Recurrent Keratoconus in a Patient with Leber Congenital Amaurosis

Josef Stoiber, M.D., Wolfgang H. Muss, Ph.D., Josef Ruckhofer, M.D., Helga Thaller-Antlanger, M.D., Egon Alzner, M.D., and Gu¨nther Grabner, M.D.

Purpose. Clinical history of a 17-year-old patient with Leber con- age of four months in December 1980. Ocular examination showed genital amaurosis (LCA) with histologically proven recurrent kera- pendular nystagmus and profound visual loss. At five years, elec- toconus (KC) two years after corneal transplantation in one eye trophysiologic testing disclosed a nearly absent ERG recording on and a recurrence-like appearance with a more global contour on the right eye and an absent ERG recording on the left eye, the the other eye four years after corneal grafting is reported. The ocular fundus showing atypical pigmentation and arterial narrow- possible mechanisms for this recurrence are discussed in light of the fact that this is, to the best of our knowledge, the first pen- ing. The diagnosis of LCA was established on the basis of these etrating keratoplasty reported in LCA. Methods. Computerized criteria. Visual acuity at that time was 20/800 in both eyes. videokeratography (CVKG) and specular microscopy were per- Strabismus surgery was performed at age eight years. Bilateral formed preoperatively. The patient underwent regrafting, and the KC was first detected in December 1991 with keratometry read- excised corneal button was examined by light microscopy and ings initially showing 5.0 diopters (D) of astigmatism in the right transmission electron microscopy. Results. Analysis of CVKG eye and 4.5 D in the left eye, rapidly progressing to 7.0 D of showed a keratoconus-like pattern on the right eye, with the left irregular astigmatism on the right and 8.0 D of irregular astigma- eye demonstrating the aspects usually seen in keratoglobus. His- tism on the left eye only six months later. Slit-lamp examination tologic examination revealed the features usually observed in pro- gressed keratoconus. Conclusion. Recurrence of keratoconus in a confirmed central thinning of the cornea and a Fleischer ring. After graft has not yet been described after such a short time until now. corneal decompensation resulting in scarring, corneal thinning, A “true” recurrence of the disease is postulated; it could be caused and further reduction of visual acuity, a 7.5-mm-diameter penetrat- by an “aggressive” genetic factor that also leads to the frequent KC ing keratoplasty was performed on the left eye in July 1994 and on in patients with LCA. This mechanism also could explain the high the right eye in July 1995. incidence and rapid progress of KC in this disease. Donor tissue was obtained from young individuals, 20 (right Key Words: Keratoconus—Penetrating keratoplasty—Recurrent eye) and 7 (left eye) years old. Corneas were stored in organ keratoconus—Congenital amaurosis of Leber. culture at 31°C for several days. At the time of transplantation both were of good quality, with normal thickness and an endothelial cell count of more than 3,000 cells/mm2. The postoperative period was Leber congenital amaurosis (LCA) is an autosomal recessive initially uneventful for both eyes; on the left eye, sutures were disorder characterized by profound visual impairment, a markedly removed at 17 months, and on the right eye, 13 months after reduced or flat electroretinogram (ERG) and a fundus appearance corneal transplantation. There was no contact lens wear in the resembling retinitis pigmentosa. LCA has frequently been associ- postoperative period. ated with keratoconus (KC),1–3 a chronic noninflammatory corneal In August 1997, 25 months after grafting, the patient was read- thinning disorder leading to scarring and progressive thinning.4–6 mitted because of sudden visual loss on the right eye due to corneal Recurrence of KC after corneal grafting was seldom described.7–13 hydrops. Slit-lamp examination revealed corneal ectasia that was We report such a recurrence in a 17-year-old patient with LCA. classified as KC, stromal edema, and two parallel, oblique ruptures of Descemet’s membrane (Fig. 1). Corneal thinning was detected in the inferior part of the graft and the adjacent segment of the CASE HISTORY recipient cornea. Seven months later, the patient was readmitted for repeated penetrating keratoplasty because of excessive corneal We report of a male patient who was first seen at the Depart- thinning and central scarring of the right eye (Fig. 2). The preop- ment of Ophthalmology of the County Hospital of Salzburg at the erative CVKG (Keratron/Optikon 2000, Rome, Italy) showed a pattern seen in advanced KC (Fig. 3). Corneal regrafting with a Submitted February 2, 1999. Revision received July 28, 1999. Accepted 8.7-mm transplant was performed on March 18, 1998. Until now July 29, 1999. no further complications were observed in the postoperative fol- From Salzburg Eye Clinic (J.S., J.R., H.T.-A., E.A., G.G.), and the low-up. Institute of Pathology (W.H.M.), LKA Salzburg, Salzburg, Austria. Address correspondence and reprint requests to Dr. J. Stoiber, Salz- On the left eye, a more globular contour and protrusion of the burg Eye Clinic, LKA Salzburg, Muellner Hauptstrasse 48, 5020 Salz- cornea (Fig. 4), which was not apparent in the early postoperative burg, Austria. follow up, was observed. In contrast to the graft tissue, which

