Optic nerve and retinal

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Optic nerve and retinal

  1. 1. Optic nerve and retinal nerve fiber layer analyzersin glaucomaDavid S. Greenfield, MDThere is mounting evidence that retinal nerve fiber layer Glaucoma is an optic neuropathy characterized by a typi-(RNFL) loss precedes detectable visual field loss in early cal pattern of visual field loss and optic nerve damageglaucomatous optic neuropathy. However, examination and resulting from retinal ganglion cell death caused by aphotography of the RNFL is a difficult technique in many number of different disorders that affect the eye. Most,patients, particularly older individuals, and eyes with small but not all, of these disorders are associated with el-pupils and media opacities. It is subjective, qualitative, variably evated intraocular pressure (IOP), which is the most im-reproducible, and often unreliable. Furthermore, optic nerve portant risk factor for glaucomatous damage. Althoughhead and RNFL photography is time consuming, operator clinical examination of the optic nerve head has beendependent, has limited sensitivity and specificity, and requires considered to be the most sensitive test for detectingstorage space. Imaging technologies have emerged which glaucomatous damage, evidence suggests that examina-enable clinicians to perform accurate, objective, and tion of the retinal nerve fiber layer (RNFL) may providequantitative measurements of the RNFL and optic nerve head important diagnostic information [1-4]. Accurate and ob-topography. There is good agreement between such jective methods of detecting disc and RNFL abnormali-measurements and clinical estimates of optic nerve head ties, and their progression, would facilitate the diagnosisstructure and visual function. The reproducibility of these and monitoring of glaucomatous optic neuropathy.instruments suggests that they have the potential to detectstructural change over time. This report will review the Clinical examination and photography of the RNFL is atechnological principles, reproducibility, sensitivity and difficult technique in many patients, particularly olderspecificity, capacity to detect glaucomatous progression, individuals, those with small pupils, and subjects withand limitations of currently available ocular imaging media opacities. It is subjective, qualitative, variably re-technologies. Curr Opin Ophthalmol 2002, 13:68–76 © 2002 Lippincott producible, and often unreliable. In addition, optic nerveWilliams & Wilkins, Inc. head and RNFL photography is time consuming, opera- tor dependent, has limited sensitivity and specificity, and requires storage space. Recently, new technologies have emerged which enable clinicians to perform accu-The Department of Ophthalmology, The University of Miami School of Medicine, rate, reproducible, objective, and quantitative measure-Bascom Palmer Eye Institute, Miami, Florida, USA. ments of the retinal nerve fiber layer and optic nerveCorrespondence to David S. Greenfield, MD, Bascom Palmer Eye Institute, 7108 head topography.Fairway Drive, Suite 340, Palm Beach Gardens, FL, 33418; e-mail:dgreenfield@med.miami.eduCurrent Opinion in Ophthalmology 2002, 13:68–76 Confocal scanning laser ophthalmoscopy (CSLO), a technology embodied in the Heidelberg RetinalAbbreviations Tomograph (HRT, Heidelberg Engineering, Heidel-CSLO confocal scanning laser ophthalmoscopyHRT Heidelberg Retinal Tomograph berg, Germany), enables the operator to evaluate three-IOP intraocular pressure dimensional characteristics of optic nerve head topogra-OCT optical coherence tomographyRNFL retinal nerve fiber layer phy quantitatively [5-8]. Thirty-two coronal sections ofSLP scanning laser polarimetry the optic nerve head are acquired over a depth of ap-ISSN 1040–8738 © 2002 Lippincott Williams & Wilkins, Inc. proximately 3.5 millimeters, and a color-coded topo- graphic map of the optic nerve head is generated. Scanning laser polarimetry (SLP) is a technology embod- ied in the GDx Nerve Fiber Analyzer (Laser Diagnostic Technologies, Inc., San Diego, CA) employs a confocal scanning laser ophthalmoscope and an integrated polar- imeter. It evaluates the thickness of the RNFL by uti- lizing the birefringent properties of the retinal ganglion cell axons [9,10]. As polarized light passes through the RNFL and is reflected back from the deeper layer, it undergoes a phase shift. The change in polarization, re-68
  2. 2. Optic nerve and retinal nerve fiber layer analyzers in glaucoma Greenfield 69ferred to as retardation, is proportional to the thickness of Figure 1. Confocal scanning laser ophthalmoscopy topographic mapthe birefringent medium, and is measured to give anindex of RNFL thickness.Optical coherence tomography (OCT, Zeiss-HumphreySystems, Dublin, CA) is a noninvasive, noncontact,transpupillary imaging technology that can image retinalstructures in vivo with a resolution of 10 to 17 microns[11,12]. Cross-sectional images of the retina are producedusing the optical backscattering of light in a fashionanalogous to B-scan ultrasonography. The anatomic lay-ers within the retina can be differentiated and retinalthickness can be measured [13].This report will review practical applications and prin-ciples underlying these posterior segment-imaging tech- A patient with moderate normal-tension glaucoma shows loss of the inferiornologies with emphasis upon strengths and limitations of neuroretinal rim (green) and associated stereometric parameters. There is a focaleach technology. depression in the double-hump pattern of the height variation diagram corresponding to the decreased inferotemporal quadrant height (below).Confocal scanning laser ophthalmoscopyTechnological principlesConfocal scanning laser ophthalmoscopy employs a 670 nm “double-hump” pattern corresponding to the thickerdiode laser beam as a light source and scans the retina in retinal ganglion cell axons along the superior and inferiorx- and y- directions [14,15]. Light originating from the portions of the optic nerve head.illuminated area passes through a diaphragm (pinhole) ina plane optically conjugate to the retina. Planes unfo- Reproducibilitycused at the aperture are blocked by the diaphragm and Various investigators have reported high levels of repro-do not reach the detector. Each image contains 256 x 256 ducibility using this technology [5,15,16] Brigatti et al. [7]pixels (picture-elements); each pixel represents the reti- found that topographic variability correlated with thenal height at that location relative to the focal plane of steepness of the corresponding region. Greater variabil-the eye. Image acquisition and processing takes approxi- ity was found at the edge of the optic disc cup and alongmately 1.6 seconds. Thirty-two coronal sections are ob- blood vessels. Weinreb et al. [14] have determined thattained progressing from anterior to the optic nerve head measurement reproducibility is improved from 35.5 µmthrough the retrolaminar portion of the nerve head. The to 25.7 µm when a series of three examinations are ob-axial distance between two adjacent sections is 50 to tained instead of a single image analysis. Based upon75 m generating an axial range of 1.5 to 3.5 mm. these data, acquiring three images per eye and creation of a mean topographic image is recommended. Finally,A standard reference plane is established parallel to the Zangwill et al. [17] have shown that image reproducibil-peripapillary retinal surface