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The Management of Endothelial Dystrophy of the Cornea*
T H E MANAGEMENT O F ENDOTHELIAL DYSTROPHY O F T H E CORNEA* ARTHUR GERARD DEVOE,
M.D.
New York et's membrane. Posteriorly the cells are firmly joined at their margins by a terminal bar extending around each cell and com pletely separating the anterior chamber from the intercellular spaces. Each cell is rather loosely attached to Descemet's mem brane by desmosomes in a manner similar to that found in the basal epithelial cells. The anatomic appearance of the corneal endothelium is such as to suggest active me tabolism. It contains numerous enzymes concerned with aerobic metabolism as well as much adenosine triphosphatase, essential in transport mechanisms and probably here related to corneal transparency. Although active cell division is common ANATOMY AND PHYSIOLOGY in the endothelium of young animals, it is All are agreed that since endothelium tech quite uncommon in the adult. This is of im nically should be restricted to epithelium lin portance in considering the life history of ing a blood vessel or lymph channel, the Fuchs' dystrophy where, following destruc proper terminology for cells lining the pos tion of endothelial cells, there does not ap terior surface of the cornea is mesenchymal pear to be significant replacement. In a nor epithelium or mesothelium. However, it is mal cornea after injury, endothelial cells too much to expect that the term corneal en rapidly mitose to replace the damaged ones. dothelium, thoroughly established in ophthal Coverage of the denuded area is assisted by mic thought and literature, will be easily migration of cells peripheral to the injury and by the expansion of cells so that each displaced. In the normal cornea these regularly covers more area. Small defects can be shaped polygonal cells, lightly attached to covered in this way, the cells increasing to Descemet's membrane, fit tightly together. twice their normal diameter. If, however, Light microscopy has not been too informa the endothelial defect is so great it cannot be tive but electron microscopy has provided a covered by migration or cell division, edema great deal of detailed information concern of the overlying stroma results. ing their structure. They contain a large Normally the endothelial cell population amount of cytoplasm, numerous mitochon varies widely between individuals and de dria, indicative of an active metabolic role, creases with age. As aging increases, there Golgi apparatus, RNP particles and cen- is a tendency for the cells to become flat trioles. Endoplasmic reticulum, found in tened and thin, as well as to decrease in such quantity, is thought to be related in part number. This variation in anatomic struc to the manufacture and repair of Descem- ture and population can account for the presence or absence of corneal edema in pa * From the Institute of Ophthalmology, Presby terian Hospital, and The Department of Ophthal tients who have suffered apparently equal mology, Columbia University. amounts of trauma after a cataract extrac1084/144
Epithelial and stromal edema secondary to disease of the endothelium has long been one of the most frustrating corneal abnor malities with which the clinician has to deal. Since the problem centers around the physiopathology of the mesothelial cells com monly called corneal endothelium, it may be worth while briefly to review current knowl edge of the anatomy and physiology of this area. In recent years widespread interest has developed around this single sheet of cells. In fact, the current "Review of the cornea" in the Archives of Ophthalmology by Donn2 is devoted entirely to a report on this membrane.
MANAGEMENT OF EPITHELIAL DYSTROPHY
tion, acute rise in pressure, or inflammatory processes in the anterior uvea. The concept of corned decompensation, which is essentially endothelial decompensa tion, is a good one. Certainly all clinicians have seen minimal surgical trauma precipi tate irreversible edema in a cornea which clinically looked no worse than others that successfully withstood cataract surgery. At the present time there is no way successfully to identify those endothelia with adequate reserve and vitality over those which lack it. A major problem to be solved in the labo ratory, and one that is being actively inves tigated, is the development of a clinically applicable test to evaluate the physiologic status of endothelium. A start has been made with the use of the oxygen electrode but at the present time this cannot be used in vivo. The function of the endothelium in regu lating corneal hydration is still not entirely clear in spite of a great deal of laboratory effort. It is apparent that endothelium serves to some extent as an inert barrier. Mishima and Hedbys 1 have demonstrated it to offer resistance to water flow about three times greater than that of the whole stromal thick ness. In addition to its barrier function, the en dothelium, in all probability, has a metabolic function related to fluid transport. Donn2 has reviewed the four mechanisms generally considered : 1. There is no real evidence that endothe lial cells act as an outward primary water pump removing water from the corneal stroma. 2. An outward ion pump has been postu lated, the endothelial cell being assumed to pump sodium into the aqueous humor against an electrochemical concentration gradient. Such would cause the aqueous to become hypertonic to the stroma and so cause its dehydration. There has been no confirmation of this theory. 3. Pinocytosis was first demonstrated in the corneal endothelium in 1961, by observ
1085/145
