Faculty Bibliography

PURPOSE: To better understand the relationship between the spatial patterns of functional (visual field [VF] loss) and structural (axon loss) abnormalities in patients with glaucomatous arcuate defects largely confined to the central 10 degrees on achromatic perimetry. METHODS: Eleven eyes (9 patients) with arcuate glaucomatous VF defects largely confined to the macula were selected from a larger group of patients with both 10-2 and 24-2 VF tests. Eyes were included if their 10-2 VF had an arcuate defect and if the 24-2 test was normal outside the central 10 degrees (i.e., did not have a cluster of three contiguous points within a hemifield). For the structural analysis, plots of retinal nerve fiber layer (RNFL) thickness of the macula were obtained with frequency-domain optical coherence tomography (fdOCT). The optic disc locations of the RNFL defects were identified on peripapillary fdOCT scans. RESULTS: The VF arcuate defects extended to within 1 degrees of fixation on the 10-2 test and were present in the superior hemifield in 10 of the 11 eyes. The arcuate RNFL damage, seen in the macular fdOCT scans of all 11 eyes, involved the temporal and inferior temporal portions of the disc on the peripapillary scans. CONCLUSIONS: Glaucomatous arcuate defects of the macula's RNFL meet the disc temporal to the peak of the main arcuate bundles and produce a range of macular VF defects from clear arcuate scotomas to a papillofoveal horizontal step ('pistol barrel scotoma'). If RGC displacement is taken into consideration, the RNFL and VF defects can be compared directly

PURPOSE: To describe the structural changes in the transition zone from relatively healthy retinal regions to severely affected regions in patients with retinitis pigmentosa (RP) using frequency domain optical coherence tomography (fdOCT). METHODS: FdOCT line scans of the horizontal meridian were obtained from one eye of 13 patients with RP and 30 control subjects. The patients had normal or near normal foveal sensitivities and visual field diameters >/=10 degrees . Using a computer-aided manual segmentation procedure, the locations at which the outer segment (OS) and outer nuclear layer plus outer plexiform layer (ONL+) thicknesses fell below the 95% confidence interval of the controls were measured, as were the locations at which the OS layer disappeared and the locations at which the ONL+ was reduced to an asymptotically small thickness. RESULTS: The progression from healthy to severely affected regions followed a common pattern in most patients. Region A, the central region including the foveal center, had normal OS and ONL+ thickness. Region B had abnormal OS but normal ONL+ thickness. Region C had abnormal but measurable OS and ONL+ thicknesses. In Region D, the OS layer disappeared, as did the IS/OS line, and the ONL+ thickness decreased further. In Region E, the ONL+ reached an asymptotic thickness. CONCLUSIONS: The structural changes in the transition zone followed an orderly progression from a thinning of the OS layer, to a thinning of the ONL+, to a loss of the OS layer, to an ONL+ reduced to an asymptotically small level

PURPOSE: To compare glaucoma progression by functional and structural tests. METHODS: The authors prospectively studied 33 glaucoma patients (55 eyes); 20 eyes (15 patients) had disc hemorrhage, and 35 eyes (18 patients) had exfoliation glaucoma. The following tests were performed at two baseline and three follow-up examinations: frequency doubling perimetry (FDT), 24-2 Humphrey visual fields (HVF), multifocal visual evoked potentials (mfVEP), and optical coherence tomography (OCT). To identify progression, the baseline measurements were averaged and compared to those obtained at the final examination. Stereophotographs of the optic disc were obtained at baseline and compared with those at the final examination. RESULTS: Patients were followed up for 21.1+/-1.8 months. For HVF there were significant changes in mean deviation (MD) in eight (14.5%) eyes but in pattern standard deviation (P/SD) in only two (3.6%) eyes. For FDT, there were significant changes in MD in 13 (23.6%) eyes. Five eyes showed changes in MD for HVF and FDT. For mfVEP, there was an increase in abnormal points in nine (16.4%) eyes. Six of these eyes did not show significant HVF or FDT changes. For OCT, RNFL average thickness values were significantly decreased in nine (16.4%) eyes. Nine (16.4%) eyes showed progression on stereophotography; four of these eyes did not show significant changes on OCT and functional tests. CONCLUSIONS: Each test showed evidence of progression in some eyes. However, agreement among tests and stereophotography regarding which eyes showed progression was poor, illustrating the importance of following up patients with a combination of functional and structural tests

