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BACKGROUND: The recent availability of genetic analyses has demonstrated the shortcomings of the current phenotypic method of corneal dystrophy classification. Abnormalities in different genes can cause a single phenotype, whereas different defects in a single gene can cause different phenotypes. Some disorders termed corneal dystrophies do not appear to have a genetic basis. PURPOSE: The purpose of this study was to develop a new classification system for corneal dystrophies, integrating up-to-date information on phenotypic description, pathologic examination, and genetic analysis. METHODS: The International Committee for Classification of Corneal Dystrophies (IC3D) was created to devise a current and accurate nomenclature. RESULTS: This anatomic classification continues to organize dystrophies according to the level chiefly affected. Each dystrophy has a template summarizing genetic, clinical, and pathologic information. A category number from 1 through 4 is assigned, reflecting the level of evidence supporting the existence of a given dystrophy. The most defined dystrophies belong to category 1 (a welldefined corneal dystrophy in which a gene has been mapped and identified and specific mutations are known) and the least defined belong to category 4 (a suspected dystrophy where the clinical and genetic evidence is not yet convincing). The nomenclature may be updated over time as new information regarding the dystrophies becomes available. CONCLUSIONS: The IC3D Classification of Corneal Dystrophies is a new classification system that incorporates many aspects of the traditional definitions of corneal dystrophies with new genetic, clinical, and pathologic information. Standardized templates provide key information that includes a level of evidence for there being a corneal dystrophy. The system is user-friendly and upgradeable and can be retrieved on the website www.corneasociety.org/ic3d . KEY WORDS: corneal dystrophy, inherited corneal disease, genetic corneal disease, corneal histopathology, gene, mutation, key reference, eponym, epithelial basement membrane dystrophy, epithelial recurrent erosion dystrophy, subepithelial mucinous corneal dystrophy, Meesmann corneal dystrophy, Lisch epithelial corneal dystrophy, gelatinous drop-like corneal dystrophy, Grayson-Wilbrandt corneal dystrophy, lattice corneal dystrophy, lattice gelsolin type dystrophy, granular corneal dystrophy 1, granular corneal dystrophy 2, Avellino corneal dystrophy, Reis-Bucklers corneal dystrophy, Thiel-Behnke corneal dystrophy, macular corneal dystrophy, Schnyder corneal dystrophy, Schnyder crystalline corneal dystrophy, congenital stromal corneal dystrophy, fleck corneal dystrophy, posterior amorphous corneal dystrophy, central cloudy dystrophy of Francxois, pre-Descemet corneal dystrophy, Fuchs endothelial corneal dystrophy, posterior polymorphous corneal dystrophy, congenital hereditary endothelial dystrophy 1, congenital hereditary endothelial dystrophy 2, X-linked endothelial corneal dystrophy

The current paper reviews the genetic basis of diseases affecting the cornea, including corneal dystrophies and systemic diseases with corneal manifestations (e.g. the mucopolysaccharidoses), discusses the mechanisms by which corneal injury and disease can affect corneal transparency and discusses stem cell therapy as a potential therapy for corneal injury and disease. Several diseases of the cornea have been described, many of which are inheritable. The identification of the genetic mutations responsible for these diseases has led to a better understanding of the mechanisms underlying their corneal manifestations. Corneal disease and injury can affect corneal transparency. Stromal keratocytes play an important role in cellular and extracellular transparency of the cornea. They synthesize type I and V collagen and keratan sulfate proteoglycans that together regulate collagen fibril size and spacing important for extracellular matrix transparency. There are strong indications that cellular transparency of keratocytes relies on the presence of corneal crystallins, which provide a uniform density of proteins in the cytoplasm that increase the spatial order necessary for transparency. After injury, activated keratocytes show heterogeneity of cytoplasmic proteins, decreased spatial ordering and increased light scattering. Stem cell transplantation is regarded as a potential new therapy that can replace keratocytes and restore corneal transparency and normal structure after injury or corneal disease.

Purpose To report the histopathologic features in an eye with Sveinsson chorioretinal atrophy (SCRA), also termed helicoid peripapillary chorioretinal degeneration , for the first time. Participant An 82-year-old woman clinically and genetically confirmed to have SCRA. Design Examination of an eye obtained after death. Method Light microscopic examination of an eye of an 82-year-old woman documented to have SCRA since the age of 10 years. Main Outcome Measure The findings in ocular tissues were determined by light microscopy. Results In the most advanced areas of chorioretinal atrophy, the sensory retina, retinal pigment epithelium (RPE), choriocapillaris, and choroid were absent. In the transition between affected and unaffected areas, the RPE and the outer segments of the photoreceptors only were affected. The optic nerve was smaller than normal, but well myelinated. Other ocular tissues retained a relatively normal appearance for a patient who had died at this age. Conclusions The mildest and presumably earliest morphologic changes involved the photoreceptor outer segments, the RPE, and choriocapillaris in this progressive degenerative disease of the retina and choroid.

