Vivienne C. Greenstein

Multifocal VEP and ganglion cell damage: applications and limitations for the study of glaucoma.

With the multifocal technique, visual evoked potentials (VEPs) can be recorded simultaneously from many regions of the visual field in a matter of minutes. Recently, the multifocal visual evoked potential technique (mfVEP) has generated considerable interest, especially among those seeking objective measures of glaucomatous damage. It is well accepted that significant ganglion cell damage can occur before functional deficits are detected with static automated achromatic perimetry, the gold standard for detecting and monitoring glaucomatous damage. In this article, we ask the following questions: What are the potential applications of the mfVEP technique? What are its limitations? To what extent will it replace or augment static automated achromatic perimetry? To answer these questions requires an understanding of the mfVEP technique, as well as techniques needed to relate its results to those of automated perimetry. describes how the mfVEP is elicited, recorded, derived and displayed. If both eyes of an individual are normal, then mfVEPs recorded for monocular stimulation of each eye are essentially identical. However, the amplitude and waveform of the mfVEP responses vary across individuals, as well as across the visual field within an individual. These variations in the normal mfVEPs are described in Section 3. In, these variations are related to cortical anatomy, and to the cortical sources contributing to the mfVEP. The mfVEP is predominantly generated in V1. Although there are undoubtedly extrastriate contributions, these contributions are probably smaller for the mfVEP than for the conventional VEP. The mfVEP is not a small version of the conventional VEP. To detect ganglion cell damage with the mfVEP requires methods for analyzing the responses and for displaying the results. In, a method for detecting ganglion cell damage is described. This method compares the monocular responses from the two eyes of an individual and produces a map of the defects. This map is in the form of a probability plot similar to the one used to display visual field defects measured with automated perimetry. Procedures are described for directly comparing these mfVEP probability plots to the probability plots for Humphrey visual fields (HVFs). The interocular mfVEP test described in will not be sensitive to bilateral damage. describes a test based upon monocular mfVEPs. The statistical basis of the monocular mfVEP test is relatively complex (see ). In any case, under many conditions the interocular test will be more sensitive and this is discussed in. summarizes a number of clinical applications of the mfVEP and concludes that the mfVEP has a place in the clinical management of glaucoma. To understand the limitations of the mfVEP, a signal-to-noise ratio (SNR) approach is described in. Using the techniques described in, the relationship between the amplitude of the mfVEP and the sensitivity loss of the HVF is discussed in. The evidence supports a simple model in which the amplitude of the signal portion, but not the noise portion, of the mfVEP response is proportional to HVF loss where HVF loss is expressed in linear, not dB, units. It is hypothesized that both the signal in the mfVEP, and the sensitivity of the HVF, are linearly related to ganglion cell loss. A theoretical approach, developed in, allows a direct comparison of the efficacy of the mfVEP and HVF in detecting glaucomatous damage. In short, when the mfVEP has a large SNR it will often be superior to the HVF in detecting damage. On the other hand, when the mfVEP has a small SNR, the HVF will probably be superior. summarizes the relative advantages of the HVF and the mfVEP. In summary, the mfVEP does have a place in the clinical management of glaucoma, although it is not likely to replace static automated achromatic perimetry in the near future. However, this is an evolving technology and the future will undoubtedly see major improvements in the mfVEP technique.

The Transition Zone between Healthy and Diseased Retina in Patients with Retinitis Pigmentosa

PURPOSEnTo 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).nnnMETHODSnFdOCT 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°. 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.nnnRESULTSnThe 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.nnnCONCLUSIONSnThe 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.

Method for deriving visual field boundaries from OCT scans of patients with retinitis pigmentosa.

The location of the loss of the inner segment (IS)/outer segment (OS) border, as seen with frequency domain optical coherence tomography (fdOCT), was determined on fdOCT scans from patients with retinitis pigmentosa. A comparison to visual field loss supported the hypothesis, based upon previous work, that the point at which the IS/OS border disappears provides a structural marker for the edge of the visual field. Repeat fdOCT measures showed good within day reproducibility, while data obtained on average 22.5 months later showed signs of progression. The IS/OS contour shows promise as a measure for following changes in patients undergoing treatment.

