Gordon K. Klintworth

Transgenic mice expressing a hemopoietic growth factor gene (GM-CSF) develop accumulations of macrophages, blindness, and a fatal syndrome of tissue damage

Transgenic mice carrying the murine granulocyte-macrophage colony stimulating factor (GM-CSF) gene expressed from a retroviral promoter exhibit elevated levels of GM-CSF in the serum, urine, peritoneal cavity, and eye. The eyes of transgenic mice are opaque, contain accumulations of macrophages, and develop retinal damage. Similarly, lesions containing macrophages develop in striated muscle. The mice also display an accumulation of large, often multinucleate, activated macrophages in the peritoneal and pleural cavities. The transgene is transcribed in peritoneal cells, as well as in eyes and infiltrated striated muscle. A high proportion of transgenic mice die with muscle wasting when aged 2-4 months, possibly because of macrophage activation resulting from the high levels of GM-CSF.

Sarcoidosis and Its Ophthalmic Manifestations

Of 532 cases of sarcoidosis in the southeastern United States, ocular manifestations were a prominent feature of the disease in 202 (38%) of the patients. Approximately one fifth of them sought medical attention because of ocular complaints. This was the second most frequent clinical manifestation, exceeded only by pulmonary symptoms. When ocular segment structures were affected, the anterior segment was involved in 171 (84.7%) of cases. Chronic granulomatous uveitis was the most common abnormality in 106 cases (52.5%). Posterior segment disease occurred in 51 (25.3%) of cases, usually in the form of chorioretinitis or preiphlebitis; it was sometimes the sole manifestation of ocular sarcoidosis, but usually accompanied abnormalities in the anterior part of the eye. The incidence of central nervous system sarcoidosis was increased when posterior segment involvement was observed. Orbital and adnexal structures, primarily lacrimal gland, were affected in 53 (27.7%) of cases.

Axenfeld-Rieger syndrome. A spectrum of developmental disorders

The clinical and histopathologic features of Axenfelds anomaly and Riegers anomaly and syndrome are reviewed, and recent findings regarding the pathogenesis of this spectrum of developmental disorders are discussed. Based on these observations, it has been suggested that a developmental arrest, in the third trimester of gestation, of tissues derived from the neural crest cells accounts for the ocular and most of the nonocular abnormalities in this group of disorders. Since previous collective terms, such as mesodermal dysgenesis and anterior chamber cleavage syndrome, are not consistent with these new observations, the alternative name, Axenfeld-Rieger syndrome, has been proposed. The differential diagnosis of the syndrome includes two additional spectra of disorders: the iridocorneal endothelial syndrome and the posterior polymorphous dystrophies. The most serious ocular problem in Axenfeld-Rieger syndrome is the associated glaucoma, which occurs in a high percentage of patients and is typically difficult to control. Recent observations regarding the mechanism of the glaucoma, as reviewed in this paper, provide guidance in the management of this aspect of Axenfeld-Rieger syndrome.

A Histopathologic Study of 716 Unselected Eyes in Patients with Cancer at the Time of Death

To determine the frequency of ocular metastases in the general population, we conducted a prospective histopathologic study of 716 eyes obtained from patients who had malignant neoplasms at the time of death. Fifty-two patients had ocular metastases; all of these individuals had widespread metastases that contributed to their deaths. The overall incidence of ocular metastases among all fatal cases of cancer was 9.3%. Thirty-three of the 117 patients with various types of leukemia and four of the 60 patients dying with lymphoma had ocular involvement. The total incidence of ocular metastases in patients dying of all types of carcinoma was 4.0%. In the nine patients dying of sarcoma, no ocular metastases were detected. We estimate that about 22,000 patients who will die of cancer in the United States during 1983 will have ocular metastases.

Advances in the molecular genetics of corneal dystrophies

PURPOSE To improve our understanding of the role of specific genes on corneal transparency through a review of linkage to specific chromosomal loci and the identification of the mutant genes dealing with the corneal dystrophies. METHOD Relevant recent literature on the corneal dystrophies is reviewed. RESULTS Molecular genetic studies of the corneal dystrophies suggest that genes on at least 10 human chromosomes are involved in the maintenance of corneal transparency (chromosomes 1, 5, 9, 10, 12, 16, 17, 20, 21, and X). Within the 10 chromosomes to which corneal dystrophies have been mapped, specific genetic mutations in seven genes (GSN, BIGH3, KRT3, See also pp. 687-691. KRT12, MSS1, GLA, and ARSC1) have been identified in 15 corneal dystrophies. Some corneal dystrophies that are considered distinct clinicopathologic entities are actually caused by different mutations in the same gene. For example, lattice dystrophy types I and IIIA, granular corneal dystrophy types I, II (Avellino dystrophy), and III (Reis-Bucklers dystrophy), and Thiel-Behnke corneal dystrophy are the result of mutations in BIGH3. Mutations in three genes (GSN, BIGH3, MSS1) are associated with amyloid deposition in the cornea. A gene for keratoconus has been mapped to chromosome 21, which is noteworthy because of the established association of keratoconus in Down syndrome (trisomy 21). CONCLUSION Recent genetic studies on the corneal dystrophies provide insight into some of these disorders at a basic molecular level. Some corneal dystrophies that were previously believed to be distinct clinicopathologic entities are closely related at the molecular level with the different phenotypes resulting from distinct mutations in the same gene. This new knowledge is leading to a revised classification of the corneal dystrophies and to the development of animal models of corneal dystrophies. The latter will lead to a better understanding of the pathogenesis of the disorders and hence to novel therapeutic approaches to those dystrophies that cause significant visual impairment. Research of this nature is only in its infancy.

