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A prospective study of the peripheral retinal vasculature in a Jamaican cohort of subjects with sickle cell disease has been in progress over a period of 12 years using fluorescein angiography. Various vascular patterns were identified but their significance was unclear since no comparable records were available in subjects of a similar age with normal (AA) haemoglobin genotype. Fluorescein retinal angioscopy and angiography have been performed in 76 haemoglobin AA controls participating in the cohort study. The peripheral retinal capillary bed could be seen and photographed in a limited portion of the temporal peripheral fundus in a majority of this group, and there was considerable variation in the vascular pattern which could be characterised. These observations allow deviations from normal to be identified in the retinal vasculature in subjects with sickle cell disease.

To introduce a revised version of the grading system established by the International ARM Epidemiological Study Group for identifying and quantifying abnormalities of age-related maculopathy (ARM) and age-related degeneration (AMD) and to investigate its reliability, specifically the inter- and intra-observer variability.Fifty eyes of 25 patients with ARM or AMD in at least one eye were randomly selected from a large ongoing collection of clinical data and DNA in a tertiary referral UK population. Stereoscopic color fundus photographs were taken with a 30 degrees fundus camera and were centered on the macula. Presence and severity of fundus abnormalities in ARM and AMD were graded using a grid to define macular subfields and standard circles to define the size of lesions. Inter-observer variability was assessed by having three retinal specialists evaluate the color slides and intra-observer variability by re-grading the same set.The inter-observer agreement for all subfields was fair to substantial for small hard drusen (70-89%; kappa=0.26-0.63) and intermediate soft drusen (76-94%; kappa=0.27-0.69). Agreement ranged between 87% and 100%, between 50% and 92%, and between 78% and 100% for larger drusen, the presence of hyperpigmentation, and the presence of hypopigmentation, respectively. Agreement was moderate to almost perfect for the presence of geographic atrophy (88-98%; kappa=0.60-0.95) and substantial to almost perfect for the presence of choroidal neovascularization (84-100%; kappa=0.62-1.00). The intra-observer variability for the grading of drusen characteristics and pigmentary changes was similar in magnitude, but slightly greater for features of advanced AMD.Reproducibility was achieved using a revised version of the grading system established by the International ARM Epidemiological Study Group. This grading system may therefore be used for phenotyping of ARM and AMD.

To test the feasibility of a new surgical technique and to assess visual function over the translocated retinal pigment epithelium (RPE) cells in patients operated on for subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (ARMD).Retrospective, noncomparative, interventional case series.Nine patients with previously untreated exudative ARMD underwent surgical excision of the subfoveal CNV with RPE translocation and were observed for 12 to 32 months.The surgery consisted of a standard three-port pars plana vitrectomy, excision of the CNV, and RPE translocation. Pre- and postoperative ocular examination included best-corrected visual acuity measurement, fundus color stereo photography, and fundus fluorescein angiography. Optical coherence tomography and confocal laser scanning ophthalmoscopy (cLSO) were performed after surgery. A crossfixation target and a single-point flashing light were projected on different areas of the posterior pole using a cLSO. Photopic 10 to 2 perimetry, photopic fine matrix mapping, and cLSO microperimetry were also performed after surgery in six patients.Optical coherence tomography cross-sectional scans and cLSO RPE autofluorescence were recorded to detect the presence of viable translocated RPE. Visual acuity, fixation, photopic 10 to 2 perimetry, photopic fine matrix mapping, and cLSO microperimetry were used to test central visual function.Retinal pigment epithelium was translocated successfully at the time of CNV removal from the edge of the RPE defect to a subfoveal location in seven of nine patients. One patient experienced proliferative vitreoretinopathy, but significant hemorrhage was not a feature. Optical coherence tomography showed the translocated RPE as an area of increased optical reflectivity with optical shadowing external to it. Confocal laser scanning ophthalmoscopy showed autofluorescence of the translocated RPE. The crossfixation target was seen when projected on the translocated RPE. During eccentric fixation, the patients could see a flashing point-target projected on the translocated RPE. Photopic 10 to 2 perimetry, photopic fine-matrix mapping, and cLSO microperimetry showed the presence of central visual function.The authors propose that translocation of RPE at the time of CNV removal, from the edge of the RPE defect to a subfoveal location, may have a role in the surgical management of ARMD.

To determine whether teletherapy with 6-mV photons can reduce visual loss in patients with subfoveal choroidal neovascularization in age-related macular degeneration.A multicenter, single-masked, randomized controlled trial of 12 Gy of external beam radiation therapy delivered to the macula of an affected eye vs observation only.Three United Kingdom-based hospital units.Patients with age-related macular degeneration, aged 60 years and older, who had subfoveal choroidal neovascularization and a visual acuity of 20/200 (logMAR 1.0) or better.Two hundred three patients were randomly assigned to radiotherapy or observation. Treatment was undertaken at designated radiotherapy centers, and patients assigned to the treatment group received a total dosage of 12 Gy of 6-mV photons in 6 fractions. Follow-up was scheduled at 3, 6, 12, and 24 months. After excluding protocol violators, the data from 199 patients were analyzed.The primary outcome measure was mean loss of distance visual acuity in the study eye at 12 and 24 months. Other outcome variables analyzed were near visual acuity and contrast sensitivity. The proportions of patients losing 3 or more or 6 or more lines of distance and near acuity and 0.3 or more or 0.6 or more log units of contrast sensitivity at each follow-up were also analyzed.At all time points, mean distance visual acuity was better in the radiotherapy-treated group than in the control group, but the differences did not reach statistical significance. At 24 months, analysis of the proportions of patients with loss of 3 or more (moderate) (P =.08) or 6 or more (severe) (P =.29) lines of distance vision showed that fewer treated patients had severe losses, but there was no statistically significant difference between groups. For near visual acuity, although there was no evidence of treatment benefit at 12 and 24 months, a significant difference in favor of treatment was present at 6 months (P =.048). When analyzed by the proportions of patients losing 3 lines of contrast sensitivity, there was a significant difference in favor of treatment at 24 months (P =.02). No adverse retinal effects were observed during the study, but transient disturbance of the precorneal tear film was noted in treated patients.The results of the present trial do not support the routine clinical use of external beam radiation therapy in subjects with subfoveal choroidal neovascularization in age-related macular degeneration.

