Search

To determine the extent of visual acuity and visual field impairment in patients with types 1 and 2 Usher syndrome.The records of 53 patients with type 1 and 120 patients with type 2 Usher syndrome were reviewed for visual acuity and visual field area at their most recent visit. Visual field areas were determined by planimetry of the II4e and V4e isopters obtained with a Goldmann perimeter. Both ordinary and logistic regression models were used to evaluate differences in visual acuity and visual field impairment between patients with type 1 and type 2 Usher syndrome.The difference in visual acuity of the better eye between patients with type 1 and type 2 varied by patient age (P=.01, based on a multiple regression model). The maximum difference in visual acuity between the 2 groups occurred during the third and fourth decades of life (with the type 1 patients being more impaired), while more similar acuities were seen in both younger and older patients. Fifty-one percent (n=27) of the type 1 patients had a visual acuity of 20/40 or better in at least 1 eye compared with 72% (n=87) of the type 2 patients (age-adjusted odds ratio, 3.9). Visual field area to both the II4e (P=.001) and V4e (P.001) targets was more impaired in the better eye of type 1 patients than type 2 patients. A concentric central visual field greater than 20 degrees in at least 1 eye was present in 20 (59%) of the available 34 visual fields of type 1 patients compared with 70 (67%) of the available 104 visual fields of type 2 patients (age-adjusted odds ratio, 2.9) with the V4e target and in 6 (21%) of the available 29 visual fields of type 1 patients compared with 36 (38%) of the available 94 visual fields of type 2 patients (age-adjusted odds ratio, 4.9) with the II4e target. The fraction of patients who had a visual acuity of 20/40 or better and a concentric central visual field greater than 20 degrees to the II4e target in at least 1 eye was 17% (n=5) in the type 1 patients and 35% (n=33) in the type 2 patients (age-adjusted odds ratio, 3.9).Visual acuity and visual field area were more impaired in patients with type 1 than type 2 Usher syndrome. Of note, 27 of 53 type 1 (51%) and 87 of 120 type 2 (72%) patients had a visual acuity of 20/40 or better in at least 1 eye. These data are useful for overall counseling of patients with Usher syndrome.

Objective To determine the safety and efficacy of subretinal gene therapy in the RPE65 form of Leber congenital amaurosis using recombinant adeno-associated virus 2 (rAAV2) carrying the RPE65 gene. Design Open-label, dose-escalation phase I study of 15 patients (range, 11-30 years of age) evaluated after subretinal injection of the rAAV2- RPE65 vector into the worse-functioning eye. Five cohorts represented 4 dose levels and 2 different injection strategies. Main outcome measures Primary outcomes were systemic and ocular safety. Secondary outcomes assayed visual function with dark-adapted full-field sensitivity testing and visual acuity with Early Treatment Diabetic Retinopathy Study charts. Further assays included immune responses to the vector, static visual fields, pupillometry, mobility performance, and optical coherence tomography. Results No systemic toxicity was detected; ocular adverse events were related to surgery. Visual function improved in all patients to different degrees; improvements were localized to treated areas. Cone and rod sensitivities increased significantly in the study eyes but not in the control eyes. Minor acuity improvements were recorded in many study and control eyes. Major acuity improvements occurred in study eyes with the lowest entry acuities and parafoveal fixation loci treated with subretinal injections. Other patients with better foveal structure lost retinal thickness and acuity after subfoveal injections. Conclusions Gene therapy for Leber congenital amaurosis caused by RPE65 mutations is sufficiently safe and substantially efficacious in the extrafoveal retina. There is no benefit and some risk in treating the fovea. No evidence of age-dependent effects was found. Our results point to specific treatment strategies for subsequent phases. Application to clinical practice Gene therapy for inherited retinal disease has the potential to become a future part of clinical practice. Trial registration clinicaltrials.gov Identifier: NCT00481546.

Objective To investigate whether mutations in NPHP5 can cause Leber congenital amaurosis (LCA) without early-onset renal disease. Methods DNA samples from 276 individuals with nonsyndromic LCA were screened for variations in the NPHP5 gene. Each had been previously screened for mutations in 8 known LCA genes without identifying a disease-causing genotype. Results Nine of the 276 LCA probands (3.2%) harbored 2 plausible disease-causing mutations (7 different alleles) in NPHP5 . Four of these have been previously reported in patients with Senior-Loken syndrome (F141del, R461X, H506del, and R489X) and 3 are novel (A111del, E346X, and R455X). All 9 patients had severe visual loss from early childhood but none had overt renal disease in the first decade of life. Two patients were diagnosed with nephronophthisis in the second decade. Retinal imaging studies showed retained photoreceptor nuclei and retinal pigment epithelium integrity mainly in the cone-rich central retina, a phenotype with strong similarities to that of NPHP6 disease. Conclusions Mutations in NPHP5 can cause LCA without early-onset renal disease. Abnormalities observed in the photoreceptor outer segments (a cilial structure) may explain the severe visual loss in NPHP5 -associated LCA. Clinical Relevance The persistence of central photoreceptor nuclei despite severe visual loss in NPHP5 disease is encouraging for future therapeutic interventions.

