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Postkeratoplasty Crystalline Deposits Mimicking Bacterial Infectious Crystalline Keratopathy
Postkeratoplasty Crystalline Deposits Mimicking Bacterial Infectious Crystalline Keratopathy Robert W. Weisenthal, M . D . , Jay H. Krachmer, M . D . , Robert Folberg, M . D . , Steven P. D u n n , M . D . , and William E. W h i t s o n , M . D .
Three corneal transplant patients developed white, crystalline, anterior stromal lesions in their grafts while receiving long-term topical corticosteroid therapy. A presumed diagnosis of infectious crystalline keratopathy was made in each case. However, histologic examination of the lesions failed to show gram-positive cocci. A fungal infiltrate was present in the first two patients, and calcium deposits pro duced the lesion in the third patient. THE
APPEARANCE
of
slowly
progressive,
white, refractile, finely branched, anterior stro mal infiltrates in patients receiving long-term topical corticosteroid therapy after corneal transplantation, or with recurrent herpes sim plex keratitis, suggests the diagnosis of infec tious crystalline keratopathy. Infectious crys talline keratopathy is caused by gram-positive cocci, usually Streptococcus viridans, which in corneal grafts is difficult to treat. The organism responds poorly to antibiotic therapy, and even if antibiotics are efficacious, significant scarring and vascularization of the graft can result in poor vision. Regrafting is usually necessary to eradicate the infectious process. We examined three patients with refractile, anterior stromal infiltrates that had been clini cally diagnosed as infectious crystalline kera topathy. No patient showed evidence of grampositive cocci. In two cases a fungal infection was demonstrated, and in the third case, focal stromal calcification was present. Accepted for publication Oct. 5, 1987. From the Department of Ophthalmology (Drs. Weis enthal, Krachmer, Folberg, and Whitson), University of Iowa, Iowa City, Iowa, and the Department of Ophthal mology (Dr. Dunn), Michigan State University, William Beaumont Hospital, Royal Oak, Michigan. This study was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc. Reprint requests to Jay H. Krachmer, M.D., Depart ment of Ophthalmology, University of Iowa, Iowa City, IA 52242. 70
Case Reports Case 1 An 85-year-old woman was referred to the Iowa Lions Cornea Center at the University of Iowa for treatment of aphakic bullous keratop athy in the left eye. The patient had undergone intracapsular cataract extractions in 1974 in the right eye and in 1975 in the left eye, as well as a trabeculectomy in 1953 in the left eye. On June 9, 1986, a penetrating keratoplasty with ante rior vitrectomy was performed in the left eye. Postoperatively, the patient was given prednisolone sodium phosphate 1% four times a day and timolol maleate 0.5% twice daily. She also received a two-week regimen of topical antibi otics. Methazolamide 50 mg twice daily was also required for intraocular pressure control. On Sept. 4,1986, three months after penetrat ing keratoplasty, while still receiving prednisolone sodium phosphate twice a day, a 0.8 x 1.0-mm, white anterior stromal crystalline opacity appeared in the corneal graft beneath intact epithelium (Fig. 1). A presumed diagno sis of infectious crystalline keratopathy was made, and an excisional biopsy was performed using a 1.5-mm corneal trephine. The entire specimen was fixed in neutral buffered forma lin for histologic study. Clinically, the infec tious infiltrate was entirely removed. Because the infection was thought to be eradicated, and to provide prophylaxis against graft rejection early in the postkeratoplasty period, an antibiotic-corticosteroid ointment was pre scribed. Histopathologic examination of the bi opsy specimen disclosed a beaded, branching, filamentous fungus suggestive of Alternaria (Fig. 2). No bacteria were demonstrated. On Sept. 18, 1986, a new fine branching white stromal opacity similar to the initial infil trate was detected at the base of the corneal biopsy site. Corticosteroid therapy was discon tinued, and the patient was given topical 0.1%
©AMERICAN JOURNAL OF OPHTHALMOLOGY 105:70-74, JANUARY, 1988
Vol. 105, No. 1
Postkeratoplasty Crystalline Deposits
71
ment. The patient has had no further recur rences and has a clear graft. Visual acuity at last examination was counting fingers secondary to optic nerve damage from glaucoma.