Age-related macular degeneration (AMD) is the most common cause of blindness in industrialized countries. There has been considerable interest in the genetics of early age-related maculopathy (ARM) and AMD, because they have phenotypes similar to inherited diseases where mutations have been identified, but the heritability of ARM and AMD is unknown.A classical twin study was performed to compare the concordance in monozygotic (MZ) and dizygotic (DZ) twins in an unselected sample of female volunteer twins.Five hundred six twin pairs, 226 MZ and 280 DZ, with a mean age of 62 years, were examined.ARM was graded from stereoscopic macular photographs of 501 of the twin pairs (99%) according to the International ARM Epidemiologic Study Group grading system. The casewise concordance was calculated for twin pairs from 2 x 2 contingency tables of affected/unaffected twins, and these tables were used in maximum likelihood genetic modeling to estimate the heritabilities of phenotypes graded.Prevalence of ARM; concordance in MZ and DZ twins of the phenotypes of ARM, soft drusen63 microm andor =125 microm diameter, pigmentary changes and hard drusen (20 andor =20 in number); heritability of ARM and subphenotypes.The overall prevalence of ARM was 14.6% (95% confidence interval [CI], 12.4%-16.8%). The concordance for ARM in MZ twins was 0.37 compared with 0.19 in DZ twins, suggesting a role for genes. Modeling confirmed a genetic effect for phenotypes of ARM, soft drusen, pigmentary changes, andor =20 hard drusen, although there was little genetic effect for scattered (20) hard drusen. The heritability of ARM was estimated as 45% (95% CI, 35%-53%). The most heritable phenotypes were soft drusenor =125 microm (57%) andor =20 hard drusen (81%), with the latter being dominantly inherited.This study confirms a significant genetic influence in ARM and suggests that future genetic studies should examine phenotypes of large (or =125 microm) soft drusen andor =20 hard drusen, because these seem to be the most heritable components.

A prospective longitudinal study was initiated to analyze the correlation between the prognosis for the second eyes of patients with unilateral late exudative AMD and the disease phenotype.Of the187 patients with unilateral late exudative AMD recruited, 130 (69.5%) had predominantly classic CNV without pigment epithelium detachment (PED) (CNV group), and 57 (30.5%) had occult CNV with serous PED (PED group). Patients were reexamined by ophthalmoscopy and angiography every 6 months for up to 80 months. The end point was ETDRS visual acuity change of 3 lines or more due to late AMD in the second eye.During follow-up 53 (28.3%) patients reached the end point: 32 (24.6%) in the CNV group and 21 (36.8%) in the PED group. The major prognostic factor for the risk of visual loss in the second eye was the type of late AMD in the first eye (CNV group 6-7% per year, PED group 15-16% per year ( P0.001). There was significant symmetry between the new exudative lesion in the second eye and that in the first, and significant differences in the density and fluorescence of drusen in the second eye between the two groups.Patients with occult CNV with serous PED in the first eye have a significantly higher risk of visual loss in the second eye than patients with CNV without PED. This distinction may be important for future clinical studies. In addition, segregation of AMD by phenotype is necessary in the analysis of genes conferring risk of AMD.

Objective To describe the phenotype in 4 families with dominantly inherited cone-rod dystrophy, 1 with an R838C mutation and 1 with an R838H mutation in the guanylate cyclase 2D (GUCY2D) gene encoding retinal guanylate cyclase-1. Methods Psychophysical and electrophysiological evaluation and confocal laser scanning ophthalmoscopic imaging was performed on 10 affected members of 4 British families. Results Although subjects had lifelong poor vision in bright light, a major reduction in visual acuity did not occur in most of them until after their late teens. Fundus abnormalities were confined to the central macula, and increasing central atrophy was noted with age. Increased background autofluorescence was observed surrounding the central atrophic area. Electrophysiological testing revealed a marked loss of cone function with only minimal rod involvement, even in older subjects. Photopic and scotopic static perimetry demonstrated central and peripheral cone-mediated threshold elevations with midperipheral sparing. Conclusion The phenotype associated with autosomal dominant cone-rod dystrophy with either an R838C or R838H mutation in GUCY2D is distinctive, with predominantly cone system involvement. There is some variation in severity within the 3 families with the R838C mutation. Clinical relevance Families with the R838C or R838H mutation have a much milder phenotype than the family previously described that had 2 sequence changes, E837D and R838S, in GUCY2D.

Retinitis pigmentosa (RP) is a genetically heterogeneous disorder characterized by progressive degeneration of the peripheral retina leading to night blindness and loss of visual fields. With an incidence of approximately 1 in 4000, RP can be inherited in X-linked, autosomal dominant or autosomal recessive modes. The RP13 locus for autosomal dominant RP (adRP) was placed on chromosome 17p13.3 by linkage mapping in a large South African adRP family. Using a positional cloning and candidate gene strategy, we have identified seven different missense mutations in the splicing factor gene PRPC8 in adRP families. Three of the mutations cosegregate within three RP13 linked families including the original large South African pedigree, and four additional mutations have been identified in other unrelated adRP families. The seven mutations are clustered within a 14 codon stretch within the last exon of this large 7 kb transcript. The altered amino acid residues at the C-terminus exhibit a high degree of conservation across species as diverse as humans, Arabidopsis and trypanosome, suggesting that some functional significance is associated with this part of the protein. These mutations in this ubiquitous and highly conserved splicing factor offer compelling evidence for a novel pathway to retinal degeneration.

OBJECTIVEAutosomal dominant drusen is of particular interest because of its phenotypic similarity to age related macular degeneration. Currently, mutation R345W ofEFEMP1 and, in a single pedigree, linkage to chromosome 6q14 have been causally related to the disease. We proposed to investigate and quantify the roles ofEFEMP1 and the 6q14 locus in dominant drusen patients from the UK and USA.DESIGNMolecular genetic analysis.PARTICIPANTSTen unrelated families and 17 young drusen patients.MAIN OUTCOME MEASURESExons 1 and 2 of EFEMP1 were characterised by 5′ rapid amplification of cDNA ends and direct sequencing. Exons 1-12 ofEFEMP1 were then investigated for mutation by direct sequencing. A HpaII restriction digest test was constructed to detect the EFEMP1R345W mutation. Marker loci spanning the two dominant drusen linked loci were used to generate haplotype data.RESULTSOnly seven of the 10 families (70%) and one of the 17 sporadic patients (6%) had the R345W mutation. The HpaII restriction digest test was found to be a reliable and quick method for detecting this. No other exonic or splice site mutation was identified. Of the three families without EFEMP1 mutation, two were linked to the 2p16 region.CONCLUSIONSEFEMP1R345W accounts for only a proportion of the dominant drusen phenotype. Importantly, other families linked to chromosome 2p16 raise the possibility of EFEMP1 promoter sequence mutation or a second dominant drusen gene at this locus. Preliminary haplotype data suggest that the disease gene at the 6q14 locus is responsible for only a minority of dominant drusen cases.

