascularization.
The pathogenesis of vascularization is still far from clearly understood. The directional growth of the vessels could be based on the presence of a chemical substance in higher concentration in the area of injury than the region of the vessels, the limbal vasculature. The angiogenic factor could be derived from the necrotic or damaged tissue, the injurious agent itself, the tear film, the reactive keratocytes, or the aqueous humor. The nature of this angiogenic factor remains enigmatic.
Corneal transplantation has become an important tool in the hands of the ophthalmic surgeons to treat and cure many cases of corneal blindness. The success rate of corneal grafts in unselected donor-recepient pair is high. Corneal homografts can become opaque due to variety of factors. The immune rejection usually occurs after about 2 weeks of the operation. In non-vascularized corneas, the rejection rate due to this cause is estimated by Vannas (quoted by Klintworth) to range from 12 to 35 percent. The vascularization of the corneal graft tremendously increases the rejection rate. The vascularized corneas also contain lymphatics which can drain the antigenic stimulus to the regional lymph nodes stimulating the immunologically competent cells leading finally to immune rejection.
Ultramicroscopic observations have shown that all the three layers of the cornea viz epithelium, stroma and endothelium are subject to immune reaction, which can occur separately in each individual layer or in three at once. The ultrastructural studies utilizing transmission and scanning electron microscopes have shown the importance of the hostgraft junction at the endothelial level. A defective healing of Descemet's membrane will facilitate the entrance of the immunologically competent cells from the scar tissue. Further, uveal leucocytes can also reach the graft via aqueous humor. The keratic precipitates in the periphery of the graft actually consist of the immunologically activated lymphocytes destroying the endothelial cells. The destroyed endothelial cells are finally replaced by a retrocorneal membrane. Polack studied endothelium and Descemet's membrane of twelve failed grafts by scanning electron microscope as well as by light and transmission electron microscopy. Loss of endothelium, abnormal multilayered endothelium, adherence of leucocytes and organised blood to the Descemet's membrane were detected. In the study on the pathogenesis of corneal graft failure, Aurora et al emphasized on the poor apposition of donor and host cornea, and post-operative infection as the important casuses of graft failure. The post-graft membrane was observed in 40 percent of the grafts by these workers.
Herman and Hughes followed patients with hereditary corneal dystrophy after uncomplicated penetrating corneal transplantation for 2.5 to 15 years. Recurrence was noted in the eye of one patient with granular dystrophy. Lattice dystrophy was observed in 11 eyes and suspected in another 3 of the total of 15 eyes. No definite recurrences were found in seven eyes operated on for macular dystrophy. This indicates that the genetically defective host tissue gradually replaces the donor tissue leading to the recurrence.
This review has attempted to give a bird's eye view of the vast subject of corneal pathology. It will be appreciated that a close cooperation between the investigative ophthalmic surgeon and the ocular pathologist will go a long way in unraveling the etiopathogenesis of ocular diseases and help in modifying the treatment for the better.
| References|| |
Ahmad, A, Hogan, M , Wood, I. and Ostler, B., 1977, Arch. Ophthal., 95, 149.
Anderson, B., Roberts, S.S. Jr., Gonzales, C. and Chick, E.W., 1959, 62, 169.
Arentsen, J.J., Rodriguer, M.M., Peter, R.L. and Barbara, S. 1977, Amer. J. Ophthal., 83, 794.
Aurora, A.L., Khandpur, R.C Singh, G., 1974, 22, Indian J. Ophthal., 11.
Aurora, A.L., Khandpur, R.C., Singh, G. and Bhatia, V.N.: 1974. Ophthal., 22, 1.
Aurora, A.L., Singh, G. and Khandpur, R.C., East. Arch. Ophthal., 2, 135.
Barsky, D.: Keratomycosis, 1959, Arch. Ophthal., 61, 547.
Beitch, I.,1970, invest. Ophthal., 9, 827.
Bietti, G B.: 1976, The role of W.H.O.: World Health, 4, February-March.
Boruchoff, A. and Kuwabara, T. 1971, Amer. J. Ophthal. 72, 879.