395 396 J. STOIBER ET AL.

FIG. 1. The right eye of the patient two years after penetrating kera- FIG. 3. Preoperative videokeratoscopy demonstrates a large central toplasty showing corneal hydrops and two ruptures in Descemet’s cone with a relatively flat region next to the cone center representing membrane. the area of scarring and resolved hydrops. showed normal thickness, the recipient cornea next to the graft– deeper stromal layers showed folds in both Descemet’s membrane host junction clearly displayed substantial thinning, especially in and the overlying stroma, with scrolls, ledges, and hyaline nodules the temporal and inferior quadrant. Both recipient and donor cor- observed in the areas of previous “ruptures” of Descemet’s mem- neas were clear. CVKG revealed a flat cornea centrally, compared brane. Sections with altered and atrophic endothelium also were with a steep corneal periphery. found. To evaluate endothelial cell morphology and density preopera- By transmission electron microscopy, abnormalities of the base- tively, we used a noncontact specular microscope (Noncon-Robo- ment membrane of the epithelium were observed in several areas Ca/Konan, Hyogo, Japan). The mean endothelial cell density was showing focal fragmentation and discontinuity of this structure. slightly >1,000 cells/mm2 on both eyes with moderate signs of Fibrillation of the collagen fibers of Bowman’s layer losing their polymegathism and pleomorphism. The excised corneal button random appearance and alterations in the anterior stroma identified was examined both by light and transmission electron microscopy. as fibrous long-spacing (FLS) collagen were found in the areas adjacent to these sections (Fig. 6). The basal layers of corneal epithelium next to the alterations of Bowman’ layer often showed HISTOPATHOLOGIC EXAMINATION signs of destruction. Their cytoplasm had numerous vacuoles and Significant alterations normally seen in advanced stages of KC altered organelles often identified as degenerated mitochondria. were detected by light microscopy. All layers of the cornea were Changes also were present in deeper layers of the cornea, disclos- found to be affected (Figs. 5A–D): The epithelium showed signs of ing thinning of Descemet’s membrane and alteration of the under- degeneration of its basal cells, folds, and (in some areas) attenu- lying endothelial cell layer (Fig. 7). ation to only two or three layers of cells. Downgrowth of epithelium, breaks, Z-shaped interruptions, and fragmentation were ob- DISCUSSION served at the level of Bowman’s layer. In some sections, Bow- man’s layer was completely missing in combination with a The origin of KC is still not yet fully understood, and recurrent compensatory epithelial hyperplasia. Corneal stroma disclosed KC after penetrating keratoplasty is a seldom reported clinical thinning and areas with newly formed connective tissue. The

FIG. 4. Oblique view of the left eye showing “globular” protrusion of FIG. 2. The right eye of the patient with the graft showing Munson’s the corneal graft and recipient four years after corneal transplanta- sign and marked central corneal scarring. tion.