Objectives To describe the phenotype and determine the genetic cause of autosomal dominant retinitis pigmentosa (adRP) in a large African American family. Methods Fourteen members from 4 generations were evaluated clinically. Visual field measurements were made for most, and electroretinography, Tubinger perimetry, and optical coherence tomographic testing were done for individual family members. Genetic screening was performed on a recently introduced adRP microarray that contains approximately 400 mutations from 13 genes. Results All of the affected members had a type 1 form of adRP, characterized by early onset of symptoms for visual impairment, marked central and peripheral vision loss, nondetectable electroretinographic responses, and decreased macular thickness on optical coherence tomographic testing. Two variants in the PRPF8 gene were identified in the proband, H2309R and IVS41-4G→A. The H2309R mutation segregated with the disease in the family, whereas the IVS41-4G→A variant did not. Conclusions The severe form of adRP was caused by the PRPF8 H2309R variant, whereas the IVS41-4G→A variant was benign. Clinical Relevance PRPF8 mutations should be suspected in patients with a type 1 form of adRP. A combination of advanced clinical workup and comprehensive genetic testing is essential for the precise diagnosis of diseases with high genetic heterogeneity such as RP.

Objective To evaluate the molecular genetic defects associated with retinitispunctata albescens (RPA) in 5 patients from 3 families with this disease. Methods We examined 3 probands and 2 clinically affected relatives with RPA.Clinical examinations included best-corrected visual acuity, visual fieldtesting, electroretinography, dilated fundus examination, and fundus photography.Leukocyte DNA was analyzed for mutations in the exons of the genes encodingcellular retinaldehyde–binding protein 1 ( RLBP1 ),11- cis -retinol dehydrogenase ( RDH5 ), interphotoreceptor retinoid–binding protein ( RBP3 ), and photoreceptor all- trans -retinoldehydrogenase ( RDH8 ). Not all patients were evaluatedfor mutations in each gene. The exons were individually amplified and screenedfor mutations by single-stranded conformational polymorphism analysis or directgenomic sequencing. Results The 3 probands had similar clinical findings, including a history ofpoor night vision, the presence of punctate white deposits in the retina,and substantially reduced or absent rod responses on electroretinogram testing.One of the probands (patient 2:III:2) had 2 novel mutations in the RLBP1 gene (Arg151Trp and Gly31[2–base pair deletion], [GGA→G–]).Segregation analysis showed that the 2 mutations were allelic and that thepatient was a compound heterozygote. Both parents of the proband manifestedround white deposits in the retina. The other 2 probands had no detected pathogenicmutations in RLBP1 or in the other 3 genes evaluated. Conclusions The identification of novel RLBP1 mutationsin 1 of our 3 probands, all with RPA, is further evidence of genetic (nonallelic)heterogeneity in this disease. The presence of round white deposits in theretina may be observed in those heterozygous for RLBP1 . Clinical Relevance Patients with a clinical presentation of RPA can have genetically differentmutations. Drusen-like lesions may be observed in heterozygotes in familieswith this disease and a mutation in RLBP1 .

Objective To identify sequence variations in theABCA4gene in a cohort of patients with autosomal recessive cone-rod dystrophy. Methods The coding sequences of theABCA4gene were analyzed in 30 unrelated probands. In those patients with plausible disease-causing variations, correlations were made between genotype and fundus phenotype as well as with electrophysiological and visual field findings. Results Sixteen (53%) of 30 probands were found to harbor plausible disease-causing variations in theABCA4gene. Two distinctly different fundus phenotypes were observed in our cohort of patients. Twelve patients showed diffuse pigmentary degenerative changes, whereas 4 showed either no pigmentary changes or only a mild degree of peripheral pigment degeneration. An associa-tion between certain sequence variations and each of these 2 different phenotypes was observed. Conclusions Our findings confirm that a substantial percentage of patients with autosomal recessive cone-rod dystrophy are likely to harbor a mutation in theABCA4gene as the cause of their disease. The fundus phenotype observed in such patients is quite variable, and certain fundus phenotypes may be more associated with certain genotypes. Clinical Relevance Identification of the molecular genetic basis for various inherited human retinal dystrophies, such as cone-rod dystrophy, facilitates a potentially better understanding of the mechanisms by which photoreceptor cells degenerate. This in turn provides guidance as to how to better proceed in identifying the most optimal future therapeutic strategies.

