- Email: [email protected]
The Diagnosis of Epithelial Downgrowth After Keratoplasty
The Diagnosis of Epithelial Downgrowth After Keratoplasty Robert S. Feder, M.D., and Jay H. Krachmer, M.D.
The concomitant presence of a corneal graft and epithelial downgrowth may lead to diagnostic confusion, delaying detection and treatment of this disorder. Epithelial downgrowth may be mistaken for other conditions such as keratoplasty rejection reaction, corticosteroid-induced glaucoma, or iritis and glaucoma of other origins. During a two-year period we diagnosed and treated epithelial downgrowth in four aphakic eyes after keratoplasty. Certain findings appear to be characteristic of epithelial downgrowth in this particular clinical setting. Once epithelial downgrowth is suspected, other maneuvers can be employed to confirm the diagnosis.
During a two-year period we diagnosed and managed four cases of epithelial downgrowth in aphakic patients (two men and two women, 42 to 76 years old) after keratoplasty. Several clinical findings seemed typical of epithelial downgrowth in this setting. When iritis was present, it was unusual in that the aqueous humor contained large clumps of cellular material and the degree of apparent inflammation was out of proportion to the ciliary flush or symptoms. A posterior corneal line was present in two cases. It resembled an endothelial graft rejection line, but there were no associated keratic precipitates. Also, no graft edema occurred peripheral to a retrocorneal line in either case. Glaucoma was abrupt in onset and difficult to treat. Cytopathologic studies of aqueous aspirate may be needed to confirm the diagnosis. The long-term prognosis for useful vision in our patients was poor but early diagnosis and surgical intervention might possibly lead to a more favorable outcome.
Subjects
There were two men and two women ranging in age from 42 to 76 years (Table). The left eye was involved in each case. All the eyes Were aphakic or pseudophakic before penetrating keratoplasty. A surgical record for the cataract procedures was available in one of the four. The procedure in this case (Patient 3) was uncomplicated. In none of the cases was there evidence of cataract wound dehiscence, wound leak, or filtration bleb before the corneal transplant. The time between the cataract procedure and the manifestation of epithelial downgrowth ranged from 12 months to 17 years. The time between penetrating keratoplasty and the clinical onset of the downgrowth ranged from four to seven months. Preoperatively there was no evidence of a posterior corneal line or membrane in any of the cases. However, good visualization was often precluded by corneal edema. Only one graft was performed before the diagnosis of epithelial downgrowth in three cases. A regraft was performed in Case 4 because the original transplant done in 1970 for keratoconus had failed. A similar penetrating keratoplasty technique was used in all four cases. An oversized donor button was sutured into position with continuous nylon. There were no intraoperative or postoperative com-
THE DOWNGROWTH of surface epithelium into the anterior chamber is a disastrous but fortunately rare complication of intraocular surgery. There are few reports of epithelial downgrowth occurring after penetrating keratoplasty in the literature. Sugar, Meyer, and Hood' diagnosed this condition in four of approximately 1,500 keratoplasties, an incidence of more than 0.25%. Each of these four patients was aphakic, whereas the other patients were presumably both phakic and aphakic. They suggested that the incidence of epithelial downgrowth in this clinical setting may not differ greatly from that in the nongrafted aphakic eye.
Accepted for publication April 8, 1985. From the Department of Ophthalmology, Northwestern University, Chicago, Illinois (Dr. Feder); and Department of Ophthalmology, University of Iowa, Iowa City, Iowa (Dr. Krachmer). Reprint requests to Robert S. Feder, M.D., 222 E. Superior Ave., Chicago, IL 60611.
©AMERICAN JOURNAL OF OPHTHALMOLOGY
99:697-703,
and Methods
JUNE,
1985
697
698
June, 1985
AMERICAN JOURNAL OF OPHTHALMOLOGY
TABLE SUMMARY OF CLINICAL DATA PATIENT 1
CLINICALDATA
Sex, age (yrs)
PATIENT 2
PATIENT 3
PATIENT 4
M,69
F,62
F, 76
M,42
Previous cataract surgery Date
January 1976
March 1980
October 1980
1966
Type'
ICCE
ICCE with implant
ICCE
ECCE
Eye
Left
Left
Left
Left
Diagnosis before
Aphakic bullous
Pseudophakic corneal
Fuchs' dystrophy
Keratoconus
keratoplasty
keratopathy
edema
Corneal surgery before downgrowth Date
March 1983
March 1982
May 1981
1970
Type
Penetrating
Penetrating keratoplasty,
Penetrating keratoplasty,
Penetrating keratoplasty,
keratoplasty,
vitrectomy, lens
vitrectomy
removal
vitrectomy
regraft May 1983
Left
Left
Left
Left
Date
August 1983
October 1982
October 1981
September 1983
Symptoms
Iritis, glaucoma,
Iritis, glaucoma
Posterior corneal
Iritis
Eye Clinical appearance of downgrowth
posterior
line
comealline Diagnostic confirmation Date
September 1983
OCtober 1982
October 1981
September 1983
Means
Paracentesis,
Paracentesis,
Paracentesis,
Paracentesis,
laser
laser
laser
laser
7 years
2 years
1 year
17 years
6 months
7 months
5 months
13 years
Date
February 1984
April 1984
September 1982
December 1983
Result
Graft decompensation,
Band keratopathy, end-
Evisceration
Phthisis bulbi
Interval between Cataract surgery and downgrowth Penetrating keratoplasty and downgrowth Final outcome
glaucoma
stage glaucoma
'ICCE, intracapsular cataract extraction; ECCE, extracapsular cataract extraction.
plications. No wound leaks or wound dehiscences were detected. In each patient the diagnosis of epithelial downgrowth was confirmed by performing an anterior chamber paracentesis. A Papanicolaou stain was prepared from each specimen of aqueous and the slide examined by a cytopathologist. In three of the four cases (Cases 1, 3, and 4) blue-green argon laser photocoagulation was applied to the iris in an effort to determine the presence and extent of an epithelial membrane. Histopathologic study of the host corneal buttons initially failed to disclose epithelial downgrowth in all four cases. After the diagnosis had been confirmed by anterior chamber paracentesis, additional
sections of the host specimens were prepared and epithelial downgrowth was identified in two of the four specimens on reexamination (Cases 3 and 4).