Cornea, Vol. 19, No. 3, 2000 RECURRENT KERATOCONUS IN LCA 397

FIG. 5. Histopathologic alterations. (A) Discontinuity in Bowman’s layer (BL) and “downgrowth” of basal epithelium. (B) Fragment of BL without contact with basal epithelium surrounded by connective tissue, and on the right side “swelling” of BL. (C) Deep stromal folds. (D) Curling of edges of ruptured Descemet’s membrane (DM), above connective tissue and fragment of DM. phenomenon, in most cases appearing many years or even decades ter10 reported on a 19-year-old patient with mental retardation who 7–9,11–13 after an initially successful corneal transplantation. developed a recurrent KC 21⁄2 years after transplantation. The very short time between grafting and recurrence and the KC is found frequently in patients with LCA, an incidence of severe histological changes normally found only in very pro- 303 to 100 percent (in a small group)2 being described. Elder1 gressed KC cases make this report of a case of recurrence in a found 10 of 35 children with LCA attending schools for the blind patient with Leber congenital amaurosis (LCA) so remarkable. As in Israel with clinical signs characteristic of KC, one with kerato- far as the speed of recurrence is concerned, only one case has been globus. He reported a significant difference in the incidence of KC, reported in the published literature that is similar. Kroll and Win- comparing these patients to the others with equally poor visual acuity but with a different diagnosis. He concluded that a genetic

FIG. 6. Area of defect in Bowman’s layer containing sections with fibrous long-spacing (FLS) collagen (arrowhead) and breaks and FIG. 7. Descemet’s membrane (DM) reduced in thickness from 4.6– fragmentation of basement membrane (arrow). Basal epithelial cells 1.2 µm, which could represent an area of future “disruption.” There is show signs of degeneration. Note destructive changes of mitochon- doubling of the endothelial cell layer in this area; EM, original mag- dria (asterisk); EM, original magnification × 17,400. nification × 5400).