Purpose To characterize the clinicopathologic phenotype as well as the molecular genetic basis of an autosomal dominant form of corneal amyloidosis. Design Clinicopathologic and molecular genetic study of a family with a form of corneal amyloidosis. Participants Forty-nine individuals from one family were studied. Methods The medical records of affected family members were reviewed, and corneal tissue from those who had undergone penetrating keratoplasty (PK) was examined. Several family members were examined clinically, and corneas were photographed. Deoxyribonucleic acid from blood or buccal swabs was extracted from each consenting family member to determine the status of their transforming growth factor β–induced (TGFBI) gene. The coding region of the TGFBI gene was analyzed for mutations in the proband's DNA, and compared with the nucleotide sequences of normal individuals. This was performed by amplifying and sequencing all exons of the TGFBI gene. In all other family members, only exons 4, 8, 11, and 12 of the gene were amplified, sequenced, and analyzed for mutations. Main outcome measures Clinicopathologic manifestations in relation to mutational status of the TGFBI gene. Results Slit-lamp biomicroscopy revealed bilateral multiple polymorphic, polygonal, refractile, chipped ice–appearing gray and white opacities. There were also occasional deep filamentous lines that did not form a distinct lattice pattern. Corneal tissue of affected individuals who underwent PK contained widespread deposits of amyloid within the corneal stroma, particularly in the deep central stroma. Twelve members of the family were found to have a heterozygous single mutation in the TGFBI gene leading to a predicted amino acid substitution of aspartic acid for alanine (A546D). Nine of these individuals had ophthalmologist-documented corneal disease. The remaining 3, who were 11, 14, and 15 years old, were asymptomatic. In addition, 4 inconsequential polymorphisms with the nucleotide changes 387 G/A (R129R), 981 G/A (V327V), 1416 T/C (L472L), and 1620 C/T (F540F) were found. Conclusion A distinct, progressive form of corneal amyloidosis with an autosomal dominant mode of inheritance is characterized clinically by the presence of refractile polymorphic corneal opacities. We have designated this entity, which is caused by an A546D mutation in the TGFBI gene, polymorphic corneal amyloidosis .

Aims: To study the long term toxic effects of intraocular benzalkonium chloride (BAC). Methods: 19 patients exposed to intraocular BAC preserved viscoelastic during cataract surgery in February 1999 developed severe striate keratopathy immediately postoperatively. 16 patients, including two who underwent penetrating keratoplasty, were studied in the period April to June 2000. Ocular symptoms, visual acuity, biomicroscopy, intraocular pressure, dilated funduscopy, specular endothelial microscopy, and corneal pachymetry findings were recorded. The corneal and iris specimens of the two patients who underwent keratoplasty were studied by light, transmission, and scanning electron microscopy. Results: Six males and 10 females, aged 64–98 years, were studied 14–16 months postoperatively. All patients were symptomatic. 12 patients had best corrected visual acuity of 6/12 or better and four patients of between 6/18 and 6/60. Five patients had corneal epithelial oedema and 11 had Descemet's membrane folds. The central corneal thickness, 620 (SD 71) μm, in affected eyes was significantly higher (p

Amyloidosis is a disease characterized by the formation of extracellular amyloid deposits. Immunoglobulin light-chain amyloidosis can appear as a local disorder presenting with mild symptoms or as a life threatening systemic disease. The systemic form of immunoglobulin light-chain amyloidosis is the most common type of amyloidosis in western countries although it is a rare disease. Identification of the proteins forming amyloid fibrils is essential for the diagnosis of the disease and knowledge about the overall protein composition of the deposits may lead to a larger understanding of the deposition events thereby facilitating a more detailed picture of the molecular pathology. In this pilot study, we investigated the protein composition of amyloid deposits isolated from human specimens of the eyelid, conjunctiva, and orbit. Deposits and internal control tissue (patient tissue without apparent deposits) were procured by laser capture microdissection. Proteins in the captured amyloid and control samples were quantified by liquid chromatography tandem mass spectrometry using the label-free exponential modified Protein Abundance Index (emPAI) method. Immunoglobulin light chain kappa or lambda was found to be the most predominant protein in the amyloid deposits from the eyelid, conjunctiva, and orbit. Five proteins, apolipoprotein A-I, carboxypeptidase B2 (TAFI), complement component C9, fibulin-1 and plasminogen were found solely across all amyloid but not in the control tissue. In addition, the protein profiles identified apolipoprotein E and serum amyloid P component to be associated with the immunoglobulin light chain deposits across all three tissues analyzed. The method used in this study provided high sensitivity and specificity for the type of amyloid and may provide additional information on the pathology of the amyloid deposits in the ocular tissues studied.

Purpose: To report the onset of malignant peripheral nerve sheath tumor of the orbit 8 years after irradiation in a patient with neurofibromatosis type-1. Methods: Case report of a young man with neurofibromatosis type-1 who received irradiation for presumed bilateral optic nerve and chiasmal gliomas and in whom a malignant peripheral nerve sheath tumor later developed. Exenteration with extirpation of the entire contents of the orbit was performed 6 times. Results: Complete recurrence of the tumor occurred after each surgical procedure until the patient died of malignancy. Conclusions: Our case underscores the risk of irradiation, especially in children with neurofibromatosis type-1, and emphasizes that radiotherapy should never be given as an empirical therapy. The authors believe that irradiation and neurofibromatosis type-1 may, in combination, pose a significant risk for the development of malignancies. Clear-cut indications and a precise tissue diagnosis are desirable before the initiation of radiotherapy, particularly in the pediatric population. We recommend that if irradiation is necessary in persons with neurofibromatosis type-1, regular follow-up is imperative. In view of the hostile nature of malignant peripheral nerve sheath tumor, early aggressive treatment appears to be the only viable alternative at present.