Usher syndrome (USH) is a combination of a progressive pigmentary retinopathy, indistinguishable from retinitis pigmentosa, and some degree of sensorineural hearing loss. USH can be subdivided in Usher type I (USHI), type II (USHII) and type III (USHIII), all of which are inherited as autosomal recessive traits. The three subtypes are genetically heterogeneous, with six loci so far identified for USHI, three for USHII and only one for USHIII. Mutations in a novel gene, USH2A, encoding the protein usherin, have recently been shown to be associated with USHII. The gene encodes a protein with partial sequence homology to both laminin epidermal growth factor and fibronectin motifs. We analysed 35 British and one Pakistani Usher type II families with at least one affected member, for sequence changes in the 20 translated exons of the USH2A gene, using heteroduplex analysis and sequencing. Probable disease-causing mutations in USH2A were identified in 15 of 36 (41.7%) Usher II families. The most frequently encountered mutation (11/15 families or 11/18 mutated alleles) was del2299G in exon 13, resulting in a frameshift and premature stop codon. Other mutations include insertions and point mutations, of which two are previously unreported. Five different polymorphisms were also detected. Our results indicate that mutations in this gene are responsible for disease in a large proportion of British Usher type II patients. Moreover, if screening for mutations in USH2A is considered, it is sensible to screen for the del2299G mutation first.

Subretinal neovascular membranes (CNV) can occur in a variety of conditions. SRNVM most commonly occur in age-related macular degeneration (AMD), punctate inner choroidopathy (PIC)/multifocal inner choroidopathy (MIC) and myopia. AMD and CNV most common cause of blindness in western world.

Purpose: To test the feasibility of a new surgical technique, and to assess visual function over the translocated retinal pigment epithelium (RPE) cells in patients operated upon for subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). Materials and methods: Six patients presenting previously untreated exudative AMD underwent surgical excision of the subfoveal CNV with RPE translocation and were followed from 1 to 10.5 months. The surgery consisted of a standard three port pars plana vitrectomy (TPPPV), excision of the CNV and RPE translocation. Pre and post-operative ocular examination included best-corrected visual acuity measurement, fundus color stereo photography and fundus fluorescein angiography. Optical coherence tomography (OCT) and confocal laser scanning ophthalmoscopy (cLSO) were performed post-operatively. A cross fixation target and a single-point flashing light were projected on different areas of the posterior pole using a cLSO. Photopic 10–2 perimetry, photopic fine matrix mapping, cLSO microperimetry were also performed pre and post-operatively in four patients. OCT cross-sectional scans and cLSO RPE autofluorescence were recorded to detect the presence of viable translocated RPE. Visual acuity, fixation, photopic 10–2 perimetry, photopic fine matrix mapping and cLSO microperimetry were tested for the presence of central visual function. Results: RPE could be effectively translocated at the time of CNV removal from the edge of the RPE defect to a subfoveal location. OCT showed the translocated RPE as an area of increased optical reflectivity with optical shadowing external to it. cLSO showed autofluorescence of the translocated RPE. The cross fixation target was seen when projected on the translocated RPE. During eccentric fixation, the patients could see a flashing point-target projected on the translocated RPE. Photopic 10–2 perimetry, photopic fine matrix mapping and cLSO microperimetry showed presence of central visual function. Conclusions: The authors propose that translocation of RPE at the time of CNV removal, from the edge of the RPE defect to a subfoveal location, may have a role in the surgical management of AMD.

Pantothenate kinase-associated neurodegeneration (PKAN; OMIM 234200) is caused by recessive mutations in PANK2 and is characterised by dystonia, cerebral iron accumulation, pathognomonic ‘eye of the tiger’ MRI finding, and pigmentary retinal degeneration.1 2 Bone spicule formation, retinal vessel attenuation and yellow-white globular deposits seen clinically have been correlated histopathologically with degeneration of photoreceptors, marked outer retinal layer thinning and accumulation of melanolipofuscin.2 In keeping with these observations, electroretinographic abnormalities, ranging from mild cone to severe rod–cone dysfunction, have been reported.3 Retinal telangiectasis, also known as Coats'-like or Coats'-type exudative vasculopathy, may occur in both syndromic and non-syndromic retinitis pigmentosa.4 However, we are not aware of previous published reports of exudative vasculopathy associated with PKAN. We have characterised a patient with a novel mutation in PANK2 that had spontaneous resolution of retinal telangiectasis. In October 2005, a 10-year-old girl was referred to Moorfields Eye Hospital …

The entry angiograms of 42 eyes with detachment of the retinal pigment epithelium in a treatment trial of laser photocoagulation were reviewed in a masked fashion by three observers in order to assess the possible presence of subpigment epithelial neovascularisation. Vascularity or avascularity was designated with reference to a list of clues believed to imply the presence of subpigment epithelial neovascularisation. As a predictor of outcome the initial assessment achieved a sensitivity and specificity of 77% and 82% respectively. Despite notable parity of the degree of sensitivity and specificity among the three observers, full agreement on the initial assessments was reached in only 23 eyes (55%), 10 with vascular and 13 with avascular outcome. Of these, only one eye which developed new vessels after 4 years had an outcome which differed from that predicted by classification of the entry angiograms.

Patients who were enrolled in a controlled treatment trial of laser grid photocoagulation for retinal pigment epithelial detachment as part of age-related maculopathy were reviewed 4 years after entry into the trial. The data imply that the original conclusion that this form of treatment did not improve the visual prognosis at 18 months was also justified at 4 years. It has become clear that lesions with evidence of subpigment epithelial new vessels were included in the trial. In a retrospective study the lesions were separated into those in which there was evidence of subretinal neovascularisation and those in which no such evidence existed. A difference was identified in the behaviour of the treated and untreated lesions designated avascular in that the treated eyes had a poorer visual outcome. These cases accounted for the different behaviour between two management groups in the initial study such that the original conclusion that grid photocoagulation of avascular pigment epithelial detachments in the elderly does not improve the visual prognosis is justified.