ing the path of electron-dense fine particles injected into the anterior chamber. Such particles adsorb to the endothelial surface facing the anterior chamber. This surface then invaginates to form vesicles within the cytoplasm of the cell. The vesicles migrate through the cytoplasm and empty into the intercellular space anterior to the terminal bar. By this mechanism, fluid and particles from the anterior chamber can be moved from the anterior chamber through the en dothelial barrier. Once in the intercellular space particles can be shown to migrate through Descemet's membrane. Although it is agreed that pinocytosis can occur, it has not been established whether this is a significant mechanism of fluid transport across the endothelium and whether it is im portant in dehydration of corneal stroma. 4. The possibility then remains of the in ward transportation of sodium. Some sup port for this lies in the behavior of the cor nea following the injection of ouabain into the anterior chamber. It is known that the cardiac glycoside, ouabain, inhibits active sodium transport systems. It is also known that ouabain injected into the anterior cham ber will cause corneal swelling. Interference with sodium transport is due to the fact that ouabain specifically inhibits sodium-potas sium-activated ATPase. Electron-microscop ic studies have demonstrated that ATPase is localized at the external wall of the cell membrane. Kaye has suggested that sodium exists in high concentration inside the cell at the membrane. Bound to a carrier, it passes into the cellular membrane driven by a con centration gradient. ATPase, existing in the membrane hydrolizes the ATP, releasing sodium and the carrier diffuses back to the inside of the membrane. Sodium, following a concentration gradient, then passes into the intercellular space. After ouabain poi soning, sodium accumulates in the cyto plasm, internal to the cell membrane, where it cannot be liberated by ATPase. Although it is difficult to see how an ion pump forcing sodium inward into the stro-
1086/146
ARTHUR GERARD D E V O E
ma could cause a reduction in hydration, such a mechanism is not completely unrea sonable. Hedbys has observed that swelling of the cornea may be independent of its os motic pressure in that the corneal stroma may be regarded as a gel with negative charges furnished by acid polysaccharides. The swelling properties of the gel may be determined by repulsive forces between these charges. Excessive negative charge would then cause the cornea to expand and absorb water. Addition of positive charges, in the form of sodium ions would eliminate this repulsive effect and cause the cornea to shrink. At the present time no completely satis factory theory of corneal deturgesence has been developed. PROBLEMS OF CLINICAL DISEASE
When considering the problem of clinical disease in corneal endothelium, we are im mediately handicapped by lack of firm knowl edge concerning its physiology and physiopathology. Treatment has therefore been largely empirical. The endothelium is sub ject to the usual disturbances of other cellu lar structures although to our knowledge no record of neoplasm originating in these cells has appeared. Because of its protected posi tion direct trauma without damage to other structures is unlikely. We are all familiar with the edema which surrounds a corneal laceration, undoubtedly due to damage to adjacent endothelial cells. Ordinarily this is promptly repaired but it is not uncommon clinically to observe areas of old injury over which a persistent and permanent epithelial edema remains. A se vere contusion of the globe resulting in mas sive hyphema with increased intraocular pressure can uncommonly produce perma nent endothelial damage. Remembering the concept of decompensa tion of the endothelium, it is possible to ra tionalize the development of stromal edema in relatively minor inflammatory conditions such as iritis or acute glaucoma. All are fa
miliar with sudden edema of the cornea which may occur about the 10th day follow ing keratoplasty and which, in all probabil ity, represents sudden destruction of en dothelial cells, a true graft rejection, associ ated with antigen-antibody reaction at the endothelial cell level. As a general rule serious corneal defects do not persist after injury to a normal en dothelial surface. Usually the presence of corneal edema suggests abnormal endotheli um. It is for this reason that particular care should be paid to a study of this structure prior to cataract extraction for if the en dothelium shows any deviation from nor mal, unusual care should be paid to the tech nique of extraction. It is fair to say that all cases of Fuchs' epithelial-endothelial dystrophy are preceded by a period of cornea guttata of greater or lesser degree. On the other hand an individ ual may maintain cornea guttata of rather marked degree for many years without showing evidence of stromal and epithelial disturbance. Compensation may be precar ious, however, and any minor inflammatory reaction of the anterior chamber or slight rise in intraocular pressure may precipitate full-fledged disease. Prevention of decompensation, although not always possible, should be uppermost in our minds when we see an individual with cornea guttata. If he has glaucoma, effort should be directed toward keeping the ten sion as low as possible. If the patient has cataract, it is probably wise to delay surgery as long as feasible. CATARACT EXTRACTION
If cataract surgery is performed, it has been recommended that the section be ex tremely deep. As originally suggested by McLean,8 it was proposed to make an inci sion in the sciera at the level of the anterior ciliary body. At the present time most sur geons do not perform this maneuver which introduces other complications but try to make their incision as far peripheral as pos-