Background Glaucoma is a group of chronic eye diseases often associated with an elevated intraocular pressure (IOP). If not controlled, the condition leads to blindness. The eye tissue responsible for maintaining aqueous humor resistance and thus normal IOP is the trabecular meshwork (TM). Adenoviral vectors are capable of transducing the TM in several rodent species. Because of the relevance of the non-human primate model in the study of glaucoma, gene transfer to the eyes of cynomolgus monkeys was investigated. Methods Four cynomolgus monkeys were injected with AdenoGFP into the anterior chamber: two monkeys received 109 pfu and the other two 107 pfu. One monkey received four consecutive injections into the same eye (107 pfu in each injection) over a 7-month period. In vivo gene transfer (fluorescence) and IOP were evaluated by standard clinical ophthalmic instruments (slit lamp biomicroscopy, gonioscopy and tonometry). Histopathology and cellular distribution were assessed postmortem. Results The first injection of the lower viral dose resulted in marked TM-preferred gene transfer visible non-invasively by in vivo gonioscopy. The expression of the transgene lasted for 3–4 weeks with little or no signs of clinical inflammation. Gene transfer was achieved on three sequential occasions (3–4 weeks each) but failed and induced substantial, albeit reversible, corneal abnormalities on the fourth occasion. Conclusions Gene transfer to the TM and cornea can be monitored non-invasively in non-human primates, allowing correlation of gene transfer with physiological parameters. Because of ocular immune privilege, repeated anterior chamber administrations of adenoviral vectors expressing appropriate genes may have therapeutic potential for glaucoma. Copyright © 2001 John Wiley & Sons, Ltd.

We describe a case of focal argyrosis of the conjunctiva clinically simulating a melanoma. An 82-year-old woman was referred for an asymptomatic pigmented conjunctival lesion. Her only significant past ocular history was strabismus surgery 76 years earlier. Biopsy of the conjunctiva and lateral rectus muscle revealed the discoloration was pigment granules. Energy-dispersive x-ray microanalysis revealed the pigmentation to be silver deposits. The patient had strabismus surgery probably using a silver clip. Argyrosis should be considered in the differential diagnosis of focal pigmented conjunctival lesions. [Ophthalmic Surg Lasers 2000;31:495-498]

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, 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.

Objective To review the cytologic findings of vitreous specimens and propose a simplified approach to them. Study design Seventy-four vitreous specimens from 60 patients obtained either during a pars plana vitrectomy or by vitreous aspiration were reviewed. Clinical correlation was obtained on all patients. Results Findings suggestive of a specific disorder were present in 30 specimens (41%); cytologic examination of the remaining 44 showed nonspecific changes. A lymphoproliferative disorder, the intraocular malignancy suspected most often in this series, was identified in eight specimens (11%). Large cell lymphomas were evident in 5 specimens, 2 specimens were suspicious for lymphoma, and 1 specimen was consistent with plasmacytoma. Twelve specimens (16%) contained hemorrhage. In rare instances, specific infectious agents, such as parasites (5%), bacteria (1%) and fungi (3%), could be identified. The diagnosis of viral infections required ancillary studies. Lens fragments were identified in four cases (5%), and a diagnosis of lens-induced endophthalmitis could be rendered in one case (1%). Changes consistent with sarcoidosis were present in 3% of cases. Conclusion Based on this experience with vitreous specimens submitted for clinical reasons, we found that they could be divided into three broad diagnostic categories: inflammation/infection (54 specimens/41 patients), hemorrhage (12 specimens/12 patients) and malignancy (8 specimens/7 patients).

BACKGROUND Second primary malignancies are common after bilateral retinoblastoma; their estimated incidence has been as high as 51% 50 years after diagnosis. Fifteen patients who developed sebaceous gland carcinoma after radiation therapy have been reported in the literature, five of whom were treated for bilateral retinoblastoma. METHODS The authors conducted a retrospective chart review of patients treated for bilateral retinoblastoma at Duke University Medical Center who later developed sebaceous gland carcinoma. RESULTS This article reports two patients who developed sebaceous gland carcinoma after radiation therapy for bilateral retinoblastoma. CONCLUSIONS Delay in diagnosis is often associated with sebaceous gland carcinoma. Because high mortality is observed with metastatic disease, the recognition of this association is important for anyone who follows patients with a history of bilateral retinoblastoma or prior cranial radiation therapy. Cancer 1998;83:767-771. © 1998 American Cancer Society.

Multicentric melanomas in the same eye are rare, with few cases substantiated by histology and serial sectioning. We report a patient with two documented choroidal malignant melanomas in one eye. The initial tumor spontaneously decreased in size for over 2 years before a second tumor appeared in a noncontiguous location in the same eye. After enucleation, serial sections showed that the two lesions were independent choroidal melanomas. We review the literature regarding multiple, independent intraocular choroidal malignant melanomas. ( Surv Ophthalmol 42 :441–448, 1998.