The aim of this work was to identify NRL mutations in a panel of 200 autosomal dominant retinitis pigmentosa (adRP) families. All samples were subjected to heteroduplex analysis of the three exons of the NRL gene, and HphI restriction digest analysis of exon 2 (to identify the S50T mutation). Families found to have the S50T mutation, and six additional larger pedigrees (which had previously been excluded from the other nine adRP loci) underwent linkage analysis using polymorphic markers located in the region of 14q11. HphI restriction analysis followed by direct sequencing of the amplified NRL exon 2 product demonstrated the presence of the NRL S50T sequence change in three adRP families. Comparison of marker haplotypes in affected individuals from these families with those of affected members of the original 14q11 linked family revealed a common disease haplotype for markers within the adRP locus. Recombination events observed in these families define an adRP critical interval of 14.9 cM between D13S72 and D14S1041. Linkage analysis enabled all six of the larger adRP pedigrees to be excluded from the 14q11 locus. The NRL S50T mutation represents another example of a ‘founder effect’ in a dominantly inherited retinal dystrophy. Identification of such ‘founder effects’ may greatly simplify diagnostic genetic screening and lead to better prognostic counselling. The exclusion of several adRP families from all ten adRP loci indicates that at least one further adRP locus remains to be found.

Editor—Retinitis pigmentosa (RP, MIM 268000) is the term applied to a clinically and genetically heterogeneous group of retinal degenerations primarily affecting the rod photoreceptors. RP is characterised by progressive loss of vision, initially manifesting as night blindness and reduction in the peripheral visual field, and later involving loss of central vision.1 Ophthalmoscopic examination typically shows pigmentary disturbances of the mid-peripheral retina. RP may be inherited as an autosomal recessive, autosomal dominant, digenic, or X linked trait. Autosomal recessive RP (ARRP) accounts for around 20% of all cases of RP, while sporadic RP, which is presumed to be recessive in most cases, accounts for a further 50%.2 Mutations causing autosomal recessive RP (ARRP) have been found in the genes encoding rhodopsin,3 the α and β subunits of rod phosphodiesterase,4 5 the α subunit of the cyclic GMP gated channel protein,6 and the genes RPE65 ,7 8 RLBP1 ,9 ABCR ,10 and TULP1 .11 12 In addition, genetic linkage studies have identified ARRP loci at 1q31-q32.1,13 14 2q31-q33,156cen-q15,16 and 16p12.1-p12.3.17 (MIM numbers for the loci identified by these studies are 180380, 180071, 180072, 123825, 180069, 180090, 601708, 600132, 600105, and 602594 respectively. No MIM number has yet been assigned to the 2q31-q33 and 6cen-q15 loci.) Of these four loci, only linkage to the 1q31-q32.1 locus (RP12) and the 6cen-q15 locus has been reported in more than one pedigree. The first report of linkage of ARRP to 1q31-q32.1 was in a large inbred Dutch family with ARRP in which most patients exhibited para-arteriolar preservation of the retinal pigment epithelium (PPRPE).13This was followed by linkage of a second, consanguineous, pedigree from Pakistan.14 In both the Dutch and the Pakistani families there was evidence that only …

The gene RPGR was previously identified in the RP3 region of Xp21.1 and shown to be mutated in 10-20% of patients with the progressive retinal degeneration X-linked retinitis pigmentosa1, 2 (XLRP). The mutations predominantly affected a domain homologous to RCC1, a guanine nucleotide exchange factor for the small GTPase Ran, although they were present in fewer than the 70-75% of XLRP patients predicted from linkage studies3, 4, 5, 6. Mutations in the RP2 locus at Xp11.3 were found in a further 10-20% of XLRP patients, as predicted from linkage studies6, 7, 8. Because the mutations in the remainder of the XLRP patients may reside in undiscovered exons of RPGR, we sequenced a 172-kb region containing the entire gene. Analysis of the sequence disclosed a new 3? terminal exon that was mutated in 60% of XLRP patients examined. This exon encodes 567 amino acids, with a repetitive domain rich in glutamic acid residues. The sequence is conserved in the mouse, bovine and Fugu rubripes genes. It is preferentially expressed in mouse and bovine retina, further supporting its importance for retinal function. Our results suggest that mutations in RPGR are the only cause of RP3 type XLRP and account for the disease in over 70% of XLRP patients and an estimated 11% of all retinitis pigmentosa patients.

Purpose To determine the yearly incidence of visual loss in the fellow eyes of patients with unilateral neovascular age-related macular degeneration (ARMD) and to assess the drusen characteristics portending the greatest risk for this outcome. Methods A total of 101 patients with unilateral exudative ARMD and drusen only in the fellow eye were entered into the study and prospectively followed up to 9 years. Visual acuity, color fundus photography, fluorescein angiography, and grading of drusen characteristics were obtained for each patient on entry into the study. Patients were followed at annual intervals with color fundus photography. The study endpoint was the development of choroidal neovascularization (CNV) or geographic atrophy (GA) in the fellow eye. Results Yearly incidence rates for the development of an endpoint lesion were between 5 and 14%. The risk of CNV peaked at 4 years and dissipated thereafter. Longer follow-up was associated with a slightly increased incidence of GA. Greater drusen number was most highly associated with the development of an endpoint lesion. Drusen size and confluence were also significant. Conclusions The risk of CNV in patients with ARMD is heralded by an increase in the number, size, and confluence of drusen. This risk eventually declines and is followed by later increased risk of GA.

Objective To examine the phenomenon of a prolonged choroidal filling phase (PCFP) as seen on fluorescein and indocyanine green (ICG) angiography in patients with early age-related macular disease (AMD). Methods One hundred eyes of consecutive patients with early AMD were studied. Patchy and slow choroidal filling in early fluorescein and distinct areas of reduced choroidal fluorescence in ICG angiography were interpreted as PCFP. In addition, associated drusen characteristics and the AMD status of the fellow eye were recorded. Results A PCFP was observed in 26% of eyes using fluorescein and 32% of eyes using ICG angiography, with good concordance between findings using both techniques (κ=0.9). A PCFP was associated with confluent drusen ( P =.01), the presence of focal retinal pigment epithelial–atrophic patches in the study eye ( P =.005), and geographic atrophy in the fellow eye ( P =.03). Other drusen characteristics and the distribution of visual acuity ( P =.90) were not different between eyes with and without PCFP. Conclusions A PCFP on fluorescein and ICG angiography is a common feature in early AMD. This sign has been interpreted as indicating reduced choroidal perfusion caused by change in diffusional characteristics of Bruch membrane. A PCFP is a clinical marker for diffuse deposits in Bruch membrane and a risk factor for the development of geographic atrophy.