MANAGEMENT OF EPITHELIAL DYSTROPHY sible and still enter the anterior chamber. I doubt, however, whether the position of the section is of critical importance. Rather it is my opinion that the size of the section and the amount of trauma to the endothelium are critical. The section should be large, greater than 180 degrees, and a complete iridectomy per formed. Minimal irrigation is urged and, if done, should be of a balanced salt solution. Under no circumstances should an instru ment touch the back of the cornea. A sliding type of lens delivery should be employed. Whether this is accomplished with the use of a superiorly placed erisophake, with for ceps, or with the freezing technique will de pend upon the personal prejudices of the operator. It is my opinion that this may be one of the few situations in which the freez ing technique may be superior in that it is possible to remove a lens by traction alone without the application of pressure from below. There has been considerable comment in the past concerning the advantages and dis advantages of the use of alpha chymotrypsin to facilitate lens extraction. The evidence seems reasonably clear that use of this drug does not particularly damage the endotheli um. However, in view of the fact that irri gation with any material may cause some physiologic disturbance, I would personally prefer not to use it unless faced with the somewhat unusual occurrence of cornea guttata in an extremely young individual. In the postoperative period, particular at tention should be paid to the depth of the anterior chamber and to the presence of herniating vitreous into the anterior cham ber. It is wise to study these patients with the slitlamp the first day or two after opera tion. If the anterior chamber remains un usually shallow or if the anterior chamber is lost on the fourth or fifth day, the presence of cornea guttata should suggest early surgi cal intervention, usually in the form of a posterior sclerotomy and air injection into the anterior chamber. If, on the other hand,
1087/147
the endothelium appears entirely normal this complication does not require immediate surgical intervention and delay can be toler ated as long as the cornea shows no evi dence of beginning stromal edema overlying the point of vitreous touch. Continued use of miotics rather than atropine in the postoperative stage has been suggested by some as an additional means of keeping the vitreous retroplaced. My own experience has not found this too helpful, the vitreous knuckling through the small pu pillary opening. Alternating use of mydriatics and miotics may be helpful. In most in stances, even with a rather marked forward displacement, the vitreous will eventually rétrocède and require no further interven tion. CORNEAL EDEMA
When faced with a fully developed case of corneal edema secondary to endothelial disease, the surgeon has a truly formidable problem. The situation is compounded by the fact that, in most instances, the disease is bilateral. The commonest cause of this condition is the entity known as Fuchs' epithelial-endothelial dystrophy. Measures em ployed in treatment can be classified under three headings: (1) medical treatment, (2) surgical procedures designed primarily for the control of symptoms, (3) surgical tech niques designed primarily for visual im provement. In the nonsurgical group systemic mea sures have been employed, such as the use of rutin and ascorbic acid as reported by Stocker.4 The rationale here has been the questionable analogy between corneal en dothelium and that of vascular endothelium and the supposed reduction in permeability of the endothelium by use of these drugs. My own experience in a few cases of this condition has been unsatisfactory. The use of a low-cholesterol, high vitamin-A diet has not been employed by me. Neither have I found the use of systemic adrenal corticotropic hormones to be effective.
1088/148
ARTHUR GERARD D E V O E
The use of carbonic anhydrase inhibitors to lower intraocular pressure can be of value in cases in which compensation is bor derline but, ordinarily, the normal eye does not lose more than several mm of pressure when acetazolamide is used systemically. I have been able to demonstrate to my satis faction, however, that intraocular pressure is an important factor in patients with endothelial dystrophy by hospitalizing several patients for intravenous urea. Reduction of intraocular pressure to 6.0 mm Hg has re sulted in clear corneas which, of course, im mediately clouded again on return of the tension to normal. This then raises the possibility frequently suggested in the past that a trephining oper ation with permanent hypotony is a desir able form of treatment. Possible this is so in an occasional critical case but prolonged hypotony in an otherwise normal eye is al most certain to lead to such complications as cataract which would ultimately require re moval with its attendant insult to the endothelium. The experience of most surgeons has been negative with respect to the value of filtering operations in this condition. The use of dehydrating agents such as hypertonic solutions and the use of the hair drier may have some temporary benefit but is not a clinically satisfactory method of long-term treatment. The most effective hy pertonic solution, anhydrous glycerin, is somewhat uncomfortable. We have found ordinary white karo syrup, as bought in a grocery store, to be as effective as any more sophisticated hypertonic prescription. BULLOUS KERATOPATHY
Recently, we have had some experience using the flush-fitting contact lens in bullous keratopathy but cannot, as yet, report au thoritatively. The patients must be watched with considerable care ; we are aware of one instance in which an ulcer developed be neath the contact lens ultimately leading to the loss of the eye. On the other hand, one young individual has responded well to such