Background: Leber congenital amaurosis (LCA) is an infrequently encountered congenital form of retinitis pigmentosa with marked genetic and clinical heterogeneity. Thus far, 10 genes have been identified in this disorder since 1996. In the future, LCA may become treatable by gene and/or pharmacological intervention, and these therapies will likely be gene specific, giving major significance to rapid gene identification and genephenotype studies. Objective: To test the hypothesis that parents of patients with LCA have identifiable electroretinographic and psychophysical changes. Subjects, Materials, and Methods: Complete eye examinations and electroretinographic studies were performed on 2 sets of parents whose offspring were diagnosed as having LCA and who were found to carry a mutation in 1 of the 10 LCA genes - GUCY2D. One set of parents also underwent static perimetry threshold measurements. Results: We found that single flash-light-adapted a- and b-wave amplitudes, 30-Hz flicker, or both cone signals were significantly decreased in amplitude in 4 heterozygotes, while 2 parents showed delayed 30-Hz flicker implicit times. Electroretinographic rod-mediated signals were normal in 2 of the heterozygotes, but subnormal in 2. Static perimetry testing showed normal thresholds in the 2 heterozygotes tested. Main Outcome Measures: Single flash-light-adapted a- and b- wave amplitudes and implicit times, 30- or 32-Hz flicker amplitudes and implicit times, rod-mediated signals, and dark-adapted, rod-mediated thresholds. Conclusions: Some carrier parents of patients with LCA and a GUCY2D mutation develop measurable, cone and possibly rod abnormalities most consistent with a mild conerod dysfunction. This correlates well with the known retinal expression pattern of GUCY2D, which is considerably higher in cone compared with rod photoreceptor cells.

Objective To report the spectrum of ophthalmic findings in patients with Stargardt dystrophy or fundus flavimaculatus who have a specific sequence variation in the ABCR gene. Patients Twenty-nine patients with Stargardt dystrophy or fundus flavimaculatus from different pedigrees were identified with possible disease-causing sequence variations in the ABCR gene from a group of 66 patients who were screened for sequence variations in this gene. Methods Patients underwent a routine ocular examination, including slitlamp biomicroscopy and a dilated fundus examination. Fluorescein angiography was performed on 22 patients, and electroretinographic measurements were obtained on 24 of 29 patients. Kinetic visual fields were measured with a Goldmann perimeter in 26 patients. Single-strand conformation polymorphism analysis and DNA sequencing were used to identify variations in coding sequences of the ABCR gene. Results Three clinical phenotypes were observed among these 29 patients. In phenotype I, 9 of 12 patients had a sequence change in exon 42 of the ABCR gene in which the amino acid glutamic acid was substituted for glycine (Gly1961Glu). In only 4 of these 9 patients was a second possible disease-causing mutation found on the other ABCR allele. In addition to an atrophic-appearing macular lesion, phenotype I was characterized by localized perifoveal yellowish white flecks, the absence of a dark choroid, and normal electroretinographic amplitudes. Phenotype II consisted of 10 patients who showed a dark choroid and more diffuse yellowish white flecks in the fundus. None exhibited the Gly1961Glu change. Phenotype III consisted of 7 patients who showed extensive atrophic-appearing changes of the retinal pigment epithelium. Electroretinographic cone and rod amplitudes were reduced. One patient showed the Gly1961Glu change. Conclusions A wide variation in clinical phenotype can occur in patients with sequence changes in the ABCR gene. In individual patients, a certain phenotype seems to be associated with the presence of a Gly1961Glu change in exon 42 of the ABCR gene. Clinical Relevance The identification of correlations between specific mutations in the ABCR gene and clinical phenotypes will better facilitate the counseling of patients on their visual prognosis. This information will also likely be important for future therapeutic trials in patients with Stargardt dystrophy.

Objectives: To assess the level of perceived difficulty experienced by patients with retinitis pigmentosa (RP) in the performance of everyday activities and to determine the correlation between patients' self-reported difficulty and clinical measures of visual function. Methods: One hundred sixty-seven patients with typical RP and Usher syndrome type 2, with a wide range of disease severity, rated their difficulty in the performance of 33 activities. We obtained data on visual acuity and visual field area for all patients, and electroretinogram (ERG) recordings on a subgroup of 49 of these patients. Results from the questionnaire were analyzed with factor analysis, and patients' self-reports were compared with their clinical data using correlational analyses and multiple regression. Results: The patients' questionnaire responses clustered into 6 factors: activities involving central vision, miscellaneous activities (no discernible common factor), activities related to mobility, driving, negotiating steps, and eating meals. Of the clinical tests, visual acuity was most strongly related to the patients' ratings of their difficulty in performance. Visual field area also was related to patients' self-assessments but not as strongly as visual acuity. Because visual field area and the ERG measures were correlated, adding ERG information did not improve predictability. Conclusions: In patients with RP, perceived difficulty in performing common tasks was most strongly related to level of visual acuity and visual fields. Although certain ERG amplitude measures did show positive correlations with some self-reported activities, overall, the ERG amplitude measures showed the least relationship with patients' self-reports. Our results provide insight into RP patients' perceived difficulties in performing everyday activities and the clinical measures of visual function that most highly correlate with these difficulties.