AIM—X linked retinitis pigmentosa (XLRP) has two genetic loci known as "RP2" and "RP3". Clinical features reported to differentiate RP2 from RP3 include a higher prevalence of myopia and primary cone dysfunction in RP2, and late onset night blindness and tapetal reflex in RP3. Members from 14 XLRP families were examined in an attempt to verify these differences. METHODS—16 affected males and 37 females from 14 XLRP families assigned as either RP2 or RP3 by haplotype analysis and/or by heterogeneity analysis were examined. Members of all 14 families who were willing to participate but unavailable for examination were contacted and detailed interviews carried out. RESULTS—No clear phenotypic differences were found that could be used to reliably differentiate RP2 from RP3 with respect to myopia and onset of night blindness. The tapetal reflex was also found to be present in carriers of both RP2 and RP3. CONCLUSIONS—XLRP is a heterogeneous class of rod degenerative disorders with no clear phenotypic differentiation between the two genetic loci RP2 and RP3. There is a continuum of clinical presentations which can be seen in both RP2 and RP3, but the features within a given family tend to be consistent. However, interfamilial variability is prevalent leading to a wide range of clinical presentations and more than one abnormal allele at each gene locus cannot be excluded.

Malattia Leventinese (ML) and Doyne honeycomb retinal dystrophy (DHRD) refer to two autosomal dominant diseases characterized by yellow-white deposits known as drusen that accumulate beneath the retinal pigment epithelium (RPE). Both loci were mapped to chromosome 2p16-21 (refs 5,6) and this genetic interval has been subsequently narrowed. The importance of these diseases is due in large part to their close phenotypic similarity to age-related macular degeneration (AMD), a disorder with a strong genetic component that accounts for approximately 50% of registered blindness in the Western world. Just as in ML and DHRD, the early hallmark of AMD is the presence of drusen. Here we use a combination of positional and candidate gene methods to identify a single non-conservative mutation (Arg345Trp) in the gene EFEMP1 (for EGF-containing fibrillin-like extracellular matrix protein 1) in all families studied. This change was not present in 477 control individuals or in 494 patients with age-related macular degeneration. Identification of this mutation may aid in the development of an animal model for drusen, as well as in the identification of other genes involved in human macular degeneration.

11 páginas, 9 figuras, 1 tabla.-- et al., [Objective]: To report the phenotype associated with the codon 172 RDS (gene for retinal degeneration slow) mutation in 11 separate families with an arginine-to-tryptophan substitution with common ancestry, and 1 family with an arginine-to-glutamine transition. [Patients]: Screening for RDS gene mutations was performed in 400 subjects with autosomal dominant retinal degeneration. Twelve families were identified with a mutation in codon 172. Haplotype analysis was performed. Full ophthalmic evaluation was performed, including electrophysiologic and psychophysical investigation and imaging of autofluorescence using confocal laser scanning ophthalmoscopy. [Results]: Haplotype analysis demonstrated that the 11 families were ancestrally related. All 12 families showed a common phenotype of macular dysfunction, with the deficit increasing with age. Abnormally high autofluorescence predated loss of visual acuity or visual field changes. Pattern electroretinographic (PERG) findings were affected early in disease. There was high intrafamilial and interfamilial consistency of phenotype. [Conclusion]: These families demonstrate a striking conformity of symptoms and signs. [Clinical Relevance]: In the codon 172 RDS mutation, unlike disease resulting from other RDS mutations, prediction of approximate age of onset and progression of visual deficit is possible. This should assist diagnosis and counseling., This work was supported by a grant from the Medical Research Council, London, England; the British Retinitis Pigmentosa Society, Surrey, England; and the Foundation Fighting Blindness, Baltimore, Md.

2 páginas, 2 figuras.-- et al., D.A.R.B. and A.M.P. are supported by the Medical Research Council of the U.K. (grant no. G9301094) and Q.-L.W. is a recipient of a Knights Templar Foundation fellowship. This research was supported by grants from the National Institutes of Health (EY11115, EY09769).

Photoreceptor apoptosis is a major cause of visual loss in retinal detachment (RD) and several other visual disorders, but the underlying mechanisms remain elusive. Recently, increased expression of monocyte chemoattractant protein 1 (MCP-1) was reported in vitreous humor samples of patients with RD and diabetic retinopathy as well as in the brain tissues of patients with neurodegenerative diseases, including Alzheimer's disease and multiple sclerosis. Here we report that MCP-1 plays a critical role in mediating photoreceptor apoptosis in an experimental model of RD. RD led to increased MCP-1 expression in the Müller glia and increased CD11b+ macrophage/microglia in the detached retina. An MCP-1 blocking antibody greatly reduced macrophage/microglia infiltration and RD-induced photoreceptor apoptosis. Confirming these results, MCP-1 gene-deficient mice showed significantly reduced macrophage/microglia infiltration after RD and very little photoreceptor apoptosis. In primary retinal mixed cultures, MCP-1 was cytotoxic for recoverin+ photoreceptors, and this toxicity was eliminated through immunodepleting macrophage/microglia from the culture. In vivo, deletion of the gene encoding CD11b/CD18 nearly eliminated macrophage/microglia infiltration to the retina after RD and the loss of photoreceptors. Thus, MCP-1 expression and subsequent macrophage/microglia infiltration and activation are critical for RD-induced photoreceptor apoptosis. This pathway may be an important therapeutic target for preventing photoreceptor apoptosis in RD and other CNS diseases that share a common etiology.