and is located 50 microns ity is improved with pupillary dilation, particularly inposterior to the retinal surface along a circle concentric eyes with small pupils and cataract.with the optic disc margin in a temporal segment be-tween 350° and 356°. Neural rim is defined as tissue Sensitivity and specificitywithin the optic disc margin and above the reference Various investigators have reported topographic differ-plane. Optic cup is defined as tissue within the disc ences between normal, ocular hypertensive, and glauco-margin and below the reference plane. matous eyes. It is essential to emphasize that the char- acteristics of the study population will influence theThe optic disc margin is outlined and a color-coded discriminating power involved in differentiating glauco-depth map is created from a mean topographic image matous from nonglaucomatous eyes. Determination ofusing a software algorithm (Fig. 1). Stereometric param- sensitivity and specificity parameters is fundamentallyeters of optic nerve head topography are generated rela- linked to the severity of glaucomatous damage amongtive to the reference plane including rim area and vol- the cohort studied. For any given technology, an instru-ume, cup area and volume, cup-disc area ratio, mean ment will appear to be more sensitive if it is used toretinal nerve fiber layer thickness, and retinal nerve fiber separate eyes with advanced glaucoma from normal sub-cross-sectional area. Parameters independent of the ref- jects compared with eyes with mild glaucoma.erence plane include mean and maximum cup depth,height variation contour, and cup-shape measure. A nor- Heidelberg Retinal Tomograph employs software withmal retinal height variation diagram demonstrates a various statistical analyses to discriminate normal from
  3. 3. 70 Glaucomaabnormal optic discs. These include a multivariate dis- variability and relevance in the course of the disease.criminant analysis based upon rim volume, height varia- High instrument reproducibility is essential with knowntion contour, and cup shape measure adjusted by age limits of variability in normals and persons with disease.[18], ranked-segment distribution curves [19,20], and re- Statistical criteria must be established for differentiatinggression analysis using a normative database of 80 normal biological change from test-retest variability. Finally,eyes from 80 white subjects with a mean age of 57 years multicenter prospective validation must be established[21]. The confidence interval limits derived from the with comparisons against an accepted gold standard.later are used commercially to generate the Moorfield’sRegression Classification Score (normal, borderline, or Confocal scanning laser ophthalmoscopy strategies foroutside normal limits). Wollstein et al. [21] reported a change detection exist including serial analyses of global84.3% sensitivity and a 96.3% specificity for separating and regional topographic indices (eg, cup-disc ratio, cupnormal and early glaucomatous eyes by taking into ac- volume, and cup-shape measure), and color-codedcount the relation between optic disc size and the rim (red/green) significance indicators of change relative toarea or cup-to-disc area ratio. In a different study, Woll- baseline. Chauhan et al. [31••] have described a sophis-stein et al. [22•] determined that by taking into account ticated change analysis algorithm based upon a probabi-the optic disc size, HRT image analysis was superior in listic approach using variability estimates that employssensitivity (84.3%) for detection of early glaucoma com- clusters of 4 x 4 pixels to create superpixels. Three fol-pared with expert assessment of stereoscopic optic disc low-up images are compared with a baseline image, andphotographs (70.6%). a change-probability map is created, characterized by ar- eas with significant progression illustrated in red.The sensitivity and specificity of various HRT param- Strengths of this algorithm include the potential abilityeters has been investigated and varies widely ranging to differentiate biological change from test-retest vari-from 62% to 94% and 74% to 96%, respectively [18,23– ability, however it has not been validated in prospective27]. Wide variability in discriminating power may be ex- clinical trials. Moreover, topographic measurements areplained in part by variable sample size, definitions of dependent upon intraocular pressure and postoperativeglaucoma, and varying degrees of glaucomatous optic and diurnal changes in IOP have been reported to pro-nerve damage. A recent study by Miglior et al. [28•] duce changes in optic disc topography thereby confound-found fair to poor agreement (␬ statistic 0.28-0.48) be- ing detection of progression.tween visual field examinations and HRT classifications Two reports have described HRT detection of change.among a population of 359 eyes (55 normal, 209 with Chauhan et al. [31••] described significant topographicOHT, and 95 with moderate POAG, average visual field change in one patient with progressive glaucomatous op-mean defect –7.6 dB) The sensitivity and specificity of tic disc cupping. Kamal et al. [32] reported topographicthe HRT examination were, respectively, 80% and 65%, disc changes in a cohort of thirteen ocular hyperten-using the Mikelberg multivariate discriminant analysis sive subjects converting to glaucoma before confirmed[18], and 31 to 53% and 90 to 92%, using ranked-segment visual changes. This study was limited, however, bydistribution curve analysis [19,20]. small sample size, reviewers unmasked to diagnosis, absence of a control arm of OHT non-converters, andUsing various HRT summary data including the reflec- inability to differentiate biological change from test-tance image, double-hump graph, stereometric analyses, retest variability.and HRT classification using a multivariate discriminantfunction [18] and ranked segment analysis [19,20], LimitationsSanchez-Galeana [29•] evaluated the sensitivity and Technological limitations exist which limit the discrimi-specificity for discriminating between 50 normal eyes nating power for disease detection. The use of a standardand 39 eyes with early to moderate glaucoma (average reference plane and need for correct placement of thevisual field mean defect –5 dB). Masked observers were disc margin by the operator can influence many of theused to generate an HRT classification (normal, glauco- topographic outcome variables generated. Moreover,matous, or undetermined) and similar classifications considerable variability in optic disc morphology existswere generated using other imaging technologies (see among normal eyes. As currently configured, softwarebelow). Using these summary data collectively, investi- algorithms designed to classify subjects as normal orgators reported a sensitivity and specificity for the HRT glaucomatous are based upon dedicated normative dataranging from 64 to 75% and 68 to 80%, respectively. of approximately 100 eyes which is insufficient for popu- lation based screening. A uniform consensus regardingDetection of progression the most appropriate summary measures remains toEssential elements for change detection algorithms have be established.been previously reviewed [30]. An accepted gold stan-dard must exist for establishing change. Surrogate mea- There is evidence that disc topography is dependentsurement parameters are necessary with little biological upon intraocular pressure [33] and cardiac pulsation [34].