a lens. Experience to date indicates that most patients are not helped much by flushfitting lenses. In advanced bullous keratopathy, patients are frequently incapacitated because of the severe pain attendant upon the rupture of bullae. These individuals can undoubtedly be relieved by removal of epithelium and transplantation of a bipedicle flap of thin conjunctiva after the principle originally de scribed by Gundersen. These flaps, even though thin, are somewhat disfiguring and do not ordinarily provide much in the way of useful vision. It has not been my experi ence to obtain useful vision even when the central portion of the flap is excised. During the past two years I have em ployed the method of Salleras8 for the relief of discomfort attendant upon bullous kera topathy. This method, as with flaps, does not provide useful vision. In essence, it con sists of the removal of epithelium followed by the application of multiple burns to Bow man's membrane with a fine diathermy tip. This apparently produces sufficient scarring to prevent the stromal fluid from percolat ing into the epithelium and markedly re duces the number of bullae. Some years ago Gundersen and Dohlman employed thin sheets of plastic film buried in the deep corneal stroma and found this to be effective in preventing edema of the stro ma and epithelium anterior to it. My experi ence with this in about half a dozen cases was not satisfactory. Following this same principle, however, Dohlman inserted buried keratoprostheses and has reported a high incidence of clear ing of the overlying stroma with, in one in stance, return of visual acuity to 20/SO.5 We have used the buried prosthesis both with and without keratoplasty in various types of corneal disease over the past four years and, although finding it well retained, we have not been able to obtain much visual im provement by this method. Currently, it is being used in bullous keratopathy, as Dohl man suggested, and, again, although finding
MANAGEMENT OF EPITHELIAL DYSTROPHY
a reduction in stromal and epithelial edema, we have not obtained much visual improve ment. It may well be, however, that this method may prove to be the one of choice in overcoming the discomfort of rupturing bullae. If visual acuity is the desired aim, pene trating keratoplasty is almost a necessity. Experience with the full-thickness lamellar keratoplasty, as described by Castroviejo,* both with and without the retention of en dothelium on the donor, has not been effec tive in my hands. For many years, it was the conviction of corneal surgeons that penetrating kerato plasty was doomed to failure in 100% of in dividuals with Fuchs' epithelial-endothelial dystrophy. In recent years this opinion has changed radically and it is now the feeling that penetrating keratoplasty in early disease, particularly when it can circumscribe the entire area of corneal edema, has a high chance of success. Because of the uncertain ties attendant upon any penetrating kerato plasty it is the general feeling that such sur gery should not be performed until vision fails to a level of 20/70. The worst of all corneal endothelial prob lems has always been the presence of ad vanced bullous keratopathy in an aphakic eye. Fine 7 has recently presented a large se ries of cases in which penetrating trans plants have been successfully performed with retention of clear grafts and good vi sion. He feels that this has been accom plished by particularly careful attention to details of technique so that a complete wa tertight seal is formed at surgery, and by as piration of vitreous so that its contact with the graft does not occur. His brilliant re sults have stimulated others to undertake the same techniques. It is clear that, when prop erly performed, penetrating keratoplasty can be successfully accomplished in individuals
1089/149
with total advanced bullous keratopathy. When all else fails there remains the pos sibility of the use of artificial corneas. The technique is far from perfect and continual adjustments are being made both in the prostheses themselves and in methods of in serting them. It can be said at this time that the penetrating keratoprosthesis has its most satisfactory result in bullous keratopathy. We have now had patients retain the im plant for over four years with good visual acuity (20/25-J1). Nevertheless, an over-all extrusion rate of about 20% implies that much remains to be done before the pene trating keratoprosthesis can be considered a satisfactory clinical weapon. At the present time it is our feeling that keratoprosthesis should be reserved for those patients who are hopelessly blind from corneal disease and who will clearly not profit by any of the more conventional types of treatment. 635 West 165th Street
(10032).
REFERENCES
1. Mishima, S., and Hedbys, B. O. : The per meability of corneal epithelium and endothelium to water. To be published. 2. Donn, A. : Cornea. Annual Review 1965. Arch. Ophth. 75:261, 1966. 3. McLean, J. M. : Personal communication. 4. Stocker, F. W. : Clinical management of cor neal dystrophies. In The Cornea World Congress. (Edited by King, J. H., and McTigue, J. W.) Wash ington, D.C., Butterworths, 1965, pp. 133-151. 5. Dohlman, C. H. : Corneal edema and vascularization. In The Cornea World Congress. (Edited by King, J. H., and McTigue, J. W.) Washington, D.C. Butterworths, 1965, pp. 80-95. 6. Buxton, J. N. : Lamellar keratoplasty : Indica tions. In The Cornea World Congress. (Edited by King, J. H., and McTigue, J. W.) Washington, D.C., Butterworths, 1965, pp. 471-484. 7. Fine, M. : Keratoplasty in aphakia. In The Cornea World Congress. (Edited by King, J. H., and McTigue, J. W.) Washington, D.C., Butter worths, 1965, pp. 538-552. 8. Salleras, A. : Bullous keratopathy in the cor nea. In The Cornea, World Congress. (Edited by King, J. H., and McTigue, J. W.) Washington, D.C., Butterworths, 1965, pp. 292-299.
