Structure WGA. Structure WGA. Structural Assessment in Glaucoma. What s New

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1 New Developments in the Structural and Functional Assessment of the Glaucomas John G. Flanagan PhD, MCOptom, FAAO Professor, School of Optometry, University of Waterloo Professor, Dept of Ophthalmol & Vis Sci, University of Toronto Director, The Toronto Hospital Glaucoma Research Unit Senior Scientist, The Toronto Western Research Institute Structure WGA 1. A method for detecting abnormality and also documenting optic nerve structure should be part of routine clinical management of glaucoma. 2. Sensitivity and specificity of imaging instruments for detection of glaucoma are comparable to that of expert interpretation of stereo color photography. 3. Digital imaging is recommended as a clinical tool to enhance and facilitate the assessment of the optic disc and retinal nerve fibre layer in the management of glaucoma. The Global Glaucoma Network Structure WGA 4. a. Automated analysis of results using appropriate databases is helpful for identifying abnormalities consistent with glaucoma. b addition: Automated analysis of change using appropriate assessment of variability is helpful for identifying change consistent with glaucoma. 5. Different imaging technologies may be complementary, and detect different abnormal features in the same patients. Structural Assessment in Glaucoma The Optic Nerve Head The Nerve Fibre Layer The Global Glaucoma Network What s New Primer Acquisition Quality Control Alignment Algorithm Larger Database Ethnic Selectable Printout Glaucoma Probability Score Glaucoma Change Analysis Enhanced Progression Analysis 1

2 Acquisition Quality Control New Image Quality Checks Image SD New quality checks Final Quality Score HRT 3 Databases Effect of Ethnic Appropriate Database: Indian Patient Caucasian database over 700 healthy eyes African Descent database over 200 healthy eyes Southeast Indian database over 100 healthy eyes Caucasian African Descent Indian Hispanic and Asian databases coming soon African American Database Caucasian Database Indian Database Disc Size OHTS Ancillary Results 1,899 2,653 3,285 Archives of Ophthalmology, September

3 The CSLO Ancillary Study to OHTS: Baseline Measurements Associated with Development of POAG Zangwill et al. Arch. Ophthalmol. 2005;123: Risk Factor IOP (per mm Hg) PSD (per 0.2 db) Age (per decade) Vertical C/D (per 0.1) CCT (per 40 microns) ---- HRT Risk Factor ---- Cup Depth (per 0.1 mm) RNFL Profile Mean Height Risk Assessment: OHTS Predictive Factors Glaucoma Predictors: Baseline Predictive Values OHTS Ancillary Study IOP 1.15 PSD 2.14 CCT 5.64 HRT (MRA Global) HRT (MRA Temp Superior) 8.88 Moorfields Temporal/Superior Moorfields Temporal/Inferior Moorfields Global Result Hazard Ratio Relative Risk 5. Zangwill LM, Weinreb RN, et al. Archives of Ophthalmol. 2005;123: Glaucoma Predictors: Baseline Predictive Values UCSD Study IOP PSD Stratus OCT 1.61 CCT 1.93 Stereo Photos 3.79 Glaucoma Probability Score: GPS Utilizes the entire 3-D Surface Topography Characterizes the image with 5 parameters 3 parameters describe the optic disc 2 parameters describe the RNFL Relative Risk 28. Lalezary M, Medeiros FA, et al. American Journal of Ophthalmol. 2006; Swindale et al. IOVS. 2000; 41: Topographic Change Analysis New alignment - automatically identifies several hundred local features Uses statistical matching of features to align images More accurate comparisons Baseline Exam TCA Printout Trend analysis Follow-up Exams 3

4 Cluster Analysis Trend Analysis Structural Assessment in Glaucoma Cluster Outline The Optic Nerve Head Volume change The Nerve Fibre Layer Area change Area and Volume of change tracked over time Scanning Laser Polarimetry Light SLP Basic Principles Polarizer Two polarized components Birefringent structure (RNFL) Retardatio Nerve fiber layer is form-birefringent Light passing through a birefringent medium: Light traveling perpendicular to fibers undergoes a phase shift Slows down" (retardation) The amount of retardation from the RNFL is directly proportional to the RNFL thickness 1. 1 Weinreb et al. Arch Ophthalmology 1990; 108: ECC versus VCC (50 yr. W, F, IOL) ECC (yellow) VCC (blue) Identify progressing patients Summary of Progression. = Possible Progression ECC method reduces measurement noise in the nasal region in the eye of a patient with IOL implant = Likely Progression (design specificity 95%) Simulated data. 4

