Glaucoma 2012

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correlating imaging and preperimetric changes

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Glaucoma 2012: Managing Challenging: Glaucoma Problems :

Glaucoma 2012: Managing Challenging: Glaucoma Problems Merging Art and Science

Correlating Ganglion Cell Loss and Peri-metric Change:

Correlating Ganglion Cell Loss and Peri -metric Change

Progressive loss of retinal ganglion cells (RGC) is a key feature of glaucoma :

Progressive loss of retinal ganglion cells (RGC) is a key feature of glaucoma Characteristic structural (Imaging) and functional (VF) Perimetry in the diagnosis and monitoring of glaucoma . The relationship between perimetric performance and RGC loss is clinically relevant. The current generation of glaucoma imaging devices mostly uses measures of optic disc topography and/or retinal nerve fiber layer thickness as surrogates for RGC loss Attempts to correlate direct measures of ganglion cell density with perimetry Generally been challenging to conduct and interpret Relied on attempts to correlate post mortem retinal histology with premortem visual field tests, either in humans or monkeys

Does RGC Loss Precede Perimetric Change?:

Does RGC Loss Precede Perimetric Change? 25%-35% loss of RGC is associated with visual field loss (Quigley)! Is it So? NO. Why? Degree of variability, even between normal subjects, in RGC counts at any given eccentricity. Estimated total RGC count in normal individuals varied by a factor of two Remember Interpreting that “loss” of RGC relative to a population average is not the same as “loss” of RGC over time by an individual. SO: No surprise that a proportion of glaucoma subjects studied by Quigley had abnormal visual fields with statistically “normal” RGC numbers Longitudinal data on how RGC density changes over time is key to understanding the relationship between RGC loss and perimetry , and this is not possible in post mortem human studies

Harwerth and co-workers:

Harwerth and co-workers Relationship between RGC loss and perimetric change investigated Monkey glaucoma model Have shown that RGC counts and perimetric performance are tightly correlated as long as appropriate measurement scales are used Effect of aging and eccentricity are considered Results have been interpreted as suggesting that structural changes occur before changes in function Often correct BUT also have shown perimetric defects can also sometimes occur in the presence of relatively normal RGC density.

clinical domain:

clinical domain Optic disc imaging is surrogate for RGC loss Large clinical trials No conclusive evidence & extremely variable Which occur first? Detectable structural or functional changes Studies: Visual field endpoint reached before a structural change Early Manifest Glaucoma Trial: 86% Ocular Hypertension Treatment Study 35 % Such results should be interpreted with care, given the widely different criteria used for structural and functional changes in clinical studies

Key Messages:

Key Messages

RGC loss in glaucoma is associated with a variety of structural changes that can be measured and that correlate with perimetric change:

RGC loss in glaucoma is associated with a variety of structural changes that can be measured and that correlate with perimetric change

PowerPoint Presentation:

Individual RGC bodies in the retina cannot currently be quantified directly with commercially available instruments Surrogate measures correlate well with RGC loss. Optic disc topography, RNFL thickness Thickness of the macular retinal ganglion cell complex Direct imaging of RGC bodies is possible in the lab using fluorescent labels The future Techniques exist to label cells undergoing apoptosis that may help with the quantification of RGC loss clinically.

PowerPoint Presentation:

Measurements of NFL thickness and optic disc topography appear to correlate relatively well with ganglion cell loss and perimetry , but different structural measures may not necessarily co-vary simultaneously

PowerPoint Presentation:

Even for a relatively clearly defined structure such as the retinal nerve fiber layer, different instruments may detect different aspects of pathology Fortune and co-workers (ARVO 2012) scanning laser polarimetry may detect nerve fiber layer changes earlier than OCT Mechanism is related to possible cytoskeletal changes that occur before axonal loss that can be detected by SLP but not OCT Structural measures of RGC features by different techniques are not necessarily interchangeable

Structural measures of RGC sickness prior to loss could be very useful Jonnal RS, Besecker JR, Derby JC, et al. Imaging outer segment renewal in living human cone photoreceptors. Opt Express. 2010; 18(5):5257-5270.:

Structural measures of RGC sickness prior to loss could be very useful Jonnal RS, Besecker JR, Derby JC, et al. Imaging outer segment renewal in living human cone photoreceptors. Opt Express. 2010; 18(5 ):5257-5270.

RGC: Injury Vs Survival:

RGC: Injury Vs Survival IS it? Quantification of RGC body survival should be the main aim of a structural test in glaucoma? BUT Extremely valuable to have tests that can assess RGC injury prior to death Recent studies suggest that the contrast sensitivity of ultrahigh-resolution OCT may allow the detection of sub-cellular changes that correlate with neuronal health or possibly even with neuronal activity

PowerPoint Presentation:

Cellular structures and processes amenable to imaging that could give an indication of neuronal dysfunction prior to death include Cyto -skeletal components, axonal transport, early events in the apoptotic cascade, and possibly electrical function using voltage-sensitive dyes Ability to detect sick RGCs at a stage when rescue is still possible would be extremely attractive, and correlation of such measures with perimetry would be very interesting.