Objective: To determine the effects of age and central vision loss on driving skills. Methods: Ten subjects with age-related macular degeneration and average binocular visual acuity of 20/70, and 11 age-similar subjects with normal vision, were examined with a battery of cognitive and visual tests, an interactive driving simulator, and an on-road driving test. Data were collected on the frequency of real-world accidents and convictions for traffic violations. Results: There were no significant differences between the two groups on any of the cognitive tests. The age-related macular degeneration group demonstrated poorer performance on the driving simulator, including delayed braking response times to stop signs, slower speeds, and more of both lane boundary crossings and simulator accidents. The age-related macular degeneration group also demonstrated poorer overall on-road test performance, including having significantly more points deducted for driving too slowly and for not maintaining proper lane position. However, these effects on the simulator and the on-road test did not translate into an increased risk of real-world accidents for the age-related macular degeneration group. Significantly more control subjects than patients with age-related macular degeneration were involved in self-reported accidents, and significantly more control subjects had state convictions for traffic violations. There was evidence of compensation in the age-related macular degeneration group in four major areas: (1) not driving in unfamiliar areas; (2) traveling at slow speeds; (3) self-restricting their nighttime driving, and (4) taking fewer risks while driving (eg, not changing lanes). There was also evidence of compensation in the older control group. Conclusions: Vision, simulator, and on-road test variables combined with subjective risk taking predicted self-reported real-world accidents in a logistic regression analysis. However, risk taking, rather than simulator or road-test performance, was the most significant predictor for both patients with age-related macular degeneration and the control group.

Purpose: To evaluate possible differences in the prevalence of clinically detectable foveal lesions between patients with type 1 and type 2 Usher's syndrome. Methods: Records of 48 patients with type 1 and 98 patients with type 2 Usher's syndrome were retrospectively evaluated for the presence of a foveal lesion. The age, gender, and racial distribution of patients were similar in the two subtypes. Two investigators reviewed fundus photographs from all patients and, when available, fluorescein angiograms. Results: In the 48 patients with type 1 Usher's syndrome, 30 (62%) showed a clinically apparent atrophic- or cystic-appearing foveal lesion, whereas in the 98 patients with type 2 Usher's syndrome, 33 (34%) had either an atrophic- or a cystic-appearing foveal lesion. Logistic regression analysis showed that the probability of exhibiting a foveal lesion in both type 1 and type 2 Usher's syndrome increases with age and that patients with type 1 Usher's syndrome are more likely to have a foveal lesion than are patients with type 2 Usher's syndrome. Conclusions: Patients with type 1 Usher's syndrome show a greater probability of having either an atrophicor cystic-appearing foveal lesion than do patients with type 2 Usher's syndrome. This higher prevalence of foveal lesions is consistent with a previous observation that the severity of visual acuity impairment with age is greater for patients with type 1 than type 2 Usher's syndrome. These data are useful in counseling such patients as to their prognosis for central visual function.

Purpose: To assess the effect of methazolamide on chronic macular edema in patients with retinitis pigmentosa in a double-masked, placebo-controlled, crossover study. Three subjects who had an initial improvement in their macular edema as demonstrated on fluorescein angiography received a continued course of methazolamide to assess its effect on macular edema. Methods: Seventeen subjects were enrolled in the initial study. On angiography, nine subjects demonstrated improvement in their macular edema with the use of methazolamide for 3 weeks; three of these continued receiving the drug at a dosage of 50 mg twice daily for either an additional 6 (one subject) or 12 (two subjects) weeks. All subjects were assessed at each visit with fluorescein angiography and on best corrected visual acuity, both undilated and dilated; a subjective impression was also documented. Results: After 6 and 12 weeks of treatment, all three subjects experienced a rebound of angiographic macular edema to some extent. The visual acuity varied only slightly (up to 7 letters) from both the baseline and most recent examinations after 6 and 12 weeks of treatment. Conclusion: Results from these few subjects suggest that at least a partial rebound of macular edema seen angiographically may occur with the continued use of methazolamide in patients with retinitis pigmentosa and chronic macular edema. Further study is required to determine if this rebound effect also occurs in treatment of other ocular disorders with chronic macular edema.

• Three members of one family and one person from another family were found to have a guanine-to-adenine transition mutation in the first nucleotide of codon 106 in the rhodopsin gene that results in a glycine-to-arginine change. All affected members presented with a similar phenotype that included a regional predilection for pigmentary changes to occur in the inferior retina as well as visual field impairment predominantly in the superior hemisphere. The distribution of pigmentary changes, pattern of visual field loss, and substantial remaining electroretinographic amplitudes with normal implicit times were consistent with a form of "sector" retinitis pigmentosa. We documented the association of a distinct phenotype of autosomal dominant retinitis pigmentosa with a better visual prognosis and a specific rhodopsin gene mutation.

• Six members of a family with autosomal dominant retinitis pigmentosa were found to have a cytosine-to-thymine transition mutation in the second nucleotide of codon 17 in the rhodopsin gene that resulted in a threonine to methionine change. Three members from another family with autosomal dominant retinitis pigmentosa showed a guanine-to-adenine transition mutation in the first nucleotide of codon 182 in the rhodopsin gene that resulted in a glycine to serine change. Each of these two mutations presented with a similar phenotype because both showed a regional predilection for pigmentary changes to occur in the inferior part of the retina as well as field impairment predominantly in the superior hemisphere. Electroretinographic amplitudes were more substantial than usually encountered in other forms of retinitis pigmentosa, a finding consistent with the better visual prognosis in patients with either of these two mutations. This article documents the association of two similar phenotypes of autosomal dominant retinitis pigmentosa with specific gene defects at a molecular level.