M.D.
New York et's membrane. Posteriorly the cells are firmly joined at their margins by a terminal bar extending around each cell and com pletely separating the anterior chamber from the intercellular spaces. Each cell is rather loosely attached to Descemet's mem brane by desmosomes in a manner similar to that found in the basal epithelial cells. The anatomic appearance of the corneal endothelium is such as to suggest active me tabolism. It contains numerous enzymes concerned with aerobic metabolism as well as much adenosine triphosphatase, essential in transport mechanisms and probably here related to corneal transparency. Although active cell division is common ANATOMY AND PHYSIOLOGY in the endothelium of young animals, it is All are agreed that since endothelium tech quite uncommon in the adult. This is of im nically should be restricted to epithelium lin portance in considering the life history of ing a blood vessel or lymph channel, the Fuchs' dystrophy where, following destruc proper terminology for cells lining the pos tion of endothelial cells, there does not ap terior surface of the cornea is mesenchymal pear to be significant replacement. In a nor epithelium or mesothelium. However, it is mal cornea after injury, endothelial cells too much to expect that the term corneal en rapidly mitose to replace the damaged ones. dothelium, thoroughly established in ophthal Coverage of the denuded area is assisted by mic thought and literature, will be easily migration of cells peripheral to the injury and by the expansion of cells so that each displaced. In the normal cornea these regularly covers more area. Small defects can be shaped polygonal cells, lightly attached to covered in this way, the cells increasing to Descemet's membrane, fit tightly together. twice their normal diameter. If, however, Light microscopy has not been too informa the endothelial defect is so great it cannot be tive but electron microscopy has provided a covered by migration or cell division, edema great deal of detailed information concern of the overlying stroma results. ing their structure. They contain a large Normally the endothelial cell population amount of cytoplasm, numerous mitochon varies widely between individuals and de dria, indicative of an active metabolic role, creases with age. As aging increases, there Golgi apparatus, RNP particles and cen- is a tendency for the cells to become flat trioles. Endoplasmic reticulum, found in tened and thin, as well as to decrease in such quantity, is thought to be related in part number. This variation in anatomic struc to the manufacture and repair of Descem- ture and population can account for the presence or absence of corneal edema in pa * From the Institute of Ophthalmology, Presby terian Hospital, and The Department of Ophthal tients who have suffered apparently equal mology, Columbia University. amounts of trauma after a cataract extrac1084/144
Epithelial and stromal edema secondary to disease of the endothelium has long been one of the most frustrating corneal abnor malities with which the clinician has to deal. Since the problem centers around the physiopathology of the mesothelial cells com monly called corneal endothelium, it may be worth while briefly to review current knowl edge of the anatomy and physiology of this area. In recent years widespread interest has developed around this single sheet of cells. In fact, the current "Review of the cornea" in the Archives of Ophthalmology by Donn2 is devoted entirely to a report on this membrane.
MANAGEMENT OF EPITHELIAL DYSTROPHY
tion, acute rise in pressure, or inflammatory processes in the anterior uvea. The concept of corned decompensation, which is essentially endothelial decompensa tion, is a good one. Certainly all clinicians have seen minimal surgical trauma precipi tate irreversible edema in a cornea which clinically looked no worse than others that successfully withstood cataract surgery. At the present time there is no way successfully to identify those endothelia with adequate reserve and vitality over those which lack it. A major problem to be solved in the labo ratory, and one that is being actively inves tigated, is the development of a clinically applicable test to evaluate the physiologic status of endothelium. A start has been made with the use of the oxygen electrode but at the present time this cannot be used in vivo. The function of the endothelium in regu lating corneal hydration is still not entirely clear in spite of a great deal of laboratory effort. It is apparent that endothelium serves to some extent as an inert barrier. Mishima and Hedbys 1 have demonstrated it to offer resistance to water flow about three times greater than that of the whole stromal thick ness. In addition to its barrier function, the en dothelium, in all probability, has a metabolic function related to fluid transport. Donn2 has reviewed the four mechanisms generally considered : 1. There is no real evidence that endothe lial cells act as an outward primary water pump removing water from the corneal stroma. 2. An outward ion pump has been postu lated, the endothelial cell being assumed to pump sodium into the aqueous humor against an electrochemical concentration gradient. Such would cause the aqueous to become hypertonic to the stroma and so cause its dehydration. There has been no confirmation of this theory. 3. Pinocytosis was first demonstrated in the corneal endothelium in 1961, by observ
1085/145