• Background: We characterized the neovascularization that follows the intracorneal injection of bovine albumin (BA) in rabbits as a model of corneal angiogenesis. • Methods: New Zealand white rabbits received intracorneal injections of phosphate-buffered saline with and without various amounts of BA. The rabbits were co-sensitized or presensitized by intramuscular BA or were not sensitized. The corneal vascular response was quantified by ranking photographs taken periodically after the injection. • Results: In pre-sensitized animals, blood vessels were apparent within 4 days and reached maximum intensity 14 days after the intracorneal injection. Corneas also vascularized in nonsensitized rabbits, but a larger dose (>0.2 mg BA) was required than in pre-sensitized animals (>0.02 mg BA). Vascularization began later in non-sensitized animals and was less extensive than in pre-sensitized animals. • Conclusion: The intracorneal injection of BA is a reproducible model of corneal angiogenesis in rabbits and should allow the involved immunological mechanisms to be elucidated.

To determine the immunophenotype or immunophenotypes of macular corneal dystrophy in Saudi Arabia.We studied 56 cases of macular corneal dystrophy. Tissue from 60 corneal transplant buttons was stained by the avidin-biotin complex method using an anti-keratan sulfate monoclonal antibody. The serum antigenic keratan sulfate was measured in 23 of the 56 patients, four unaffected relatives, and 13 individuals with chronic actinic keratopathy. Serum and corneal tissue were studied in 17 of the 50 affected individuals with corneal transplant material.Thirty-five corneas (58.3%) of 29 of 50 patients did not react with anti-keratan sulfate monoclonal antibody. The stroma and abnormal intracellular and extracellular corneal accumulations reacted with anti-keratan sulfate monoclonal antibody in seven corneas (11.7%). The stroma in the other 18 corneas (30.0%) from 15 patients did not react with the anti-keratan sulfate monoclonal antibody, but corneal fibroblasts did. Twenty-one of the 23 patients with macular corneal dystrophy had no detectable serum antigenic keratan sulfate (9 ng/ml); two had values of 12 and 51 ng/ml, respectively, and their corneal stroma and abnormal accumulations reacted with anti-keratan sulfate monoclonal antibody.We detected macular corneal dystrophy type IA, a new immunophenotype characterized by the lack of detectable antigenic keratan sulfate in the serum (9 ng/ml), and a corneal stroma that did not react with the keratan sulfate monoclonal antibody but in which corneal fibroblasts did react with keratan sulfate monoclonal antibody (in 15 of 50 patients).

To study the leading indications and changing trends for penetrating keratoplasty (PK) over the past 3 decades.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.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.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.

Corneal endothelial decompensation is a frequent complication when silicone oil is used as a tamponade following vitrectomy for treatment of proliferative vitreoretinopathy in an aphakic eye. We evaluated the clinical, histopathological, and ultrastructural features of silicone oil-induced keratopathy in 10 patients who developed corneal complications requiring penetrating keratoplasty. Clinically, some cases showed corneal edema, corneal hypesthesia, endothelial opacification, band keratopathy, and peripheral corneal vascularization. Histopathologically, retrocorneal membranes were present, and different degrees of stromal hypercellularity, superficial stromal calcification, and vascularization were noted. The ultrastructural features of endothelial cell loss and retrocorneal membrane formation are consistent with changes previously reported in rabbits and cats receiving intracameral silicone oil injections.

Background: The recent availability of genetic analyses has demonstrated the shortcomings of the current phenotypic method of corneal dystrophy classification. Abnormalities in different genes call Cause a single phenotype, whereas different defects in a single gene can Cause different phenotypes. Sonic disorders termed corneal dystrophies do not appear to have a genetic basis. Purpose: The purpose Of this Study was to develop a new classification system for corneal dystrophies, integrating up-to-date information on phenotypic description, pathologic examination, and genetic analysis. Methods: The International Committee for Classification of Corneal Dystrophies (IC3D) was created to devise a current and accurate nomenclature. Results: This anatomic classification continues to Organize dystrophies according to the level chiefly affected. Each dystrophy has a template summarizing genetic, clinical, and pathologic information. A category number from I through 4 is assigned, reflecting the level of evidence supporting the existence of a given dystrophy. The most defined dystrophies belong to category 1 (a well-defined corneal dystrophy in which a gene has been mapped and identified and specific imitations are known) and the least defined belong to category 4 (a suspected dystrophy where the clinical and genetic evidence is not yet convincing). The nomenclature may be updated over time as new information regarding the dystrophies becomes available. Conclusions: The IC3D Classification of Corneal Dystrophies is a new classification system that incorporates many aspects of the traditional definitions of corneal dystrophies with new genetic, clinical, and pathologic information. Standardized templates provide key information that includes a level of evidence for there being a corneal dystrophy. The system is User-friendly and upgradeable and call be retrieved on the website www.corneasociety.org/ic3d.