• Of 31 patients with retinitis pigmentosa, 18 (58%) had lesions of the retinal pigmentary epithelium within the maculae of both eyes. Six of the 31 patients (19%) showed macular cysts or holes (five bilateral, one unilateral) without angiographic evidence of leakage from perifoveal capillaries, while seven patients (23%) had macular cysts in both eyes associated with cystoid macular edema evident by fluorescein angiography. We believe that the macular cysts or holes were caused by changes at the vitreoretinal interface, eg, vitreous traction and preretinal membranes. Other pathologic sequences may also be responsible, such as an intrinsic increase in the permeability of retinal capillaries. (Arch Ophthalmol95:798-803, 1977)

• Sperm of patients with X-linked retinitis pigmentosa (RP) was studied to assess the state of the axoneme in this genetic subtype. Semen samples were collected from eight patients with X-linked RP and compared with a database of 31 controls. Semen was also collected from two patients with other retinal degenerations (choroideremia and fundus flavimaculatus) and patients with simplex RP. All controls and patients were studied under a masked protocol. There was a significant increase in the percentage of abnormal sperm tails at both the light and electron microscopic levels in patients with X-linked RP only. Thus, X-linked RP is associated with an alteration in sperm axoneme structure. Sperm cell analysis may serve as a useful model system for additional investigations into the pathogenesis of this disease.

• Postmortem donor eyes from a 69-year-old man with Best's vitelliform macular dystrophy showed retinal pigment epithelial cells across the entire fundus that had accumulated an excessive amount of lipofuscin as defined by ultrastructural appearance, autofluorescence studies, and staining properties. Lipofuscin accumulation was particularly notable in some pigment epithelial cells in the fovea. An accumulation of heterogeneous material located between Bruch's membrane and the pigment epithelium in the fovea was believed to represent the location of a previtelliform lesion. This material appeared to be derived from degenerating pigment epithelial cells and contained few intact lipofuscin granules. Foveal photoreceptor loss occurred above the lesion and in midperipheral sites where the subretinal space contained collections of outer segment debris and phagocytic cells. Best's vitelliform macular dystrophy appears to be a generalized disorder of the pigment epithelium that secondarily affects focal areas of the retina.

• Using a life-table analysis, visual acuity loss with age was determined for a population of 106 patients with type 1 (N = 35) and type 2 (N = 71) Usher's syndrome. The cumulative percentage of patients maintaining visual acuity of 6/12 (20/40) or better in at least one eye by age 29 years was 69% for type 1 patients and 94% for type 2 patients. The cumulative percentage maintaining visual acuity of 6/24 (20/80) or better at this age was 89% for type 1 and 98% for type 2 patients. Within each subtype, the cumulative percentage maintaining 6/60 (20/ 200) or better was similar to the percentage maintaining 6/24 (20/80) or better. Knowledge of these data provides an objective basis for counseling patients with Usher's syndrome about their probability of developing loss of central visual acuity with age.

• We assessed blood-retinal barrier function by vitreous fluorophotometry in 24 patients with either cone or cone-rod dystrophy who were segregated into three subgroups. Compared with a normal population, the patients demonstrated increased vitreous fluorescence (breakdown of the blood-retinal barrier) that positively correlated with peripheral pigmentary changes and an appreciable reduction in electroretinographic scotopic b-wave amplitude. A unique subgroup of three women with supernormal electroretinographic scotopic b-wave amplitudes to a high-intensity stimulus had an abnormal increase in permeability of the blood-retinal barrier even without peripheral pigmentary fundus changes.

• There is electrophysiologic evidence that photoreceptors have normal visual pigment density (outer segment length) at a stage of ocular siderosis when the photoreceptor membrane function is defective. The early receptor potentials (ERPs) from two patients showed normal amplitudes, although the electroretinograms (ERGs) had reduced a- and b-waves for both cone and rod ERG responses. Since the ERP is generated by photolysis of visual pigment and requires orientation of the pigment molecules by outer segment disc membranes, the normal ERP amplitudes suggest that the photoreceptor outer segments have normal photopigment density, are of normal length, and are properly oriented. However, the transduction mechanism that converts visual pigment photolysis into membrane electrical potentials (the ERG a wave) is defective at this stage of ocular siderosis.

Autosomal dominant vitreoretinochoroidopathy is a newly described fundus dystrophy characterized by abnormal chorioretinal hypopigmentation and hyperpigmentation, usually lying between the vortex veins and the ora serrata for 360 degrees. In this zone, there are a discrete posterior boundary, preretinal punctate white opacities, retinal arteriolar narrowing and occlusion, and, in some cases, choroidal atrophy. Most affected family members have diffuse retinal vascular incompetence, cystoid macular edema, and presenile cataracts. The vitreous is characterized by fibrillar condensation and a moderate number of cells. Electroretinograms are normal in younger affected individuals and are only moderately abnormal in older ones. Preretinal neovascularization, present in the posterior pole, is progressive in the proband. There are no identifiable systemic or skeletal abnormalities, high myopia, optically empty vitreous, lattice degeneration, areas of white-without-pressure, retinal breaks, or retinal detachment; thus, previously described vitreoretinopathies can be excluded from diagnostic consideration. Progression of this diagnostic seems to be extremely slow in most family members.