A Refractive and Histopathologic Study of Excimer Laser Keratectomy in Primates

Using a 193-nm excimer laser, we produced wide-area, refractive keratectomies on 18 cynomolgus monkey corneas and followed them up for up to 18 months. All corneas developed some subepithelial haze by one month. Electron microscopy disclosed epithelial thickening, absence of Bowmans layer, and subepithelial activated fibroblasts surrounded by disorganized collagen. By six months, the haze faded to a variable degree, the epithelium regained normal thickness, and the collagen was more organized. Persistent corneal haze at 12 months in some corneas correlated with electronlucent spaces in the subepithelial zone. Corneas were 90 microns thinner centrally two weeks after myopic ablation, but returned to preoperative thickness by six months. Myopic flattening and hyperopic steepening of 6 diopters were targeted, and over 7 diopters of each were achieved initially. Regression of induced curvature stabilized over several months. At 18 months, 4.4 diopters of myopic flattening and 5.2 diopters of hyperopic steepening remained.

Human Excimer Laser Lamellar Keratectomy: A Clinical Study+++

The first ten blind human eyes in the United States to receive excimer laser (ArFl 193 nm) lamellar keratectomy (reprofiling) are presented. Seven of these patients were followed 6 to 12 months after ablation. All eyes are grossly clear in the region of ablation. Results of slit-lamp examination of all flattened ablated areas show mild superficial haze at the epithelial/stromal interface. This haze might not interfere significantly with vision in patients 7 to 10. Serial pachymetry and keratometry measurements, refraction, and digital keratoscopy show a progressive filling in of the excavated area by approximately two thirds but a loss of initial diopteric correction of only one third. Histopathologic analysis was obtained for four eyes. Transmission electron microscopy of three eyes enucleated 3 to 12 days after ablation shows 40-microns ablation depths through Bowmans layer and superficial stroma with minimal adjacent tissue damage and no inflammatory cells. The epithelium is increased in thickness by 50%, and firmly attached to the underlying stroma. A 4-month postablation specimen shows keratocyte activation with increased protein synthesis (presumed collagen and ground substance).

Missense Mutations in TCF8 Cause Late-Onset Fuchs Corneal Dystrophy and Interact with FCD4 on Chromosome 9p

Fuchs corneal dystrophy (FCD) is a degenerative genetic disorder of the corneal endothelium that represents one of the most common causes of corneal transplantation in the United States. Despite its high prevalence (4% over the age of 40), the underlying genetic basis of FCD is largely unknown. Here we report missense mutations in TCF8, a transcription factor whose haploinsufficiency causes posterior polymorphous corneal dystrophy (PPCD), in a cohort of late-onset FCD patients. In contrast to PPCD-causing mutations, all of which are null, FCD-associated mutations encode rare missense changes suggested to cause loss of function by an in vivo complementation assay. Importantly, segregation of a recurring p.Q840P mutation in a large, multigenerational FCD pedigree showed this allele to be sufficient but not necessary for pathogenesis. Execution of a genome-wide scan conditioned for the presence of the 840P allele identified an additional late-onset FCD locus on chromosome 9p, whereas haplotype analysis indicated that the presence of the TCF8 allele and the disease haplotype on 9p leads to a severe FCD manifestation with poor prognosis. Our data suggest that PPCD and FCD are allelic variants of the same disease continuum and that genetic interaction between genes that cause corneal dystrophies can modulate the expressivity of the phenotype.

Trends in the indications for penetrating keratoplasty, 1980-2001.

Purpose: To study the leading indications and changing trends for penetrating keratoplasty (PK) over the past 3 decades. Methods: This is a retrospective review of 696 cases of PK. The indications for PKs performed at the Duke University Eye Center during the years 1980-1981, 1990- 1991, and 2000-2001 were tabulated to determine trends over the past 3 decades. The main outcome measures were indications for PK. Results: During this study, 696 PKs were performed. The leading indications for PK and their respective frequencies during 1980-1981, 1990-1991, and 2000-2001 were failed grafts (10.8%, 19.0%, 27.0%, respectively), pseudophakic bullous keratopathy (PBK)/aphakic bullous keratopathy (ABK) (19.4%, 20.6%, 16.7%, respectively), Fuchs dystrophy (15.6%, 13.0%, 23.8%, respectively), keratoconus (13.4%, 8.2%, 11.8%, respectively), and corneal scar (7.0%, 8.9%, 10.7%, respectively). The number of PKs for failed grafts and Fuchs dystrophy increased over time. Conclusions: In this study, failed graft has gradually become the leading indication for PK, whereas most other studies have reported PBK as the leading indication. Unlike many other studies, Fuchs dystrophy was a common indication for PK.

Analysis of Corneal Crystalline Deposits in Multiple Myeloma

A 46-year old woman and a 59-year-old man had corneal crystals, multiple myeloma, and IgG kappa hypergammaglobulinemia. In one case, crystalline deposits were also present in the lens. In both patients there was a marked decrease in the amount of crystals during chemotherapy. The crystals within the cornea of one case were identified by light and electron microscopy in material obtained during a lamellar keratoplasty. The crystalline deposits were located only in the corneal epithelium, and their regular repeating internal arrangement was confirmed by monochromatic optical diffraction of electron micrographs of sections through them. By immunofluorescent and immunoperoxidase techniques, the crystals reacted positively for immunoglobulin and particularly IgG kappa chains.