OBJECTIVE: To determine whether visual field expansion occurs with visual restoration therapy (VRT), using fundus-controlled microperimetry to assess visual fields. DESIGN: This longitudinal cohort analysis assesses patients' visual fields before and after visual restoration therapy using microperimetry and standard high-resolution perimetry. SUBJECTS: Seven patients with stroke-induced homonymous field cuts were studied. INTERVENTION: Visual restoration therapy is a computerized, home-based treatment aimed at reducing the size of the visual field defect of stroke patients with hemianopia through repetitive stimulation of the visual borderzone adjacent to the blind field. During twice-daily therapy for three months patients maintain central fixation while responding to eccentrically placed stimuli in the visual borderzone. The programme is adjusted monthly to changes in the patient's visual field. Controversy exists as to whether expansion of visual fields measured at home with high-resolution perimetry is due to inadvertent eye movements and therefore would overrepresent the treatment's effect. MAIN MEASURES: Microperimentry uses an infrared camera to track retinal vessels so that any shift or movement between the reference image and the real-time fundus image corrects the stimulus position, thus delivering stimuli to known retinal locations, and allowing accurate assessment of visual fields independent of eye movements. RESULTS: There was an average improvement in stimulus detection rate by microperimetry of 12.5% (range -1.4% to 38.9%, P =0.033). Six of 7 patients had >/= 3% improvement in stimulus detection by home-based perimetry. CONCLUSION: Our results demonstrate modest but real expansion in visual fields following visual restoration therapy which is not due to eye movements

To compare the ability of the multifocal electroretinogram (mfERG) and frequency domain optical coherence tomography (fdOCT) to detect retinal abnormalities. A total of 198 eyes (100 patients) were referred by neuro-ophthalmologists to rule out a retinal etiology of visual impairment. All patients were evaluated with static automated perimetry (SAP) (Humphrey Visual Field Analyzer; Zeiss Meditec), mfERG (Veris, EDI) and fdOCT (3D-OCT 1000, Topcon). The mfERG was performed with 103 scaled hexagons and procedures conforming to ISCEV standards (Hood DC et al. (2008) Doc Ophthalmol 116(1):1-11). The fdOCT imaging included horizontal and vertical line scans through the fovea. Local mfERG and fdOCT abnormalities were compared to local regions of visual field sensitivity loss measured with SAP and categorized as normal/inconclusive or abnormal. 146 eyes were categorized as normal retina on both fdOCT and mfERG. The retina of 52 eyes (36 patients) was categorized as abnormal based upon mfERG and/or fdOCT. Of this group, 25 eyes (20 patients) were abnormal on both tests. However, 20 eyes (13 patients) were abnormal on mfERG, while the fdOCT was normal/inconclusive; and 7 eyes (7 patients) had normal or inconclusive mfERG, but abnormal fdOCT. Considerable disagreement exists between these two methods for detection of retinal abnormalities. The mfERG tends to miss small local abnormalities that are detectable on the fdOCT. On the other hand, the fdOCT can appear normal in the face of clearly abnormal mfERG and SAP results. While improved imaging and analysis may show fdOCT abnormalities in some cases, in others early damage may not appear on structural tests

PURPOSE: To compare visual field defects obtained with both multifocal visual evoked potential (mfVEP) and Humphrey visual field (HVF) techniques to topographic optic disc measurements in patients with normal tension glaucoma (NTG) and high tension glaucoma (HTG). METHODS: We studied 32 patients with NTG and 32 with HTG. All patients had reliable 24-2 HVFs with a mean deviation of -10 dB or better, a glaucomatous optic disc and an abnormal HVF in at least 1 eye. Multifocal VEPs were obtained from each eye and probability plots created. The mfVEP and HVF probability plots were divided into a central 10-degree radius and an outer arcuate subfield in both superior and inferior hemifields. Cluster analyses and counts of abnormal points were performed in each subfield. Optic disc images were obtained with the Heidelberg Retina Tomograph III. Eleven stereometric parameters were calculated. Moorfields regression analysis and the glaucoma probability score were performed. RESULTS: There were no significant differences in mean deviation and pattern standard deviation values between NTG and HTG eyes. However, NTG eyes had a higher percentage of abnormal test points and clusters of abnormal points in the central subfields on both mfVEP and HVF than HTG eyes. For Heidelberg Retina Tomograph III, there were no significant differences in the 11 stereometric parameters or in the Moorfields regression analysis and glaucoma probability score analyses of the optic disc images. CONCLUSIONS: The visual field data suggest more localized and central defects for NTG than HTG

PURPOSE: To improve the understanding of Stargardt disease by comparing structural changes seen on spectral domain optical coherence tomography (SD-OCT) to those visible on fundus autofluorescence (FAF). METHODS: FAF and SD-OCT were performed on 22 eyes of 11 patients with Stargardt disease. SD-OCT images were obtained at the fovea and at the eccentric preferred retinal locus (PRL). The diameters of absent (hypoautofluorescence) and abnormal FAF areas were measured. The extent of the transverse defect of the junction between the inner and outer segments of the photoreceptors (IS-OS) was measured in the foveal area. The PRL was evaluated with fundus photography and microperimetry. RESULTS: Twenty-one of 22 eyes showed defective FAF. In 17 eyes, FAF was absent in the fovea and in four eyes, FAF was abnormal. All eyes showed disorganization and/or loss of the IS-OS junction in the foveal area on SD-OCT. The diameter of the absent FAF area was smaller than the measurement of the IS-OS junction loss; the latter was closer to the diameter of the abnormal FAF area. Seventeen eyes had an eccentric PRL associated with a retinal area with no defects on FAF. CONCLUSIONS: In the majority of eyes, changes shown by SD-OCT correlated well with changes in FAF. However, in three patients, photoreceptor abnormalities were seen in the fovea on SD-OCT without an equivalent abnormality on FAF. This result suggests that in these patients, the structural integrity of the photoreceptors may be affected earlier than changes in the RPE at least as detected by FAF