Progressive Constriction of the Hyperautofluorescent Ring in Retinitis Pigmentosa

PURPOSEnTo evaluate the constriction of the hyperautofluorescent ring over time in patients with retinitis pigmentosa (RP).nnnDESIGNnProspective study.nnnMETHODSnFourteen eyes of 14 RP patients with a hyperautofluorescent ring were studied. Ring constriction was evaluated by measurements of its external and internal boundaries along the vertical and horizontal axes at baseline and at 12-, 24-, 36-, and 48-month follow-ups. Repeat fundus autofluorescence was obtained at 12, 24, 36, and 48 months in 13, 7, 5, and 1 eyes respectively. Spectral-domain optical coherence tomography (SD-OCT) images were obtained on 8 eyes and the horizontal extent of the inner segment/outer segment (IS/OS) junction was measured. SD-OCT was repeated at 12 and 24 months in 6 and 4 eyes respectively.nnnRESULTSnThe external boundaries of the ring were identified along the horizontal axis in 12 eyes and along the vertical axis in 13. Internal boundaries were identified in 7 eyes. Constriction was demonstrated in all patients except 1 who demonstrated minimal expansion of the internal boundary along the horizontal axis. SD-OCT measurements showed a decrease in the IS/OS junction length.nnnCONCLUSIONnProgressive constriction of the hyperautofluorescent ring and a concordant decrease in IS/OS junction length were observed over time.

Transition zones between healthy and diseased retina in choroideremia (CHM) and Stargardt disease (STGD) as compared to retinitis pigmentosa (RP).

PURPOSEnTo describe the structural changes across the transition zone (TZ) in choroideremia (CHM) and Stargardt disease (STGD) and to compare these to the TZ in retinitis pigmentosa (RP).nnnMETHODSnFrequency-domain (Fd)OCT line scans were obtained from seven patients with CHM, 20 with STGD, and 12 with RP and compared with those of 30 previously studied controls. A computer-aided manual segmentation procedure was used to determine the thicknesses of the outer segment (OS) layer, the outer nuclear layer plus outer plexiform layer (ONL+), the retinal pigment epithelium plus Bruchs membrane (RPE+BM), and the outer retina (OR).nnnRESULTSnThe TZ, while consistent within patient groups, showed differences across disease groups. In particular, (1) OS loss occurred before ONL+ loss in CHM and RP, whereas ONL+ loss occurred before OS loss in STGD; (2) ONL+ was preserved over a wider region of the retina in CHM than in RP; (3) RPE+BM remained normal across the RP TZ, but was typically thinned in CHM. In some CHM patients, it was abnormally thin in regions with normal OS and ONL+ thickness. In STGD, RPE+BM was thinned by the end of the TZ; and (4) the disappearances of the IS/OS and OLM were more abrupt in CHM and STGD than in RP.nnnCONCLUSIONSnOn fdOCT scans, patients with RP, CHM, and STGD all have a TZ between relatively healthy and severely affected retina. The patterns of changes in the receptor layers are similar within a disease category, but different across categories. The findings suggest that the pattern of progression of each disease is distinct and may offer clues for strategies in the development of future therapies.

A comparison of multifocal and conventional visual evoked potential techniques in patients with optic neuritis/multiple sclerosis

Purpose To compare conventional visual evoked potential (cVEP) and multifocal visual evoked potential (mfVEP) methods in patients with optic neuritis/multiple sclerosis (ON/MS). Methods mfVEPs and cVEPs were obtained from eyes of the 19 patients with multiple sclerosis confirmed on MRI scans, and from eyes of 40 normal controls. For the mfVEP, the display was a pattern-reversal dartboard array, 48° in diameter, which contained 60 sectors. Monocular cVEPs were obtained using a checkerboard stimulus with check sizes of 15′ and 60′. For the cVEP, the latency of P100 for both check sizes were measured, while for the mfVEP, the mean latency, percent of locations with abnormal latency, and clusters of contiguous abnormal locations were obtained. Results For a specificity of 95%, the mfVEP(interocular cluster criterion) showed the highest sensitivity (89.5%) of the 5 monocular or interocular tests. Similarly, when a combined monocular/interocular criterion was employed, the mfVEP(cluster criterion) had the highest sensitivity (94.7%)/specificity (90%), missing only one patient. The combined monocular/interocular cVEP(60′) test had a sensitivity (84.2%)/specificity (90%), missing 3 patients, 2 more than did the monocular/interocular mfVEP(cluster) test. Conclusion As the cVEP is more readily available and currently a shorter test, it should be used to screen patients for ON/MS with mfVEP testing added when the cVEP test is negative and the damage is local.

