Visual outcome following subretinal hemorrhage in Best disease.

PURPOSE: To review cases of Best disease associated with subretinal hemorrhage to better understand their long-term visual prognosis. SUBJECT AND METHODS: Patients were identified through the photographic file database at the University of Iowa. Seventy-eight files of patients with clinical evidence of Best disease were reviewed and 12 patients (14 eyes) were identified with subretinal hemorrhage. The visual acuity and clinical course were reviewed in all of these patients when possible. Three patients demonstrated subretinal hemorrhage on their last follow-up visit. Nine patients (11 eyes) were followed through to resolution of subretinal hemorrhage. Eight patients were screened on the VMD2 gene and all were found to have disease-causing sequence variations. RESULTS: All patients noted visual loss at presentation with subretinal hemorrhage (median 20/100; range 20/30-20/400). The median final visual acuity in the 11 eyes with follow-up was 20/50 (20/16-20/400 range). Ten of 11 eyes demonstrated improvement of vision with 9/11 having a final visual acuity of 20/50 or better. CONCLUSION: The natural history of patients with Best disease with subretinal hemorrhage and moderate visual loss is relatively good. The presence of subretinal hemorrhage in Best disease may be related to mild, incidental trauma.

Clinical and electroretinographic findings of female carriers and affected males in a progressive X-linked cone-rod dystrophy (COD-1) pedigree.

OBJECTIVE: To study the clinical and electroretinographic findings of affected males and female carriers in a family with X-linked cone-rod dystrophy (COD-1). DESIGN: Observational case series. PARTICIPANTS: Twenty-five members of a five-generation pedigree were examined. METHODS: A history of visual impairment including age at onset, loss of acuity, color vision abnormalities, photophobia, and nyctalopia was obtained. A complete ophthalmologic examination was performed, including kinetic perimetry with a Goldmann perimeter, FM 100-hue testing, and standardized Ganzfeld electroretinography following the ISCEV protocol. MAIN OUTCOME MEASURES: Patients were classified as affected or unaffected on the basis of the clinical examination. All carrier females had affected sons. RESULTS: Nine affected males and seven female carriers were identified. Affected males noted decreased visual acuity and poor color vision within the first two decades of life. Early in the disease, macular retinal pigment epithelial (RPE) changes were found that progressed to an atrophic macular scar by the fifth decade. Evidence of progression from macular pigment mottling to an atrophic macular lesion over a 13-year period was identified in one patient. The photopic, single-flash, b-wave amplitude was low in all affected males and declined with age. The 30-Hz flicker b-wave implicit times were abnormally prolonged in all affected males. Female carriers were asymptomatic although three had slightly abnormal color vision and small paracentral field defects and subtle RPE defects were found in three carriers. Carriers demonstrated prolongation of the 30-Hz flicker b-wave implicit time and interocular asymmetry. Five of seven carriers and two affected males demonstrated reduced oscillatory potentials and an abnormal-appearing flattened photopic a-wave. Five men and two women demonstrated a characteristic tapetal-like retinal sheen. CONCLUSIONS: Affected patients in this pedigree demonstrate early loss of visual acuity and poor cone function with late rod involvement. Female carriers may appear clinically normal or may be identified by subtle color vision defects, fundus abnormalities, prolongation of the 30-Hz flicker implicit time with interocular asymmetry, or an abnormal flattened photopic a-wave. Genetic linkage analysis of this family was recently reported and the disease-causing gene has been mapped to an approximately 1-Mb interval on chromosome Xp11.4.

Linkage analysis of X-linked cone-rod dystrophy: localization to Xp11.4 and definition of a locus distinct from RP2 and RP3.