Fig. 1 (Weisenthal and associates). Case 1. Slitlamp photograph of white anterior stromal crystal line infiltrate in the corneal graft beneath an intact epithelium. Note the needle-like projections of the infiltrate (arrows). There was no surrounding inflam mation. amphotericin B every hour while awake, and every two hours at night. Because the infiltrate enlarged, the lesion was scraped and cultured for bacteria and fungi. Treatment was changed to topical 5% natamycin every two hours. The cultures grew one colony of Staphylococcus epidermidis, which was probably a contaminant. The infiltrate slowly decreased, responding well to natamycin therapy. Eventually a small scar formed in the area of previous involve-
Fig. 2 (Weisenthal and associates). Case 1. Photo micrograph of the biopsy specimen shows a beaded, branching, filamentous fungus, consistent with Alternaria. No bacteria were demonstrated (periodic acid-Schiff, x 100).
Case 2 A 75-year-old woman was first examined by one of us (S.P.D.) in September 1985, with pseudophakic bullous keratopathy in her left eye. An uncomplicated penetrating keratoplasty was performed on Oct. 25, 1985. Postoperatively she was treated with topical gentamicin sulfate 3 mg/ml, atropine sulfate 1%, and prednisolone acetate 1%. Her postoperative course was uneventful until late November 1985, at which time a single, small, branching anterior and midstromal lesion appeared beneath intact epithelium at the 7 o'clock meridian in the graft. The infiltrate was refractile in retroillumination. No surrounding inflammation was noted. Bacterial and fungal cultures were negative. A presumed diagnosis of infectious crystalline keratopathy was made and the patient was given hourly topical cefazolin 50 mg/ml; the topical corticosteroid was discon tinued. The infiltration became smaller and scarred. Topical antibiotics were gradually ta pered over the next four months. In April 1986 the patient was found to have multiple keratic precipitates. Prednisolone ace tate 1% was begun four times a day to treat a presumed mild graft rejection. The topical cor ticosteroid was tapered over a month. On May 7, 1986, the patient complained of irritation in the left eye. Examination disclosed two areas of mid to deep stromal infiltration at the site of the original infection (Fig. 3). There was a mild anterior chamber reaction. A presumed diagno sis of recurrent infectious bacterial crystalline keratopathy was made. However, corneal cul tures and the biopsy specimen grew Candida tropicalis. A regimen of topical amphotericin B 0.15% every hour was begun. Two weeks later a small vitreous opacity was observed and oral ketoconazole 200 mg was administered every four hours. A diagnostic and therapeutic vitrectomy with intraoperative injection of amphotericin B was performed on May 29, 1986. Intraoperative cultures grew C. tropicalis, which was sensitive to amphotericin B, ketoconazole, miconazole, and flucytosine. Oral ketoconazole was used until the patient developed increased levels of hepatic enzymes. Topical amphotericin B was then given for four months. The infiltrate slowly decreased in size and scarred with treatment. The patient was again found to have subepi-
72
AMERICAN JOURNAL OF OPHTHALMOLOGY
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examination best corrected visual acuity was 20/100 secondary to cystoid macular edema.
Fig. 3 (Weisenthal and associates). Case 2. Slitlamp photograph of two areas of retractile stromal opacities associated with discrete, fine, fern-like pro jections (arrows). thelial infiltrates and scattered keratic precipi tates in November 1986. Prednisolone acetate solution was begun every hour along with dexamethasone 0.1% ointment at night. The rejection reaction responded to topical therapy. However, the corneal infiltrate increased in size, necessitating a repeat corneal transplant on Dec. 22, 1986. Cultures and pathologic sec tions confirmed the presence of Candida (Fig. 4). Her postoperative course has been unevent ful, with no evidence of recurrence. At the last
Fig. 4 (Weisenthal and associates). Case 2. The superficial stroma is infiltrated by Candida organ isms. S, cornea! surface; arrow, pseudohypha (peri odic acid-Schiff, x50).