ing the path of electron-dense fine particles injected into the anterior chamber. Such particles adsorb to the endothelial surface facing the anterior chamber. This surface then invaginates to form vesicles within the cytoplasm of the cell. The vesicles migrate through the cytoplasm and empty into the intercellular space anterior to the terminal bar. By this mechanism, fluid and particles from the anterior chamber can be moved from the anterior chamber through the en dothelial barrier. Once in the intercellular space particles can be shown to migrate through Descemet's membrane. Although it is agreed that pinocytosis can occur, it has not been established whether this is a significant mechanism of fluid transport across the endothelium and whether it is im portant in dehydration of corneal stroma. 4. The possibility then remains of the in ward transportation of sodium. Some sup port for this lies in the behavior of the cor nea following the injection of ouabain into the anterior chamber. It is known that the cardiac glycoside, ouabain, inhibits active sodium transport systems. It is also known that ouabain injected into the anterior cham ber will cause corneal swelling. Interference with sodium transport is due to the fact that ouabain specifically inhibits sodium-potas sium-activated ATPase. Electron-microscop ic studies have demonstrated that ATPase is localized at the external wall of the cell membrane. Kaye has suggested that sodium exists in high concentration inside the cell at the membrane. Bound to a carrier, it passes into the cellular membrane driven by a con centration gradient. ATPase, existing in the membrane hydrolizes the ATP, releasing sodium and the carrier diffuses back to the inside of the membrane. Sodium, following a concentration gradient, then passes into the intercellular space. After ouabain poi soning, sodium accumulates in the cyto plasm, internal to the cell membrane, where it cannot be liberated by ATPase. Although it is difficult to see how an ion pump forcing sodium inward into the stro-
1086/146
ARTHUR GERARD D E V O E
ma could cause a reduction in hydration, such a mechanism is not completely unrea sonable. Hedbys has observed that swelling of the cornea may be independent of its os motic pressure in that the corneal stroma may be regarded as a gel with negative charges furnished by acid polysaccharides. The swelling properties of the gel may be determined by repulsive forces between these charges. Excessive negative charge would then cause the cornea to expand and absorb water. Addition of positive charges, in the form of sodium ions would eliminate this repulsive effect and cause the cornea to shrink. At the present time no completely satis factory theory of corneal deturgesence has been developed. PROBLEMS OF CLINICAL DISEASE
When considering the problem of clinical disease in corneal endothelium, we are im mediately handicapped by lack of firm knowl edge concerning its physiology and physiopathology. Treatment has therefore been largely empirical. The endothelium is sub ject to the usual disturbances of other cellu lar structures although to our knowledge no record of neoplasm originating in these cells has appeared. Because of its protected posi tion direct trauma without damage to other structures is unlikely. We are all familiar with the edema which surrounds a corneal laceration, undoubtedly due to damage to adjacent endothelial cells. Ordinarily this is promptly repaired but it is not uncommon clinically to observe areas of old injury over which a persistent and permanent epithelial edema remains. A se vere contusion of the globe resulting in mas sive hyphema with increased intraocular pressure can uncommonly produce perma nent endothelial damage. Remembering the concept of decompensa tion of the endothelium, it is possible to ra tionalize the development of stromal edema in relatively minor inflammatory conditions such as iritis or acute glaucoma. All are fa
miliar with sudden edema of the cornea which may occur about the 10th day follow ing keratoplasty and which, in all probabil ity, represents sudden destruction of en dothelial cells, a true graft rejection, associ ated with antigen-antibody reaction at the endothelial cell level. As a general rule serious corneal defects do not persist after injury to a normal en dothelial surface. Usually the presence of corneal edema suggests abnormal endotheli um. It is for this reason that particular care should be paid to a study of this structure prior to cataract extraction for if the en dothelium shows any deviation from nor mal, unusual care should be paid to the tech nique of extraction. It is fair to say that all cases of Fuchs' epithelial-endothelial dystrophy are preceded by a period of cornea guttata of greater or lesser degree. On the other hand an individ ual may maintain cornea guttata of rather marked degree for many years without showing evidence of stromal and epithelial disturbance. Compensation may be precar ious, however, and any minor inflammatory reaction of the anterior chamber or slight rise in intraocular pressure may precipitate full-fledged disease. Prevention of decompensation, although not always possible, should be uppermost in our minds when we see an individual with cornea guttata. If he has glaucoma, effort should be directed toward keeping the ten sion as low as possible. If the patient has cataract, it is probably wise to delay surgery as long as feasible. CATARACT EXTRACTION
If cataract surgery is performed, it has been recommended that the section be ex tremely deep. As originally suggested by McLean,8 it was proposed to make an inci sion in the sciera at the level of the anterior ciliary body. At the present time most sur geons do not perform this maneuver which introduces other complications but try to make their incision as far peripheral as pos-
