FUNDUS CHANGES IN BRANCH RETINAL ARTERIOLAR OCCLUSION.

PURPOSE: To investigate systematically various fundus changes in branch retinal arteriolar occlusion (BRAO) and their natural history. METHODS: The study comprised a cohort of 123 consecutive patients (135 eyes) with BRAO. Ophthalmic evaluation at initial and follow-up visits included recording visual acuity, visual fields, and detailed anterior segment and fundus examinations, and at initial visit fluorescein fundus angiography. RESULTS: Probability estimates of retinal infarct still present were 89% 1 week after BRAO onset, 69% after 2 weeks, 67% after 3 weeks, 34% after 1 month, and 13% after 3 months. Optic disk pallor in the involved region developed in 21% within 1 month from onset, in 42% by 2 months, and in 65% by 3 months. Retinal arteriolar attenuation developed in 19% within 1 month from onset, and in 28% by 6 months. Arteriolar sheathing developed in 19% within 1 month and 25% within 12 months. Arteriolar emboli were found in 58%; 65% of those were at initial visit, in BRAO seen within 1 week of onset. CONCLUSION: Most common cause of BRAO is embolism from the heart or carotid arteries; emboli usually get impacted at the arteriolar bifurcation. Migration and disappearance of retinal emboli is a common finding. Evolution of the retinal and optic disk changes is described.

Amaurosis fugax in ocular vascular occlusive disorders: prevalence and pathogeneses.

PURPOSE: To investigate systematically the prevalence of amaurosis fugax (AF) in various ocular vascular occlusive disorders individually and to discuss the pathogeneses of each. METHODS: The study comprised patients with central retinal artery occlusion (271 eyes), branch retinal artery occlusion (169 eyes), ocular ischemic syndrome (39 eyes), central retinal vein occlusion (864 eyes), hemi-central retinal vein occlusion (67 eyes), branch retinal vein occlusion (285 eyes), nonarteritic anterior ischemic optic neuropathy (946 eyes), and giant cell arteritis with visual loss (147 eyes). At first visit, all patients had a detailed ophthalmic and medical history and comprehensive ophthalmic evaluation and systemic evaluation. RESULTS: Prevalence of AF was 12.18% in central retinal artery occlusion, 14.20% in branch retinal artery occlusion, 15.38% in ocular ischemic syndrome, 4.86% in central retinal vein occlusion, 37.84% in central retinal vein occlusion with cilioretinal artery occlusion, 13.43% in hemi-central retinal vein occlusion, 0.35% in branch retinal vein occlusion, and 2.54% in nonarteritic anterior ischemic optic neuropathy. In giant cell arteritis, 32.4% of patients with ocular involvement had a history of AF or 26.5% of the involved eyes. Amaurosis fugax in central retinal artery occlusion, branch retinal artery occlusion, and nonarteritic anterior ischemic optic neuropathy is mostly because of transient embolism. The pathogenesis of AF in each ocular vascular occlusive disorder is discussed. CONCLUSION: Prevalence and pathogenesis of AF in various ocular vascular occlusive disorders varies widely. Amaurosis fugax may be the presenting symptom in these disorders and that always requires urgent evaluation.

Pathogenesis of Terson syndrome.

Purpose: The aim of this experimental study was to investigate the pathogenesis of Terson syndrome (TS), which currently is controversial. Methods: The central retinal artery (in 39 orbits), posterior ciliary arteries (in 8 orbits), and central retinal vein (CRV in 21 orbits) were occluded in rhesus monkeys by exposing them to lateral orbitotomy. Fundus examination and fluorescein fundus angiography were performed before and immediately after cutting the vessels and serially thereafter during the follow-up period. The rationale of the experimental study design is discussed. Results: In eyes with central retinal artery occlusion, retinal hemorrhages were seen soon after the procedure in 7 eyes, and on follow-up in a total of 15 eyes. In posterior ciliary artery occlusion, retinal hemorrhages were seen soon after the procedure in one eye, and on follow-up in a total of three eyes. In eyes with CRV, all eyes had extensive scattered retinal hemorrhages. Conclusion: The findings of this experimental study, and my basic, experimental, and comprehensive clinical studies on CRVO, suggest the following concept of the pathogenesis of TS: Compression of the CRV plays a crucial role in the development of TS. The CRV is compressed, as it lies in the subarachnoid space of the optic nerve sheath, by raised cerebrospinal fluid pressure and/or accumulated blood. . This results in retinal: venous stasis and raised venous pressure in the retinal veins, leading to venous engorgement, rupture of the retinal capillaries. and: retinal hemorrhages. The clinical importance of compression of the CRV and not occlusion of CRV in TS is that optic nerve sheath decompression by opening it and releasing the blood and raised cerebrospinal fluid (CSF) pressure, would result in immediate decompressing of the CRV in the subarachnoid space and restoration of normal circulation and prevent visual loss.