Case 3 A 58-year-old man was examined at the Iowa Lions Cornea Center on Dec. 14, 1985, with a severe herpes simplex keratouveitis in the left eye. Visual acuity was R.E.: 20/20 and L.E.: hand motions. No afferent pupillary defect was present. Corneal sensation was absent in the left eye. On slit-lamp examination the right eye was normal. In the left eye there was a central 2 x 2-mm geographic epithelial defect, with underlying stromal edema and folds in Descemet's membrane. There was 2+ cell and flare in the anterior chamber. Intraocular pressure was R.E.: 19 mm Hg and L.E.: 50 mm Hg. The patient was given prednisolone sodium phos phate 1% and trifluridine four times a day, as well as timolol maleate 0.5% and acetazolamide 500 mg twice daily. The patient was subse quently lost to follow-up. On Feb. 10, 1986, the patient returned to the clinic with a central corneal perforation. The perforation was initially treated with tissue adhesive and a bandage soft contact lens. How ever, the area of perforation continued to leak and on March 14, 1986, an 8.0-mm penetrating keratoplasty was performed. Postoperatively the graft did not reepithelialize, despite a pro longed regimen of patching followed by a ban dage soft contact lens. On June 16, 1986, a partial tarsorrhaphy was performed. The pa tient was given neomycin sulfate-dexamethasone sodium phosphate ointment, and timolol maleate 0.5% and trifluridine solution twice daily. The epithelium healed slowly over the next several months, and the inflammation subsided. On Nov. 19, 1986, while still using neomycin sulfate-dexamethasone sodium phosphate ointment, the patient complained of a red itchy eye; the tarsorrhaphy was opened. The corneal graft was hazy with epithelial and stromal edema. The sutures were loose and an epitheli al defect was present inferonasally associated with a wound leak. A crystalline-appearing stromal opacity measuring l x l mm was seen superficially in the superonasal quadrant of the graft (Fig. 5). There were fine branching pe ripheral finger-like projections. The anterior chamber was shallow but quiet, and a dense cataract was present. The diagnosis of graft failure with wound leak was made. Because of the clinical appearance of the crystalline infil trate, a presumed diagnosis of infectious crys talline keratopathy was also made. A second
Vol. 105, No. 1
Postkeratoplasty Crystalline Deposits
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tive. Postoperatively erosions and ulcers recal citrant to medical therapy developed. A conjunctival flap was performed, which limited visual acuity to counting fingers at our last examination.
Discussion
Fig. 5 (Weisenthal and associates). Case 3. Slitlamp photograph of anterior stromal crystalline opacity in the superonasal portion of the corneal graft. Note the peripheral finger-like projections (ar rows) and the lack of surrounding inflammation. penetrating keratoplasty with extracapsular cataract extraction was performed to remove the failed graft and excise the crystalline infil trate. Histopathologic examination of the graft dis closed calcium deposits in the area of the crys talline opacities, with no evidence of bacteria or fungi (Fig. 6). Cultures of the graft were nega-
Fig. 6 (Weisenthal and associates). Case 3. Basophilic calcium deposits (arrowheads) seen in the corneal specimen excised at the time of surgery. No bacteria or fungi were noted. The incision is the site of the graft-host interface (hematoxylin and eosin, xl6).
Infectious crystalline keratopathy, a term coined by Meisler and associates, 1 is character ized by a slowly progressive, superficial infil trate found in patients receiving long-term corticosteroid therapy. Gorovoy and associates 2 initially described the keratopathy as a non inflammatory colonization of bacteria, because there were no signs of ocular inflammation in the presence of a bacterial infection. They spec ulated that long-term corticosteroid therapy inhibited inflammatory response to this infec tion. This is supported by a recent case report by Samples, Baumgartner, and Binder, 3 in which a suppurative process developed upon cessation of corticosteroid therapy. In a review of the literature, Reiss, Campbell, and Bourne 4 compiled eight cases of infectious crystalline keratopathy based on clinical diag nosis. Seven patients had previous corneal transplants, two of which were for the treat ment of herpes simplex keratitis. One patient had recurrent herpes simplex keratouveitis without a history of surgery. In four of eight cases, S. viridans was cultured from a biopsy specimen of the infiltrate. In seven patients the trilamellar cell wall characteristic of a coccal bacteria was demonstrated on transmission electron microscopy. Recently, two additional cases of midstromal, crystalline, bacterial infil trates in corneal grafts have been reported. 