Leber congenital amaurosis (LCA) is an autosomal recessive disorder characterized by profound visual impairment, a markedly reduced or flat electroretinogram (ERG) and a fundus appearance resembling retinitis pigmentosa. LCA has frequently been associated with keratoconus (KC), 1–3 a chronic noninflammatory corneal thinning disorder leading to scarring and progressive thinning. 4–6 Recurrence of KC after corneal grafting was seldom described. 7–13 We report such a recurrence in a 17-year-old patient with LCA.
We report of a male patient who was first seen at the Department of Ophthalmology of the County Hospital of Salzburg at the age of four months in December 1980. Ocular examination showed pendular nystagmus and profound visual loss. At five years, electrophysiologic testing disclosed a nearly absent ERG recording on the right eye and an absent ERG recording on the left eye, the ocular fundus showing atypical pigmentation and arterial narrowing. The diagnosis of LCA was established on the basis of these criteria. Visual acuity at that time was 20/800 in both eyes.
Strabismus surgery was performed at age eight years. Bilateral KC was first detected in December 1991 with keratometry readings initially showing 5.0 diopters (D) of astigmatism in the right eye and 4.5 D in the left eye, rapidly progressing to 7.0 D of irregular astigmatism on the right and 8.0 D of irregular astigmatism on the left eye only six months later. Slit-lamp examination confirmed central thinning of the cornea and a Fleischer ring. After corneal decompensation resulting in scarring, corneal thinning, and further reduction of visual acuity, a 7.5-mm-diameter penetrating keratoplasty was performed on the left eye in July 1994 and on the right eye in July 1995.
Donor tissue was obtained from young individuals, 20 (right eye) and 7 (left eye) years old. Corneas were stored in organ 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 initially uneventful for both eyes; on the left eye, sutures were removed at 17 months, and on the right eye, 13 months after corneal transplantation. There was no contact lens wear in the postoperative period.
In August 1997, 25 months after grafting, the patient was readmitted because of sudden visual loss on the right eye due to corneal hydrops. Slit-lamp examination revealed corneal ectasia that was 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 recipient cornea. Seven months later, the patient was readmitted for repeated penetrating keratoplasty because of excessive corneal thinning and central scarring of the right eye (Fig. 2). The preoperative CVKG (Keratron/Optikon 2000, Rome, Italy) showed a pattern seen in advanced KC (Fig. 3). Corneal regrafting with a 8.7-mm transplant was performed on March 18, 1998. Until now no further complications were observed in the postoperative follow-up.
On the left eye, a more globular contour and protrusion of the cornea (Fig. 4), which was not apparent in the early postoperative follow up, was observed. In contrast to the graft tissue, which showed normal thickness, the recipient cornea next to the graft–host junction clearly displayed substantial thinning, especially in the temporal and inferior quadrant. Both recipient and donor corneas were clear. CVKG revealed a flat cornea centrally, compared with a steep corneal periphery.
To evaluate endothelial cell morphology and density preoperatively, we used a noncontact specular microscope (Noncon-Robo-Ca/Konan, Hyogo, Japan). The mean endothelial cell density was slightly >1,000 cells/mm2 on both eyes with moderate signs of polymegathism and pleomorphism. The excised corneal button was examined both by light and transmission electron microscopy.
Significant alterations normally seen in advanced stages of KC were detected by light microscopy. All layers of the cornea were found to be affected (Figs. 5A–D): The epithelium showed signs of degeneration of its basal cells, folds, and (in some areas) attenuation to only two or three layers of cells. Downgrowth of epithelium, breaks, Z-shaped interruptions, and fragmentation were observed at the level of Bowman's layer. In some sections, Bowman's layer was completely missing in combination with a compensatory epithelial hyperplasia. Corneal stroma disclosed thinning and areas with newly formed connective tissue. The deeper stromal layers showed folds in both Descemet's membrane and the overlying stroma, with scrolls, ledges, and hyaline nodules observed in the areas of previous “ruptures” of Descemet's membrane. Sections with altered and atrophic endothelium also were found.
By transmission electron microscopy, abnormalities of the basement membrane of the epithelium were observed in several areas showing focal fragmentation and discontinuity of this structure. Fibrillation of the collagen fibers of Bowman's layer losing their random appearance and alterations in the anterior stroma identified 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 signs of destruction. Their cytoplasm had numerous vacuoles and altered organelles often identified as degenerated mitochondria. Changes also were present in deeper layers of the cornea, disclosing thinning of Descemet's membrane and alteration of the underlying endothelial cell layer (Fig. 7).