Case Reports Case 1 A 69-year-old bilaterally aphakic man underwent an uncomplicated penetrating keratoplasty with anterior vitrectomy for aphakic bullous keratopathy in his left eye on March 12, 1983. The eye had undergone intracapsular cataract extraction seven years previously.
Vol. 99, No.6
Epithelial Downgrowth After Keratoplasty
699
Fig. 1 (Feder and Krachmer). Case 1. Retrocorneal epithelial membrane. The line (arrow) noted on the posterior surface of the graft is typical of that found in epithelial downgrowth.
Five months postoperatively the patient complained of soreness of the left eye. The graft appeared to be clear, but mild iritis was present. Treatment for a possible graft rejection was instituted, but despite systemic, periocular, and frequent topical corticosteroids, the anterior segment inflammation persisted. The intraocular pressure was 26 mm Hg. Six months postoperatively, a posterior corneal line (Fig. 1) was recognized on the superior aspect of the graft and epithelial downgrowth was suspected. An anterior chamber paracentesis was performed on Sept. 12, 1983, and cytologic examination confirmed the presence of epithelial cells in the aqueous. The extent of iris involvement was determined with the argon laser. On Oct. 5, a pars plana approach was used to excise the involved iris as far peripherally as possible. External single-freeze cryotherapy was applied to the entire host rim and the involved superior half of the graft. Three weeks after this procedure there was no evidence of epithelium on the posterior surface of the cornea, but six months later the graft began to fail. The intraocular pressure was 34 mm Hg despite treatment with timolol maleate 0.5% and systemic acetazolamide. Two to three large white cells per high power field were noted in the anterior chamber. Case 2 A 62-year-old woman developed pseudophakic corneal decompensation of the left eye two years after intracapsular cataract extraction with implantation of an iris-supported intraocular lens. On March 15, 1982, she underwent a penetrating keratoplasty in
her left eye with removal of the intraocular lens implant and anterior vitrectomy. The procedure and postoperative course were unremarkable. On Sept. 2, 1982, she complained of blurred vision and irritation of the operated on eye. The graft was clear, but mild ciliary flush, a mild anterior chamber reaction, and an intraocular pressure of 34 mm Hg were noted. The intraocular pressure was initially controlled medically, but four weeks later it was 62 mm Hg despite treatment with acetazolamide, timolol maleate 0.5%, dipivefrin Hel 0.1%, fluorometholone, and scopolamine hydrobromide 0.25%. Moderate microcystic edema and uveitis were present. Because of the rather abrupt onset of glaucoma and iritis in this patient, epithelial downgrowth was suspected. A diagnostic anterior chamber paracentesis confirmed the diagnosis. The patient refused any intraocular procedure directed at removal of the epithelial downgrowth. On April 26, 1984, after several cyclotherapy procedures, her visual acuity had decreased to light perception because of end-stage glaucoma and band keratopathy. Case 3 A 77-year-old woman with confluent cornea guttata underwent an uncomplicated intracapsular cataract extraction in the left eye on Oct. 24, 1980. Six months later corneal decompensation was noted and a penetrating keratoplasty with anterior vitrectomy was performed on the left eye on May 15, 1981. On Oct. 20, 1981, the patient had a posterior corneal line, mild epithelial edema, a mild uveitic reaction, the suggestion of a membrane at the pupillary mar-
700
June, 1985
AMERICAN JOURNAL OF OPHTHALMOLOGY
gin, and an intraocular pressure of 22 mm Hg. An anterior chamber paracentesis confirmed the diagnosis of epithelial downgrowth and the argon laser was used to determine that the anterior surface of the entire iris was covered by epithelium. Reexamination of the host corneal button removed at surgery disclosed epithelium on the posterior surface, suggesting that epithelial downgrowth was present before the penetrating keratoplasty. On Oct. 23, the patient underwent a pars plana total iridectomy and anterior vitrectomy. Cryotherapy was applied externally over the iris root and internally to the endothelial surface of the host rim and involved portion of the graft. Despite this procedure, the epithelial downgrowth progressed, large cells were seen in the anterior chamber, and glaucoma developed. Repeat external cryotherapy was applied to the entire cornea, but a large chronic epithelial erosion developed. Cyclocryotherapy was attempted in an effort to control the glaucoma. On Sept. 20, 1982, the left eye was eviscerated after a large corneal perforation with prolapse of retinal tissue had occurred. Case 4 A 43-year-old man with bilateral keratoconus and cataracts associated with atopic disease underwent extracapsular cataract extractions in the left eye in 1966 and in the right eye in 1968. He later underwent bilateral penetrating keratoplasties (left eye, 1970; right eye, 1975). On May 18, 1983, he underwent a repeat penetrating keratoplasty, with anterior vitrectomy and excision of a secondary cataract on the left eye because the previous graft had failed. Postoperative stromal graft edema resolved slowly during the next eight weeks. No other complications were detected until Sept. I, 1983, when the intraocular pressure had increased to 30 mm Hg. Although the intraocular pressure was initially controlled, three weeks later it was 34 mm Hg despite maximal medical therapy. An examination disclosed epithelial edema and a moderate uveitic reaction with occasionallarge clumps of material in the anterior chamber. The suggestion of a membrane on the surface of the iris on gonioscopy was confirmed with the argon laser. Epithelial downgrowth was diagnosed after an anterior chamber paracentesis. The host button from the second corneal transplant was reexamined and epithelial downgrowth was found, suggesting that this condition antedated the second graft. On Sept. 28, 1982, the patient underwent a pars plana total iridectomy and anterior vitrectomy and 300-degree cyclocryotherapy along with cryotherapy to the corneoscleral limbus in the same 300-degree distribution. The iridectomy was complicated by
hemorrhage from the ciliary body or iris root. The intraocular pressure could not be easily controlled postoperatively and a second pars plana vitrectomy was performed to remove the residual blood. This procedure controlled the intraocular pressure only transiently and in late October an excisional trabeculectomy was performed. No epithelium was found on the excised specimen. A retinal detachment developed and phthisis bulbi occurred after attempted surgical repair.