Purpose: To evaluate prophylactic laser treatment of the macula in reducing the risk of visual loss in the fellow eye of patients with a retinal pigment epithelial tear caused by age-related macular degeneration in the first eye. Methods: In a prospective study, 12 patients with a retinal pigment epithelial tear in one eye caused by age-related macular degeneration and drusen in the fellow eye received prophylactic laser treatment of the retina in their fellow eyes and were followed up for 2 years or more after prophylactic treatment. Results: In 12 fellow eyes that received prophylactic laser treatment, a reduction in best-corrected visual acuity to 20/80 or worse occurred in one (8%) of 12 eyes in the first year and two (18%) of the remaining 11 eyes in the second year after treatment. The cumulative risk of visual loss in the treated fellow eye was 25% in 2 years. Conclusions: In historical control subjects in a natural history study of patients with retinal pigment epithelial tear in one eye, central visual loss occurred in 16 (37%) of 43 eyes in the first year and in seven (30%) of 23 eyes in the second year for a cumulative loss of 59% in the first 2 years. Compared with these historical control subjects, our findings suggest that visual loss in the fellow eyes of patients with a retinal pigment epithelial tear in the first eye is reduced by prophylactic low intensity laser photocoagulation of the macula.

The dominant cone‐rod dystrophy gene CORD6 has previously been mapped to within an 8 cM interval on chromosome 17p12‐p13. The retinal-specific guanylate cyclase gene (RETGC-1), which maps to within this genetic interval and previously was implicated in Leber’s congenital amaurosis, was screened for mutations within this family and in a panel of small families and individuals with various cone and cone‐ rod dystrophy phenotypes. A missense mutation (E837D) was identified in affected members of the CORD6 family, as well as a second missense mutation (R838C) in three other families with dominant cone‐rod dystrophy. RETGC-1 is only the fourth gene to be implicated in cone‐rod dystrophy and this is the first report of dominant mutations in this gene.

AIMS—To characterise retinal function using electrophysiological and psychophysical tests in 17 patients with helicoidal peripapillary chorioretinal degeneration. METHODS—The electroretinogram (ERG) was recorded using gold foil corneal electrodes. The electro-oculogram (EOG) was recorded using a standard protocol. Dark adaptometry was recorded with an SST-1 dark adaptometer and colour vision assessed with Ishihara plates and Farnsworth D-15. RESULTS—All subjects had a recordable ERG. The amplitudes and implicit times of the a- and b-waves were within normal limits at all luminances in five subjects (age 21-70 years, mean 40 years). The ERG of six (age 26-55 years, mean 40.7 years) had subnormal amplitudes at all luminances, but normal implicit times, and six (age 38-81 years, mean 60.7 years) had abnormal ERGs with marked reduction of a- and b-waves, and delayed implicit times of the b-wave. The implicit times of the a-wave were normal in all subjects. A reduction in the b/a wave ratios was not found, nor was there selective loss of scotopic, mixed rod/cone, or cone responses. The light/dark ratio of the EOG was subnormal (150-185%) or abnormal (below 150%) in all but three subjects. Two patients with normal EOG showed normal ERGs in both eyes, but one had subnormal ERGs in both eyes. The scotopic sensitivity was normal in all subjects and dark adaptation showed a normal time course. Colour vision was normal in all patients. CONCLUSION—The results suggest that in most cases the function of the retinal pigment epithelium is affected by this disease before any changes in the function of the sensory retina are detectable by our methods, and that retinal dysfunction is focal rather than diffuse. Keywords: chorioretinal degeneration; electroretinogram; dark adaptation; colour vision

Objective: To report the prevalence of age-related maculopathy (ARM) in Salandra, a small, isolated southern Italian community, to test the hypothesis that an environmental factor, scarce in such a remote community but ubiquitous in modern industrial societies, might modify the risk of developing ARM. Design: Population-based cross-sectional survey. Main Outcome Measures: Prevalence of advanced age-related macular degeneration (ARMD) (geographic atrophy or exudative maculopathy) and ARM (large, soft drusen or retinal pigment epithelium changes, or both) defined by fundus biomicroscopy and 30° stereoscopic macular photography. Self-sustenance was assessed by interview of participants and local shop retailers. The degree of genetic isolation was computed using a model that fits the genetic population structure with the frequency distribution of surnames in the community. Results: A full ophthalmic examination was undertaken in 366 (63.5%) of 576 eligible participants, 354 (96.7%) of whom had clinical or photographic assessment for the presence of ARMD and 310(84.6%) of whom had drusen characteristics graded on color transparencies for ARM. The overall prevalence of ARMD was 1.1%. Drusen larger than 50 μm and more numerous than 10 were found in 4.5% of subjects. Salandra was the birthplace of 87.2% of participants and for 77.3% of both parents of each subject. People in the community tended to consume homegrown products. Conclusion: The prevalence of ARM may be lower in this self-sustained farming community than elsewhere in the industrialized world.

Objective: To document the deviation from normal of fundus autofluorescence in patients with inherited macular dystrophies. Methods: The intensity and spatial distribution of fundus autofluorescence was documented in 118 patients with inherited macular dystrophies by means of a confocal laser scanning ophthalmoscope, and the images were compared with the fundus appearance and fluorescein angiograms. Results: Background autofluorescence appears to be elevated in all forms of macular dystrophies examined. The pale deposits at the level of the retinal pigment epithelium in disorders such as Best disease, adult vitelliform macular dystrophy, and fundus flavimaculatus were consistently associated with higher levels of autofluorescence than the background signal. There was no strong correlation between the intensity of autofluorescence and the fluorescein angiographic sign of a dark choroid. Increased levels of autofluorescence were present in a subject with a mutation known to cause macular dystrophy but in whom there were no manifest ophthalmoscopic or functional abnormalities. Conclusions: All dystrophies examined have in common accumulation of autofluorescent material in the retinal pigment epithelium to a greater degree than that seen with age. The abnormal high background autofluorescence associated with inherited macular dystrophies confirms the impression derived from histological studies that these disorders affect the entire retinal pigment epithelium. The lack of correlation between autofluorescence and the presence of a dark choroid implies that there may be different fluorophores in different disorders. The pale deposits at the level of the retinal pigment epithelium—Bruch membrane seen in macular dystrophies have similar autofluorescence characteristics. This technique may be useful in detecting the abnormal phenotype in early disease.