The aim of this study was to characterize the pathological and functional consequences of the G1961E mutant allele in the Stargardt disease gene ABCA4. Data from 15 patients were retrospectively reviewed and all the patients had at least one G1961E mutation. Comprehensive ophthalmic examination, full-field and pattern electroretinograms, and fundus autofluorescence (FAF) imaging were performed on all patients. Microperimetry, spectral-domain optical coherence tomography (OCT), and fluorescein angiography were performed in selected cases. Genetic screening was performed using the ABCR400 micro-array that currently detects 496 distinct ABCA4 variants. All patients had normal full-field scotopic and photopic electroretinograms (ERGs) and abnormal pattern electroretinograms (PERGs) performed on both eyes, and all the fundi had bull's eye maculopathy without retinal flecks on FAF. On OCT, 1 patient had disorganization of photoreceptor outer segment, 2 had outer nuclear layer (ONL) thinning likely due to photoreceptor atrophy proximal to the foveal center, and 3 had additional retinal pigment epithelium (RPE) atrophy. On microperimetry, 6 patients had eccentric superior fixation and amongst this group, 5 had an absolute scotoma in the foveal area. DNA analysis revealed that 3 patients were homozygous G1961E/G1961E and the rest were compound heterozygotes for G1961E and other ABCA4 mutations. The G1961E allele in either homozygosity or heterozygosity is associated with anatomical and functional pathologies limited to the parafoveal region and a trend to delayed onset of symptoms, relative to other manifestations of ABCA4 mutations. Our observations support the hypothesis that the G1961E allele contributes to localized macular changes rather than generalized retinal dysfunction, and is a cause of bull's eye maculopathy in either the homozygosity or heterozygosity state. In addition, genetic testing provides precise diagnosis of the underlying maculopathy, and current non-invasive imaging techniques could be used to detect photoreceptor damage at the earliest clinical onset of the disease

PURPOSE: To analyze the retinal structure underlying the hyperautofluorescent ring visible on fundus autofluorescence in patients with retinitis pigmentosa. METHODS: Twenty-four eyes of 13 patients with retinitis pigmentosa, aged 13 years to 67 years, were studied. The integrity of the photoreceptor cilia, also known as the inner/outer segment junction of the photoreceptors, the outer nuclear layer, and retinal pigment epithelium, was evaluated outside, across, and inside the ring with spectral-domain optical coherence tomography (OCT). RESULTS: Inside the foveal area, fundus autofluorescence did not detect abnormalities. Outside the ring, fundus autofluorescence revealed hypoautofluorescence compatible with the photoreceptor/retinal pigment epithelium degeneration. Spectral-domain OCT inside the ring, in the area of normal foveal fundus autofluorescence, revealed an intact retinal structure in all eyes and total retinal thickness values that were within normal limits. Across the ring, inner/outer segment junction disruption was observed and the outer nuclear layer was decreased in thickness in a centrifugal direction in all eyes. Outside the hyperautofluorescent ring, the inner/outer segment junction and the outer nuclear layer appeared to be absent and there were signs of retinal pigment epithelium degeneration. CONCLUSION: Disruption of the inner/outer segment junction and a decrease in outer retinal thickness were found across the central hyperautofluorescent ring seen in retinitis pigmentosa. Outer segment phagocytosis by retinal pigment epithelium is necessary for the formation of an hyperautofluorescent ring

PURPOSE: To describe a method for monitoring progression of glaucoma using the multifocal visual evoked potential (mfVEP) technique. METHODS: Eighty-seven patients diagnosed with open-angle glaucoma were divided into two groups. Group I, comprised 43 patients who had a repeat mfVEP test within 50 days (mean 0.9 +/- 0.5 months), and group II, 44 patients who had a repeat test after at least 6 months (mean 20.7 +/- 9.7 months). Monocular mfVEPs were obtained using a 60-sector pattern reversal dartboard display. Monocular and interocular analyses were performed. Data from the two visits were compared. The total number of abnormal test points with P < 5% within the visual field (total scores) and number of abnormal test points within a cluster (cluster size) were calculated. Data for group I provided a measure of test-retest variability independent of disease progression. Data for group II provided a possible measure of progression. RESULTS: The difference in the total scores for group II between visit 1 and visit 2 for the interocular and monocular comparison was significant (P < 0.05) as was the difference in cluster size for the interocular comparison (P < 0.05). Group I did not show a significant change in either total score or cluster size. CONCLUSION: The change in the total score and cluster size over time provides a possible method for assessing progression of glaucoma with the mfVEP technique