Progressive X-linked cone-rod dystrophy (COD1) is a retinal disease affecting primarily the cone photoreceptors. The COD1 locus originally was localized, by the study of three independent families, to a region between Xp11.3 and Xp21.1, encompassing the retinitis pigmentosa (RP) 3 locus. We have refined the COD1 locus to a limited region of Xp11.4, using two families reported elsewhere and a new extended family. Genotype analysis was performed by use of eight microsatellite markers (tel-M6CA, DXS1068, DXS1058, DXS993, DXS228, DXS1201, DXS1003, and DXS1055-cent), spanning a distance of 20 cM. Nine-point linkage analysis, by use of the VITESSE program for X-linked disorders, established a maximum LOD score (17.5) between markers DXS1058 and DXS993, spanning 4.0 cM. Two additional markers, DXS977 and DXS556, which map between DXS1058 and DXS993, were used to further narrow the critical region. The RP3 gene, RPGR, was excluded on the basis of two obligate recombinants, observed in two independent families. In a third family, linkage analysis did not exclude the RPGR locus. The entire coding region of the RPGR gene from two affected males from family 2 was sequenced and was found to be normal. Haplotype analysis of two family branches, containing three obligate recombinants, two affected and one unaffected, defined the COD1 locus as distal to DXS993 and proximal to DXS556, a distance of approximately 1.0 Mb. This study excludes COD1 as an allelic variant of RP3 and establishes a novel locus that is sufficiently defined for positional cloning.

Autoimmune retinopathy in the absence of cancer.

PURPOSE: To report the clinical and immunologic features of two patients with progressive retinal degeneration and circulating antiretinal antibodies without systemic malignancy. METHODS: Two patients were followed up for 5 to 7 years. Comprehensive medical and ophthalmic examinations and visual function testing included manual perimetry and standardized electroretinography. Patient sera were tested for antiretinal antibodies by Western blot and immunoperoxidase indirect cytochemistry techniques. RESULTS: Two patients had family history of autoimmune disease. Each had severe monocular visual loss with photopsia, a ring scotoma, and abnormal electroretinogram despite a normal-appearing ocular fundus. One had a flat electroretinogram; the other had inner retina dysfunction, with selective b wave loss and abnormal oscillatory potentials. Both patients' sera had antiretinal antibodies that specifically labeled the inner plexiform layer of donor retina by indirect immunoperoxidase testing. Neither had any sign of cancer. CONCLUSIONS: In two patients without systemic malignancy, the symptoms, perimetric findings, and normal fundus appearance resembled cancer associated retinopathy. Electroretinography and antibody findings indicating dysfunction of the inner retina are distinct from those of cancer-associated retinopathy. These two cases raise the possibility of an autoimmune mechanism for retinal degeneration that is not cancer associated. Further study is necessary to determine the role of antiretinal antibodies in these patients.

Visual prognosis of multifocal choroiditis, punctate inner choroidopathy, and the diffuse subretinal fibrosis syndrome.

PURPOSE: To characterize the visual prognosis of patients with multifocal choroiditis and panuveitis (MCP), punctate inner choroidopathy (PIC), and the diffuse subretinal fibrosis (DSF) syndrome. METHODS: Forty-one patients with MCP, 16 with PIC, and 5 with DSF syndrome were evaluated. The mean follow-up was approximately 39 months for patients with MCP, 51 months for patients with PIC, and 59 months for patients with DSF syndrome. Complete ophthalmic examinations were performed, and photofiles were reviewed. RESULTS: The final average visual acuity for patients with MCP was 20/50. Forty-five of the 68 involved eyes (66%) had 20/40 visual acuity or better. Choroidal neovascularization (CNV) developed within choroiditis lesions in 22 (19 patients) of 68 eyes, causing visual acuity poorer than 20/50 in 14 eyes. The final average visual acuity in patients with PIC was 20/39; 23 (77%) of the 30 involved eyes had visual acuity of 20/40 or better. Six of the seven eyes with 20/50 or poorer vision had CNV. Six other eyes had CNV within the macula that regressed spontaneously with good resultant vision. Seven of the ten involved eyes with DSF syndrome had 20/200 or poorer vision. Poor vision was due to fibrosis and atrophy within the macula. CONCLUSION: Most patients with MCP and PIC retained visual acuity of 20/40 or better. In nearly one third of patients with MCP and PIC, CNV developed. Severe visual loss in these diseases was usually due to subfoveal CNV. Patients with DSF syndrome had a poor prognosis due to fibrosis and atrophy involving the macula.

Enlarged blind spots in chorioretinal inflammatory disorders.