Structural and Functional Changes Associated with Normal and Abnormal Fundus Autofluorescence in Patients with Retinitis Pigmentosa

Purpose To analyze the structure and visual function of regions bordering the hyperautofluorescent ring/arcs in retinitis pigmentosa. Methods Twenty-one retinitis pigmentosa patients (21 eyes) with rings/arcs and 21 normal individuals (21 eyes) were studied. Visual sensitivity in the central 10° was measured with microperimetry. Retinal structure was evaluated with spectral-domain optical coherence tomography. The distance from the fovea to disruption/loss of the inner outer segment (IS/OS) junction and thicknesses of the total receptor plus retinal pigment epithelial complex and outer segment plus retinal pigment epithelial complex layers were measured. Results were compared with measurements of the distance from the fovea to the inner and outer borders of the ring/arc seen on fundus autofluorescence. Results Disruption/loss of the inner outer segment junction occurred closer to the inner border of the ring/arc and it was closer to the fovea in eight eyes. For 19 eyes, outer segment plus and receptor plus RPE complex thicknesses were significantly decreased at locations closer to the fovea than the appearance of the inner border of hyperautofluorescence. Mean visual sensitivity was decreased inside, across, and outside the ring/arc by 3.5 ± 3.8, 8.9 ± 4.8, and 17.0 ± 2.4 dB, respectively. Conclusion Structural and functional changes can occur inside the hyperfluorescent ring/arc in retinitis pigmentosa.

A Comparison of Functional and Structural Measures for Identifying Progression of Glaucoma

PURPOSEnTo compare glaucoma progression by functional and structural tests.nnnMETHODSnThe 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.nnnRESULTSnPatients 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.nnnCONCLUSIONSnEach 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.

Correlations Among Near-Infrared and Short-Wavelength Autofluorescence and Spectral-Domain Optical Coherence Tomography in Recessive Stargardt Disease

PURPOSEnShort-wavelength (SW) fundus autofluorescence (AF) is considered to originate from lipofuscin in retinal pigment epithelium (RPE) and near-infrared (NIR) AF from melanin. In patients with recessive Stargardt disease (STGD1), we correlated SW-AF and NIR-AF with structural information obtained by spectral-domain optical coherence tomography (SD-OCT).nnnMETHODSnTwenty-four STGD1 patients (45 eyes; age 8 to 61 years) carrying confirmed disease-associated ABCA4 mutations were studied prospectively. Short-wavelength AF, NIR-AF, and SD-OCT images were acquired.nnnRESULTSnFive phenotypes were identified according to features of the central lesion and extent of fundus change. Central zones of reduced NIR-AF were typically larger than areas of diminished SW-AF and reduced NIR-AF usually approximated areas of ellipsoid zone (EZ) loss identified by SD-OCT (group 1; r, 0.93, P < 0.0001). In patients having a central lesion with overlapping parafoveal rings of increased NIR-AF and SW-AF (group 3), the extent of EZ loss was strongly correlated with the inner diameter of the NIR-AF ring (r, 0.89, P < 0.0001) and the eccentricity of the outer border of the NIR-AF ring was greater than that of the SW-AF ring.nnnCONCLUSIONSnLesion areas were more completely delineated in NIR-AF images than with SW-AF. In most cases, EZ loss was observed only at locations where NIR-AF was reduced or absent, indicating that RPE cell atrophy occurs in advance of photoreceptor cell degeneration. Because SW-AF was often increased within the central area of EZ disruption, degenerating photoreceptor cells may produce lipofuscin at accelerated levels. Consideration is given to mechanisms underlying hyper-NIR-AF in conjunction with increased SW-AF.

A comparison of multifocal ERG and frequency domain OCT changes in patients with abnormalities of the retina

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.