Discussion Several clinical features found in our four patients seem to be typical of this condition in grafted eyes. These include anterior chamber cells or iritis (minimal ciliary flush if the intraocular pressure is less than 30 mm Hg, clumps of cellular material in the aqueous, minimal to absent keratic precipitates, and resistance to corticosteroid therapy), glaucoma (abrupt onset; quickly unresponsive to conventional therapy), posterior corneal line (trace to absent graft edema between line and graft wound; may progress quickly), and iris membrane (smoothing of iris architecture, faint white veil over iris and wrapping around the pupillary margin; gonioscopy helpful). Cytopathologic studies of aqueous aspirate may demonstrate one or more of the three types of epithelial cells: the flat, rectangular surface type, the rounded basal type, and vacuolated cells (degenerated epithelial cells vs goblet cells). Recognition of these findings may assist in the differentiation of corneal graft rejection reaction or corticosteroidinduced glaucoma from underlying epithelial downgrowth. In three of our four cases we observed an unusual form of "iritis" early in the clinical course. The iritis was typified by clumps of cellular material in the anterior chamber. Despite a mild-to-moderate uveitic reaction, ciliary flush and patient discomfort were minimal when the intraocular pressure was below 30 mm Hg. In none of the four cases were keratic precipitates or subepithelial infiltrates detected. Keratic precipitates are often associated with moderate degrees of iritis. Both keratic precipitates and subepithelial infiltrates are reportedly associated with the cornea transplant rejection reaction." Intensive corticosteroid administration, varying from hourly topical application to a combination of topical, periocular, and systemic administration failed to suppress the cellular reaction. The appearance of a line on the posterior surface of the graft was noted in two of the four cases (Patients
Vol. 99, No.6
Epithelial Downgrowth After Keratoplasty
1 and 3). Noticeable movement of the line centrally across the graft occurred in as little as one to two weeks. In none of these cases was graft edema present peripheral to the line. Corneal edema between the rejection line and the graft wound is a common feature of endothelial rejection. The absence of corneal edema in association with an endothelial line indicates that epithelial downgrowth is a possible diagnosis. When glaucoma occurred in the presence of epithelial downgrowth, it had a relatively abrupt onset. The intraocular pressure quickly became unresponsive to the usual medical therapy. This glaucoma was unilateral and of the secondary open-angle type. In each of our four cases, epithelial downgrowth was not initially considered at the onset of increased intraocular pressure. When increased intraocular pressure and apparent iritis occur in a patient with no history of glaucoma who has undergone corneal transplant surgery, the clinician may at first consider the increased intraocular pressure to be corticosteroid-induced or the result of chronic inflammation. If the underlying cause of the glaucoma is epithelial downgrowth, neither discontinuing corticosteroids nor intensive corticosteroid therapy will control the intraocular pressure. Finally, careful examination of the iris by direct slit-lamp illumination and by gonioscopy may disclose a membrane on the anterior surface. The membrane may cause a smoothing of the normal iris architecture. This occurred in one of our four cases (Case 4). It is our impression that the presentation and clinical course of epithelial downgrowth in the aphakic eye after keratoplasty are not appreciably different from that in the nongrafted aphakic eye. The relative lack of external signs and symptoms of inflammation in our patients may be attributed to the use of topical corticosteroids. The duration of topical corticosteroid administration after corneal transplant surgery is typically longer than after cataract extraction. Before the diagnosis is clinically suspected, the pathologist may confirm the presence of epithelial downgrowth after a careful examination of the host corneal button. A sheet of epithelium discovered on the endothelial surface of the host button suggests that epithelial downgrowth existed before the corneal transplant surgery. The clinical findings of epithelial downgrowth may escape detection before keratoplasty because of poor slit-lamp visualization of the anterior segment. Indeed, this condition may occasionally be diagnosed unexpectedly in an apparent case of aphakic bullous keratopathy after pathologic study of the host speci-
701
men. After keratoplasty the pathologist may also miss the diagnosis if the entire corneal specimen has not been submitted, if only a few tissue sections are studied, or if the area of downgrowth is small. In none of our cases was epithelial downgrowth suspected before corneal transplant surgery. However, in Cases 3 and 4 epithelium was found on the posterior surface of the host buttons, confirming that this condition was present before the keratoplasties. In both cases the initial routine pathologic examination failed to identify epithelial downgrowth. The condition was discovered only after further tissue sections were prepared and examined. If epithelial downgrowth is clinically suspected and careful examination of the host button fails to confirm the diagnosis, an aqueous humor aspirate should be obtained and examined cytopathologically. Cytologic confirmation of downgrowth was obtained in all of our cases. Engel and associates" described three types of epithelial cells seen on cytologic examination in several cases of epithelial downgrowth. Cells can be the flattened, rectangular, surface type (Fig. 2, top left) or the rounded, basal type (Fig. 2, top right). A third cell containing large vacuoles was identified as a goblet cell (Fig. 2, bottom left). It is not clear how Engel and associates determined that these were goblet cells. Similar cells have been described as part of intraocular epithelial membranes seen in histopathologic preparations of globes enucleated because of epithelial downgrowth.v' In two of our cases vacuolated epithelial cells were found on cytologic examination of the aqueous (Cases 2 and 4). In one of these two cases (Case 2), the vacuolated cells stained positively with mucicarmine stain for mucin, as would a goblet cell, This finding must be interpreted with caution because degenerating epithelial cells may stain artifactually. Are these cells goblet cells? It is our opinion that this question cannot be answered with certainty at this time. Goblet cells, a normal constituent of conjunctival epithelium, are not found in corneal epithelium. The proven presence of goblet cells in the anterior chamber or as part of an intraocular epithelial membrane might suggest that the conjunctiva was the source of the epithelium. For now, the significance of these vacuolated epithelial cells found on microscopic study of an aqueous humor aspirate is unknown. What is the significance of an aqueous humor aspirate without epithelial cells despite clinical findings suggestive of epithelial downgrowth? Epithelial downgrowth mayor may not have been present. If the downgrowth was present, the number of cells in the aqueous humor may have been too few to
702
AMERICAN JOURNAL OF OPHTHALMOLOGY
June, 1985
Fig. 2 (Feder and Krachmer). Three types of epithelial cells found on Papanicolaou stain of an aqueous aspirate in epithelial downgrowth. Top left, Flattened, surface type. Top right, Rounded, basal type. Bottom left, Vacuolated cells may possibly be goblet cells.