5 6 In both cases cultures were negative, but grampositive cocci were demonstrated on histologic examination. Thus, it appears that histologic examination is more sensitive than culture for diagnosis. Streptococcus viridans has been identified as the cause of the infiltrate in almost all previous ly reported cases. It is a fastidious organism that grows slowly in culture, and is not usually virulent. Recently, anaerobic peptostreptococcus 7 and Haemophilus aphrophiluss have also been reported to cause an anterior stromal or midstromal filamentous keratitis clinically sim ilar to infectious crystalline keratopathy. Therapy for infectious crystalline keratop athy from bacterial infection requires discon tinuation of topical corticosteroids and fre-
74
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AMERICAN JOURNAL OF OPHTHALMOLOGY
quent application of fortified broad-spectrum antibiotics. However, as emphasized by Kincaid and Snip, 5 the infection is usually pro gressive despite intensive antibiotic therapy. In ten previously reported cases of infectious crystalline keratopathy, at least five patients required repeat corneal grafts to eradicate the infection.1"6,9 In the other cases extensive scarring and vascularization developed in the areas of involvement, producing opacified or edematous grafts with poor vision (D. M. Meisler, M.D., oral communication). Herein, we described three patients with white, refractile, superficial and midstromal infiltrates that were initially incorrectly diag nosed as infectious bacterial crystalline kera topathy. All patients had corneal transplants, were receiving long-term topical corticosteroid therapy, and had a clinical picture similar to those cases described previously. 16,9 Because the medical history and clinical findings were consistent with infectious crystalline keratop athy, we did not consider any other infectious agents. However, rather than being secondary to S. viridans, the infiltrate was caused by fun gus in two patients and calcium deposits in the third patient. Although fungal infections can appear as fine, filamentous stromal infiltrates, in our two patients the lesions also had a crystalline appearance. This prompted us to diagnose infectious crystalline keratopathy, and not suspect an underlying fungal infec tion. In the first patient a small excisional biopsy and aggressive antifungal therapy were suffi cient to resolve the fungal infection without need for further surgery. In the second patient the fungal infiltrate was partially treated, and then progressed when topical corticosteroids were required to treat a rejection reaction. In the third patient the calcium deposits were innocuous. In cases of crystalline deposits in corneal transplants, we recommend an excisional biop sy and microbiologic and histologic studies be
performed to rule out possible causes other than infectious crystalline keratopathy. Histo logic examination is more sensitive than cul ture in identifying both S. viridans and fungal organisms, especially in partially treated infec tions. Although infection secondary to S. viridans is difficult to treat and often requires penetrating keratoplasty, there are other more benign causes of this same clinical picture that offer a better prognosis with appropriate treat ment.
References 1. Meisler, D. M., Langston, R. H. S., Naab, T. J., Aaby, A. A., McMahon, J. T., and Tubbs, R. R.: Infectious crystalline keratopathy. Am. J. Ophthalmol. 97:337, 1984. 2. Gorovoy, M. S., Stern, G. A., Hood, C. I., and Allen, C.: Intrastromal noninflammatory bacterial colonization of a corneal graft. Arch. Ophthalmol. 101:1749, 1983. 3. Samples, J. R., Baumgartner, S. D., and Binder, P. S.: Infectious crystalline keratopathy. An electron microscope analysis. Cornea 4:118, 1985/1986. 4. Reiss, G. R., Campbell, J., and Bourne, W. ML: Infectious crystalline keratopathy. Surv. Ophthal mol. 31:69, 1986. 5. Kincaid, M. C , and Snip, R. C: Antibiotic re sistance of crystalline bacterial ingrowth in a corneal graft. Ophthalmic Surg. 18:268, 1987. 6. Nanda, M., Soong, K. H., Krenz, M. D., and Green, W. R.: Intracorneal bacterial colonization in a crystalline pattern. Graefes Arch. Clin. Exp. Oph thalmol. 224:251, 1986. 7. Eiferman, R. A.,-Ogden, L. L., and Snyder, J.: Anaerobic peptostreptococcal keratitis. Am. J. Oph thalmol. 100:335, 1985. 8. Groden, L. R., Pascucci, S. E., and Brinser, J. H.: Haemophilus aphrophilus as a cause of crystalline keratopathy. Am. J. Ophthalmol. 104:89, 1987. 9. Meisler, D. M., Langston, R. H. S., Aaby, A. A., Stern, G. S., and Binder, P. S.: Infectious corneal crystalline formation. ARVO Abstracts. Sup plement to Invest. Ophthalmol. Vis. Sci. Philadel phia, J. B. Lippincott, 1984, p. 23.