Bourne, W.M. and Kaufman, H.E., Clinical specular microscopy of the corneal endothelium, Current Concepts in Ophthalm, ed. Kaufman, H.E. and Zimmerman, T.J. 5, 264. The C.V. Mosby Co., Saint Louis.
Brown, S.I., 1975, Mooren's ulcer. 1. Brit. J. Ophthal. 59, 670.
Brown, S.I., 1975, Brit. Jour. Ophthal., 59, 675.
Brownstein, S., Fine, B.S., Sherman, M.E. and Zimmerman, L.E. 1974, Airier. J. Ophthal., 77,701.
Brownsten, S., Rodrigues, M.M., Fine, B.S. and Albert, E.N., 1973, Amer. J. Ophthal., 75, 799.
Campbell, F.W. and Michaelson, I.C. 1949, Brit. J. Ophthal., 33, 248.
Cannon, Ald. J. and Foster, C.S. 1978, Invest. Ophthal. Visual Sci., 17, 63.
Cassady, J.V.: 1959, Amer. J. Ophthal. 48, 741.
Cogan, D.G. and Kuwabara, T. 1971, Trans. Ophthal, Soc. U.K., 91, 875.
Cogan, D., Kuwabara,, T., Donaldson, D. and Collins, E. Arch. Ophthal. 92, 470.
Collins, H.B. and Abelson, M.B., 1977, Arch. Ophthal., 94, 1726.
Dark, A.J., 1977, Brit. J. Ophthal., 61, 65.
Ehlers, N. and Mathiessen, M. E., 1973, Acta Ophthal , 51, 316.
Fine, B.S., Townsend, W.M., Zimmerman, L.E. and Lashkari, M.H. 1974, Amer. J. Ophthal. 78, 12.
Font, R.L., 1973, Arch. Ophthal., 90, 282.
Fraunfelder, F.T. and Hanna, C. 1973, Amer, J. Ophthal., 76, 41
Garner, A., Morgan, G. and Tripathi, R.C. 1973, Arch. Ophthal., 89, 198.
Gasset, A.R.: Keratoconus, Current concepts in Ophthal., ed. Kaufman, H.E. and Zimmerman, T.J. 5, 164. The C.V. Mos by Co., Saint Louis.
Ghosh, M. and McCulloch, C, 1977, Canad. J. Ophthal., 12, 121.
Gimbrone, M.A. Jr., Cotran, R.S., Leapman, S.B. and Folkman, J., Jour. Natl. Cancer. Inst., 52, 413.
Herman, S.J. and Hughes, W.E., 1973, Amer. J. Ophthal., 75, 689.
Hogan, M.J., Alvarado, J.A. and Weddll, J.E., 1971, Histology of the human eye. An Atlas and Textbook. 55, W.B. Saunders Co., Philadelphia.
Hogan, M.J., Kimura, S.J. and Thygeson, P.: 1964, Amer. J. Ophthal., 57, 551.
Hogan, M.J., Wood, I. and Fine, M. 1974, Amer. J. Ophthal. 78, 363.
Hogan, M.J. and Zimmerman, L.E., 1962, Ophthalmic pathology. A Atlas and Textbook. 2nd edition, 277., W.B. Saunders Co., Philadelphia.
Jayanthi, K. and Aurora, A.L., 1977, Indian J. Ophthal., 25, 31.
Johnson, G.J. and Ghosh, M.: 1975, Canad. J. Ophthal., 10, 119.
Jndisch, G.F., Waziri, M. and Krachmer, J.H., 1976, Arch. Ophtha ., 94, 1489.
Kanai, A. and Kaufman, 1973, Ann. Ophthal., 5,285.
Kaufman, H.E. and Wood, R.M., 1965, Amer. J. Ophthal., 59, 993.
Kirk, H.Q., Rabb, M., Hattenhauer, J. and Smith, R., 1973, Trans. Amer. Acad. Ophthal. Otolaryngol., 77, 411.
Klintworth, G.K., 1972, Amer. J. Pathol., 67, 327.