detect, the volume of aqueous humor collected may have been inadequate, or the slide may have been improperly prepared or interpreted. We conclude that if the possibility of epithelial downgrowth remains high, even after reportedly noncontributory aqueous humor studies, a repeat anterior chamber paracentesis should be considered. Confirmation of the presence of an epithelial membrane on the iris can be obtained with photocoagulation." A 500-~m argon laser burn on the anterior surface of the iris turns white if an epithelial membrane is present (Fig. 3). The laser can be used to map the distribution of epithelial involvement of the iris for planned surgical excision. Why did epithelial downgrowth occur in these
aphakic patients after essentially uncomplicated corneal transplant surgery? We propose several possible explanations. First, this condition may have developed as a direct result of the penetrating keratoplasty. Epithelial downgrowth and an epithelial inclusion cyst of the iris have each been reported after phakic transplants.?" The epithelium may be introduced into the anterior chamber at the time of surgery, as a result of a graft wound dehiscence, or through a suture track. In none of our cases was a wound leak or dehiscence identified. The occurrence of the downgrowth only four to seven months after the corneal transplant suggests that the penetrating keratoplasty may have had either a direct or an indirect role in the development of this condition.
Vol. 99, No.6
Epithelial Downgrowth After Keratoplasty
Fig. 3 (Feder and Krachmer). Case 1. The arrow indicates where a 500-lLm, 400-mW, O.l-sec argon laser burn caused edema of an epithelial membrane on the iris, turning it white.
As mentioned, epithelial downgrowth may already be present at the time of keratoplasty. This occurred in Cases 3 and 4, in which epithelial cells were later discovered on the posterior surface of the host corneal button. In Case 4 the downgrowth must have occurred either after the cataract surgery or the initial graft. In none of our cases was this condition suspected before the keratoplasty. None of the patients had an apparent epithelial line on the posterior corneal surface or iritis before to the corneal surgery. However, in these patients poor anterior segment visualization may have prevented detection of these findings. We suspect that in certain instances epithelial downgrowth may exist in a dormant or slowly progressive form. Corneal transplant surgery may have a stimulating effect on the condition. The penetrating keratoplasties in Cases 3 and 4 may have aggravated the pre-existing epithelial downgrowth, causing the condition to progress more rapidly. In our four cases the visual prognosis for an aphakic eye with epithelial downgrowth after keratoplasty was poor (Table). Despite excision of the involved iris with a vitreous suction-cutting device through a pars plana site, combined with cryotherapy of the involved cornea, eyes treated surgically fared no better than the one eye that was not treated in this way (Case 2). Longer follow-up is needed to evaluate the surgical treatment in Case 1. Others have reported better short-term surgical results in cataract patients with epithelial downgrowth. Stark and associates'" reported improvement of visual acuity in eight of ten patients by means of a similar surgical technique. We have also had good results in nontransplant patients. The presence of a corneal transplant
703
in our patients may have delayed recognition of the true underlying diagnosis. Perhaps earlier surgical intervention would have improved the prognosis. As part of the surgical approach to epithelial downgrowth in the aphakic eye, previous reports have advocated exploration of the cataract wound for fistulous tracks.v" If the tracks are detected, excision and closure are recommended. Although no graft wound leaks were found in our cases, our surgical approach did not include exploration of the previous cataract wound for fistulous tracks. Perhaps this should be a part of the surgical management of this condition after penetrating keratoplasty in the aphakic eye. The primary goal of any treatment of epithelial downgrowth is the complete destruction or removal of epithelium from the interior of the eye. An aggressive approach may in certain cases result in decompensation of the corneal transplant, but if the epithelial downgrowth is successfully treated a regraft may be possible. A clear graft will not be of benefit if the eye is lost because of progression of the downgrowth.
References 1. Sugar, A., Meyer, R. F., and Hood, C. 1.: Epithelial downgrowth following penetrating keratoplasty in the aphake. Arch. Ophthalmol. 95:464, 1977. 2. Alldredge, O. C.; and Krachmer, J. H.: Clinical types of corneal transplant rejection. Their manifestations, frequency, preoperative correlates and treatment. Arch. Ophthalmol. 99:599, 1981. 3. Engel, H. M., Green, W. R., Michels, R. G., Rice, T. A., and Erozan, Y. 5.: Diagnostic vitrectomy. Retina 1:128, 1981. 4. Calhoun, F. P.: The clinical recognition and treatment of epithelization of the anterior chamber following cataract extraction. Trans. Am. Ophthalmol. Soc. 47:498, 1949. 5. Terry, T. L., Chisholm, J. F., [r., and Schonberg, A. L.: Studies on surface-epithelium invasion of the anterior segment of the eye. Am. J. Ophthalmol. 22:1083, 1939. 6. Maumenee, A. E.: Treatment of epithelial downgrowth and intraocular fistula following cataract extraction. Trans. Am. Ophthalmol. Soc. 62:153, 1964. 7. Mazow, M. L., and Stephens, R. W.: An unusual complication after keratoplasty. Surv. Ophthalmol. 11:205, 1966. 8. Leibowitz, H. M., Elliot, J. H., and Boruchoff, S. A.: Epithelization of the anterior chamber following penetrating keratoplasty. Arch. Ophthalmol. 78:613, 1967. 9. Bennett, T., and D'Amico, R. A.: Epithelial inclusion cyst of iris after keratoplasty. Am. J. Ophthalmol. 77:87, 1974. 10. Stark, W. J., Michels, R. G., Maumenee, A. E., and Cupples, H.: Surgical management of epithelial ingrowth. Am. J. OphthalmoI. 85:772, 1978.