Three corneal transplant patients developed white, crystalline, anterior stromal lesions in their grafts while receiving long-term topical corticosteroid therapy. A presumed diagnosis of infectious crystalline keratopathy was made in each case. However, histologic examination of the lesions failed to show gram-positive cocci. A fungal infiltrate was present in the first two patients, and calcium deposits pro duced the lesion in the third patient. THE
APPEARANCE
of
slowly
progressive,
white, refractile, finely branched, anterior stro mal infiltrates in patients receiving long-term topical corticosteroid therapy after corneal transplantation, or with recurrent herpes sim plex keratitis, suggests the diagnosis of infec tious crystalline keratopathy. Infectious crys talline keratopathy is caused by gram-positive cocci, usually Streptococcus viridans, which in corneal grafts is difficult to treat. The organism responds poorly to antibiotic therapy, and even if antibiotics are efficacious, significant scarring and vascularization of the graft can result in poor vision. Regrafting is usually necessary to eradicate the infectious process. We examined three patients with refractile, anterior stromal infiltrates that had been clini cally diagnosed as infectious crystalline kera topathy. No patient showed evidence of grampositive cocci. In two cases a fungal infection was demonstrated, and in the third case, focal stromal calcification was present. Accepted for publication Oct. 5, 1987. From the Department of Ophthalmology (Drs. Weis enthal, Krachmer, Folberg, and Whitson), University of Iowa, Iowa City, Iowa, and the Department of Ophthal mology (Dr. Dunn), Michigan State University, William Beaumont Hospital, Royal Oak, Michigan. This study was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc. Reprint requests to Jay H. Krachmer, M.D., Depart ment of Ophthalmology, University of Iowa, Iowa City, IA 52242. 70
Case Reports Case 1 An 85-year-old woman was referred to the Iowa Lions Cornea Center at the University of Iowa for treatment of aphakic bullous keratop athy in the left eye. The patient had undergone intracapsular cataract extractions in 1974 in the right eye and in 1975 in the left eye, as well as a trabeculectomy in 1953 in the left eye. On June 9, 1986, a penetrating keratoplasty with ante rior vitrectomy was performed in the left eye. Postoperatively, the patient was given prednisolone sodium phosphate 1% four times a day and timolol maleate 0.5% twice daily. She also received a two-week regimen of topical antibi otics. Methazolamide 50 mg twice daily was also required for intraocular pressure control. On Sept. 4,1986, three months after penetrat ing keratoplasty, while still receiving prednisolone sodium phosphate twice a day, a 0.8 x 1.0-mm, white anterior stromal crystalline opacity appeared in the corneal graft beneath intact epithelium (Fig. 1). A presumed diagno sis of infectious crystalline keratopathy was made, and an excisional biopsy was performed using a 1.5-mm corneal trephine. The entire specimen was fixed in neutral buffered forma lin for histologic study. Clinically, the infec tious infiltrate was entirely removed. Because the infection was thought to be eradicated, and to provide prophylaxis against graft rejection early in the postkeratoplasty period, an antibiotic-corticosteroid ointment was pre scribed. Histopathologic examination of the bi opsy specimen disclosed a beaded, branching, filamentous fungus suggestive of Alternaria (Fig. 2). No bacteria were demonstrated. On Sept. 18, 1986, a new fine branching white stromal opacity similar to the initial infil trate was detected at the base of the corneal biopsy site. Corticosteroid therapy was discon tinued, and the patient was given topical 0.1%
©AMERICAN JOURNAL OF OPHTHALMOLOGY 105:70-74, JANUARY, 1988
Vol. 105, No. 1
Postkeratoplasty Crystalline Deposits
71
ment. The patient has had no further recur rences and has a clear graft. Visual acuity at last examination was counting fingers secondary to optic nerve damage from glaucoma.