5 OCT Stratus Michelson Interferometer Reference Mirror SLD Light Source Beam Splitter Photo Detector A-Scan or OCT Signal Identification of Retinal Layers NFL ILM GCL IPL OPL RNFL Analysis Stratus OCT in Glaucoma Three 1.73mm radius circle scans IS/OS RPE/CC Choroid Stratus OCT Optic Nerve Head Analysis Six 4mm radial line scans NFL: Nerve Fiber Layer IS/OS: Junction of inner and outer ILM: Inner Limiting Membrane photoreceptor segments GCL: Ganglion Cell Layer RPE: Retinal Pigment Epithelium CC: Choriocapillaris Cross-sectional image of live tissue; a virtual biopsy IPL: Inner Plexiform Layer OPL: Outer Plexiform Macular Analysis Six 6mm radial line scans Early Glaucoma Physiological Cupping 5

6 Stratus GPA Serial Analysis Old OCT Does Not Account for Eye Movement TSNIT overlays Average thickness plots OU analysis 2003 IEEE Tracking the Optic Nervehead in OCT Video Koozekanani, et al, 2003 While Time Domain OCT scans, the eye keeps moving The black line is the camera s perspective The white line is the actual scan path Scan location and eye movements affects results Broadband Light Source SLD Time Domain OCT Interferometer Lens Reference mirror moves back and forth Distance determines depth in A scan Properly centered Poorly centered: too inferior Poorly centered: too superior Creates A scan 1 pixel at a time Detector Combines light from reference with reflected light from retina Scanning mirror directs SLD beam on retina T S N I T T S N I T T S N I T Normal Double Hump Inferior RNFL Loss Superior RNFL Loss Data Acquisition Processing Final A scan Process repeated many times to create B scan Slide courtesy of Dr. Yimin Wang, USC Fourier Domain OCT Comparison of OCT Images Broadband Light Source SLD Interferometer Reference mirror stationary OCT 1 (Time Domain) 1996 Grating splits signal by wavelength Combines light from reference with reflected light from retina Stratus OCT (Time Domain) 2002 Spectrometer analyzes signal by wavelength Slide courtesy of Dr. Yimin Wang, USC Spectral interferogram FFT Fourier transform converts signal to typical A scan Entire A scan created at a single time Process repeated many times to create B scan RTVue (Fourier Domain)

7 OCT from Carl Zeiss Meditec Cirrus HD-OCT Spectral Domain OCT for ocular imaging. Developed in collaboration with Univ. Vienna, Univ. Miami, & Univ. Pittsburgh Commercial introduction ,000 A-Scans per second, 5 micron axial resolution Time Domain and Spectral Domain Stratus OCT Time domain OCT for ocular imaging. Developed in collaboration with and licensed from Massachusetts Institute of Technology Commercial introduction in clinical use 400 A-Scans per second, 10 micron axial resolution Stratus OCT Healthy Retina Healthy Retina Stratus OCT high-resolution line scan and the Cirrus HD-OCT scan reveal details of retinal structure Glaucoma RNFL Thickness Analysis An OU analysis example OCT from Opto-Vue RTVue Glaucoma Analysis with the RTVue Nerve Head Map (NHM) Ganglion Cell Map (MM7) 3-D Optic Disc Data Captured: 9,510 A scans (pixels) Time: 370 msec Area covered: 4 mm diameter circle Provides Cup Area Rim Area RNFL Map Data Captured: 14,810 A scans (pixels) Time: 570 msec Area covered: 7 x 7 mm Provides Ganglion cell complex assessment in macula Inner retina thickness is: NFL Ganglion cell body Dendrites Data Captured: 51,712 A scans (pixels) Time: 2 seconds Area covered: 4 x 4 X 2 mm Provides 3 D map Comprehensive assessment The Ganglion Cell Complex (ILM IPL) Inner retinal layers provide complete Ganglion cell assessment: Nerve fiber layer (g-cell axons) Ganglion cell layer (g-cell body) Inner plexiform layer (g-cell dendrites) TSNIT graph Images courtesy of Dr. Ou Tan, USC 7

8 Normal vs Glaucoma Early Glaucoma NHM4 Cup Rim RNFL Borderline Sector results in Superiortemporal region Abnormal parameters OS Normal GCC Normal Ganglion cell assessment with inner retinal layer map Glaucoma TSNIT dips below normal TSNIT shows significant Asymmetry Anterior Chamber Module High Resolution Cross Scan Cornea Adapter Lens (CAL) 3 D Angle assessment Pachymetry Maps 8