The concomitant presence of a corneal graft and epithelial downgrowth may lead to diagnostic confusion, delaying detection and treatment of this disorder. Epithelial downgrowth may be mistaken for other conditions such as keratoplasty rejection reaction, corticosteroid-induced glaucoma, or iritis and glaucoma of other origins. During a two-year period we diagnosed and treated epithelial downgrowth in four aphakic eyes after keratoplasty. Certain findings appear to be characteristic of epithelial downgrowth in this particular clinical setting. Once epithelial downgrowth is suspected, other maneuvers can be employed to confirm the diagnosis.
During a two-year period we diagnosed and managed four cases of epithelial downgrowth in aphakic patients (two men and two women, 42 to 76 years old) after keratoplasty. Several clinical findings seemed typical of epithelial downgrowth in this setting. When iritis was present, it was unusual in that the aqueous humor contained large clumps of cellular material and the degree of apparent inflammation was out of proportion to the ciliary flush or symptoms. A posterior corneal line was present in two cases. It resembled an endothelial graft rejection line, but there were no associated keratic precipitates. Also, no graft edema occurred peripheral to a retrocorneal line in either case. Glaucoma was abrupt in onset and difficult to treat. Cytopathologic studies of aqueous aspirate may be needed to confirm the diagnosis. The long-term prognosis for useful vision in our patients was poor but early diagnosis and surgical intervention might possibly lead to a more favorable outcome.
Subjects
There were two men and two women ranging in age from 42 to 76 years (Table). The left eye was involved in each case. All the eyes Were aphakic or pseudophakic before penetrating keratoplasty. A surgical record for the cataract procedures was available in one of the four. The procedure in this case (Patient 3) was uncomplicated. In none of the cases was there evidence of cataract wound dehiscence, wound leak, or filtration bleb before the corneal transplant. The time between the cataract procedure and the manifestation of epithelial downgrowth ranged from 12 months to 17 years. The time between penetrating keratoplasty and the clinical onset of the downgrowth ranged from four to seven months. Preoperatively there was no evidence of a posterior corneal line or membrane in any of the cases. However, good visualization was often precluded by corneal edema. Only one graft was performed before the diagnosis of epithelial downgrowth in three cases. A regraft was performed in Case 4 because the original transplant done in 1970 for keratoconus had failed. A similar penetrating keratoplasty technique was used in all four cases. An oversized donor button was sutured into position with continuous nylon. There were no intraoperative or postoperative com-
THE DOWNGROWTH of surface epithelium into the anterior chamber is a disastrous but fortunately rare complication of intraocular surgery. There are few reports of epithelial downgrowth occurring after penetrating keratoplasty in the literature. Sugar, Meyer, and Hood' diagnosed this condition in four of approximately 1,500 keratoplasties, an incidence of more than 0.25%. Each of these four patients was aphakic, whereas the other patients were presumably both phakic and aphakic. They suggested that the incidence of epithelial downgrowth in this clinical setting may not differ greatly from that in the nongrafted aphakic eye.
Accepted for publication April 8, 1985. From the Department of Ophthalmology, Northwestern University, Chicago, Illinois (Dr. Feder); and Department of Ophthalmology, University of Iowa, Iowa City, Iowa (Dr. Krachmer). Reprint requests to Robert S. Feder, M.D., 222 E. Superior Ave., Chicago, IL 60611.
©AMERICAN JOURNAL OF OPHTHALMOLOGY
99:697-703,
and Methods
JUNE,
1985
697
698
June, 1985
AMERICAN JOURNAL OF OPHTHALMOLOGY
TABLE SUMMARY OF CLINICAL DATA PATIENT 1
CLINICALDATA
Sex, age (yrs)
PATIENT 2
PATIENT 3
PATIENT 4
M,69
F,62
F, 76
M,42
Previous cataract surgery Date
January 1976
March 1980
October 1980
1966
Type'
ICCE
ICCE with implant
ICCE
ECCE
Eye
Left
Left
Left
Left
Diagnosis before
Aphakic bullous
Pseudophakic corneal
Fuchs' dystrophy
Keratoconus
keratoplasty
keratopathy
edema
Corneal surgery before downgrowth Date
March 1983
March 1982
May 1981
1970
Type
Penetrating
Penetrating keratoplasty,
Penetrating keratoplasty,
Penetrating keratoplasty,
keratoplasty,
vitrectomy, lens
vitrectomy
removal
vitrectomy
regraft May 1983
Left
Left
Left
Left
Date
August 1983
October 1982
October 1981
September 1983
Symptoms
Iritis, glaucoma,
Iritis, glaucoma
Posterior corneal
Iritis
Eye Clinical appearance of downgrowth
posterior
line
comealline Diagnostic confirmation Date
September 1983
OCtober 1982
October 1981
September 1983
Means
Paracentesis,
Paracentesis,
Paracentesis,
Paracentesis,
laser
laser
laser
laser
7 years
2 years
1 year
17 years
6 months
7 months
5 months
13 years
Date
February 1984
April 1984
September 1982
December 1983
Result
Graft decompensation,
Band keratopathy, end-
Evisceration
Phthisis bulbi
Interval between Cataract surgery and downgrowth Penetrating keratoplasty and downgrowth Final outcome
glaucoma
stage glaucoma
'ICCE, intracapsular cataract extraction; ECCE, extracapsular cataract extraction.
plications. No wound leaks or wound dehiscences were detected. In each patient the diagnosis of epithelial downgrowth was confirmed by performing an anterior chamber paracentesis. A Papanicolaou stain was prepared from each specimen of aqueous and the slide examined by a cytopathologist. In three of the four cases (Cases 1, 3, and 4) blue-green argon laser photocoagulation was applied to the iris in an effort to determine the presence and extent of an epithelial membrane. Histopathologic study of the host corneal buttons initially failed to disclose epithelial downgrowth in all four cases. After the diagnosis had been confirmed by anterior chamber paracentesis, additional
sections of the host specimens were prepared and epithelial downgrowth was identified in two of the four specimens on reexamination (Cases 3 and 4).