PURPOSE: This study was undertaken to better characterize patients with multifocal choroiditis and panuveitis (MCP), punctate inner choroidopathy (PIC), multiple evanescent white dot syndrome (MEWDS), and diffuse subretinal fibrosis syndrome. The specific aim was to determine whether these disorders were different entities or part of a spectrum of diseases with similar features. METHODS: Seventy-nine patients were included in this study. Most of the patients have been followed up prospectively since July 1980 with some found retrospectively. RESULTS: Forty-one patients had MCP, 16 had PIC, 6 had diffuse subretinal fibrosis syndrome, and 16 had MEWDS. Patients with MCP had visual loss and visual field defects caused directly by visible lesions or recurrent inflammation around old lesions. In particular, clustering of lesions around the optic nerve and nasal periphery was seen in patients with MCP and appeared to be related to visual field loss. Patients with PIC also had enlarged blind spot and other field defects explained by fundus lesions. Patients with PIC and MCP did not have recurrent lesions on extended follow-up. Patients with diffuse subretinal fibrosis syndrome represented a subset of patients characterized with lesions in the posterior pole, sever scarring, and visual loss. Patients with MEWDS had the least inflammation with symmetrically distributed lesions. Minimal permanent chorioretinal scarring was seen in patients with MEWDS. Visual field defects improved in most patients with MEWDS and PIC, whereas most patients with MCP and diffuse subretinal fibrosis syndrome did not improve. CONCLUSIONS: Although enlarged blind spots are a feature of all four disorders, other clinical, angiographic, and electroretinographic evidence suggest that these are different entities.

The use of intravitreal tissue plasminogen activator in the treatment of experimental subretinal hemorrhage in the pig model.

PURPOSE: To clinically and surgically evaluate clot lysis in an animal model of subretinal hemorrhage after intravitreal injection of tissue plasminogen activator. METHODS: Autologous subretinal hemorrhages were created via a transvitreal approach in 18 pigs. The next day (day 1) animals were randomly selected to receive either an intravitreal injection of 0.1 mL balanced salt solution or 0.1 mL tissue plasminogen activator (25 micrograms) followed by observation or vitrectomy a day later. On day 2, six pigs (all treated with tissue plasminogen activator) underwent a vitrectomy in which aspiration of the subretinal hemorrhage was attempted. The other eyes were evaluated for clot lysis by ophthalmoscopy at days 3, 10, and 30. All eyes were examined histopathologically. RESULTS: The eyes that had been treated with tissue plasminogen activator demonstrated a color change at the peripheral margin, which suggested that clot lysis had occurred. At the time of the vitrectomy, the clots were liquefied partially; removal by aspiration alone, however, was not possible. Photoreceptor damage was moderate to severe by day 10 in all eyes, whether they were treated with tissue plasminogen activator or balanced salt solution. All eyes that underwent vitrectomy had moderate to severe photoreceptor damage. CONCLUSIONS: In this animal model, intravitreal tissue plasminogen activator was associated with features that suggested partial clot lysis; tissue plasminogen activator did not produce sufficient lysis to allow surgical removal by aspiration alone, however.

Genetic linkage of Wagner disease and erosive vitreoretinopathy to chromosome 5q13-14.

BACKGROUND: Wagner disease and erosive vitreoretinopathy are potentially blinding autosomal dominant diseases that share some similarities with Stickler syndrome. However, both disorders have associated retinal pigment epithelial changes, poor night vision, visual field defects, and abnormal electroretinographic findings, which are not found in families with COL2A1-associated Stickler syndrome. In addition, rhegmatogenous retinal detachments are uncommon in Wagner disease but occur in approximately 50% of patients with either Stickler syndrome or erosive vitreoretinopathy. OBJECTIVES: To identify the chromosomal location of the genes involved in Wagner disease and erosive vitreoretinopathy and to distinguish these conditions genetically from Stickler syndrome. METHODS: Fifteen affected members of a family affected with erosive vitreoretinopathy and 24 affected descendants of the pedigree described by Wagner were genotyped with a set of short tandem repeat polymorphisms distributed across the genome. RESULTS: Significant linkage was observed in each family between the disease phenotype and markers that map to chromosome 5q13-14. The highest lod score for the family affected with erosive vitreoretinopathy was 4.2 and was obtained with marker GATA3H06 (theta = 0). The highest lod score for the family affected with Wagner disease was 5.8 and was obtained with marker D5S815 (theta = 0). A candidate gene (cartilage link protein) that is known to lie near the linked interval was screened for mutations, but none was found in either family. CONCLUSIONS: These data suggest that erosive vitreoretinopathy and Wagner disease are allelic disorders and demonstrate that they are genetically distinct from COL2A1-associated Stickler syndrome.