The origin of KC is still not yet fully understood, and recurrent KC after penetrating keratoplasty is a seldom reported clinical phenomenon, in most cases appearing many years or even decades after an initially successful corneal transplantation. 7–9,11–13
The very short time between grafting and recurrence and the severe histological changes normally found only in very progressed KC cases make this report of a case of recurrence in a patient with Leber congenital amaurosis (LCA) so remarkable. As far as the speed of recurrence is concerned, only one case has been reported in the published literature that is similar. Kroll and Winter 10 reported on a 19-year-old patient with mental retardation who developed a recurrent KC 2½ years after transplantation.
KC is found frequently in patients with LCA, an incidence of 30 3 to 100 percent (in a small group) 2 being described. Elder 1 found 10 of 35 children with LCA attending schools for the blind in Israel with clinical signs characteristic of KC, one with keratoglobus. He reported a significant difference in the incidence of KC, comparing these patients to the others with equally poor visual acuity but with a different diagnosis. He concluded that a genetic factor, in addition to “eye-rubbing” known to occur in blind or visually severely handicapped children, had to be responsible for the development of KC. Excessive eye-rubbing (which was not admitted by our patient) was postulated as one of the important etiologic causes by other authors. 13,14 The proposed genetic factor seems to be very “aggressive” in patients with LCA and serves well to explain the early appearance and the rapid progression of primary KC and early recurrence in our patient.
To the best of our knowledge, this is the first report on the outcome of penetrating keratoplasty for KC in a patient with LCA. This could be because the majority of patients are born with vision of light perception only and only rarely with slightly better visual acuities, 2,15,16 so that corneal transplantation is seldom warranted although patients may have advanced forms of KC. The visual acuity of our patient seems to be in the upper range regarding the diagnosis of LCA; therefore, a benefit from corneal grafting was assumed and also confirmed by the patient. Visual acuity increased from 20/1000 before surgery to 20/400 nine months after corneal transplantation. At first sight, this seems to be a poor result, but the personal benefit for the patient's way of living was substantial.
Regarding the pathogenesis of KC, Teng 17 suggested that KC was a degenerating disease beginning in the basal epithelium, followed by secondary destruction of the deeper layers of the cornea by the release of proteolytic enzymes from dead cells. This hypothesis was confirmed by Sawaguchi et al. 18,19 who found an increase in lysosomal enzymes in the basal epithelium and a decrease of α1-proteinase inhibitor levels. Because donor epithelium is eventually replaced by diseased recipient epithelium within several months, it is conceivable that these changes could affect the donor cornea in a similar way to cause recurrent KC. The “aggressive” genetic factor postulated earlier and leading to KC in patients with LCA would explain an early recurrence, as in our patient.
An undetected KC in the donor cornea was proposed by several authors as an explanation for a “recurrence” in the graft. 13,20,21 As the donor cornea in our case was examined preoperatively in our own cornea bank according to established routines and normal slit-lamp appearance and corneal thickness was confirmed, it seems very unlikely that this was the reason for the ectasia. Nevertheless, more accurate methods of screening donor eyes for the presence of KC would be desirable, but there are still no clinically reliable devices for analyzing corneal topography several hours after death because of development of intraocular hypotony. In addition, the fellow donor cornea developed no signs of corneal ectasia for more than three years after grafting. Although KC is often highly asymmetrical in its presentation, we are confident that this case represents a true recurrence of the disease in the graft.
On the left eye, a more “globular” protrusion of the cornea was detected devoid of the classic pattern of a keratoglobus-like generalized stromal thinning, as outlined in the literature, despite although an association between LCA and this very rare disease has been found. 2,22 Keratoglobus after penetrating keratoplasty has been described by Cameron, 22 who found a marked limbus-to-limbus thinning and a globular corneal thinning in a patient who underwent two keratoplasties on that same eye previously. Wound weakness in the area of the graft–host junction was suggested as a possible cause for the thinning and might contribute to the development of the globular contour. Histologic findings of excised keratoglobus cornea buttons closely resemble those normally seen in advanced KC, 23 indicating a common pathomechanism in these two types of thinning disorders. Further long-term observation will demonstrate whether the thinning process again encroaches from the recipient onto the donor cornea, which until now has maintained normal central and peripheral thickness.
This study was supported in part by Verein der Foerderer der Landesaugenklinik Salzburg.
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