Case Reports Case 1 A 69-year-old bilaterally aphakic man underwent an uncomplicated penetrating keratoplasty with anterior vitrectomy for aphakic bullous keratopathy in his left eye on March 12, 1983. The eye had undergone intracapsular cataract extraction seven years previously.
Vol. 99, No.6
Epithelial Downgrowth After Keratoplasty
699
Fig. 1 (Feder and Krachmer). Case 1. Retrocorneal epithelial membrane. The line (arrow) noted on the posterior surface of the graft is typical of that found in epithelial downgrowth.
Five months postoperatively the patient complained of soreness of the left eye. The graft appeared to be clear, but mild iritis was present. Treatment for a possible graft rejection was instituted, but despite systemic, periocular, and frequent topical corticosteroids, the anterior segment inflammation persisted. The intraocular pressure was 26 mm Hg. Six months postoperatively, a posterior corneal line (Fig. 1) was recognized on the superior aspect of the graft and epithelial downgrowth was suspected. An anterior chamber paracentesis was performed on Sept. 12, 1983, and cytologic examination confirmed the presence of epithelial cells in the aqueous. The extent of iris involvement was determined with the argon laser. On Oct. 5, a pars plana approach was used to excise the involved iris as far peripherally as possible. External single-freeze cryotherapy was applied to the entire host rim and the involved superior half of the graft. Three weeks after this procedure there was no evidence of epithelium on the posterior surface of the cornea, but six months later the graft began to fail. The intraocular pressure was 34 mm Hg despite treatment with timolol maleate 0.5% and systemic acetazolamide. Two to three large white cells per high power field were noted in the anterior chamber. Case 2 A 62-year-old woman developed pseudophakic corneal decompensation of the left eye two years after intracapsular cataract extraction with implantation of an iris-supported intraocular lens. On March 15, 1982, she underwent a penetrating keratoplasty in
her left eye with removal of the intraocular lens implant and anterior vitrectomy. The procedure and postoperative course were unremarkable. On Sept. 2, 1982, she complained of blurred vision and irritation of the operated on eye. The graft was clear, but mild ciliary flush, a mild anterior chamber reaction, and an intraocular pressure of 34 mm Hg were noted. The intraocular pressure was initially controlled medically, but four weeks later it was 62 mm Hg despite treatment with acetazolamide, timolol maleate 0.5%, dipivefrin Hel 0.1%, fluorometholone, and scopolamine hydrobromide 0.25%. Moderate microcystic edema and uveitis were present. Because of the rather abrupt onset of glaucoma and iritis in this patient, epithelial downgrowth was suspected. A diagnostic anterior chamber paracentesis confirmed the diagnosis. The patient refused any intraocular procedure directed at removal of the epithelial downgrowth. On April 26, 1984, after several cyclotherapy procedures, her visual acuity had decreased to light perception because of end-stage glaucoma and band keratopathy. Case 3 A 77-year-old woman with confluent cornea guttata underwent an uncomplicated intracapsular cataract extraction in the left eye on Oct. 24, 1980. Six months later corneal decompensation was noted and a penetrating keratoplasty with anterior vitrectomy was performed on the left eye on May 15, 1981. On Oct. 20, 1981, the patient had a posterior corneal line, mild epithelial edema, a mild uveitic reaction, the suggestion of a membrane at the pupillary mar-
700
June, 1985
AMERICAN JOURNAL OF OPHTHALMOLOGY
gin, and an intraocular pressure of 22 mm Hg. An anterior chamber paracentesis confirmed the diagnosis of epithelial downgrowth and the argon laser was used to determine that the anterior surface of the entire iris was covered by epithelium. Reexamination of the host corneal button removed at surgery disclosed epithelium on the posterior surface, suggesting that epithelial downgrowth was present before the penetrating keratoplasty. On Oct. 23, the patient underwent a pars plana total iridectomy and anterior vitrectomy. Cryotherapy was applied externally over the iris root and internally to the endothelial surface of the host rim and involved portion of the graft. Despite this procedure, the epithelial downgrowth progressed, large cells were seen in the anterior chamber, and glaucoma developed. Repeat external cryotherapy was applied to the entire cornea, but a large chronic epithelial erosion developed. Cyclocryotherapy was attempted in an effort to control the glaucoma. On Sept. 20, 1982, the left eye was eviscerated after a large corneal perforation with prolapse of retinal tissue had occurred. Case 4 A 43-year-old man with bilateral keratoconus and cataracts associated with atopic disease underwent extracapsular cataract extractions in the left eye in 1966 and in the right eye in 1968. He later underwent bilateral penetrating keratoplasties (left eye, 1970; right eye, 1975). On May 18, 1983, he underwent a repeat penetrating keratoplasty, with anterior vitrectomy and excision of a secondary cataract on the left eye because the previous graft had failed. Postoperative stromal graft edema resolved slowly during the next eight weeks. No other complications were detected until Sept. I, 1983, when the intraocular pressure had increased to 30 mm Hg. Although the intraocular pressure was initially controlled, three weeks later it was 34 mm Hg despite maximal medical therapy. An examination disclosed epithelial edema and a moderate uveitic reaction with occasionallarge clumps of material in the anterior chamber. The suggestion of a membrane on the surface of the iris on gonioscopy was confirmed with the argon laser. Epithelial downgrowth was diagnosed after an anterior chamber paracentesis. The host button from the second corneal transplant was reexamined and epithelial downgrowth was found, suggesting that this condition antedated the second graft. On Sept. 28, 1982, the patient underwent a pars plana total iridectomy and anterior vitrectomy and 300-degree cyclocryotherapy along with cryotherapy to the corneoscleral limbus in the same 300-degree distribution. The iridectomy was complicated by
hemorrhage from the ciliary body or iris root. The intraocular pressure could not be easily controlled postoperatively and a second pars plana vitrectomy was performed to remove the residual blood. This procedure controlled the intraocular pressure only transiently and in late October an excisional trabeculectomy was performed. No epithelium was found on the excised specimen. A retinal detachment developed and phthisis bulbi occurred after attempted surgical repair.