To determine the relationship of foveal absolute thresholds to visual acuity in retinitis pigmentosa, we measured thresholds in 40 patients with various forms of retinitis pigmentosa (including Usher's syndrome) whose Snellen visual acuities were 20/30 or better. At all visual acuity levels, the patients' foveal thresholds were significantly higher than those of 20 similarly aged normal observers; threshold elevations tended to be greater for a 500-nm than for a 655-nm test flash. Foveal cone spatial summation functions were normal (test flash diameter range, 7' to 1.7 degrees), indicating that the patients' threshold elevations did not result from altered summation properties. A significant correlation between foveal cone thresholds and the midpoints of the patients' Rayleigh matches demonstrated that the threshold elevations resulted in part from a decreased cone optical density.

• The function of the blood-retinal barrier was assessed by vitreous fluorophotometry in 12 patients with various genetic types of retinitis pigmentosa and in 11 normal subjects. The measurements were corrected to minimize the effect of artifacts. We evaluated the inward penetration of fluorescein sodium across the blood-retinal barrier and determined the outward permeability coefficient for fluorescein by interpreting the data with a pharmacokinetic computer model. Patients with retinitis pigmentosa had increased inward permeability and decreased outward permeability to fluorescein in comparison with values of normal subjects.

An evaluation of 56 patients with X-linked retinitis pigmentosa revealed a profile of findings that include the following: night blindness within the first two decades of life; spherical refractive errors of -2.00 diopters or greater in addition to an increased prevalence of a cylindrical correction of +1.50 diopters or greater; appreciable impairment of central visual acuity to 20/200 or less by the fifth decade of life; characteristic patterns of field loss; presence of a foveal lesion in up to 75% of the study group; posterior subcapsular lens opacities; and nondetectable electroretinographic amplitudes in more than two thirds of the patients (using conventional full-field recording procedures). These observations are of general value in diagnosis of this disease and for counseling of patients afflicted with this severe form of hereditary night blindness.

• Globular excrescences of the optic nerve associated with retinitis pigmentosa have been interpreted as drusen or as astrocytic hamartomas. The histopathologic and ultrastructural findings of globular excrescences of the peripapillary region of the optic nerve associated with retinitis pigmentosa were described in a 22-year-old patient who died in a car accident. From our findings we conclude that the globular excrescences of the optic nerve associated with retinitis pigmentosa are definitely drusen and not astrocytic hamartomas.

• Twelve patients with diffuse drusen of Bruch membrane had their condition evaluated by electro-oculography (EOG). All had normal EOG light-peak/dark-trough ratios, which suggests that the disease does not involve a diffuse functional abnormality of the retinal pigment epithelium. This finding is in contrast to the abnormal EOG ratios reported in patients with fundus flavimaculatus. Categorizing these two diseases along with fundus albipunctatus as flecked retina syndrome should be continued on the basis of the somewhat similar morphologic appearance of the lesions, rather than because of similar results on functional testing.

• The blood-retinal barrier was assessed by vitreous fluorophotometry in eight patients with fundus flavimaculatus (Stargardt's macular dystrophy). Although clinically and histologically lesions are noted at the level of the outer blood-retinal barrier (retinal pigment epithelium), this barrier was intact in all eight patients studied by our fluorophotometric technique.

• We developed a corneal wick electrode that is free of photovoltaic artifact when used with a bright flash strobe and is convenient for routine clinical application. The corneal wick electrode is employed for bright flash electroretinogram (ERG) recordings and for research measurements of the early receptor potential. The wick electrode gives accurate, stable, reproducible recordings with an amplitude comparable to that obtained with standard contact lens electrodes.

In Reply. —We selected patients who had either clear media or, at most, minimal yellowing of the lens nucleus and/or small white, peripheral cortical opacities, none of which obscured clear visibility of the macula. Of the 29 eyes, 18 had a wet type of macular degeneration based on subretinal and/or subpigment neovascularization evident on fluorescein angiography with varying amounts of retinal edema, hemorrhage, exudate, and/or a fibrotic macular scar. Eleven eyes showed none of the above but did manifest macular drusen, which was associated with an atrophic macular lesion in ten eyes. Our article did not mention the presence of macular cysts, holes, or cystoid macular edema because none was present in any of our cases. We also did not refer to the term geographic atrophy , as we consider this a descriptive as much as a diagnostic term. Had we studied patients with a localized, atrophic, circumscribed, macular lesion not

• Of seven intraocular and 13 aphakic hard contact lenses evaluated for their transmission characteristics to near UV radiation, all intraocular lenses and 12 of 13 hard contact lenses showed high transmission peaks for UV radiation between 300 and 400 nm.