MANAGEMENT OF EPITHELIAL DYSTROPHY sible and still enter the anterior chamber. I doubt, however, whether the position of the section is of critical importance. Rather it is my opinion that the size of the section and the amount of trauma to the endothelium are critical. The section should be large, greater than 180 degrees, and a complete iridectomy per formed. Minimal irrigation is urged and, if done, should be of a balanced salt solution. Under no circumstances should an instru ment touch the back of the cornea. A sliding type of lens delivery should be employed. Whether this is accomplished with the use of a superiorly placed erisophake, with for ceps, or with the freezing technique will de pend upon the personal prejudices of the operator. It is my opinion that this may be one of the few situations in which the freez ing technique may be superior in that it is possible to remove a lens by traction alone without the application of pressure from below. There has been considerable comment in the past concerning the advantages and dis advantages of the use of alpha chymotrypsin to facilitate lens extraction. The evidence seems reasonably clear that use of this drug does not particularly damage the endotheli um. However, in view of the fact that irri gation with any material may cause some physiologic disturbance, I would personally prefer not to use it unless faced with the somewhat unusual occurrence of cornea guttata in an extremely young individual. In the postoperative period, particular at tention should be paid to the depth of the anterior chamber and to the presence of herniating vitreous into the anterior cham ber. It is wise to study these patients with the slitlamp the first day or two after opera tion. If the anterior chamber remains un usually shallow or if the anterior chamber is lost on the fourth or fifth day, the presence of cornea guttata should suggest early surgi cal intervention, usually in the form of a posterior sclerotomy and air injection into the anterior chamber. If, on the other hand,
1087/147
the endothelium appears entirely normal this complication does not require immediate surgical intervention and delay can be toler ated as long as the cornea shows no evi dence of beginning stromal edema overlying the point of vitreous touch. Continued use of miotics rather than atropine in the postoperative stage has been suggested by some as an additional means of keeping the vitreous retroplaced. My own experience has not found this too helpful, the vitreous knuckling through the small pu pillary opening. Alternating use of mydriatics and miotics may be helpful. In most in stances, even with a rather marked forward displacement, the vitreous will eventually rétrocède and require no further interven tion. CORNEAL EDEMA
When faced with a fully developed case of corneal edema secondary to endothelial disease, the surgeon has a truly formidable problem. The situation is compounded by the fact that, in most instances, the disease is bilateral. The commonest cause of this condition is the entity known as Fuchs' epithelial-endothelial dystrophy. Measures em ployed in treatment can be classified under three headings: (1) medical treatment, (2) surgical procedures designed primarily for the control of symptoms, (3) surgical tech niques designed primarily for visual im provement. In the nonsurgical group systemic mea sures have been employed, such as the use of rutin and ascorbic acid as reported by Stocker.4 The rationale here has been the questionable analogy between corneal en dothelium and that of vascular endothelium and the supposed reduction in permeability of the endothelium by use of these drugs. My own experience in a few cases of this condition has been unsatisfactory. The use of a low-cholesterol, high vitamin-A diet has not been employed by me. Neither have I found the use of systemic adrenal corticotropic hormones to be effective.
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ARTHUR GERARD D E V O E
The use of carbonic anhydrase inhibitors to lower intraocular pressure can be of value in cases in which compensation is bor derline but, ordinarily, the normal eye does not lose more than several mm of pressure when acetazolamide is used systemically. I have been able to demonstrate to my satis faction, however, that intraocular pressure is an important factor in patients with endothelial dystrophy by hospitalizing several patients for intravenous urea. Reduction of intraocular pressure to 6.0 mm Hg has re sulted in clear corneas which, of course, im mediately clouded again on return of the tension to normal. This then raises the possibility frequently suggested in the past that a trephining oper ation with permanent hypotony is a desir able form of treatment. Possible this is so in an occasional critical case but prolonged hypotony in an otherwise normal eye is al most certain to lead to such complications as cataract which would ultimately require re moval with its attendant insult to the endothelium. The experience of most surgeons has been negative with respect to the value of filtering operations in this condition. The use of dehydrating agents such as hypertonic solutions and the use of the hair drier may have some temporary benefit but is not a clinically satisfactory method of long-term treatment. The most effective hy pertonic solution, anhydrous glycerin, is somewhat uncomfortable. We have found ordinary white karo syrup, as bought in a grocery store, to be as effective as any more sophisticated hypertonic prescription. BULLOUS KERATOPATHY
Recently, we have had some experience using the flush-fitting contact lens in bullous keratopathy but cannot, as yet, report au thoritatively. The patients must be watched with considerable care ; we are aware of one instance in which an ulcer developed be neath the contact lens ultimately leading to the loss of the eye. On the other hand, one young individual has responded well to such