Cellular Pathology. Apoptosis. Wound Healing... Immunological Processes in Disease. Intraocular Manifestations of Immunological Processes. Extraocular Manifestations of Immune Disease. The Eye in Systemic Immune Disorders. Viral Disease. Chlamydial Infections. Bacterial Infections. Fungal Infections. Protozoal Infections. Ocular Diseases Due to Helminths. Ocular Diseases Due to Arthropods. Ocular Trauma. Aging. Age-Related Maculopathy. The Aging Lens. Anterior Segment Changes in Glaucoma. Posterior Segment Changes in Glaucoma. The Causes, Types, and Morphology of Cataracts. Biochemistry of Cataracts. Pseudoexfoliation Syndrome. Myopia. Other Degenerative and Related Disorders of the Retina and Choroid. Retinal Detachment. Disorders of the Vitreous. Degenerations, Depositions, and Miscellaneous Reactions of the Ocular Anterior Segment. Overview of Genetic Disorders.Genetic Disorders of the Cornea. Genetic Disorders of the Lens. Genetics of Glaucoma. Genetic Disorders of the Retina. Ocular Proteonomics. Amyloidosis. Lysosomal Storage and Transport Disorders. Glycogen Storage Diseases. Disorders of Glycosaminoglycans (Mucopolysaccharides) and Proteoglycans. Sphingolipidoses and Neuronal Ceroid Lipofuscinosis. Mucolipidoses. Disorders of Amino Acid Metabolism. Disorders of Collagen. Disorders of Monosaccharide Metabolism. Disorders of Lipid and Lipoprotein Metabolism. Dysthyroid Eye Disease. Metabolic Disorders Involving Metals. Nutritional Deficiencies and Excesses. Toxicology. Embryological Development of the Eye. Developmental Anomalies of the Eye. Ambyopia. Overview of Oncogenesis. Metastases. Tumor Immunology. Hereditary Neoplasia syndromes. Tumors of the Eyelids. Tumors of the Ocular Surface. Intraocular Epithelial Tumors and Cysts. Uveal Tumors. Melanocytic tumors. Retinoblastoma. Tumors of the Lacrimal gland and Lacrimal drainage apparatus. Vascular Tumors. Tumors of the Optic Nerve, Peripheral Nerve, and Autonomic Nervous System. Tumors of Soft Tissue. Tumors of Bone and Cartilage. Tumors of Lymphoid Tissue. Vascular Diseases. Vasculitis. Angiogenesis. Ocular Involvement in Disorders of the Nervous System. Muscular Disorders.

To explain the marked variation in the reported incidence of how often leukemic cells infiltrate the eye in fatal cases of leukemia, we tested the hypothesis that ocular leukemic infiltration is related to the peripheral leuko cyte count during the final hours of life. We reviewed tissue sections, as well as autopsy and clinical records, from 135 patients who had fatal leukemia and had their eyes examined after death at Duke University Medical Center. Infiltrates of leukemic cells were found in the eyes of 42 of 135 patients (31.1%), with the choroid being the most frequently involved site. We detected a significant positive correlation between the ocular leukemic infiltration and an agonal leukocyte count as well as the severity of systemic disease. Differences in the agonal circulating leukocyte count may partly explain variations in the incidence of leukemic infiltrates in different postmortem studies.

PURPOSE To determine the genetic basis for lattice corneal dystrophy (LCD) in an extensively studied family. METHODS Ten affected family members were examined clinically, and three individuals were studied with in vivo confocal microscopy and optical coherence tomography (OCT). Corneal tissues from eight affected family members were examined histopathologically. The status of the transforming growth factor beta-induced gene (TGFBI) gene was determined in each consenting family member (six affected, seven nonaffected) by amplifying, sequencing, and analyzing exons 4 and 12 of TGFBI for mutations. All exons from the entire coding region of TGFBI of one affected person were analyzed for mutations. RESULTS Slit lamp biomicroscopy disclosed the clinical features of LCD in both eyes of affected individuals. In vivo confocal microscopy confirmed the presence of deposits as bright lesions within the corneal stroma. OCT revealed increased reflectivity within the corneal stroma. The corneal stroma in persons undergoing penetrating keratoplasty contained amyloid. Affected members of the family were found to have two heterozygous single-nucleotide mutations in exon 12 of the TGFBI gene (C1637A and C1652A) leading to predicted amino acid substitutions in the encoded TGFbeta-induced protein (A546D and P551Q). Mutations were not detected in exon 4. In addition, an inconsequential single-nucleotide polymorphism T1620C (F540F) was found in some affected and nonaffected family members. CONCLUSIONS Two mutations in the TGFBI gene (A546D and P551Q) cosegregated with LCD in an extensively studied family that lacked the R124C mutation that frequently accompanies this form of corneal amyloidosis.