Heritable features of the optic disc: a novel twin method for determining genetic significance.

PURPOSE: Numerous genetic diseases and environmental stimuli affect optic nerve morphology. The purpose of this study was to identify the principal heritable components of visible optic nerve head structures in a population-based sample of twins. METHODS: Fifteen optic nerve specialists viewed stereoscopic optic nerve head photographs (Stereo Viewer-II; Pentax Corp., Tokyo, Japan) from 50 randomly selected monozygotic or dizygotic twin pairs. Before viewing, each expert was questioned about which optic nerve head traits they believed were inherited. After viewing a standardized teaching set, the experts indicated which twin pairs they thought were monozygotic. Participants were then questioned about how their decisions were reached. A rank-ordered Rasch analysis was used to determine the relative weighting and value applied to specific optic nerve head traits. RESULTS: The proportion of twin pairs for which zygosity was correctly identified ranged from 74% to 90% (median, 82%) across the panel. Experts who correctly identified the zygosity in more than 85% of cases placed most weighting on shape and size of the optic disc and cup, whereas experts with the lowest scores placed greater weighting on the optic nerve head vasculature in reaching their decisions. CONCLUSIONS: In determining the genetic components of the optic nerve head, the results of this study suggest that the shape and size of the optic disc and cup are more heritable and should receive a greater priority for quantification than should vascular features.

Mitochondrial variant G4132A is associated with familial non-arteritic anterior ischemic optic neuropathy in one large pedigree.

OBJECTIVE: To identify the genetic factors associated with familial non-arteritic anterior ischemic optic neuropathy (NA-AION) in a large pedigree. METHODS: Eleven family members of a single pedigree, including six affected with NA-AION, underwent detailed clinical examinations. The mitochondrial DNA of the proband was sequenced in its entirety in search of disease-causing mutations associated with NA-AION in the pedigree. A control panel comprising 1488 patients suspected of having Leber hereditary optic neuropathy (LHON) and 97 general-population control subjects was screened for the mitochondrial sequence variant identified in the family. RESULTS: Affected family members were all male and exhibited classic features of NA-AION. Their mean age was 50.2 +/- 5.0 years. A total of 23 sequence variations were detected in the mitochondrial genome of the proband, including one novel sequence variation (G4132A, Ala276Thr) in the NADH dehydrogenase subunit 1 gene (ND1). The G4132A mitochondrial variant was detected in six members of a single pedigree with NA-AION. The G4132A variation was not observed in any of the 1585 subjects in the control panel. Moreover, this variant was not identified in over 2469 ethnically diverse individuals previously evaluated through the Human Mitochondrial Genome Database. None of the three major mutations associated with LHON (G3460A, G11778A, T14484C) were identified in the family. CONCLUSION: The G4132A mitochondrial variation is associated with familial NA-AION in our pedigree.

Lamina cribrosa thickness correlated with posterior scleral thickness and axial length in monkeys.

PURPOSE: To explore associations of lamina cribrosa thickness with axial length and thickness of the posterior sclera in monkeys. METHODS: Examining histological sections by light microscopy, we measured the thickness of the lamina cribrosa and posterior sclera and axial length. RESULTS: The study included 28 animals (28 eyes) with a mean age of 13.3 ± 4.9 years (range: 3-24 years) and mean axial length of 18.9 ± 1.4 mm (range: 17-21 mm) (22 eyes after experimental temporary central retinal artery occlusion; four eyes after a permanent occlusion of the posterior ciliary artery; and two eyes without any intervention). Mean thickness of the lamina cribrosa was 167 ± 30 µm (range: 115-273 µm). Thinner lamina cribrosa thickness was significantly associated with longer axial length (standardized correlation coefficient beta: -0.42; p = 0.026), with thinner sclera at the posterior pole (beta: 0.56; p = 0.002) and with thinner sclera at the disc border (beta: 0.55; p = 0.002). Lamina cribrosa thickness was not significantly related to temporary central retinal artery occlusion (p = 0.14) or to permanent posterior ciliary artery occlusion (p = 0.49) or age (p = 0.46). CONCLUSIONS: As in humans, lamina cribrosa thickness in non-glaucomatous monkeys got thinner with longer axial length and with thinner posterior sclera. These data may be of interest for studies on the process of emmetropization/myopization in monkeys, and they may be of interest for the studies on the biomechanics of the optic nerve head.