Discussion Several clinical features found in our four patients seem to be typical of this condition in grafted eyes. These include anterior chamber cells or iritis (minimal ciliary flush if the intraocular pressure is less than 30 mm Hg, clumps of cellular material in the aqueous, minimal to absent keratic precipitates, and resistance to corticosteroid therapy), glaucoma (abrupt onset; quickly unresponsive to conventional therapy), posterior corneal line (trace to absent graft edema between line and graft wound; may progress quickly), and iris membrane (smoothing of iris architecture, faint white veil over iris and wrapping around the pupillary margin; gonioscopy helpful). Cytopathologic studies of aqueous aspirate may demonstrate one or more of the three types of epithelial cells: the flat, rectangular surface type, the rounded basal type, and vacuolated cells (degenerated epithelial cells vs goblet cells). Recognition of these findings may assist in the differentiation of corneal graft rejection reaction or corticosteroidinduced glaucoma from underlying epithelial downgrowth. In three of our four cases we observed an unusual form of "iritis" early in the clinical course. The iritis was typified by clumps of cellular material in the anterior chamber. Despite a mild-to-moderate uveitic reaction, ciliary flush and patient discomfort were minimal when the intraocular pressure was below 30 mm Hg. In none of the four cases were keratic precipitates or subepithelial infiltrates detected. Keratic precipitates are often associated with moderate degrees of iritis. Both keratic precipitates and subepithelial infiltrates are reportedly associated with the cornea transplant rejection reaction." Intensive corticosteroid administration, varying from hourly topical application to a combination of topical, periocular, and systemic administration failed to suppress the cellular reaction. The appearance of a line on the posterior surface of the graft was noted in two of the four cases (Patients
Vol. 99, No.6
Epithelial Downgrowth After Keratoplasty
1 and 3). Noticeable movement of the line centrally across the graft occurred in as little as one to two weeks. In none of these cases was graft edema present peripheral to the line. Corneal edema between the rejection line and the graft wound is a common feature of endothelial rejection. The absence of corneal edema in association with an endothelial line indicates that epithelial downgrowth is a possible diagnosis. When glaucoma occurred in the presence of epithelial downgrowth, it had a relatively abrupt onset. The intraocular pressure quickly became unresponsive to the usual medical therapy. This glaucoma was unilateral and of the secondary open-angle type. In each of our four cases, epithelial downgrowth was not initially considered at the onset of increased intraocular pressure. When increased intraocular pressure and apparent iritis occur in a patient with no history of glaucoma who has undergone corneal transplant surgery, the clinician may at first consider the increased intraocular pressure to be corticosteroid-induced or the result of chronic inflammation. If the underlying cause of the glaucoma is epithelial downgrowth, neither discontinuing corticosteroids nor intensive corticosteroid therapy will control the intraocular pressure. Finally, careful examination of the iris by direct slit-lamp illumination and by gonioscopy may disclose a membrane on the anterior surface. The membrane may cause a smoothing of the normal iris architecture. This occurred in one of our four cases (Case 4). It is our impression that the presentation and clinical course of epithelial downgrowth in the aphakic eye after keratoplasty are not appreciably different from that in the nongrafted aphakic eye. The relative lack of external signs and symptoms of inflammation in our patients may be attributed to the use of topical corticosteroids. The duration of topical corticosteroid administration after corneal transplant surgery is typically longer than after cataract extraction. Before the diagnosis is clinically suspected, the pathologist may confirm the presence of epithelial downgrowth after a careful examination of the host corneal button. A sheet of epithelium discovered on the endothelial surface of the host button suggests that epithelial downgrowth existed before the corneal transplant surgery. The clinical findings of epithelial downgrowth may escape detection before keratoplasty because of poor slit-lamp visualization of the anterior segment. Indeed, this condition may occasionally be diagnosed unexpectedly in an apparent case of aphakic bullous keratopathy after pathologic study of the host speci-
701
men. After keratoplasty the pathologist may also miss the diagnosis if the entire corneal specimen has not been submitted, if only a few tissue sections are studied, or if the area of downgrowth is small. In none of our cases was epithelial downgrowth suspected before corneal transplant surgery. However, in Cases 3 and 4 epithelium was found on the posterior surface of the host buttons, confirming that this condition was present before the keratoplasties. In both cases the initial routine pathologic examination failed to identify epithelial downgrowth. The condition was discovered only after further tissue sections were prepared and examined. If epithelial downgrowth is clinically suspected and careful examination of the host button fails to confirm the diagnosis, an aqueous humor aspirate should be obtained and examined cytopathologically. Cytologic confirmation of downgrowth was obtained in all of our cases. Engel and associates" described three types of epithelial cells seen on cytologic examination in several cases of epithelial downgrowth. Cells can be the flattened, rectangular, surface type (Fig. 2, top left) or the rounded, basal type (Fig. 2, top right). A third cell containing large vacuoles was identified as a goblet cell (Fig. 2, bottom left). It is not clear how Engel and associates determined that these were goblet cells. Similar cells have been described as part of intraocular epithelial membranes seen in histopathologic preparations of globes enucleated because of epithelial downgrowth.v' In two of our cases vacuolated epithelial cells were found on cytologic examination of the aqueous (Cases 2 and 4). In one of these two cases (Case 2), the vacuolated cells stained positively with mucicarmine stain for mucin, as would a goblet cell, This finding must be interpreted with caution because degenerating epithelial cells may stain artifactually. Are these cells goblet cells? It is our opinion that this question cannot be answered with certainty at this time. Goblet cells, a normal constituent of conjunctival epithelium, are not found in corneal epithelium. The proven presence of goblet cells in the anterior chamber or as part of an intraocular epithelial membrane might suggest that the conjunctiva was the source of the epithelium. For now, the significance of these vacuolated epithelial cells found on microscopic study of an aqueous humor aspirate is unknown. What is the significance of an aqueous humor aspirate without epithelial cells despite clinical findings suggestive of epithelial downgrowth? Epithelial downgrowth mayor may not have been present. If the downgrowth was present, the number of cells in the aqueous humor may have been too few to
702
AMERICAN JOURNAL OF OPHTHALMOLOGY
June, 1985
Fig. 2 (Feder and Krachmer). Three types of epithelial cells found on Papanicolaou stain of an aqueous aspirate in epithelial downgrowth. Top left, Flattened, surface type. Top right, Rounded, basal type. Bottom left, Vacuolated cells may possibly be goblet cells.