Ocular findings associated with a Cys39Arg mutation in the Norrie disease gene.

OBJECTIVE: To diagnose the carriers and noncarriers in a family affected with Norrie disease based on molecular analysis. DESIGN: Family members from three generations, including one affected patient, two obligate carriers, one carrier identified with linkage analysis, one noncarrier identified with linkage analysis, and one female family member with indeterminate carrier status, were examined clinically and electrophysiologically. Linkage analysis had previously failed to determine the carrier status of one female family member in the third generation. Blood samples were screened for mutations in the Norrie disease gene with single-strand conformation polymorphism analysis. The mutation was characterized by dideoxy-termination sequencing. RESULTS: Ophthalmoscopy and electroretinographic examination failed to detect the carrier state. The affected individuals and carriers in this family were found to have a transition from thymidine to cytosine in the first nucleotide of codon 39 of the Norrie disease gene, causing a cysteine-to-arginine mutation. Single-strand conformation polymorphism analysis identified a patient of indeterminate status (by linkage) to be a noncarrier of Norrie disease. CONCLUSION: Ophthalmoscopy and electroretinography could not identify carriers of this Norrie disease mutation. Single-strand conformation polymorphism analysis was more sensitive and specific than linkage analysis in identifying carriers in this family.

Electrophysiology testing and the ophthalmic registered nurse.

Ophthalmologists employ electrophysiologic testing to diagnose and manage a variety of ocular conditions. The most common reason these tests are performed is to diagnose inherited vitreoretinal diseases. Patients of all ages may require electrophysiologic testing. The purpose of this article is to provide the ophthalmic registered nurse with a working knowledge of the three most commonly used electrophysiologic tests. We will provide background and practical information on how we perform electroretinography (ERG), electroculography (EOG), and dark adaptometry. Knowledge of the basics of this specialized testing will allow the ophthalmic nurse to provide more information for the patient. This knowledge will hopefully reduce patient anxiety and with better cooperation produce more accurate test results.

RDS gene mutations causing retinitis pigmentosa or macular degeneration lead to the same abnormality in photoreceptor function.

PURPOSE: To investigate functional abnormalities in mutations in the peripherin (RDS) gene leading to different clinical types of autosomal dominant retinal disease--macular degeneration and retinitis pigmentosa. METHODS: Patients from two families, one with a mutation in codon 167 (Gly167Asp) leading to macular degeneration and another with a mutation in codon 210 (Pro210Ser) leading to retinitis pigmentosa, were studied with clinical examinations and measurements of rod and cone sensitivities and dark adaptation, electroretinography, and rhodopsin levels. RESULTS: Mildly affected patients had sizable rod and cone electroretinograms, reduced levels of rhodopsin, and minor losses of sensitivity. In both mutations, there were delays of rod and cone dark adaptation after bleaching, and the adaptational abnormalities were observed in peripheral and central retinal locations. Analysis of the kinetics of rod adaptation indicates that the underlying abnormalities are similar in both mutations and that the effects of the mutations are similar to those caused by mild systemic vitamin A deficiency. CONCLUSIONS: Patients with the Gly167Asp and Pro210Ser mutations in the peripherin/RDS gene have widely different clinical phenotypes but show the same abnormality, slowed dark adaptation, of rod and cone photoreceptor function. The similarities of the characteristics of the adaptational abnormalities in the two genotypes suggest that, in addition to the structural roles normally assumed for it, peripherin influences or participates in the function of the visual cycle.

Clinical features of a Stargardt-like dominant progressive macular dystrophy with genetic linkage to chromosome 6q.