The pertinent literature on inherited corneal diseases is reviewed in terms of the chromosomal localization and identification of the responsible genes. Disorders affecting the cornea have been mapped to human chromosome 1 (central crystalline corneal dystrophy, familial subepithelial corneal amyloidosis, early onset Fuchs dystrophy, posterior polymorphous corneal dystrophy), chromosome 4 (Bietti marginal crystalline dystrophy), chromosome 5 (lattice dystrophy types 1 and IIIA, granular corneal dystrophy types 1, 2 and 3, Thiel-Behnke corneal dystrophy), chromosome 9 (lattice dystrophy type II), chromosome 10 (Thiel-Behnke corneal dystrophy), chromosome 12 (Meesmann dystrophy), chromosome 16 (macular corneal dystrophy, fish eye disease, LCAT disease, tyrosinemia type II), chromosome 17 (Meesmann dystrophy, Stocker-Holt dystrophy), chromosome 20 (congenital hereditary endothelial corneal dystrophy types I and II, posterior polymorphous corneal dystrophy), chromosome 21 (autosomal dominant keratoconus) and the X chromosome (cornea verticillata, cornea farinata, deep filiform corneal dystrophy, keratosis follicularis spinulosa decalvans, Lisch corneal dystrophy). Mutations in nine genes (ARSC1, CHST6, COL8A2, GLA, GSN, KRT3, KRT12, M1S1and TGFBI [BIGH3]) account for some of the corneal diseases and three of them are associated with amyloid deposition in the cornea (GSN, M1S1, TGFBI) including most of the lattice corneal dystrophies (LCDs) [LCD types I, IA, II, IIIA, IIIB, IV, V, VI and VII] recognized by their lattice pattern of linear opacities. Genetic studies on inherited diseases affecting the cornea have provided insight into some of these disorders at a basic molecular level and it has become recognized that distinct clinicopathologic phenotypes can result from specific mutations in a particular gene, as well as some different mutations in the same gene. A molecular genetic understanding of inherited corneal diseases is leading to a better appreciation of the pathogenesis of these conditions and this knowledge has made it imperative to revise the classification of inherited corneal diseases.

s d R p w d c B ECAUSE OF THE NEED FOR A WORLDWIDE STANdardized nomenclature for the corneal dystrophies, an international committee brought together the iverse literature on these disorders and recommended referred names for each entity. Each corneal dystrophy eeds a specific name because all of these entities do not ffect the same parts of the cornea or have the same ethod of inheritance, pathogenesis, prognosis, or treatent. Like many other genetically determined diseases, nowledge about each corneal dystrophy passes through a ontinuum from clinical discovery, to a clinicopathologic haracterization, to chromosomal mapping, to gene idenification, and to the detection of mutations. As this nowledge advances over time, some designations gradully fall by the wayside and better terms are proposed based n clinical or clinicopathologic observations or an imroved understanding of their cause, pathogenesis, and athobiologic features. However, attempts to provide ore accurate appropriate appellations often are unsucessful. After an extended period of use, the names of some iseases become so ingrained in the literature that they are ifficult to replace. For example, retinitis pigmentosa is a rime example of a misnomer, because inflammation of the etina (retinitis) is not a feature of this retinopathy. evertheless, despite attempts to replace this designation ith the more precise name of pigmentary retinopathy, the ld name lives on. Even corneal dystrophy is a misnomer ecause entities embraced under this umbrella do not arise rom defective or faulty nutrition, as implied by the word ystrophy derived from the Latin term dystrophia. Particuarly for the lay public, this is probably good because hanges in nomenclature are not always easy to compreend. To rename diseases frequently as knowledge adances may provide precision, as hematopathologists have one with the lymphomas, but for those who are not xperts in particular diseases, the changes in nomenclature an create an aura of chaos. At anyone point in time, all diseases are not known and ew ones come to light, as occurred with the sudden mergence of retinopathy of prematurity, AIDS, and seere acute respiratory syndrome. If a new corneal disease is uspected, it is essential to determine that it has not been escribed previously. It is also necessary to make sure that he condition is not a variant of a known entity. The age f the patient, the duration of signs and symptoms, as well

Hereditary benign intraepithelial dyskeratosis is a rare autosomal dominant disorder of the oral and ocular mucosa initially described in the Haliwa-Saponi Native American tribe of North Carolina. We describe 2 sisters with the characteristic oral and ocular findings. This entity should be distinguished from several other diseases that cause white lesions in the mouth including white sponge nevus.

Gliomas of the optic nerve, although typically of pilocytic (WHO grade I) histology, can present within the spectrum of astrocytic neoplasia including glioblastoma (WHO grade IV). In certain cases, histologic features alone make the distinction between pilocytic and diffuse astrocytomas difficult. We reviewed 22 cases of optic nerve gliomas, 19 of which were pilocytic astrocytomas (PA), and 3 of which were diffuse, non-pilocytic astrocytomas. The cases were evaluated for their clinical course, radiographic appearance, histologic grade, and proliferation indices as detected by MIB-1 (Ki-67) and p53 antibodies. Of the 19 PA, 14 showed no tumor growth by magnetic resonance imaging, and had Ki-67 and p53 labeling indices (LI) of1%. The other 5 PA exhibited aggressive behavior manifest by marked diffuse infiltrative tumor growth causing death in 2 patients, 1 of whom was diagnosed with neurofibromatosis type 1 (immunoperoxidase and radiographs not available), and marked local growth with an average time to growth of 39.3 months, a Ki-67 LI of 2-3%, and a p53 LI of1% in three others. Three of the five aggressive PA histologically demonstrated a finely reticulated pattern, a pattern that appears as an exaggeration or expansion of the normal neuroglia of the optic nerve, and may simulate a diffuse low-grade astrocytoma. Two demonstrated the coarsely reticulated pattern, with the biphasic and microcystic pattern typical of PA. Three diffuse astrocytomas (2 anaplastic astrocytomas and 1 glioblastoma) originated clinically and radiographically from the optic nerve, and revealed a Ki-67 LI of 2-12%, a p53 LI of 2-8%, and an average time to growth of 8 months. We conclude that the majority of PA of the optic nerve are non-aggressive, stabilize radiographically, and have Ki-67 and p53 LI1%. However, a subpopulation of PA has a propensity for aggressive behavior, and are identified by a Ki-67 LI of 2-3% and a p53 LI of1%. Diffuse astrocytomas have both Ki-67 and p53 LI2%. Thus, in cases of aggressive optic nerve tumors in which the histologic review of biopsy material cannot confidently confirm the diagnosis of pilocytic or diffuse fibrillary glioma, a p53 LI of1% appears to favor the diagnosis of diffuse astrocytoma.