Cornea, Vol. 19, No. 3, 2000 398 J. STOIBER ET AL. factor, in addition to “eye-rubbing” known to occur in blind or possible cause for the thinning and might contribute to the devel- visually severely handicapped children, had to be responsible for opment of the globular contour. Histologic findings of excised the development of KC. Excessive eye-rubbing (which was not keratoglobus cornea buttons closely resemble those normally seen admitted by our patient) was postulated as one of the important in advanced KC,23 indicating a common pathomechanism in these etiologic causes by other authors.13,14 The proposed genetic factor two types of thinning disorders. Further long-term observation will seems to be very “aggressive” in patients with LCA and serves demonstrate whether the thinning process again encroaches from well to explain the early appearance and the rapid progression of the recipient onto the donor cornea, which until now has main- primary KC and early recurrence in our patient. tained normal central and peripheral thickness. To the best of our knowledge, this is the first report on the outcome of penetrating keratoplasty for KC in a patient with LCA. Acknowledgment: This study was supported in part by Verein der This could be because the majority of patients are born with vision Foerderer der Landesaugenklinik Salzburg. of light perception only and only rarely with slightly better visual acuities,2,15,16 so that corneal transplantation is seldom warranted REFERENCES although patients may have advanced forms of KC. The visual acuity of our patient seems to be in the upper range regarding the 1. Elder MJ. Leber congenital amaurosis and its association with kera- diagnosis of LCA; therefore, a benefit from corneal grafting was toconus and keratoglobus. J Pediatr Ophthalmol Strabismus 1994;31: 38–40. assumed and also confirmed by the patient. Visual acuity increased 2. Gillespie F. Congenital amaurosis of Leber. Am J Ophthalmol 1966; from 20/1000 before surgery to 20/400 nine months after corneal 61:874–80. transplantation. At first sight, this seems to be a poor result, but the 3. Alstrom CH, Olson O. Heredo-retinopathia congenitalis. Monohybrida personal benefit for the patient’s way of living was substantial. recessiva autosomalis. Hereditas 1957;43:1–177. Regarding the pathogenesis of KC, Teng17 suggested that KC 4. Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998;42:297–319. 5. Krachmer JH, Feder RS, Belin MW. Keratoconus and related nonin- was a degenerating disease beginning in the basal epithelium, fol- flammatory corneal thinning disorders. Surv Ophthalmol 1984;28: lowed by secondary destruction of the deeper layers of the cornea 293–322. by the release of proteolytic enzymes from dead cells. This hy- 6. Leibowitz HM, Morello S. Keratoconus and noninflammatory thin- pothesis was confirmed by Sawaguchi et al.18,19 who found an ning disorders. In: Leibowitz HM, Waring GO III, eds. Corneal disorders: clinical diagnosis and management. Philadelphia: W.B. Saun- increase in lysosomal enzymes in the basal epithelium and a de- ders, 1998:349–74. ␣ crease of 1-proteinase inhibitor levels. Because donor epithelium 7. Abelson MB, Collin HB, Gilette TE, Dohlmann CH. Recurrent kera- is eventually replaced by diseased recipient epithelium within sev- toconus after keratoplasty. Am J Ophthalmol 1980;90:672–6. eral months, it is conceivable that these changes could affect the 8. Bechrakis N, Blom ML, Stark WJ, Green WR. Recurrent keratoconus. donor cornea in a similar way to cause recurrent KC. The “ag- Cornea 1994;13:73-7. 9. Kremer I, Eagle RC, Rapuano CJ, Laibson PR. Histologic evidence of gressive” genetic factor postulated earlier and leading to KC in recurrent keratoconus seven years after keratoplasty. Am J Ophthalmol patients with LCA would explain an early recurrence, as in our 1995;119:511–2. patient. 10. Kroll G, Winter R. Keratokonus-Rezidiv. Spektrum der Augen- An undetected KC in the donor cornea was proposed by several heilkunde 1991;5:35–6. 13,20,21 11. Nirankari VS, Karesh J, Bastion F, Lakhanpal V, Billings E. Recur- authors as an explanation for a “recurrence” in the graft. As rence of keratoconus in donor cornea 22 years after successful kera- the donor cornea in our case was examined preoperatively in our toplasty. Br J Ophthalmol 1983;67:23–8. own cornea bank according to established routines and normal 12. Nose W, Nose RM, Burnier MN. Recurrent keratoconus: clinical and slit-lamp appearance and corneal thickness was confirmed, it histopathological study. Arq Bras Ophthalmol 1988;51:138–40. seems very unlikely that this was the reason for the ectasia. Nev- 13. Rubinfeld RS, Traboulsi EI, Arentsen JJ, Eagle RC Jr. Keratoconus after penetrating keratoplasty. Ophthalmic Surg 1990;21:420–2. ertheless, more accurate methods of screening donor eyes for the 14. Karseras AG, Ruben M. Aetiology of keratoconus. Br J Ophthalmol presence of KC would be desirable, but there are still no clinically 1976;60:522-5. reliable devices for analyzing corneal topography several hours 15. Schroeder R, Mets MB, Maumence IH. Leber’s congenital amaurosis. after death because of development of intraocular hypotony. In Arch Ophthalmol 1987;105:356–9. addition, the fellow donor cornea developed no signs of corneal 16. Edwards WC, Price WD, MacDonald R. Congenital amaurosis of reti- nal origin (Leber). Am J Ophthalmol 1971;72:724–8. ectasia for more than three years after grafting. Although KC is 17. Teng CC. Electron microscope study of the pathology of keratoconus: often highly asymmetrical in its presentation, we are confident that part I. Am J Ophthalmol 1963;55:18–47. this case represents a true recurrence of the disease in the graft. 18. Sawaguchi S, Yue BYJT, Sugar J, Gilboy JE. Lysosomal enzyme On the left eye, a more “globular” protrusion of the cornea was abnormalities in keratoconus. Arch Ophthalmol 1989;107:1507–10. 19. Sawaguchi S, Twinning SS, Yue BYJT, Wilson PM, Sugar J, Chan detected devoid of the classic pattern of a keratoglobus-like gen- S-K. Alpha-1 proteinase inhibitor levels in keratoconus. Exp Eye Res eralized stromal thinning, as outlined in the literature, despite al- 1990;50:549–54. though an association between LCA and this very rare disease has 20. Eiferman RA. Recurrence of keratoconus (letter). Br J Ophthalmol been found.2,22 Keratoglobus after penetrating keratoplasty has 1984;68:289–90. been described by Cameron,22 who found a marked limbus-to- 21. Tuft SJ, Gregory W. Long-term refraction and keratometry after penetrating keratoplasty for keratoconus. Cornea 1995;14:614–7. limbus thinning and a globular corneal thinning in a patient who 22. Cameron JA. Keratoglobus. Cornea 1993;12:124–30. underwent two keratoplasties on that same eye previously. Wound 23. Knieper P, Rochels, R, Nover A. Zur Histologie des Keratoglobus. weakness in the area of the graft–host junction was suggested as a Klin Monatsbl Augenheilkd 1980;177:58–62.

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