Objective: To assess the rate of change in the central retinal venous closing pressure in central retinal vein obstruction over time, and its relationship to visual acuity improvement and the development of rubeosis iridis. Methods: Fifty patients presenting with central retinal vein obstruction of less than three months' duration, between the ages of 40 and 80 years, were reviewed prospectively. The central retinal venous closing pressure was measured by digital ocular compression. Patients were discharged from the study after the six-month visit. Results: All patients had elevated venous closing pressure at presentation, whereas at six months only 24 patients had persistent elevation. Of 16 patients with lowering of the venous closing pressure within four months of onset of central retinal vein obstruction, 11 (69%) had two or more lines of visual acuity improvement. Only two of 10 patients (20%) developing lowering of the venous closing pressure thereafter had visual improvement. No patient developed rubeosis iridis after the venous closing pressure lowered. Conclusion: The central retinal venous closing pressure is raised in central retinal vein obstruction to about central retinal arterial diastolic pressure, and is its pathognomonic sign. This sign is easily elicited via digital pressure on the eyelid, and has prognostic significance for visual acuity improvement and the development of rubeosis iridis.

Purpose: Central retinal vein obstruction (CRVO) has significant visual morbidity. We prospectively evaluated an outpatient haemodilution (HD) regimen for CRVO. Methods: We recruited 59 patients with CRVO of less than three months' duration and visual acuity (VA) worse than or equal to 6/9.5. Thirty patients underwent HD (packed cell volume of

X-linked retinitis pigmentosa (xlRP) is a severe progressive retinal degeneration which affects about 1 in 25,000 of the population. The most common form of xlRP, RP3, has been localised to the interval between CYBB and OTC in Xp21.1 by linkage analysis and deletion mapping. Identification of microdeletions within this region has now led to the positional cloning of a gene, RPGR, that spans 60 kg of genomic DNA and is ubiquitously expressed. The predicted 90 kD protein contains in its N-terminal half a tandem repeat structure highly similar to RCC1 (regulator of chromosome condensation), suggesting an interaction with a small GTPase. The C-terminal half contains a domain, rich in acidic residues, and ends in a potential isoprenylation anchorage site. The two intragenic deletions, two nonsense and three missense mutations within conserved domains provide evidence that RPGR (retinitis pigmentosa GTPase regulator) is the RP3 gene.

Progressive bifocal chorioretinal atrophy (PBCRA) is a rare, autosomal dominant congenital chorioretinal dystrophy. We have performed genetic linkage analysis on a five-generation British pedigree. Two-point linkage analysis showed significant linkage with nine microsatellite marker loci mapping to chromosome 6q. Multipoint analysis gave a maximum lod score of 11.8 (theta = 0.05) between D6S249 and D6S283. This region overlaps with that to which the gene for North Carolina macular dystrophy (MCDR1) has been assigned. However, given the range of differences in phenotype between these two retinal disorders, it is likely that different mutation mechanisms are responsible for each disease.

Purpose To assess the state of knowledge of photoreceptor dystrophies. Methods The current literature concerning photoreceptor dystrophies is reviewed, and their potential impact on concepts of pathogenesis of disease and clinical practice is assessed. Results As a result of cooperative investigative work between researchers in various disciplines, major advances in the classification of retinal photoreceptor dystrophies have been made. Until recently, classification of retinal dystrophies was based on clinical observation alone, and it was evident that this method was imprecise and of limited value. Largely through the work of molecular biologists, it has been shown that diseases clinically indistinguishable from one another may be a result of mutations on a variety of genes; conversely, different mutations on a single gene may give rise to a variety of phenotypes. It is reassuring that it is possible to generate concepts as to potential pathogenetic mechanisms that exist in retinal dystrophies in light of this new knowledge. More important for the clinician is the potential impact on clinical practice. There is as yet no therapy by which the course of most of these disorders can be modified. However, there is a considerable body of work in which therapeutic intervention is being explored, and many researchers now see treatment as a justifiable objective of their work. Conclusions Knowledge of the causative mutation is of value to the clinician in that it provides a precise diagnosis and allows the distribution of the abnormal gene to be documented fully within a family. To take full advantage of the opportunities provided by current research, clinical practice will have to be modified, particularly if therapy can be justified.

BACKGROUND--Variation of fluorescence derived from lipofuscin in the retinal pigment epithelium has been recorded with age and in retinal diseases. Studies have been based largely on in vitro observations on eye bank eyes which has placed severe limitations on the data available. METHODS--A technique is described whereby in vivo imaging of autofluorescence of the fundus was achieved using a scanning laser ophthalmoscope. RESULTS--The optical characteristics, distribution, and variation with disease imply that the fluorescence is derived from lipofuscin in the pigment epithelium. Autofluorescence is shown to be abnormally high in certain inherited diseases, and low in the presence of retinal atrophy. CONCLUSION--This technique may be useful both in clinical practice and research. It may allow the detection of the abnormal phenotype in genetically determined disease at a time when other techniques may not. Longitudinal studies of age related macular disease would permit correlation between changes in the pigment epithelium and Bruch's membrane to be established.

Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is commonly believed to be a benign disease with excellent visual prognosis. Identification of cases with poor visual outcome prompted this retrospective study of 33 eyes of 18 patients with this disorder. Loss of visual acuity at presentation was recorded in 25 eyes (76%), 22 of which had lesions at the fovea. Visual acuity quickly returned to normal or near normal levels (even when it was as poor as counting fingers at entry) in all but 7 eyes of 7 patients, in which visual acuity failed to recover to better than 6/24 over a period of several months. All these eyes had poor acuity and foveal involvement when first seen, and at least one of the following atypical features: age older than 60 years, unilaterality, an interval before involvement of the second eye of at least 6 months, recurrence of the disease, leakage from choroidal vein. One additional patient whose foveae were initially not involved lost vision in one eye because of the development of choroidal neovascularisation. Caution should be exercised in giving a prognosis in cases when the fovea is involved and the acuity markedly reduced, particularly if one or more atypical features is present.

OBJECTIVE: To describe the phenotype in a family with dominantly inherited cone-rod dystrophy with chromosome assignment to a 19q locus, and to correlate this with current classifications of this retinal dystrophy. DESIGN: A detailed clinical examination including Goldmann perimetry was undertaken in all family members. Six members under the age of 30 years underwent dark-adapted electroretinography, color contrast-sensitivity measurement, dark-adapted static perimetry, and dark adaptometry. PATIENTS: The study included 34 affected and 22 unaffected patients in four generations of a pedigree that manifested autosomal dominant cone-rod retinal dystrophy linked to a chromosome 19q locus by genetic linkage analysis. RESULTS: Loss of visual acuity occurred in the first decade of life, onset of night blindness occurred after 20 years of age, and little visual function remained after the age of 50 years. Central and, later, peripheral retinal fundus changes were associated with central scotoma, pseudoaltitudinal field defects, and finally global loss of function. Psychophysical and electrophysiologic testing before the age of 26 years showed more marked loss of cone than rod function. CONCLUSIONS: The phenotype associated with this mutation does not fit well into previous subtypes of cone-rod dystrophy. Further studies will be needed to correlate specific genetic mutations in this group of conditions with the various clinical phenotypes.