The first application of electron probe X-ray microanalysis (EPXMA) in ophthalmic pathology was reported in 1963 by Tousimis and Adler, using the electron probe X-ray microanalyzer at the US Geological Survey in Washington, DC. They were able to demonstrate deposits of copper in Descemet's membrane, using formalin-fixed, paraffin-embedded tissue sections of corneas obtained at autopsy from patients with Wilson's disease (hepatolenticular degeneration) compared with normal control eyes. Since then, this valuable addition to the ophthalmic pathologist's armamentarium has aided in the characterization of a variety of ocular disorders, and has been particularly useful in the elemental analysis of foreign materials. Soft contact lenses are used to correct refractive errors, such as myopia and the hyperopia of surgical aphakia. Soft bandage lenses are also beneficial in the therapy of patients with certain corneal diseases and eyelid abnormalities. Silicon has been demonstrated by X-ray diffraction and atomic absorption analyses within contact lenses. The source of this element may be casual contaminants or silicone derivatives used as fillers in the lens polishing process. Calcification of soft contact lenses may be clinically significant in certain instances, as when the tear calcium concentration becomes elevated.

Deposition of abnormal sub-epithelial matrix and posterior collagenous layer by epithelium and endothelium, respectively, in Fuchs' dystrophy gives us the opportunity to determine if these tissues synthesize beta ig-h3.Immunohisto-/immunocytochemistry of corneas were conducted with rabbit anti-human beta ig-h3 and monoclonal anti-human type VI collagen. Labeled sense and anti-sense beta ig-h3 oligonucleotide probes were used for in situ hybridization.beta ig-h3-specific fluorescence was found just beneath detached epithelium in the sub-epithelial matrix, abnormal Descemet's membrane and posterior collagenous layer. Type VI collagen co-localized with beta ig-h3 within abnormal sub-epithelial matrix and corneal stroma adjacent to Descemet's membrane. beta ig-h3 mRNA was detected in corneal epithelium of dystrophic corneas.Expression of beta ig-h3 in sub-epithelial matrix and posterior collagenous layer of Fuchs' dystrophy is consistent with the synthesis of new extracellular matrices by epithelial and endothelial tissues. beta ig-h3 mRNA in corneal epithelium further supports an epithelial source of this protein. Endothelial synthesis of beta ig-h3 is based on circumstantial evidence due to cell loss during surgical and histological procedures. Co-localization of beta ig-h3 with type VI collagen in abnormal sub-epithelial matrix and at the stromal/Descemet's membrane interface suggest this collagen in association with beta ig-h3 interacts with these tissues and anchors them to the adjacent stroma.

Fuchs endothelial corneal dystrophy (FECD) is a common progressive disorder of the corneal endothelium that becomes symptomatic with aging.1 It appears as guttae progressively form on Descemet’s membrane along with corneal edema and stromal clouding leading to impaired vision. FECD has been one of the main indications for corneal transplantation in many countries, including the United States,2 with the main treatment modality being a penetrating keratoplasty, until the advent of various types of endothelial keratoplasty. FECD typically becomes symptomatic during the fifth or sixth decade of life and predominantly affects women, who comprise three of four affected individuals.3 The pathogenesis of FECD remains unknown, but the corneal endothelial cells are arrested in the G1 phase of the cell cycle and do not undergo mitosis.4 During a normal state, the cornea is kept in a state of deturgescence by endothelial cell Na+/K+ ATPases that remove fluid from the stroma and by tight junctions between endothelial cells that limit fluid entry.1 This maintains the stroma’s ordered arrangement of collagen and with it, the transparency of the cornea. In states of low endothelial cell density, the loss of the endothelium’s barrier function causes corneal edema. Damage to the endothelial cell layer therefore results in irreparable tissue damage that necessitates endothelial or penetrating keratoplasty.1 It is well established that FECD can affect multiple family members and that several genetic factors underlie the development of the disorder.5 However, the use of genetic approaches to identify the genes underlying the development of FECD is complicated by the late onset of the disease, so that parents and even siblings of the proband are often unavailable for study. In addition, younger individuals in a family may not clinically exhibit the disease because they may not be old enough to manifest the disorder. The first progress toward identifying gene mutations associated with familial FECD was provided by a rare subtype of FECD characterized by onset in early childhood. Early-onset FECD was found to be caused by a missense mutation, Q455K, in the COL8A2 gene (MIM: 120252), which encodes for the α2 subtype of collagen VIII, a major component of Descemet’s membrane. Three other missense mutations within COL8A2—R155Q, R304Q, and R434H—were found in patients with late-onset FECD, but their role remains uncertain, as R155Q has the same frequency in normal controls.6 Another mutation in COL8A2, L450W, that is believed to be pathogenic has been detected in a family with atypical FECD.7,8 Although mutations in COL8A2 have been linked to early-onset FECD, to date, mutations in the COL8A2 gene have not been associated with the much more common late-onset FECD.9–11 Heterozygous single nucleotide polymorphisms in the SLC4A11 gene on chromosome 20 (20p13) have recently been detected in four Chinese and Indian patients with the common phenotype of FECD,12 but they contribute to only ∼5% of the genetic burden of the disease. Family-based studies have mapped late-onset FECD susceptibility loci to 13ptel-13q12.1313 and 18q21.2-q21.32,14 in one and three large multigenerational FECD families, respectively. However, to date, there have been no FECD genetic linkage studies involving a large number of affected families. In this study, we performed the first whole-genome linkage scan for late-onset FECD in 22 families (linkage panel IV; Illumina, Inc., San Diego, CA).