BACKGROUND AND OBJECTIVE: We identified a large family affected with a macular dystrophy whose main clinical features are similar to those of Stargardt's disease. Unlike true Stargardt's disease, the disorder in this family is inherited in an autosomal dominant fashion. We sought to identify the chromosomal location of the disease-causing gene and to clinically define the phenotype in a number of affected family members. METHODS: Thirty-two family members underwent clinical examination. A total of 23 affected family members were identified, and these patients were genotyped at candidate loci with short tandem repeat polymorphisms. The LINKAGE computer program was used for linkage calculations. RESULTS: Affected patients had normal vision in early childhood but began to experience difficulty with central vision between 5 and 23 years of age. Fundus examination early in the disease course revealed flecks in the macula. Central atrophy developed later, with visual acuity decreasing to 20/200 or worse in all patients older than 31 years. Fluorescein angiography revealed no evidence of choroidal silence. Electroretinograms were near normal in younger affected individuals and were most notable for prolonged implicit times in a 73-year-old patient. Chromosome linkage analysis revealed the disease-causing gene to be located near the centromere on the long arm of chromosome 6. The maximum lod score was 5.5 (theta = 0) with marker D6S280. Multipoint analysis resulted in a peak lod score of 6.2 in the interval between markers D6S313 and D6S252 and excluded the interval containing the North Carolina macular dystrophy gene. CONCLUSIONS: This autosomal dominant macular dystrophy is clinically similar to Stargardt's disease, with the exception of its pattern of inheritance. The clearly progressive nature of the disease distinguishes it from North Carolina macular dystrophy, whose causative gene is also located on the long arm of chromosome 6. Identification of the gene involved in this disease may provide clues to the pathogenesis of age-related macular degeneration.

Erosive vitreoretinopathy. A new clinical entity.

PURPOSE: Vitreoretinopathies are disorders characterized by an abnormal vitreous gel structure and associated retinal changes. The authors report a pedigree with vitreous changes characteristic of the vitreoretinopathies, but with retinal pigment epithelial changes, electroretinographic abnormalities, and a clinical course distinct from previously described entities. METHODS: Twenty-six family members were examined. Complete ophthalmologic examinations, electroretinography, and perimetry were performed on patients who were at genetic risk for the disease. Particular attention was given to vitreous morphology and examination of the retinal and retinal pigment epithelium (RPE). RESULTS: Fifteen individuals affected with an autosomal dominant vitreoretinal degeneration were identified. The disease is characterized by nyctalopia, progressive visual field loss, marked vitreous syneresis, progressive RPE atrophy, and combined traction-rhegmatogenous retinal detachments (11 patients). Thinning or "erosion" of the RPE in younger patients permits increased visualization of the choroidal vessels. In advanced conditions, equatorial areas are seen that appear clinically devoid of RPE, with extensive posterior atrophy in older patients. Diffuse rod-cone dysfunction is demonstrated by electroretinography. High myopia, epiphyseal dysplasia, orofacial anomalies, and systemic manifestations characteristic of other vitreoretinopathies are not present. CONCLUSION: The authors describe an entity clinically distinct from other vitreoretinopathies. The disease is characterized by pronounced vitreous abnormalities, complicated retinal detachments, and a progressive pigmentary retinopathy. The most unusual and constant feature is the progressive change in RPE with concurrent visual field constriction and electroretinographic abnormalities. Because the RPE initially seems normal and progressively thins or "erodes" in the equatorial periphery, the descriptive name "erosive" vitreoretinopathy is proposed.

Butterfly-shaped pigment dystrophy of the fovea caused by a point mutation in codon 167 of the RDS gene.

Butterfly-shaped pigment dystrophy of the fovea is an autosomal dominant eye disease characterized by a bilateral accumulation of yellowish or pigmented material at the level of the retinal pigment epithelium. It shares some clinical and histopathologic features with age related macular degeneration which is the most common cause of legal blindness in older patients. We screened affected patients from a three generation family with butterfly dystrophy for mutations in candidate genes. A base substitution was identified in the peripherin (RDS) gene and DNA sequencing revealed a G to A transition in codon 167 that substitutes aspartic acid for a highly conserved glycine. The mutation segregates with the disease phenotype (Zmax = 4, theta = 0) strongly suggesting that it causes the macular disease in this family.