We still need both structural and functional measures clinically:

We still need both structural and functional measures clinically Structural or functional measures may be more useful at different stages of the glaucomatous disease process Structural changes may be very useful early in the disease as an indica tor of progression in the presence of normal standard automated perimetry Current generation of structural tests may be less valuable than perimetry late in the disease, when further RGC structural attrition may be difficult to detect structurally but causes progressive loss of function

Combined structure–function indices are evolving rapidly and are likely to be widely used in future:

Combined structure–function indices are evolving rapidly and are likely to be widely used in future Current work Medeiros FA, Zangwill LM, Girkin CA, Liebmann JM, Weinreb RN . Combining structural and functional measurements to improve estimates of rates of glaucomatous progression. Am J Ophthalmol . 2012 ; 153(6):1197-1205 e1

Perimetric Rate of Change :

Perimetric Rate of Change

Measurement of rates of change in glaucoma: SAP: white on White:

Measurement of rates of change in glaucoma: SAP: white on White Why? To identify patients who are deteriorating quickly To distinguish them from those who are worsening slowly Fast progressors may require suitably aggressive treatment Slow progressors might be spared the expense and morbidity of unnecessary treatments Why Important? Aging population with limited resources for medical care Goals To reliably measure the rate of functional decline in glaucoma To use it to identify the fast progressors , To provide clinically useful forecasts of the disease to help guide treatment . Should perform well across the entire range of disease severity .

Hypothesis & What is required :

Hypothesis & What is required progression in glaucoma is frequently nonuniform Possible to identify a faster spatial component for visual field decay that can be distinguished from the remaining test locations that have a slower rate of decay . Include components related to aging and media opacity Some cases the slow component may indeed represent true glaucomatous progression Method to measure visual field decay with a large cohort of glaucoma patients with long-term follow-up Identifies visual field locations progressing at the fastest rates, Provides a method to spatially separate test locations demonstrating slower progression from those showing faster progression Predicts future visual field measurements with appropriate confidence intervals while preserving spatial information

Fast and Slow Progressors:

Fast and Slow Progressors Average slow component rate is 0%/year, while the average faster component rate is 30 %/year. spatial distribution of test locations assigned to faster and slower components of exponential decay

PowerPoint Presentation:

Top left: grayscale of the initial visual field in the series. Top middle: grayscale of the grayscale of the final visual field in the series. Top right: grayscale of the rate of decay (%/year) at each test location. Middle left: spatial partition of the visual field into slower (gray) and faster (black) components. Middle and middle right: average rates of decay of the slower (gray) and faster (black) components superimposed on gridlines for exponential decay. Bottom row: gray scale predictions for the visual field thresholds at final follow-up for the 10th percentile, 50th percentile (median), and 90 th percentile confidence intervals; predictions were calculated based on the regression slopes derived from the first half of follow-up.

Problems:

Problems A low signal-to-noise ratio Requirement of multiple tests to reduce the noise Requirement of confirmatory tests to validate the signal Inherent lack of external validation to evaluate any new method

visual field index (VFI) – Bengtsson and Heijl & Global Indices:

visual field index (VFI) – Bengtsson and Heijl & Global Indices VFI Method to estimate global rates of visual field progression in glaucoma, Index is weighted more heavily toward the central visual field in proportion to the cortical representation of vision Normalized to the entire range of visual field function provides some predictive capability as a linear extrapolation of the index use of proprietary stored normative data Assumes a linear rate of worsening Global indices: Lack of any spatial information with regard to the regions of the visual field showing faster progression.

Structural Rate of Change:

Structural Rate of Change Glaucoma treatment : Directed toward slowing down the rate of change to a level where disability from the disease will be unlikely during the remaining projected years of life An accurate and precise determination of the rate of change is essential to guide aggressiveness of therapy and need for follow-up . Although rates of change are frequently assessed using standard automated perimetry (SAP), sole reliance on SAP to assess rates of change may result in underestimation of rates of neural damage in early to moderate stages of the disease .

May result in delayed diagnosis and underestimation of the risk of developing functional impairment:

May result in delayed diagnosis and underestimation of the risk of developing functional impairment Several longitudinal studies have shown that imaging technologies can provide reliable, objective, and quantitative estimates of rates of structural progression in glaucoma that can easily be incorporated into clinical practice Most studies have shown that straightforward strategies such as assessment of global average Retinal nerve fiber layer thickness or measurements of neuroretinal rim area over time seem to perform well for assessment of rates of change.

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