In Reply. —Drs Slusher and O'Steen have misunderstood the intentions of my editorial, which addressed the issue of the potential consequences resulting from premature speculation as to the application of preliminary laboratory advances to human disorders. The editorial makes no "pointed allegation," but rather intends to stimulate the readership to exercise a note of caution and concern when interpreting the consequences and application of research that is communicated initially or primarily through the lay press. The editorial was occasioned by an article inThe New York Times(September 25, 1988, p 13) that highlighted findings on the transplantation of retinal pigment epithelial (RPE) cells as a means of "treating" retinal degeneration in the RCS rat. Even a casual reader of the article would immediately grasp the intended message that a major breakthrough had occurred, with likely implications for human patients with macular degeneration and possibly also those with retinitis pigmentosa.

A recent article in theNew York Times(Sept 25, 1988, p 13) highlighted findings on the transplantation of retinal pigment epithelial (RPE) cells as a means of "treating" retinal degeneration in the Royal College of Surgeons (RCS) rat. The article stated that this procedure not only was successful in treating retinal degeneration in this animal model but also held promise for success in treating human degenerative retinal disorders, including retinitis pigmentosa and age-related macular degeneration. James E. Turner, PhD, and Linxi Li, MD, from the Bowman Gray School of Medicine, Winston-Salem, NC, have successfully transplanted healthy RPE cells from a normal group of rats into the subretinal space of a congenic (similar hereditary background) strain of RCS rats with retinal degeneration.1After performing a sclerotomy and penetrating the choroid in the superior quadrant of the eye, the investigators injected a 1-μL suspension of approximately 40 000 to 60

This book represents the published proceedings from a symposium on applications of psychophysics to clinical problems conducted under the combined auspices of the Committee on Vision of the National Research Council and the Second Study Group on Human Vision in San Francisco, Oct 30, 1978. The conference that generated this 304-page, hard-covered volume was fueled by the growing awareness of the National Advisory Eye Council, among other organizations, that "little current eye research was being reflected in clinical application." The publication of this volume was at least a partial attempt to overcome this deficiency and to "advertise more broadly the need for increased interaction between basic and clinical sciences." Three problem areas were selected for consideration—the use of recently developed tests for contrast-sensitivity, the assessment and development of vision in infants, and localization of anomalies in the visual pathway. The stated aim of the first section is to provide the

Various stages of fundus flavimaculatus seen ophthalmoscopically were correlated with findings on electrophysiologic and psychophysical tests. A new classification of fundus flavimaculatus into stages recognizes the nuances in genetic expression and their correlation with findings on retinal function testing.

This book includes presentations from the Proceedings of the International Symposium on Human and Animal Models held in Roros, Norway, in June, 1980. The introduction includes the source of funds to study this disease and the initial description by Otto Christian Stengel. A section describes the clinical course of this disease and its variations, and the tests used in diagnosis, viz, the electroretinogram, electro-oculogram, visual evoked potential, color vision tests, and fluorescein angiography. The pathology, with well-reproduced electron micrographs, depicts the stages of degeneration within central and peripheral nerves resulting from deposition of ceroid-lipofuscin. The study of peripheral blood lymphocytes with the electron microscope is advocated as an easy procedure to establish the diagnosis of juvenile ceroidlipofuscinosis. In the canine model, peroxides increase along with the accumulation of lipopigments in cerebral neurons and glial cells. The isolation, identification, and quantitation of ceroid-lipofuscin pigment is described. Animal models include the English

The SPECIAL ARTICLE in this issue of theArchives 1 on a standard protocol for electroretinographic (ERG) testing represents a major advance for clinical electroretinography. Although the ERG has been used clinically for more than 40 years, to date there has been no uniformly accepted method for recording the signal, since various laboratories have employed different technologies and recording conditions (for such components as flash intensity, duration of adaptation, and stimulus color). As a consequence, it is difficult to compare ERG data throughout the world, either for the purpose of interpreting scientific literature or for the benefit of an individual patient who may be seen in different laboratories. Other medical tests such as the electrocardiogram and electroencephalogram have been standardized to varying degrees, while the ERG remains vulnerable to individual bias. We can now anticipate that standards will be developed before long for other ophthalmic procedures such as electro-oculography, visual-evoked

Twelve patients with retinitis pigmentosa and chronic macular edema were prospectively treated for 2-week periods with acetazolamide or a placebo in a masked, crossover study. Ten of the 12 patients had both subjective and objective improvement in visual acuity when treated with acetazolamide. Improvement was seen even in patients with an acuity as good as 20/25 at baseline as well as in patients with macular edema present for more than a decade. A dosage of 500 mg/d was found to be more effective than 250 mg/d. Six patients (50%) showed lessening of their macular edema on fluorescein angiography. This angiographically demonstrated improvement was predominantly due to less detectable leakage from retinal capillaries rather than from choroidal capillaries through the retinal pigment epithelium. Improvement in visual acuity was seen in some patients without a detectable change in the amount of angiographic fluorescein leakage.