  4. 4. Optic nerve and retinal nerve fiber layer analyzers in glaucoma Greenfield 71Postoperative [35,36 ] and diurnal [37] changes in IOP Figure 2. Scanning laser polarimetry imagemay produce changes in optic disc topography therebyconfounding detection of glaucomatous progression. Inaddition, CSLO cannot discern vessel shift or other non-quantitative features (eg, pallor or disc hemorrhage)often associated with progression. Finally, as with perim-etry, short and long-term fluctuation exists and confi-dence intervals need to be validated to interpret mea-surements obtained.Scanning laser polarimetryTechnological principlesScanning laser polarimetry (SLP) is a technology that A patient with moderate primary open-angle glaucoma shows reduced retardation within the superior arcuate retinal nerve fiber layer bundle. Twoprovides quantitative assessment of the peripapillary retardation parameters were classified as abnormal (outside 95% confidenceRNFL using a polarized diode laser light source (780 limits, illustrated in red) and four parameters were classified as borderlinenm). The parallel arrangement of neurotubules within (outside 90% confidence limits, illustrated in yellow).the RNFL produces linear birefringence. Thus, changesin the polarization state may be measured when lightpasses through such tissue [9,10,38-40]. The change in superior/temporal), symmetry measurements betweenpolarization of the scanning beam (retardation) is linearly superior and inferior quadrants, and modulation param-correlated to the thickness of the polarizing medium, and eters (an indication of the difference between the thick-is computed to give an index of RNFL thickness. A est and thinnest parts of the RNFL) are generated. Apolarization detection unit measures the retardation of neural network number is also calculated which islight emerging from the eye; 256 by 256 pixels (65,536) thought to reflect the likelihood of glaucoma on a scale ofare acquired in 0.7 seconds and a computer algorithm 0 to 100.calculates retardation at each retinal position. ReproducibilityAn anterior segment compensator is incorporated within Intraoperator measurement reproducibility has beenthe technology to neutralize the polarization effects of shown by Weinreb et al. [10] (mean coefficient of varia-the cornea and crystalline lens. It consists of a fixed re- tion (CV) of 4.5%) and Chi et al. [46] (CV ranging fromtarder to adjust for the corneal retardation and assumes 3.59–10.20% for both normal and glaucomatous sub-all individuals have a slow axis of corneal birefringence jects). Swanson et al. [47] found significant interoperator15 degrees nasally downward and a magnitude of 60 nm variability with the NFA I, among 4 operators all of[41,42 ]. Recent studies have demonstrated that the mag- whom only scanned each of the 11 subjects twice. Thenitude [43] and axis [44] of corneal polarization are vari- primary source of error was attributed to the variability inable, and are strongly correlated with RNFL thickness the criterion used for establishing intensity setting. Thisassessments obtained with SLP. problem was subsequently reduced in the NFA II with a hardware modification to the light system.At least three images are acquired using a field of view of15 x 15 degrees and a baseline retardation map is created. Retinal nerve fiber layer thickness measurements usingImages may be obtained through an undilated pupil with the NFA II have been reported to have high levels ofa minimum diameter of 2 mm. However, uniformity in measurement reproducibility [40,48]. Hoh et al. [40] de-pupil size is essential when longitudinally evaluating scribed excellent intraoperator reproducibility and foundRNFL measurements.[45] The probability of obtaining that variability between operators can be minimized bya satisfactory baseline image (mean pixel SD </= 8 µm) using a single measurement ellipse acquired from theimproves from 62 to 98% if the number of scans available original baseline image. As investigators have reportedfor selection is increased from three to five.[40] The high levels of measurement variability adjacent to retinalretardation map represents a false color image with areas blood vessels [49,50], an automated blood vessel removalof high retardation displayed in yellow and white, and algorithm has been incorporated in the third generationareas of low retardation displayed in blue (Fig. 2). device, GDx.The operator outlines the optic disc margin, and a ten-pixel-wide measurement ellipse is automatically gener- Sensitivity and specificityated, 1.75x greater than the disc diameter. A computer As described with CSLO, there is a wide range in RNFLalgorithm automatically generates retardation mea- thickness values among normal individuals and consid-surements throughout the peripapillary region and along erable measurement overlap between normal and glau-the measurement ellipse. Average quadrantic measure- comatous eyes may exist. Determination of sensitivityments, measurement ratios (eg, superior/nasal, and specificity parameters is fundamentally linked to the