a lens. Experience to date indicates that most patients are not helped much by flushfitting lenses. In advanced bullous keratopathy, patients are frequently incapacitated because of the severe pain attendant upon the rupture of bullae. These individuals can undoubtedly be relieved by removal of epithelium and transplantation of a bipedicle flap of thin conjunctiva after the principle originally de scribed by Gundersen. These flaps, even though thin, are somewhat disfiguring and do not ordinarily provide much in the way of useful vision. It has not been my experi ence to obtain useful vision even when the central portion of the flap is excised. During the past two years I have em ployed the method of Salleras8 for the relief of discomfort attendant upon bullous kera topathy. This method, as with flaps, does not provide useful vision. In essence, it con sists of the removal of epithelium followed by the application of multiple burns to Bow man's membrane with a fine diathermy tip. This apparently produces sufficient scarring to prevent the stromal fluid from percolat ing into the epithelium and markedly re duces the number of bullae. Some years ago Gundersen and Dohlman employed thin sheets of plastic film buried in the deep corneal stroma and found this to be effective in preventing edema of the stro ma and epithelium anterior to it. My experi ence with this in about half a dozen cases was not satisfactory. Following this same principle, however, Dohlman inserted buried keratoprostheses and has reported a high incidence of clear ing of the overlying stroma with, in one in stance, return of visual acuity to 20/SO.5 We have used the buried prosthesis both with and without keratoplasty in various types of corneal disease over the past four years and, although finding it well retained, we have not been able to obtain much visual im provement by this method. Currently, it is being used in bullous keratopathy, as Dohl man suggested, and, again, although finding
MANAGEMENT OF EPITHELIAL DYSTROPHY
a reduction in stromal and epithelial edema, we have not obtained much visual improve ment. It may well be, however, that this method may prove to be the one of choice in overcoming the discomfort of rupturing bullae. If visual acuity is the desired aim, pene trating keratoplasty is almost a necessity. Experience with the full-thickness lamellar keratoplasty, as described by Castroviejo,* both with and without the retention of en dothelium on the donor, has not been effec tive in my hands. For many years, it was the conviction of corneal surgeons that penetrating kerato plasty was doomed to failure in 100% of in dividuals with Fuchs' epithelial-endothelial dystrophy. In recent years this opinion has changed radically and it is now the feeling that penetrating keratoplasty in early disease, particularly when it can circumscribe the entire area of corneal edema, has a high chance of success. Because of the uncertain ties attendant upon any penetrating kerato plasty it is the general feeling that such sur gery should not be performed until vision fails to a level of 20/70. The worst of all corneal endothelial prob lems has always been the presence of ad vanced bullous keratopathy in an aphakic eye. Fine 7 has recently presented a large se ries of cases in which penetrating trans plants have been successfully performed with retention of clear grafts and good vi sion. He feels that this has been accom plished by particularly careful attention to details of technique so that a complete wa tertight seal is formed at surgery, and by as piration of vitreous so that its contact with the graft does not occur. His brilliant re sults have stimulated others to undertake the same techniques. It is clear that, when prop erly performed, penetrating keratoplasty can be successfully accomplished in individuals
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with total advanced bullous keratopathy. When all else fails there remains the pos sibility of the use of artificial corneas. The technique is far from perfect and continual adjustments are being made both in the prostheses themselves and in methods of in serting them. It can be said at this time that the penetrating keratoprosthesis has its most satisfactory result in bullous keratopathy. We have now had patients retain the im plant for over four years with good visual acuity (20/25-J1). Nevertheless, an over-all extrusion rate of about 20% implies that much remains to be done before the pene trating keratoprosthesis can be considered a satisfactory clinical weapon. At the present time it is our feeling that keratoprosthesis should be reserved for those patients who are hopelessly blind from corneal disease and who will clearly not profit by any of the more conventional types of treatment. 635 West 165th Street
(10032).
REFERENCES
1. Mishima, S., and Hedbys, B. O. : The per meability of corneal epithelium and endothelium to water. To be published. 2. Donn, A. : Cornea. Annual Review 1965. Arch. Ophth. 75:261, 1966. 3. McLean, J. M. : Personal communication. 4. Stocker, F. W. : Clinical management of cor neal dystrophies. In The Cornea World Congress. (Edited by King, J. H., and McTigue, J. W.) Wash ington, D.C., Butterworths, 1965, pp. 133-151. 5. Dohlman, C. H. : Corneal edema and vascularization. In The Cornea World Congress. (Edited by King, J. H., and McTigue, J. W.) Washington, D.C. Butterworths, 1965, pp. 80-95. 6. Buxton, J. N. : Lamellar keratoplasty : Indica tions. In The Cornea World Congress. (Edited by King, J. H., and McTigue, J. W.) Washington, D.C., Butterworths, 1965, pp. 471-484. 7. Fine, M. : Keratoplasty in aphakia. In The Cornea World Congress. (Edited by King, J. H., and McTigue, J. W.) Washington, D.C., Butter worths, 1965, pp. 538-552. 8. Salleras, A. : Bullous keratopathy in the cor nea. In The Cornea, World Congress. (Edited by King, J. H., and McTigue, J. W.) Washington, D.C., Butterworths, 1965, pp. 292-299.