• The status of the blood-retinal barrier (BRB) in carriers of choroideremia and X-linked retinitis pigmentosa (XLRP) was determined by vitreous fluorophotometry (VF) and compared with that in female control subjects. Electroretinographic (ERG) amplitudes were measured to determine the overall functional integrity of retinal rods and cones. Comparison of the VF results showed an abnormal BRB in at least some carriers of XLRP, particularly those with peripheral fundus pigmentary changes, but not in carriers of choroideremia with even moderately extensive pigmentary changes. The abnormal BRB in XLRP carriers, with or without peripheral fundus pigmentary changes, was associated with at least moderate to moderately extensive reduction in scotopic ERG amplitudes, while the normal VF results in choroideremia carriers were associated with normal scotopic ERG amplitudes. However, in XLRP carriers, mild to modest reductions in ERG scotopic responses were seen in the presence of normal VF findings.

• We performed electrophysiologic studies of photoreceptor function in three patients with multiple evanescent white dot syndrome. During the acute stage, while the visual acuity was impaired, the electroretinogram (ERG) a-wave and the early receptor potential (ERP) amplitudes were profoundly decreased. The ERP regeneration times, determined for one subject, were prolonged. These findings suggest that photoreceptor function was impaired (abnormal a-wave), the effective visual pigment optical density of the outer segments was markedly reduced (ERP amplitude), and visual pigment regeneration was abnormal (ERP regeneration kinetics). During the recovery stage, the ERG and ERP amplitudes and visual acuity returned to normal. Our patients' disease seemed to be primarily of the retinal pigment epithelium (RPE). The decreased visual pigment density and prolonged regeneration kinetics emphasize the physiologic dependence of the sensory retina on the RPE.

• A total of 174 patients (347 eyes) with retinitis pigmentosa were categorized by genetic type and assessed as to the degree of central visual loss. The degree of central visual loss was mildest in cases of autosomal-dominant inheritance and most extensive in cases of X-linked recessive inheritance. Slightly more than one third (34%) of all eyes had acuity of 20/ 200 or less, while only 55% had vision of 20/60 or better. The data in this study provide general guidelines for counseling individual patients with retinitis pigmentosa as to the potential and extent of future central visual loss.

This volume, which is one in a series onPerspective in Vision Research, is an authoritative and comprehensive text that traces the development of our knowledge of retinal ganglion cells, receptive fields, and the overall development of the visual system. Part I includes three chapters that pertain to the classification of retinal ganglion cells. The material includes studies of the conduction velocity groupings among optic nerve axons, the receptive fields of retinal ganglion cells, and the morphology of retinal ganglion cells. Part II contains two chapters on the methodology of classification, while part III contains seven chapters on the impact of ganglion cell classification. The text is detailed and mainly relevant to readers who already have some background in visual system function and anatomy. However, it has individual sections that will be informative to the casual reader with a more comprehensive appreciation of the evolutionary development in our understanding of

• The conditions of 70 patients with Usher's syndrome were studied by ophthalmic and neuro-otologic examinations. Two distinct clinical and presumed genetic types were discernible on the basis of differences in hearing impairment, vestibular sensitivity, and, to a lesser extent, deterioration in retinal photoreceptor function. Distinguishing these two types has relevance for both diagnosis and genetic counseling of patients with Usher's syndrome.

• We evaluated 46 carriers of X-linked recessive retinitis pigmentosa for the prevalence of fundus changes, refractive errors, central visual impairment, and electroretinographic abnormalities. Of the 46 carriers, 40 (87%) could be identified by characteristic fundus changes and 37 (86%) of 43 by reductions in electroretinographic amplitude. Interestingly, 36 carriers (78%) had a refractive cylindrical correction of +1.50 diopters (D) or greater in at least one eye, while 25 (54%) had a best corrected visual acuity of 20/30 or less in at least one eye. Fundus examination coupled with an electroretinographic recording was diagnostic of the carrier state in virtually all 46 patients. The presence of a refractive cylinder of +1.50 D or greater should appreciably increase the index of suspicion when assessing the possibility of the carrier state in X-linked retinitis pigmentosa.

• Sixty-eight patients with autosomal dominant retinitis pigmentosa were divided into two distinct subtypes and studied for visual function using a life-table analysis. Type 1 patients (n = 23) had diffuse pigmentation, concentric visual field loss, and no recordable electroretinogram. Type 2 patients (n = 45) as a group had regionalized pigmentation, sectorial field loss, and some recordable electroretinogram. The cumulative probability of maintaining a visual acuity of 6/12 (20/40) or better over each decade of life decreased rapidly in eyes of type 1 patients; for type 2 eyes, this probability remained above 90% through the fifth decade of life. The presence of an atrophic-appearing foveal lesion was associated with a reduction in visual acuity to 6/15 (20/50) or worse in a majority of patients. Data from this study indicate that investigators should look for subtypes within the major genetic groupings of retinitis pigmentosa for more accurate assessment of a patient's potential for maintaining good central visual acuity.