  5. 5. 72 Glaucomaseverity of glaucomatous damage among the cohort stud- tion axis has been shown to significantly increaseied [24]. Sensitivity and specificity values will be greater the correlation between RNFL structural damage andin studies involving eyes with advanced glaucoma than visual function, and significantly improve the discri-in studies involving eyes with mild to moderate glau- minating power of SLP for detection of mild to moder-coma. Tjon-Fo-Song and Lemij [38] evaluated the sen- ate glaucoma.sitivity and specificity of the first generation device,NFA I, for detecting glaucoma among a diverse group of Garcia-Sanchez et al. [29] evaluated the sensitivity and200 eyes with early to advanced glaucoma (average visual specificity of the HRT, GDx, and OCT summary data forfield mean deviation –10.33 decibels) compared with a detection of early to moderate glaucoma (average visualnormal population. The sensitivity and specificity was field mean defect –5.0 dB) among three masked reviewersreported to be 96 and 93%, respectively. Weinreb et al. (see Table 1). For the GDx, sensitivity and specificity[51] reported a sensitivity of 74% and specificity of 92% ranged from 72 to 82% and 56 to 82%, respectively.using a newer version of SLP with a linear discriminant Detection of progressionfunction to label glaucomatous damage among a popula- Scanning laser polarimetry strategies for change detec-tion with early to moderate glaucoma. Garcia-Sánchez tion exist including evaluation of change in absolute val-et al. [52] found the sensitivity and specificity of the GDx ues of retardation measurements, change in quadranticto be 78% and 86%, respectively. The most sensitive and RNFL thickness measurements, change in double-specific parameters in their study were ellipse modula- hump RNFL thickness profile, and color-coded map oftion, superior/nasal ratio, and maximum modulation. RNFL thickness change relative to baseline. However, as with OCT, statistical units of change probability areIn a cross-sectional study comparing OCT and SLP, Hoh absent limiting the ability to differentiate change fromet al. [53] found that structural information generated measurement variability, and there has been no prospec-from both technologies was significantly correlated with tive validation of this algorithmvisual function in glaucomatous eyes (average visual fieldmean deviation –7.7 decibels). However, retardation pa- Two published reports have described SLP evidence oframeters providing summary measures of RNFL thick- change detection in eyes with non-glaucomatous opticness (eg, average thickness and integral measurements) neuropathy. Colen et al. [55] described a patient withhad a weaker correlation with visual field mean defect acute nonarteritic anterior ischemic optic neuropathy(R = 0.17 to 0.27) than with constructed retardation pa- who developed progressive loss of retardation over arameters (eg, modulation scores, ratio parameters, and 5-week period corresponding to a dense altitudinal visualnumber; R = 0.36 to –0.51). Bowd et al. [54] recently field depression. Medeiros and Susanna [56] reportedreported that constructed SLP parameters (modulation, progressive RNFL loss over a 90-day period in a patientratio, number, and linear discriminant function values) with traumatic optic neuropathy.have the greatest discriminating power. This is ex-plained by recent evidence [44] suggesting that interin- Limitationsdividual variability in corneal birefringence has falsely Employment of a fixed corneal compensator has pro-broadened the normative database of RNFL thick- duced considerable measurement overlap among normalness assessments, and reduced the sensitivity and speci- and glaucomatous eyes. Variability in corneal polariza-ficity of this technology. Correction for corneal polariza- tion axis (CPA) [57••] and magnitude has been de-Table 1. Comparison of scanning laser ophthalmoscopy, scanning laser polarimetry, and optical coherence tomography GDx HRT OCTTechnological principle Birefringence SLO InterferometryPixels 65,000 65,000 50,000Pupillary dilation No No YesReproducibility (CV) 5%–10% [40] 5%–10% [67] 5%–10% [63]Parameters measured Peripapillary RNFL Optic Disc Topography Peripapillary RNFLNormative database 1200 eyes [68] 45, [19] 100 [19] or 112 [21] eyes 150 eyes*Sensitivity [29] 72%–82% 64%–75% 76%–79%Specificity [29] 56%–82% 68%–80% 68%–81%Change detection algorithm Yes Yes YesChange probability algorithm No Yes NoProspective validation of algorithm No No NoEvidence to detect change Yes [55, 56] Yes [31, 32] NoLimitations Fixed corneal compensator; Universal reference plane; Sampling data limited to 100 unable to differentiate topography is dependent A-scans; unable to differentiate variability from progression upon IOP variability from progressionSLO, scanning laser ophthalmoscopy; CV, coefficient of variation.*Personal communication (Zeiss-Humphrey Systems, Dublin, CA).