Variations in the myocilin gene in patients with open-angle glaucoma.

OBJECTIVE: To determine the prevalence and associated phenotype of myocilin (MYOC) coding sequence variations and a specific promoter polymorphism (MYOC.mt1) in patients with glaucoma and glaucoma suspects. METHODS: A consecutive, unselected series of 779 patients (652 with open-angle glaucoma and 127 glaucoma suspects) were recruited from a university medical center and clinically characterized. The coding sequences of the MYOC gene and the MYOC.mt1 locus in the promoter region were screened for sequence variations. We determined the prevalence of MYOC coding sequence mutations and the MYOC.mt1 promoter polymorphism. We also compared the clinical features of individuals with and without mutations and the MYOC.mt1 promoter polymorphism. RESULTS: Plausible disease-causing sequence variations (DCVs) in the MYOC gene were found in 3.0% of the entire group. Such variations were found in patients with most forms of open-angle glaucoma studied. Patients with primary open-angle glaucoma (POAG) who harbored coding sequence DCVs were clinically similar to patients without them. Patients who harbored the rarer allele of the MYOC.mt1 promoter polymorphism were no different in any measure of disease severity from those who harbored the more common allele. CONCLUSIONS: MYOC DCVs were found in approximately 3% of patients with glaucoma and glaucoma suspects. The 2 alleles of the MYOC.mt1 promoter polymorphism were equally distributed among patients with POAG and healthy control subjects. Patients with POAG who harbored the rarer allele of the MYOC.mt1 promoter polymorphism were no different from those with the more common variant in any measure of disease severity. CLINICAL RELEVANCE: Testing for the MYOC.mt1 promoter polymorphism appears to be of no value in the evaluation of patients with glaucoma.

Evaluation of optineurin sequence variations in 1,048 patients with open-angle glaucoma.

PURPOSE: To investigate the association of sequence variations in the optineurin (OPTN) gene in patients with open-angle glaucoma. DESIGN: Prospective case control study. METHODS: The OPTN gene was screened for sequence variations using a combination of single-strand conformational polymorphism analysis and automated DNA sequencing. A total of 1,299 subjects (1048 glaucoma patients and 251 controls) were screened for variations in the four portions of the gene that had been previously associated with glaucoma. A subset of these subjects (376 patients and 176 controls) was screened for variations in the entire coding sequence. Twenty-four percent of the patients and 35% of the controls were Japanese, whereas the remainder were predominantly Caucasian. Allele frequencies were compared with the Fisher exact test. RESULTS: The OPTN sequence variations were not significantly associated with any form of high-tension open-angle glaucoma. One proband with familial normal-tension glaucoma was found to harbor the previously reported Glu50Lys variation. Another previously reported change, Met98Lys, was associated with normal-tension glaucoma in Japanese but not in Caucasian patients. CONCLUSIONS: This study provides some additional evidence for the association of the Glu50Lys OPTN sequence variation with familial normal tension glaucoma. However, because familial normal-tension glaucoma is so rare, this change seems to be responsible for less than 0.1% of all open-angle glaucoma. The Arg545Gln variation is likely to be a nondisease-causing polymorphism. The Met98Lys change may be associated with a fraction of normal-tension glaucoma in patients of Japanese ethnicity.

Clinicopathological correlation of parapapillary atrophy in monkeys with experimental glaucoma and temporary central retinal artery occlusion.

OBJECTIVE: To investigate the clinicopathological correlation of parapapillary atrophy. MATERIALS AND METHODS: The study included 16 eyes of rhesus monkeys (Macaca mulatta) - 4 eyes with experimental glaucoma, 11 eyes after experimental temporary occlusion of the central retinal artery, and 1 normal eye. On histological sections, we measured zones with different histological characteristics.On fundus photographs, alpha zone and beta zone of parapapillary atrophy were measured and correlated with the histological data. RESULTS: The size of the clinical alpha zone of parapapillary atrophy was significantly correlated with the size of the histological region with irregularities of the retinal pigment epithelium (P = 0.05; correlation coefficient r = 0.49) and with the size of the histological region with a decreased density of retinal photoreceptors (P = 0.01; r = 0.60). The size of clinical beta zone of parapapillary atrophy significantly correlated with the size of the histological region with complete loss of the retinal pigment epithelium (P <0.001; r = 0.91), with the size of the histological zone with a complete loss of photoreceptors (P <0.001; r = 0.81), and with the size of the histological zone with a closed choriocapillaris (P <0.001; r = 0.89). CONCLUSIONS: The clinically seen alpha zone of parapapillary atrophy correlates with histological parapapillary irregularities of the retinal pigment epithelium and decreased density of retinal photoreceptors. The clinically seen beta zone of parapapillary atrophy correlates with histological complete loss of the retinal pigment epithelium and of the photoreceptors, and a closure of the choriocapillaris.