Fig. 1 (Weisenthal and associates). Case 1. Slitlamp photograph of white anterior stromal crystal line infiltrate in the corneal graft beneath an intact epithelium. Note the needle-like projections of the infiltrate (arrows). There was no surrounding inflam mation. amphotericin B every hour while awake, and every two hours at night. Because the infiltrate enlarged, the lesion was scraped and cultured for bacteria and fungi. Treatment was changed to topical 5% natamycin every two hours. The cultures grew one colony of Staphylococcus epidermidis, which was probably a contaminant. The infiltrate slowly decreased, responding well to natamycin therapy. Eventually a small scar formed in the area of previous involve-
Fig. 2 (Weisenthal and associates). Case 1. Photo micrograph of the biopsy specimen shows a beaded, branching, filamentous fungus, consistent with Alternaria. No bacteria were demonstrated (periodic acid-Schiff, x 100).
Case 2 A 75-year-old woman was first examined by one of us (S.P.D.) in September 1985, with pseudophakic bullous keratopathy in her left eye. An uncomplicated penetrating keratoplasty was performed on Oct. 25, 1985. Postoperatively she was treated with topical gentamicin sulfate 3 mg/ml, atropine sulfate 1%, and prednisolone acetate 1%. Her postoperative course was uneventful until late November 1985, at which time a single, small, branching anterior and midstromal lesion appeared beneath intact epithelium at the 7 o'clock meridian in the graft. The infiltrate was refractile in retroillumination. No surrounding inflammation was noted. Bacterial and fungal cultures were negative. A presumed diagnosis of infectious crystalline keratopathy was made and the patient was given hourly topical cefazolin 50 mg/ml; the topical corticosteroid was discon tinued. The infiltration became smaller and scarred. Topical antibiotics were gradually ta pered over the next four months. In April 1986 the patient was found to have multiple keratic precipitates. Prednisolone ace tate 1% was begun four times a day to treat a presumed mild graft rejection. The topical cor ticosteroid was tapered over a month. On May 7, 1986, the patient complained of irritation in the left eye. Examination disclosed two areas of mid to deep stromal infiltration at the site of the original infection (Fig. 3). There was a mild anterior chamber reaction. A presumed diagno sis of recurrent infectious bacterial crystalline keratopathy was made. However, corneal cul tures and the biopsy specimen grew Candida tropicalis. A regimen of topical amphotericin B 0.15% every hour was begun. Two weeks later a small vitreous opacity was observed and oral ketoconazole 200 mg was administered every four hours. A diagnostic and therapeutic vitrectomy with intraoperative injection of amphotericin B was performed on May 29, 1986. Intraoperative cultures grew C. tropicalis, which was sensitive to amphotericin B, ketoconazole, miconazole, and flucytosine. Oral ketoconazole was used until the patient developed increased levels of hepatic enzymes. Topical amphotericin B was then given for four months. The infiltrate slowly decreased in size and scarred with treatment. The patient was again found to have subepi-
72
AMERICAN JOURNAL OF OPHTHALMOLOGY
January, 1988
examination best corrected visual acuity was 20/100 secondary to cystoid macular edema.
Fig. 3 (Weisenthal and associates). Case 2. Slitlamp photograph of two areas of retractile stromal opacities associated with discrete, fine, fern-like pro jections (arrows). thelial infiltrates and scattered keratic precipi tates in November 1986. Prednisolone acetate solution was begun every hour along with dexamethasone 0.1% ointment at night. The rejection reaction responded to topical therapy. However, the corneal infiltrate increased in size, necessitating a repeat corneal transplant on Dec. 22, 1986. Cultures and pathologic sec tions confirmed the presence of Candida (Fig. 4). Her postoperative course has been unevent ful, with no evidence of recurrence. At the last
Fig. 4 (Weisenthal and associates). Case 2. The superficial stroma is infiltrated by Candida organ isms. S, cornea! surface; arrow, pseudohypha (peri odic acid-Schiff, x50).