  6. 6. Optic nerve and retinal nerve fiber layer analyzers in glaucoma Greenfield 73scribed; there is evidence that CPA strongly effects peri- transpupillary imaging technology which can image reti-papillary retardation measurements (Fig. 3). nal structures in vivo with a resolution of 10 to 17 microns [11,12]. Cross-sectional images of the retina are producedAlthough, there is good one-year stability of CPA mea- using the optical backscattering of light in a fashionsurements [58], long-term stability and the effect of in- analogous to B-scan ultrasonography. The anatomic lay-traocular and refractive surgery upon such measurements ers within the retina can be differentiated and retinalremains unknown. Furthermore, anterior and posterior thickness can be measured [13].segment pathology may produce spurious RNFL mea-surements [59], and caution should be used when inter- Optical coherence tomography images are obtained us-preting images in eyes with ocular surface disease, pre- ing a transpupillary delivery of low coherence near-vious keratorefractive surgery, media opacification, and infrared light (850nm) from a super-luminescent diodeextensive peripapillary atrophy. laser [11–13,60]. Backscatter from the retina is captured using the same delivery optics and resolved using a fiber-Although a change analysis algorithm exists, statistical optic interferometer set in a standard Michelson con-units of probability are absent. Thus, biological change figuration. Modulating the reference arm allows longitu-cannot be differentiated from measurement variability. dinal information to be extracted to the resolution asFinally, prospective studies are necessary to validate defined by the low coherence super-luminescent diode.change analysis strategies. Cross-sectional OCT images of the retina are con-Optical coherence tomography structed from the backscattering information providedTechnological principles by 100 individual longitudinal A-scans. A digitized,Optical coherence tomography (OCT, Zeiss-Humphrey composite image of the 100 A-scans is produced on aSystems, Inc., Dublin, CA) is a noninvasive, noncontact, monitor with a false color scale representing the degree of light backscattering from tissues at different depthsFigure 3. Peripapillary retinal nerve fiber layer retardation map within the retina.and thickness plot A minimum pupillary diameter of 5 mm is required to obtain satisfactory OCT image quality. Images may be acquired using either a linear or circular scanning beam. Scanning acquisition time is approximately one second. A circular scan of the RNFL is generally performed with a diameter of 3.4 mm (Fig. 4) to avoid areas of peri- papillary atrophy. Circular scans of this diameter contain 100 axial scans spaced 110 microns apart. This scan is then converted into a radial image by an automated “smoothing” technique. A computer algorithm identifies and demarcates the signal corresponding to the RNFL, and mean quadrantic and individual clock hours of RNFL thickness measurements are calculated. Reproducibility Schuman et al. [61] evaluated the reproducibility of reti- nal and RNFL thickness measurements using circular scans around the optic nerve head in normal and glau- comatous eyes. Scan diameters of 2.9, 3.4, and 4.5 mm were evaluated and internal fixation was compared with external fixation. Measurement SDs were approximately 10 to 20 µm for overall RNFL thickness, and 5 to 9 µm for retinal thickness. The authors found a circle diameter of 3.4 mm to be superior; internal fixation was signifi-Peripapillary retinal nerve fiber layer (RNFL) retardation map (A) and cantly less variable than external fixation. Baumann et al.corresponding RNFL thickness plot (B) in the right eyes of six normal individuals [62] found that the mean coefficient of varation of retinalwith different corneal polarization axis values (18°, 27°, 37°, 52°, 59°, 76° nasally thickness measurements at locations outside of 500 µmdownward from top left to bottom right). Upper and lower margins in (B)represent 95% confidence intervals. Note that peripapillary retardation and from fixation in normal eyes was 10%. The authors usedmeasured RNFL thickness increase with increasing corneal polarization axis. an OCT prototype characterized by a 2.5 second scan(Reprinted with permission: Greenfield DS, Knighton RW: Stability of corneal acquisition time. Recently, Blumenthal et al. [63] evalu-polarization axis measurements for scanning laser polarimetry. Ophthalmology2001, 108:1065–1069. Figure 3). ated the CV for mean RNFL thickness in normal and glaucomatous eyes (6.9% and 11.8% respectively) using a
  7. 7. 74 GlaucomaFigure 4. Optical coherence tomography image of a normal receiver operator characteristic (ROC) curve was foundeye obtained using a 3.4 mm peripapillary measurement scan for OCT inferior quadrant thickness, followed by the FDT number of total deviation plot points </= 5%, SLP linear discriminant function, and SWAP pattern SD. Zangwill et al. [66• ] compared the ability of OCT, HRT, and GDx to discriminate between normal eyes and eyes with early to moderate glaucomatous visual field loss. No significant differences were found between area under the ROC curve and the best parameter from each instru- ment: OCT inferior RNFL thickness, HRT mean height contour in the inferior nasal position, and GDx linear discriminant function). Garcia-Sanchez et al. [29] evaluated the sensitivity and specificity of the HRT, GDx, and OCT summaryThe anterior and posterior limits of the retinal nerve fiber layer (RNFL) aredemarcated using a computer algorithm (arrows) and clock hour and quadrantic data for detection of early to moderate glaucoma (aver-RNFL thickness measurements are obtained. age visual field mean defect –5.0 dB) among three masked reviewers (see Table 1). For the OCT, sensi- tivity and specificity ranged from 76 to 79% and 68 tocommercially available device capable of performing 81%, respectively.scan acquisition times in one second. Detection of progressionPublished series of peripapillary retinal nerve fiber layer Change analysis software has only recently been intro-measurement using optical coherence tomography have duced; therefore