A method is described which permits measurement of colour contrast sensitivity in the retinal periphery. It has been applied to patients with autosomal dominant retinitis pigmentosa, in which the defect is caused by a defect in the gene coding for rhodopsin. In early and in mild cases, in which retinal function as judged by quantitative perimetry, threshold measurement and electroretinography is normal or nearly normal, there is a profound loss of colour contrast sensitivity outside the rod-free area. This may occur although cone thresholds are normal. An explanation may be that affected rods can inject ‘noise’ signals into the cone pathways.

OBJECTIVE: To define the phenotype of a retinal dystrophy associated with a 4-base pair insertion at codon 140 of the peripherin/RDS gene. PATIENTS: Six affected members spanning two generations of a single family were examined. Five were studied in detail electrophysiologically and psychophysically. METHODS: Psychophysical testing included color vision testing, photopic and scotopic static threshold perimetry, and dark adaptometry. Electrophysiological testing included flash and pattern electroretinography, as well as electrooculography. RESULTS: Clinical findings ranged from subtle pigmentary changes at the level of the retinal pigment epithelium to more widespread pigmentary changes associated with choroidal neovascularization. Those with severe fundus changes exhibited greater abnormalities in psychophysical and electrophysiological testing than those with minimal fundus changes. CONCLUSIONS: This particular peripherin/RDS gene mutation is associated with dominantly inherited pattern dystrophy of the retina. The phenotypic expression is variable in a manner not explained by age.

Dystrophies of the outer retina comprise a variety of disparate genetically determined conditions that differ from one to another in their mode of inheritance, their pattern of visual loss and their ophthalmoscopic appearances. Over the past few years, as a result of research by clinicians, biochemists, cell biologists and molecular biologists, an increasing number of distinct disorders have been recognized within this heterogeneous group, and some clues as to their pathogeneses have emerged. A number of nosological entities have been identified by detection of point mutations causing both autosomal dominant and recessive disease. In addition, in other conditions the locus of the abnormal gene has been defined. These discoveries are already having an impact on clinical management and the effect is likely to increase greatly in the near future.

To document the progression of a break in the photoreceptor inner segment/outer segment (IS/OS) junction layer and its functional correlates over time in the natural history of type 2 idiopathic macular telangiectasia (type 2 MacTel).Patients with at least 1 year of follow-up were selected from the MacTel Study. En face images were created by manual segmentation of the IS/OS junctional line in volume scans acquired using a spatial-domain optical coherence tomography retinal imaging unit. Retinal sensitivity thresholds were determined using a retinal microperimeter unit. Aggregate retinal sensitivity loss within IS/OS lesions was calculated. Changes over time in an area of IS/OS defects and retinal sensitivity were analyzed.thirty-nine eyes of 23 patients (mean age: 62.3 ± 9.2 years) were analyzed. Mean follow-up time was 1.9 years (range: 1-3 years). Mean IS/OS break area at baseline was 0.575 mm(2) (SE = 0.092, 95% confidence interval [CI]: 0.394-0.756 mm(2)). The cluster-adjusted mean annual progression rate in IS/OS break area was 0.140 mm(2) (SE = 0.040, 95% CI: 0.062-0.218 mm(2), P0.001). Mean aggregate retinal sensitivity loss was at baseline 28.56 dB (SE = 5.43, 95% CI: 17.32-39.80 dB, n = 28), a positive correlation with IS/OS lesion area was present (P0.001). The mean annual rate of change in aggregate sensitivity loss was 5.14 dB (SE = 1.51, 95% CI: 2.19-8.10 dB, P0.001, n = 37), a significant correlation with lesion area increase was found (P = 0.006).Both IS/OS break area and rate of enlargement correlate with aggregate retinal sensitivity loss in type 2 MacTel. En face OCT imaging of the IS/OS layer provides a functionally relevant method for documenting disease progression in type 2 MacTel.

We investigated abnormalities of the photoreceptor inner/outer segment (IS/OS) junction layer viewed "en face" and their functional correlates in type 2 idiopathic macular telangiectasia (type 2 MacTel).Segmentation and "en face" imaging of the IS/OS lines in spectral domain optical coherence tomographic (SD-OCT) volumes were performed manually. Mesopic retinal sensitivity thresholds were determined using a Nidek MP1 microperimeter. "En face" SD-OCT images and microperimetric data were superimposed over images of the fundus. Retinal structure and characteristics of type 2 MacTel were analyzed, and associations of structural changes with function were investigated.We examined 49 eyes of 28 patients (mean age 62.6 ± 9.4 years). Total IS/OS break area ranged from 0.04 to 2.23 mm² (mean 0.63 mm², SD 0.53 mm²) and 0.03 to 1.49 mm² (mean 0.49 mm², SD 0.42 mm²) in right and left eyes, respectively. A correlation between fellow eyes was present (Spearman correlation ρ = 0.770, P0.01). An assessment of the repeatability of IS/OS lesion area measurements (n = 19 eyes) revealed an intra-class correlation coefficient of 0.99 (95% confidence interval [CI] of 0.975-0.996). Retinal areas corresponding to an IS/OS break showed a mean retinal sensitivity of 8.3 ± 5.8 and 8.7 ± 5.7 decibels (dB) in right and left eyes, respectively. Mean sensitivity over retinal areas outside the lesion was significantly higher, 17.0 ± 3.3 and 16.7 ± 3.6 dB in right and left eyes, respectively (paired t-test, P0.01). Mean aggregate retinal sensitivity loss was 33.5 ± 30.4 dB (n = 40), correlating well with IS/OS lesion area (Pearson correlation coefficient = 0.848, P0.01)."En face" OCT imaging of the IS/OS junction layer provides a functionally relevant method for assessing disease severity in type 2 MacTel.