9 Visante OCT Anterior chamber (15 7 mm) Narrow Angle OCT from Topcon Circle OCT Image OCT from Heidelberg Engineering High Resolution Cross Section 40,000 scans per second HRA-OCT Spectralis Normal Eye 9

10 Spectralis Tracks Change Over Time Real-time alignment Reference scan Accurate measurement of change Exam 1 Exam 2 Cross section scan EYE TRACKING Cross section Real-time scanned alignment at same location Heidelberg Image Filtering Technology Multiple images are captured at the same location Noise is identified as points itnot common to the set of images The noise is filtered from the final image Image 1 Image 2 Heidelberg Image Filtering produces higher quality images, compared to higher resolution images without IF Spectralis - Spectral Domain OCT Heidelberg Engineering, Inc. All Rights Reserved. Optic Nerve Head Detail Spectralis ONH Thickness Graph GCL RNFL RPE ends BMO PLT Sclera BTE Spectralis - Spectral Domain OCT LC Spectralis - Spectral Domain OCT Functional Assessment of the Glaucomas John G. Flanagan PhD, MCOptom, FAAO Professor, Dept of Ophthalmol & Vis Sci, University of Toronto Professor, School of Optometry, University of Waterloo Director, The Toronto Hospital Glaucoma Research Unit Senior Scientist, The Toronto Western Research Institute Standard Automated Perimetry Purpose of routine visual field examination is the early and efficient detection, the assessment and the follow-up of functional loss in the visual system Greve

11 Standard Automated Perimetry Clinical Gold Standard Oldest, most documented test of visual function >3000 refs since 1980 (VF and glaucoma) Standardized testing parameters Comparision with normal data Assumed relationship between loss of visual function and retinal ganglion cell loss Perimetry and the Detection of Progression Detection of progression limited by: Physiologic fluctuation Short term fluctuations Test-retest measurement error Long term fluctuations Drift in biologic system Learning effect Progression in Glaucoma Identifying Progression in Visual Fields Earliest diagnosis Disease management Forecasting Rate of progression Quality of vision Normal eshold Retested Thre Impaired Not Progressing Normal Vision Progressing Test-Retest Variability Tested Threshold Perfect Test Result Impaired Vision Progression defined as repeatable change Contributors to variability: Deviation from normal Eccentricity Patient ability Test strategy Glaucoma database defines expected variability GPA flags progression at points exceeding expected patient variability Glaucoma Progression Analysis Multiple Exams Baseline Follow-up Inter-individual variability of progression rates (treated EMGT cohort) MD (db) /27/97 12/15/98 4/18/ /18/02 11/20/02-20 Rate of Progression Plot Age (years) 11

12 Progression Analysis Baseline exams. Establishes initial visual field status. VFI Rate of Progression Analysis. Trend Analysis of patients overall visual field history Today s Visual Field. Complete report of current visual field exam including PD, VFI, progression analysis and GPA Alert. 1.1 Function WGA 1. A method for detecting abnormality and documenting functional status should be part of routine clinical management of glaucoma. 2. It is unlikely that one functional test assesses the whole dynamic range. 3. SAP as usually employed in clinical practice, is not optimal for early detection. Function WGA 5. With appropriate norms, there is emerging evidence that SWAP and possibly also FDT may accurately detect glaucoma earlier than SAP. Updated comment 2007: SAP-SITA has similar sensitivity to detect visual field abnormalities as SWAP-full threshold. h 6. Little evidence to support the use of a particular selective visual function test in clinical practice as there are few studies with adequate comparisons. Updated comment 2007: FDT N30 may provide better sensitivity than SAP-SITA or SWAP-full threshold. Evidence concerning the sensitivity of SWAP-SITA and FDT Matrix 24-2 is not yet available. The Global Glaucoma Network The Global Glaucoma Network Visual Function Specific Perimetry SWAP SITA Matrix - FDP HEP - Flicker Defined Form Others: Flicker Motion Pulsar High-Pass Resolution Perimetry Rarebit Resolution Perimetry Human Retinal Ganglion Cells 12