Case 3 A 58-year-old man was examined at the Iowa Lions Cornea Center on Dec. 14, 1985, with a severe herpes simplex keratouveitis in the left eye. Visual acuity was R.E.: 20/20 and L.E.: hand motions. No afferent pupillary defect was present. Corneal sensation was absent in the left eye. On slit-lamp examination the right eye was normal. In the left eye there was a central 2 x 2-mm geographic epithelial defect, with underlying stromal edema and folds in Descemet's membrane. There was 2+ cell and flare in the anterior chamber. Intraocular pressure was R.E.: 19 mm Hg and L.E.: 50 mm Hg. The patient was given prednisolone sodium phos phate 1% and trifluridine four times a day, as well as timolol maleate 0.5% and acetazolamide 500 mg twice daily. The patient was subse quently lost to follow-up. On Feb. 10, 1986, the patient returned to the clinic with a central corneal perforation. The perforation was initially treated with tissue adhesive and a bandage soft contact lens. How ever, the area of perforation continued to leak and on March 14, 1986, an 8.0-mm penetrating keratoplasty was performed. Postoperatively the graft did not reepithelialize, despite a pro longed regimen of patching followed by a ban dage soft contact lens. On June 16, 1986, a partial tarsorrhaphy was performed. The pa tient was given neomycin sulfate-dexamethasone sodium phosphate ointment, and timolol maleate 0.5% and trifluridine solution twice daily. The epithelium healed slowly over the next several months, and the inflammation subsided. On Nov. 19, 1986, while still using neomycin sulfate-dexamethasone sodium phosphate ointment, the patient complained of a red itchy eye; the tarsorrhaphy was opened. The corneal graft was hazy with epithelial and stromal edema. The sutures were loose and an epitheli al defect was present inferonasally associated with a wound leak. A crystalline-appearing stromal opacity measuring l x l mm was seen superficially in the superonasal quadrant of the graft (Fig. 5). There were fine branching pe ripheral finger-like projections. The anterior chamber was shallow but quiet, and a dense cataract was present. The diagnosis of graft failure with wound leak was made. Because of the clinical appearance of the crystalline infil trate, a presumed diagnosis of infectious crys talline keratopathy was also made. A second
Vol. 105, No. 1
Postkeratoplasty Crystalline Deposits
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tive. Postoperatively erosions and ulcers recal citrant to medical therapy developed. A conjunctival flap was performed, which limited visual acuity to counting fingers at our last examination.
Discussion
Fig. 5 (Weisenthal and associates). Case 3. Slitlamp photograph of anterior stromal crystalline opacity in the superonasal portion of the corneal graft. Note the peripheral finger-like projections (ar rows) and the lack of surrounding inflammation. penetrating keratoplasty with extracapsular cataract extraction was performed to remove the failed graft and excise the crystalline infil trate. Histopathologic examination of the graft dis closed calcium deposits in the area of the crys talline opacities, with no evidence of bacteria or fungi (Fig. 6). Cultures of the graft were nega-
Fig. 6 (Weisenthal and associates). Case 3. Basophilic calcium deposits (arrowheads) seen in the corneal specimen excised at the time of surgery. No bacteria or fungi were noted. The incision is the site of the graft-host interface (hematoxylin and eosin, xl6).
Infectious crystalline keratopathy, a term coined by Meisler and associates, 1 is character ized by a slowly progressive, superficial infil trate found in patients receiving long-term corticosteroid therapy. Gorovoy and associates 2 initially described the keratopathy as a non inflammatory colonization of bacteria, because there were no signs of ocular inflammation in the presence of a bacterial infection. They spec ulated that long-term corticosteroid therapy inhibited inflammatory response to this infec tion. This is supported by a recent case report by Samples, Baumgartner, and Binder, 3 in which a suppurative process developed upon cessation of corticosteroid therapy. In a review of the literature, Reiss, Campbell, and Bourne 4 compiled eight cases of infectious crystalline keratopathy based on clinical diag nosis. Seven patients had previous corneal transplants, two of which were for the treat ment of herpes simplex keratitis. One patient had recurrent herpes simplex keratouveitis without a history of surgery. In four of eight cases, S. viridans was cultured from a biopsy specimen of the infiltrate. In seven patients the trilamellar cell wall characteristic of a coccal bacteria was demonstrated on transmission electron microscopy. Recently, two additional cases of midstromal, crystalline, bacterial infil trates in corneal grafts have been reported. 