Klintworth, G.K., 1977, Amer. J. Pathol., 89, 719.
Krane, S.M., Pinnell, S.R. and Frbe, R.W., 1972, Proc. Natl. Acad. Sci., 69, 2899.
Kuwabara, T and Ciccarelli, E.C., 1964, Arch. Ophthal., 71, 676.
Least, R.J., Eugene Wolff's Anatomy of the Eye and Orbit. Sixth edition, 1969, pp. 34-48. W.B. Saunders Co., Philadelphia.
McPherson, S:D. Jr., Kiffney, G.T. Jr. and Freed, C.C. 1966, Amer: J. Ophthal., 62, 1025.
Nagataki, S., Tanishima, T. and Sakimoto, T., 1972, JPN Jour. Ophthalm., 16, 107.
Nakanishi, I. and Brown, S.I., 1971, Amer. J. Ophthal.72, 801.
Polack, F., 1974, Invest. Ophthal., 13, 913.
Polack, F.M , 1975, Amer. J. Ophthal, 79, 251.
Polack, F.M. 1976, Surv. Ophthal., 20, 375.
Puttana, S.T., 1967, J. All India Ophthal. Soc., 15, 11.
Ramsey, M.S., Fine, B.S. and Cohen, S.W., 1972, Amer. J. Ophthal. 560. 73,
Rodrigues, M., Fine, B., Laibson, P. and Zimmerman, L., 1974, Arch. Ophthal., 92, 457.
Shaw, E.L., Rao, G.N., Arthus, E.J., and Aquavella, J.V., 1978, The functional reserve of corneal endothelium, Ophthal. 85, 643.
Singh, G. and Malik, S.R.K., 1972 Brit J. Ophthal., 56, 41.
Sood, N.N., Ratnaraj, A., Balaraman, G. and Madhavan, 1968, H.N., Orient. Arch. Ophthal., 6, 93.
Sood, N.N., Ratnaraj, A., Shenoy, B.P. and Madhavan, H.N., Orient. Arch. Ophthal., 6, 100-108.
Stoesser, T.R., Church, R.L. and Brown, S.I., 1978, invest. Ophthal, Visual Sci., 17, 264.
Stone, D.L., Kenyon, K.R., Green, W.R. and Ryan, S.J., 1976, Amer. J. Ophthal., 81, 173.
Stuarat, J.C., Mund, M.L., Iwanato, T., Troutnman, R.C., White, H.C. and De Voe, A.G., 1975, Amer. J. Ophthal., 79, 18.
Sugar, A. and Kaufman, H.E., 1967, Current Concepts in Ophthalmology. ed. Kaufman, H.E. and Zimmerman, T.J., 5, 1. The C.V. Mos by Co. Saint Louis.
Suie, T., Blatt, M.M., Havener, W.H., Sroufe, S.A. and Balstad, P., 1959, Amer. J. Ophthal., 48, 775-777.
Teng, C.C., 1963, Amer. J. Ophthal., 55, 18.
Teng, C.C., 1966, Amer. J. Ophthal., 62, 436.
Thomsitt, J. and Bron, A. J., 1975, Brit. J. Ophthal., 59, 125.
Townsend, W.M., Font, R.L. and Zimmerman, L.E., 1974, Amer. J. Ophthal., 77, 192.
Townsend W.M., Font, R.L. and Zimmerman, L.E., 1974, Amer. J. Ophthal.,77, 400-412.
Trelstad, R. L., 1971, Jour. Cell. Biol., 48, 689.
Waring, G., Laibson, P. and Rodrigues,M., 1974, Surv. Ophthal., 18, 325.
Weingeist, T. and Blodi, F., 1971, Arch. Ophthal., 85, 169.
Wilson, W.S., Duncan, A.J, and Jay, J.L., 1975, Brit. J. Ophthal. 59, 667.
Young, J.D.H. and Finlay, R.D., 1975, Amer. J. Ophthal., 79, 129.
Zimmerman, L.E., 1962, Lab. Invest., 11, 1151.