13 Photoreceptors Inner Retina Ganglion Cells Visual Function Glaucoma: Structure vs Function L cones Red P-cells Visual Acuity HRP RNFL & ONH change (detectable) M cones Green S cones Blue Rods UAL ESSING VIS PROCE K-cells M-cells SWAP B Flicker Motion Y FDT & FDF RNFL & LC change (undetectable) Ganglion cell death and axon loss Initiation of apoptosis & remodelling of LC Normal SWAP/FDP VF changes SAP VF change Visual Function Specific Perimetry VF change (mod) VF change (severe) Blindness after C. Johnson, University of Iowa Courtesy of R. Weinreb MD, 2003 (adapted) #91 Pattern Deviation W-W W-W SWAP SWAP: Rationale for the Technique Blue Stimulus To preferentially stimulate the short wavelength sensitive (SWS) pathway High Luminance Yellow Background To saturate both the middle and long wavelength sensitive pathways To suppress rod activity Baseline + 1 year + 2 years + 3 years + 4 years Diagnostic Performance Delgado et al, Ophthalmic Technology Assessment: Automated Perimetry. Ophthalmology, December, 2002 Early yglaucoma: 88% sensitivity and 92% specificity Improvements with SITA SWAP: Speed and Sensitivity Full Threshold Test time: 12:50 Fastpac Test time: 7:50 SITA Test time: 3:56 SWAP is a lengthy, demanding test, is sensitive to media opacities, and has a greater magnitude of longterm fluctuation..which makes it difficult to assess progression accurately. Stimulus: V, Blue Background: Yellow Stimulus: V, Blue Background: Yellow Stimulus: V, Blue Background: Yellow Courtesy of Boel Bengtsson Dept of Ophthalmol Malmo University Hospital, Sweden 13

14 Short Wavelength Automated Perimetry (SWAP) Who should undergo SWAP testing? Patients with ocular hypertension Glaucoma suspects Patients with early glaucoma Diabetics non-proliferative retinopathy DME Optic neuritis FDP: Underlying principles Preferentially stimulates the magnocellular pathway (M-cells) Particularly subset with non-linear contrast response (M γ -cells) Maddess & Henry, 1992 M γ -cells have large axons M γ -cells constitute c.20% of magnocellular system therefore only 3-5% of nerve fibres FD Illusion is cortically driven White et al, 2002, Quaid et al, 2003 Diagnostic Performance Delgado et al, Ophthalmic Technology Assessment: Automated Perimetry. Ophthalmology, December, 2002 Early Glaucoma: 85% sensitivity and 90% specificity Moderate + Severe: >97% sensitivity and specificity FDP has a short testing time and is resistant to blur and pupil size..may be useful as a screening tool. FDT Summary FDT is as close as we have to a test that meets the requirements of Case-Finding screening One Minute Test High sensitivity and specificity, for early disease Very high for moderate disease Level I evidence that predictive of SAP HFA & Matrix - Glaucoma Patient The Heidelberg Edge Perimeter 14

15 Flicker Defined Form (FDF) Originally described High temporal frequency stimulus (> 15Hz) Counterphase flicker Creates a phantom contour illusion 2,3 Considered a magnocellular-dominated illusion 1,2,4 1. Ramachandran V.S., Rogers-Ramachandran D. Phantom Contours: A New Class of Visual Patterns that Selectively Activates the Magnocellular Pathway in Man. Bulletin of the Psychonomic Society, 29, 391 (1991) 2. Rogers-Ramachandran D., Ramachandran V.S. Psychophysical Evidence for Boundary and Surface Systems in Human Vision. Vision Research, 38, (1998). 3. Flanagan J.G., Williams-Lyn D., Trope G.E., Hatch W. and Harrison E. The Phantom Contour Illusion Letter Test: A New Psychophysical Test for Glaucoma? Perimetry Update 1994/ Quaid P., Flanagan J.G. Vision Research (2005). Flicker Defined Form (FDF) Phase 1 + Phase 2 = Illusory Edge or Contour = C:\Documents ettings\jgflanag\ Diagnostic Performance? Test-Retest Characteristics Structure (HRT) and Function (HEP) Structure (HRT) and Function (HEP) 15

16 Structure and Function Map Structure and Function Map Inner Ring: HRT MRA Structure Outer Ring: HEP Function Legend: Within Normal Limits Borderline Outside Normal Limits Structure & Function WGA 1. Published literature often lags behind the introduction of new technology. Therefore literature based on previous versions of current technology should be viewed ed with caution. 2. In different cases, either structural examination or functional testing may provide more definitive evidence of glaucoma, so both are needed for detection and confirmation of the subtle early stages of the disease. The Global Glaucoma Network 16