5 6 In both cases cultures were negative, but grampositive cocci were demonstrated on histologic examination. Thus, it appears that histologic examination is more sensitive than culture for diagnosis. Streptococcus viridans has been identified as the cause of the infiltrate in almost all previous ly reported cases. It is a fastidious organism that grows slowly in culture, and is not usually virulent. Recently, anaerobic peptostreptococcus 7 and Haemophilus aphrophiluss have also been reported to cause an anterior stromal or midstromal filamentous keratitis clinically sim ilar to infectious crystalline keratopathy. Therapy for infectious crystalline keratop athy from bacterial infection requires discon tinuation of topical corticosteroids and fre-
74
January, 1988
AMERICAN JOURNAL OF OPHTHALMOLOGY
quent application of fortified broad-spectrum antibiotics. However, as emphasized by Kincaid and Snip, 5 the infection is usually pro gressive despite intensive antibiotic therapy. In ten previously reported cases of infectious crystalline keratopathy, at least five patients required repeat corneal grafts to eradicate the infection.1"6,9 In the other cases extensive scarring and vascularization developed in the areas of involvement, producing opacified or edematous grafts with poor vision (D. M. Meisler, M.D., oral communication). Herein, we described three patients with white, refractile, superficial and midstromal infiltrates that were initially incorrectly diag nosed as infectious bacterial crystalline kera topathy. All patients had corneal transplants, were receiving long-term topical corticosteroid therapy, and had a clinical picture similar to those cases described previously. 16,9 Because the medical history and clinical findings were consistent with infectious crystalline keratop athy, we did not consider any other infectious agents. However, rather than being secondary to S. viridans, the infiltrate was caused by fun gus in two patients and calcium deposits in the third patient. Although fungal infections can appear as fine, filamentous stromal infiltrates, in our two patients the lesions also had a crystalline appearance. This prompted us to diagnose infectious crystalline keratopathy, and not suspect an underlying fungal infec tion. In the first patient a small excisional biopsy and aggressive antifungal therapy were suffi cient to resolve the fungal infection without need for further surgery. In the second patient the fungal infiltrate was partially treated, and then progressed when topical corticosteroids were required to treat a rejection reaction. In the third patient the calcium deposits were innocuous. In cases of crystalline deposits in corneal transplants, we recommend an excisional biop sy and microbiologic and histologic studies be
performed to rule out possible causes other than infectious crystalline keratopathy. Histo logic examination is more sensitive than cul ture in identifying both S. viridans and fungal organisms, especially in partially treated infec tions. Although infection secondary to S. viridans is difficult to treat and often requires penetrating keratoplasty, there are other more benign causes of this same clinical picture that offer a better prognosis with appropriate treat ment.
References 1. Meisler, D. M., Langston, R. H. S., Naab, T. J., Aaby, A. A., McMahon, J. T., and Tubbs, R. R.: Infectious crystalline keratopathy. Am. J. Ophthalmol. 97:337, 1984. 2. Gorovoy, M. S., Stern, G. A., Hood, C. I., and Allen, C.: Intrastromal noninflammatory bacterial colonization of a corneal graft. Arch. Ophthalmol. 101:1749, 1983. 3. Samples, J. R., Baumgartner, S. D., and Binder, P. S.: Infectious crystalline keratopathy. An electron microscope analysis. Cornea 4:118, 1985/1986. 4. Reiss, G. R., Campbell, J., and Bourne, W. ML: Infectious crystalline keratopathy. Surv. Ophthal mol. 31:69, 1986. 5. Kincaid, M. C , and Snip, R. C: Antibiotic re sistance of crystalline bacterial ingrowth in a corneal graft. Ophthalmic Surg. 18:268, 1987. 6. Nanda, M., Soong, K. H., Krenz, M. D., and Green, W. R.: Intracorneal bacterial colonization in a crystalline pattern. Graefes Arch. Clin. Exp. Oph thalmol. 224:251, 1986. 7. Eiferman, R. A.,-Ogden, L. L., and Snyder, J.: Anaerobic peptostreptococcal keratitis. Am. J. Oph thalmol. 100:335, 1985. 8. Groden, L. R., Pascucci, S. E., and Brinser, J. H.: Haemophilus aphrophilus as a cause of crystalline keratopathy. Am. J. Ophthalmol. 104:89, 1987. 9. Meisler, D. M., Langston, R. H. S., Aaby, A. A., Stern, G. S., and Binder, P. S.: Infectious corneal crystalline formation. ARVO Abstracts. Sup plement to Invest. Ophthalmol. Vis. Sci. Philadel phia, J. B. Lippincott, 1984, p. 23.