Thickness of the lamina cribrosa and peripapillary sclera in Rhesus monkeys with nonglaucomatous or glaucomatous optic neuropathy.

PURPOSE: To measure the thickness of the lamina cribrosa and peripapillary sclera in monkeys with a nonglaucomatous optic nerve damage and to compare that with those of monkeys with glaucomatous optic neuropathy. METHODS: The study included 22 monkey eyes (Macaca mulatta) which had undergone a temporary experimental central retinal artery occlusion (CRAO) and seven monkey eyes in which experimental glaucoma was unilaterally produced. We measured histomorphometrically the thickness of the lamina cribrosa and peripapillary sclera. RESULTS: The lamina cribrosa was significantly thicker in the CRAO group than in the glaucoma group (central region: 212 ± 46 µm versus 167 ± 17 µm; p = 0.009). The thickness of the peripapillary sclera at the optic disc border (253 ± 39 µm versus 192 ± 21 µm; p = 0.001) and outside of the optic nerve meninges (408 ± 70 µm versus 314 ± 64 µm; p = 0.006) was significantly greater in the CRAO group. CONCLUSIONS: In monkey eyes with a temporary CRAO as a model for nonglaucomatous optic nerve damage, the lamina cribrosa is significantly thicker than in monkey eyes with experimental glaucomatous optic nerve damage. It may suggest that the loss of optic nerve fibres might not be the reason for the thinning of the lamina cribrosa in eyes with advanced glaucoma. The thinner peripapillary sclera in the glaucomatous eyes may suggest that the monkey sclera is more vulnerable to stretching with increased intraocular pressure than the human eye for which no glaucoma-related lengthening of the eyeball and thinning of the peripapillary sclera have been observed.

Rate and pattern of visual field decline in primary open-angle glaucoma.

PURPOSE: To study the rate and pattern of visual field decline in primary open-angle glaucoma. DESIGN: Retrospective observational case series. PARTICIPANTS: Forty eyes of 40 patients with primary open-angle glaucoma that were followed longitudinally with serial Goldmann visual fields for a minimum period of 8 years in an academic institution. Eyes with any other ocular disease except for mild cataract were excluded. METHODS: Visual fields obtained with worse than 20/50 Snellen visual acuity from cataract were excluded from analysis. In the remainder (671 Goldmann visual fields), the I4e isopter was quantified manually using a grid template previously described by Esterman. The visual field was divided into central and peripheral, superior and inferior, and nasal and temporal regions, all centered at the blind spot. The rate of visual field decline was estimated for each visual field region (including the four quadrants: superonasal [SN], superotemporal [ST], inferotemporal [IT], and inferonasal [IN]) using linear regression. Asymmetry of visual field progression was determined by comparing the rates of progression among the four quadrants. Pertinent clinical factors were evaluated for association with the asymmetry of visual field progression. MAIN OUTCOME MEASURES: Rates of visual field decline for the entire visual field and each region. Long-term clinical outcome measures, including visual acuity, cataract and cup-to-disc ratio progression, intraocular pressures, and medical and surgical interventions were also studied. RESULTS: The rate of visual field change was -1.3% per year for the entire visual field. The rates of visual field section change (in % per year) were -1.3 (central), -1.4 (peripheral), -1.5 (superior), -1.2 (inferior), -1.4 (nasal), -1.2 (temporal), -1.8 (SN), -1.3 (IT), -1.2 (IN), and -1.1 (ST). About half the patients showed symmetric visual field decline, whereas others showed a more asymmetric pattern. Asymmetric visual field progression was associated with the presence of disc hemorrhage, overall rate of visual field progression, and surgical intervention for glaucoma. CONCLUSIONS: In this group of selected patients with primary open-angle glaucoma with a long-term follow-up, all sections of the visual field declined over time. Disc hemorrhage was associated with more asymmetric visual field progression, implicating focal damage to the optic disc.