detect, the volume of aqueous humor collected may have been inadequate, or the slide may have been improperly prepared or interpreted. We conclude that if the possibility of epithelial downgrowth remains high, even after reportedly noncontributory aqueous humor studies, a repeat anterior chamber paracentesis should be considered. Confirmation of the presence of an epithelial membrane on the iris can be obtained with photocoagulation." A 500-~m argon laser burn on the anterior surface of the iris turns white if an epithelial membrane is present (Fig. 3). The laser can be used to map the distribution of epithelial involvement of the iris for planned surgical excision. Why did epithelial downgrowth occur in these
aphakic patients after essentially uncomplicated corneal transplant surgery? We propose several possible explanations. First, this condition may have developed as a direct result of the penetrating keratoplasty. Epithelial downgrowth and an epithelial inclusion cyst of the iris have each been reported after phakic transplants.?" The epithelium may be introduced into the anterior chamber at the time of surgery, as a result of a graft wound dehiscence, or through a suture track. In none of our cases was a wound leak or dehiscence identified. The occurrence of the downgrowth only four to seven months after the corneal transplant suggests that the penetrating keratoplasty may have had either a direct or an indirect role in the development of this condition.
Vol. 99, No.6
Epithelial Downgrowth After Keratoplasty
Fig. 3 (Feder and Krachmer). Case 1. The arrow indicates where a 500-lLm, 400-mW, O.l-sec argon laser burn caused edema of an epithelial membrane on the iris, turning it white.
As mentioned, epithelial downgrowth may already be present at the time of keratoplasty. This occurred in Cases 3 and 4, in which epithelial cells were later discovered on the posterior surface of the host corneal button. In Case 4 the downgrowth must have occurred either after the cataract surgery or the initial graft. In none of our cases was this condition suspected before the keratoplasty. None of the patients had an apparent epithelial line on the posterior corneal surface or iritis before to the corneal surgery. However, in these patients poor anterior segment visualization may have prevented detection of these findings. We suspect that in certain instances epithelial downgrowth may exist in a dormant or slowly progressive form. Corneal transplant surgery may have a stimulating effect on the condition. The penetrating keratoplasties in Cases 3 and 4 may have aggravated the pre-existing epithelial downgrowth, causing the condition to progress more rapidly. In our four cases the visual prognosis for an aphakic eye with epithelial downgrowth after keratoplasty was poor (Table). Despite excision of the involved iris with a vitreous suction-cutting device through a pars plana site, combined with cryotherapy of the involved cornea, eyes treated surgically fared no better than the one eye that was not treated in this way (Case 2). Longer follow-up is needed to evaluate the surgical treatment in Case 1. Others have reported better short-term surgical results in cataract patients with epithelial downgrowth. Stark and associates'" reported improvement of visual acuity in eight of ten patients by means of a similar surgical technique. We have also had good results in nontransplant patients. The presence of a corneal transplant
703
in our patients may have delayed recognition of the true underlying diagnosis. Perhaps earlier surgical intervention would have improved the prognosis. As part of the surgical approach to epithelial downgrowth in the aphakic eye, previous reports have advocated exploration of the cataract wound for fistulous tracks.v" If the tracks are detected, excision and closure are recommended. Although no graft wound leaks were found in our cases, our surgical approach did not include exploration of the previous cataract wound for fistulous tracks. Perhaps this should be a part of the surgical management of this condition after penetrating keratoplasty in the aphakic eye. The primary goal of any treatment of epithelial downgrowth is the complete destruction or removal of epithelium from the interior of the eye. An aggressive approach may in certain cases result in decompensation of the corneal transplant, but if the epithelial downgrowth is successfully treated a regraft may be possible. A clear graft will not be of benefit if the eye is lost because of progression of the downgrowth.
References 1. Sugar, A., Meyer, R. F., and Hood, C. 1.: Epithelial downgrowth following penetrating keratoplasty in the aphake. Arch. Ophthalmol. 95:464, 1977. 2. Alldredge, O. C.; and Krachmer, J. H.: Clinical types of corneal transplant rejection. Their manifestations, frequency, preoperative correlates and treatment. Arch. Ophthalmol. 99:599, 1981. 3. Engel, H. M., Green, W. R., Michels, R. G., Rice, T. A., and Erozan, Y. 5.: Diagnostic vitrectomy. Retina 1:128, 1981. 4. Calhoun, F. P.: The clinical recognition and treatment of epithelization of the anterior chamber following cataract extraction. Trans. Am. Ophthalmol. Soc. 47:498, 1949. 5. Terry, T. L., Chisholm, J. F., [r., and Schonberg, A. L.: Studies on surface-epithelium invasion of the anterior segment of the eye. Am. J. Ophthalmol. 22:1083, 1939. 6. Maumenee, A. E.: Treatment of epithelial downgrowth and intraocular fistula following cataract extraction. Trans. Am. Ophthalmol. Soc. 62:153, 1964. 7. Mazow, M. L., and Stephens, R. W.: An unusual complication after keratoplasty. Surv. Ophthalmol. 11:205, 1966. 8. Leibowitz, H. M., Elliot, J. H., and Boruchoff, S. A.: Epithelization of the anterior chamber following penetrating keratoplasty. Arch. Ophthalmol. 78:613, 1967. 9. Bennett, T., and D'Amico, R. A.: Epithelial inclusion cyst of iris after keratoplasty. Am. J. Ophthalmol. 77:87, 1974. 10. Stark, W. J., Michels, R. G., Maumenee, A. E., and Cupples, H.: Surgical management of epithelial ingrowth. Am. J. OphthalmoI. 85:772, 1978.