no reports have described longitudinalsampled 100 evenly-distributed points on a 360 degree change in patients with disease progression. As presentlyperipapillary circular scan. Ozden et al. [64] evaluated configured, this algorithm generates a serial analysis ofwhether a four-fold increase in sampling density im- RNFL thickness measurements among two OCT im-proves the reproducibility of OCT measurement. ages, however statistical units of change probability areTwenty-two eyes of 22 patients (normal subjects, 3 eyes; not provided. Thus, true biological change cannot beocular hypertension, 2 eyes; glaucoma, 17 eyes) were differentiated from test-retest variability.evaluated. Optical coherence tomography scanning con-sisted of three superior and inferior quadrantic scans Limitations(100 sampling points/ quadrant) and three circular scans Currently, no statistical units of change probability are(25 points/quadrant). Retinal nerve fiber layer thickness absent from the change analysis software, therefore onemeasurements and CV were calculated for the superior cannot differentiate biological change from measure-and inferior quadrants for each sampling density tech- ment variability by performing serial analysis of abso-nique. Normal eyes showed no difference between the lute RNFL thickness values. Pupillary dilation is re-25 point/quadrant and 100 point/quadrant scans, respec- quired to obtain acceptable peripapillary measurementtively. Among glaucomatous eyes, however, the CV in scans. Finally, sampling is limited to 25 A-scans per25-point/quadrant scans (25.9%) was significantly higher quadrant, which may limit the ability to detect localizedthan that in 100-point/quadrant scans (11.9%, p = 0.01). change [64].Sensitivity and specificity ConclusionsCross-sectional studies have compared OCT with CSLO Recent advances in ocular imaging technology provide a[65] and SLP [53] in normal, ocular hypertensive, and means to obtain accurate, objective, quantitative, andglaucomatous eyes. OCT was capable of differentiating reproducible structural measurements of optic disc to-glaucomatous from non-glaucomatous eyes, and RNFL pography and RNFL thickness. Current imaging sys-thickness measurements using OCT correlated with re- tems can differentiate between normal eyes and eyestardation measurements using SLP and topographic with mild to moderate glaucomatous optic neuropathy.measurements using CSLO. Although conflicting data exists, sensitivity and specific- ity values approximate 70 to 80% depending uponBowd et al. [54] compared the discriminating powers of sample size, definition of glaucoma, and severity of glau-SLP, OCT, short-wavelength automated perimetry comatous damage. Any one technology will have limited(SWAP), frequency-doubling technology perimetry usefulness as a single test to diagnose glaucoma and at(FDT) for detection of early glaucoma (average visual the present juncture should not be used as an indepen-field mean defect –4.0 dB). The largest area under the dent diagnostic screening test. However, these instru-
  8. 8. Optic nerve and retinal nerve fiber layer analyzers in glaucoma Greenfield 75ments have considerable potential for use as adjunctive References and recommended readingmeasures of glaucomatous damage along with careful Papers of particular interest, published within the annual period of review,clinical and perimetric examination. have been highlighted as: • Of special interest •• Of outstanding interestThere is no uniform agreement regarding the most ap- 1 Sommer A, Miller NR, Pollack I, et al.: The nerve fiber layer in the diagnosis ofpropriate technology for the evaluation of structural glaucoma. Arch Ophthalmol 1977, 95:2149.damage in eyes with glaucomatous optic neuropathy. 2 Quigley HA, Dunkelberger GR, Green WR: Retinal ganglion cell atrophy cor-Furthermore, among proponents of any given technol- related with automated perimetry in human eyes with glaucoma. Am J Oph- thalmol 1989, 107:453–464.ogy, there is no consensus on the most appropriate sum- 3 Quigley HA: Better methods in glaucoma diagnosis. Arch Ophthalmol 1985,mary measure to represent ganglion cell loss. It is im- 103:186.portant to recognize that the parameter or technology 4 Sommer A, Katz J, Quigley HA, et al.: Clinically detectable nerve fiber layermost useful in the detection of glaucomatous damage atrophy precedes the onset of glaucomatous field loss. Arch Ophthalmolmay vary from individual to individual and may differ 1991, 109:77–83.from the parameter or technology most useful for de- 5 Lusky M, Bosem ME, Weinreb RN: Reproducibility of optic nerve head to- pography measurements in eyes with undilated pupils. J Glaucoma 1993,tection of glaucomatous change. The most appropriate 2:104–109.measure(s) of disease detection will unlikely be the 6 Weinreb RN, Dreher AW, Bille JF: Quantitative assessment of the optic nervemost sensitive indicator of glaucomatous change. At head with the laser tomographic scanner. Int Ophthalmol 1989, 13:25.the present time, limited information exists regarding 7 Brigatti L, Weitzman M, Caprioli J: Regional test-retest variability of confocal scanning laser tomography. Am J Ophthalmol 1995, 120:433–440.the relation between glaucomatous progression and 8 Zangwill L, Schakiba S, Caprioli J, et al.: Agreement between clinicians and aRNFL/topographic measures. confocal scanning laser ophthalmoscope in estimating cup-to-disc ratios. Am J Ophthalmol 1995; 119:415–421.Currently available imaging technologies hold consider- 9 Dreher AW, Reiter K, Weinreb RN: Spatially resolved birefringence of theable promise for detection of glaucomatous change. retinal nerve fiber layer assessed with a retinal ellipsometer. Applied OpticsMethods for change detection exist but have not been 1992, 31:3730–3749.prospectively validated in large populations. Moreover, 10 Weinreb RN, Shakiba S, Zangwill L: Scanning laser polarimetry to measure the nerve fiber layer of normal and glaucomatous eyes. Am J Ophthalmolnew strategies for detection of progressive structural 1995, 119:627–636.change need to be validated against accepted measures 11 Huang D, Swanson EA, Lin CP, et al.: Optical coherence tomography. Sci-of structural (stereoscopic disc photography) and func- ence 1991 254:1178–1181.tional (psychophysical) change. Statistical units of 12 Izatt JA, Hee MR, Swanson EA, et al.: Micrometer-scale resolution imaging of the anterior eye in vivo with optical coherence tomography. Arch Ophthalmolchange probability are essential to differentiate true bio- 1994, 112:1584–1589.logical change from variability (eg, microsaccades during 13 Hee MR, Izatt JA, Swanson EA, et al.: Optical coherence tomography of thefixation, vessel pulsations, instrument or operator- human retina. Arch Ophthalmol 1995, 113:325–332.induced variability). A significant challenge to the inves- 14 Weinreb RN, Lusky M, Bartsch D, et al.: Effect of repetitive imaging on topo- graphic measurements of the optic nerve head. Arch Ophthalmol 1993,tigator has been the reality that technology improves 111:636–638.with time. Rapidly evolving hardware and software re- 15 Mikelberg FS, Wijsman K, Schulzer M: Reproducibility of topographic param-sults in alteration of baseline measurements. This has eters obtained with the Heidelberg Retina Tomograph. J Glaucoma 1993, 2:101–103.produced instability in longitudinal data collection and 16 Dreher AW, Tso PC, Weinreb RN: Reproducibility of topographic measure-has limited, in part, our ability to critically evaluate the ments of the normal and glaucomatous optic nerve head with the laser tomo-efficacy of these instruments to detect structural change graphic scanner. Am J Ophthalmol 1991, 111:221.over time. Presently, it is unclear whether automated 17 Zangwill L, Irak I, Berry CC, et al.: Effect of cataract and pupil size on image quality with confocal scanning laser ophthalmoscopy. Arch Ophthalmoldetection of structural change meets or exceeds current 1997, 115:983–990.standard of care measures. 18 Mikelberg FS, Parfitt CM, Swindale NV, et al.: Ability of the Heidelberg retina tomograph to detect early glaucomatous field loss. J Glaucoma 1995,In summary, each ocular imaging technology has specific 4:242–247.advantages and disadvantages. One instrument may not 19 Bartz-Schmidt KU, Sengersdorf A, Esser P, et al.: The cumulative normalisedbe best for all purposes and all patients, and different rim/disc area ratio curve. Graefes Arch Clin Exp Ophthalmol 1006, 234:227– 231.analysis strategies may not agree. Because measure- 20 Asawaphureekorn S, Zangwill L, Weinreb RN: Ranked-segment distributionment reproducibility is high, each technology holds curve for interpretation of optic nerve topography. J Glaucoma 1996,promise for improving our ability to detect glaucoma- 5:79–90.tous change. As with perimetry, it is not recommended 21 Wollstein G, Garway-Heath DF, Hitchings RA: Identification of early glau- coma cases with the scanning laser ophthalmoscope. Ophthalmology 1998,that isolated clinical decisions be based solely upon 105:1557–1563.ocular imaging results. Clinical correlation should be 22 Wollstein G, Garway-Heath DF, Fontana L, et al.: Identifying early glaucoma-performed and treatment recommendations should • tous changes: comparison between expert clinical assessment of optic disc photographs and confocal scanning ophthalmoscopy. Ophthalmology 2000,be individualized. 107:2272–2277. This study found the Heidelberg Retinal Tomograph to be superior to clinical evalu-Acknowledgments ation of optic disc stereophotographs but was limited by the use of disparate ob- servers with limited levels of agreement.Supported in part by the New York Community Trust, New York, New York; TheKessel Foundation, Bergenfield, New Jersey; The Boyer Foundation, Melbourne, 23 Iester M, Mikelberg FS, Drance SM: The effect of optic disc size on diagnosticFL; and NIH Grant R01-EY08684, Bethesda, Maryland. The author has no propri- precision with the Heidelberg retina tomograph. Ophthalmology 1997,etary interest in any of the products or techniques described in this manuscript. 104:545–548.
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J Glaucoma 1997, 6:384–389.27 Swindale NV, Stjepanovic G, Chin A, et al.: Automated analysis of normal and 49 Tjon-Fo-Sang MJH, van Strik R, de Vries J, et al.: Improved reproducibility of glaucomatous optic nerve head topography images. Invest Ophthalmol Vis measurements with the Nerve Fiber Analyzer. J Glaucoma 1997, 6:203–211. Sci 2000, 41:1730–1742. 50 Waldock A, Potts MJ, Sparrow JM, et al.: Clinical evaluation of scanning laser28 Miglior S, Casula M, Guareschi M, et al.: Clinical ability of Heidelberg Retinal polarimetry: Intraoperator reproducibility and design of a blood vessel re- Tomograph examination to detect glaucomatous visual field changes. Oph- moval algorithm. Br J Ophthalmol 1998, 82:252–259.• thalmology 2001, 2001:1621–1627. 51 Weinreb RN, Zangwill L, Berry CC, et al.: Detection of glaucoma with scan-In a broad clinical setting of 359 normal, ocular hypertensive, or glaucomatous ning laser polarimetry. Arch Ophthalmol 1998, 116:1583–1589.eyes, this study found that the Heidelberg Retinal Tomograph lacked sensitivity andspecificity when using commercially available ranked-segment distribution curves, 52 Garcia-Sanchez J, Garcia-Feijoo J, Arias-Puente A, et al.: Accuracy of theand Mikelberg’s multivariate discriminant analysis, respectively. GDx system for the diagnosis of glaucoma. Invest Ophthalmol Vis Sci 1998, 38:933.29 Sanchez-Galeana C, Bowd C, Blumenthal EZ, et al.: Using optical imaging summary data to detect glaucoma. Ophthalmology 2001, 108:1812–1818. 53 Hoh ST, Greenfield DS, Mistlberger A, et al.: Optical coherence tomography•This report evaluated the sensitivity and specificity of ocular imaging summary data and scanning laser polarimetry in normal, ocular hypertensive, and glaucoma-using three experienced observers with high levels of agreement and found similar tous eyes. Am J Ophthalmol 2000, 129:129–135.discriminating powers among HRT, GDx, and OCT. 54 Bowd CA, Zangwill LM, Berry CC, et al.: Detecting early glaucoma by as- sessment of retinal nerve fiber layer thickness and visual function. Invest Oph-30 Anderson DR, Chauhan B, Johnson C, et al.: Criteria for progression of glau- thalmol Vis Sci 2001, 42:1993–2003. coma in clinical management and in outcome studies. Am J Ophthalmol 2000, 130:827–829. 