The investigators reviewed the pathologic findings of 21 senile scleral plaques in 17 enucleated globes. Eyes were fixed in formalin and routinely processed for light microscopic examination. Two representative calcified scleral plaques were subjected to energy-dispersive x-ray microanalysis. Plaques were located in the sclera just anterior to the insertion of the horizontal rectus muscles. Microspic examination of the involved scleral disclosed a spectrum of histopathologic changes involving increased hematoxylinophilia of the scleral collagen, decreased stromal cellularity, the presence of scleral fibers with a unique corkscrew appearance, and calcium deposition. The calcified plaques contained calcium phosphate as indicated by histochemical methods and energy-dispersive x-ray microanalysis. Conjunctival elastosis was present in 12 of the 14 eyes in which sufficient conjunctiva was present for histologic evaluation. Accumulated actinic damage from solar irradiation may play a role in the pathogenesis of senile scleral plaques.

We evaluated the effect of corneal anesthesia produced by retrobulbar injections of bupivicaine and epinephrine on corneal neovascularization in the rat. The eyelids were sutured closed to prevent dessication and ulceration of the insensitive corneas. The amount of corneal neovascularization induced in animals receiving a retrobulbar anesthetic did not differ from those receiving control solutions. However, rats receiving retrobulbar injections exhibited greater corneal neovascularization than those that did not. Rats that had their eyelids sutured or patched closed also had more neovascularization than animals that did not. Likewise, rats that had sutures placed in the upper and lower eyelids, without palpebral immobilization, manifested more neovascularization than rats without sutures. These studies suggest that corneal anesthesia does not affect neovascularization induced by silver/potassium nitrate cauterization and that retrobulbar injections and eyelid closure enhance corneal neovascularization.

Several investigators have focused on the source of the angiogenic activity and progress is only now beginning in the assessment of the relative roles of the many potential participants in corneal angiogenesis. In theory the angiogenic factor(s) responsible for corneal vascularization could arise from one or more of the following sources: the denatured tissue, the injurious agent, corneal cells, cells of noncorneal origin, pericorneal vascular cells, serum, tears, or the aqueous humor.

Valuable insights into the pathogenesis of neovascularization in the cornea are gained by an understanding of circumstances that suppress and enhance angiogenesis in this tissue. Studies in a variety of experimental models have demonstrated a suppression of corneal neovascularization in leukopenic animals. Corneal angiogenesis induced by chemical cautery is severely suppressed under situations that inhibit the inflammatory response and most notably the leukocytic infiltration into the cornea. As described below, this occurs following treatment with corticosteroids, non-steroidal anti-inflammatory drugs and irradiation (head irradiation, total body irradiation, total lymphoid irradiation, and total body irradiation followed by bone marrow transplantation) Together these findings add further support to the hypothesis that corneal vascularization is a component of inflammation and that leukocytes play a cardinal role.

Numerous investigators have studied the ultrastructure of growing blood vessels has been studied in the cornea of the rat (377,666,667,736,737) and rabbit (504,505,728,817,818) but the chain of events that precedes and follows the induction of corneal neovascularization has been studied in relatively few experimental models (18,63,106,108,116,143,194,263–265,416,524,666,694). The endothelial cell-specific tubular organelles (Weibel-Palade bodies) that contain a specific glycoprotein involved in blood coagulation (von Willebrand factor) (523) have been observed in growing corneal blood vessels (326,504).

Many factors influence capillary growth and numerous theories have been proposed to account for the formation of new capillaries in different situations (114,649).

A wide variety of disorders of the cornea culminate in angiogenesis and a considerable amount of information has accumulated about the circumstances under which newly formed blood vessels sprout and extend centripetally into the cornea. In man corneal neovascularization complicates numerous infections (including trachoma, herpes simplex keratitis, leishmaniasis and onchocerciasis), immunologic processes (Stevens-Johnson’s syndrome, graft rejection), alkali burns, as well as traumatic, inflammatory, toxic and nutritional deficiency states and the wearing of some contact lenses (11,104,130,184,190,273,388,638,645). It is noteworthy that corneal vascularization is relatively uncommon in fungal keratitis (184).