55 Colen TP, Van Everdingen JAM, Lemij HG: Axonal loss in a patient with an- terior ischemic optic neuropathy as measured with scanning laser polarim-31 Chauhan BC, Blanchard JW, Hamilton DC, et al.: Technique for detecting etry. Am J Ophthalmol 2000, 130:847–850.•• serial topographic changes in the optic disc and peripapillary retina using scanning laser tomography. Invest Ophthalmol Vis Sci 2000, 41:775–782. 56 Medeiros FA, Susanna R: Retinal nerve fiber layer loss after traumatic opticThis study describes a novel change analysis algorithm for differentiating test- neuropathy detected by scanning laser polarimetry. Arch Ophthalmol 2001,retest variability from statistically significant change in optic disc topography and is 119:920–921.currently employed within the latest version of HRT software. 57 Greenfield DS, Huang X-R, Knighton RW: Effect of corneal polarization axis32 Kamal DS, Viswanathan AC, Garway-Heath DF, et al.: Detection of optic disc •• on assessment of retinal nerve fiber layer thickness by scanning laser polar- change with the Heidelberg Retina Tomograph before confirmed visual field imetry. Am J Ophthalmol 2000, 129:715–722. change in ocular hypertensives converting to early glaucoma. Br J Ophthalmol This report describes the effect of corneal birefringence upon RNFL thickness 1999, 83:290–294. determinations using the GDx nerve fiber analyzer and outlines the optical limita- tions of using a fixed corneal compensator to neutralize anterior segment polariza-33 Lusky M, Morsman D, Weinreb RN: Effects of intraocular pressure on optic tion. A novel method for estimating corneal birefringence is described using macu- nerve head topography. Curr Opin Ophthalmol 1993, 4:40–44. lar birefringence characteristics.34 Chauhan BC, MacDonald CA: Influence of time separation on variability es- 58 Greenfield DS, Knighton RW: Stability of corneal polarization axis measurements timates of topographic measurements with confocal scanning laser tomog- for scanning laser polarimetry. Ophthalmology 2001, 108:1065–1069. raphy. J Glaucoma 1995, 4:189–193. 59 Hoh ST, Greenfield DS, Ishikawa H, et al.: Factors affecting image acquisition35 Lesk MR, Spaeth GR, Azuara-Blanco A, et al.: Reversal of optic disc cupping during scanning laser polarimetry. Ophthalmic Surg and Lasers 1998, after glaucoma surgery analyzed with a scanning laser tomograph. Ophthal- 29:545–551. mology 1999, 106:1013–1018. 60 Fercher AF, Hitzenberger CK, Drexler W, et al.: In vivo optical coherence36 Irak I, Zangwill L, Garden V, et al.: Change in optic disk topography after tomography. Am J Ophthalmol 1993, 116:113–114. trabeculectomy. Am J Ophthalmol 1996, 122:690–695. 61 Schuman JS, Pedut-Kloizman T, Hertzmark E, et al.: Reproducibility of nerve37 Lee BL, Zangwill L, Weinreb RN: Change in optic disc topography associated fiber layer thickness measurements using optical coherence tomography. with diurnal variation of intraocular pressure. J Glaucoma 1999; 8:221–223. Ophthalmology 1996, 103:1889–1898.38 Tjon-Fo-Sang MJ, Lemij HG: The sensitivity and specificity of nerve fiber layer 62 Baumann M, Gentile RC, Liebmann JM, et al.: Reproducibility of retinal thick- measurements in glaucoma as determined with scanning laser polarimetry. ness measurements in normal eyes using optical coherence tomography. Am J Ophthalmol 1997, 123:62–69. Ophthalmic Surg Lasers 1998, 29:280–285. 63 Blumenthal EZ, Williams JM, Weinreb RN, et al.: Reproducibility of nerve fiber39 Niessen AGJE, Van Den Berg TJTP, Langerhorst CT, et al.: Retinal nerve fiber layer thickness measurements by use of optical coherence tomography. Oph- layer assessment by scanning laser polarimetry and standardized photogra- thalmology 2000, 107:2278–2282. phy. Am J Ophthalmol 1996, 121:484–493. 64 Ozden RG, Ishikawa HI, Liebmann JM, et al.: Increasing sampling density40 Hoh ST, Ishikawa H, Greenfield DS, et al.: Peripapillary nerve fiber layer thick- improves optical coherence tomography measurement reproducibility. J ness measurement reproducibility using scanning laser polarimetry. J Glau- Glaucoma 1999, 8:238–241. coma 1998, 7:12–15. 65 Mistlberger A, Liebmann JM, Greenfield DS, et al.: Heidelberg retina tomog-41 Reiter K, Dreher A, inventors; Laser Diagnostic Technologies, Inc., assignee. raphy and optical coherence tomography in normal, ocular hypertensive and Eye examination apparatus employing polarized light probe. 1998 Aug 4. glaucomatous eyes. Ophthalmology 1999, 106:2027–2032. United States Patent No. 5,787,890. 66 Zangwill LM, Bowd C, Berry CC, et al.: Discriminating between normal and42 Dreher A, Reiter K, inventors; Laser Diagnostic Technologies, Inc., assignee. • glaucomatous eyes using the Heidelberg Retina Tomograph, GDx Nerve Fi- Retinal eye disease diagnostic system. 1994 April 19. United States Patent ber Analyzer, and Optical Coherence Tomograph. Arch Ophthalmol 2001, No. 5,303,709. 119:985–993. This report provides a comparison of the ability of OCT, GDx, and HRT to discrimi-43 Knighton RW, Huang W-R, Greenfield DS: Linear birefringence measured in nate between healthy eyes and eyes with mild to moderate glaucoma and found no the central cornea of a normal population. Invest Ophthalmol Vis Sci 2002, differences between the best parameter for each instrument using receiver opera- 43:82–86. tor characteristic curves.44 Greenfield DS, Knighton RW, Feuer W, et al.: Correction for corneal polar- 67 Kruse FE, Burk ROW, Volcker H-E, et al.: Reproducibility of topographic mea- ization axis improves the discriminating power of scanning laser polarimetry. surements of the optic nerve head with laser tomographic scanning. Ophthal- Invest Ophthalmol Vis Sci 2001; 42:S314. mology 1989, 96:1320–1324.45 Hoh ST, Greenfield DS, Liebmann JM, et al.: Effect of pupillary dilation on 68 Choplin NT, Lundy DC, Dreher AW: Differentiating patients with glaucoma retinal nerve fiber layer thickness measurement using scanning laser polarim- from glaucoma suspects and normal subjects by nerve fiber layer assessment etry. J Glaucoma 1999, 8:159–163. with scanning laser polarimetry. Ophthalmology 1998, 105:2068–2076.

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