Editorial
Defining the structure/function relationshipin glaucoma
The classic teaching is that when assessing a glaucomapatient we should look for a concordance between struc-tural changes in the optic disc and functional changes asdetected by perimetry. When this is identified, such as inthe case of focal loss of neuroretinal rim (e.g. an inferiornotch) combined with a well-defined scotoma (e.g. a supe-rior arcuate defect), we are reassured that what we arelooking at is definitely glaucoma, and it makes sense withregard to our understanding of the pathological process.If there is a mismatch then we should consider otherdiagnoses. Of course the site of primary damage is still indebate, but loss of a bundle of nerve fibres and death of thecorresponding retinal ganglion cells will typically producea nicely defined scotoma that matches the topography ofthe retinal nerve fibres. However, we know in the clinicthat it does not always work this way, and we are fre-quently confounded by our interpretation of discs wherethe structural appearance and the functional loss do notmatch as well as we might have expected. The recent addi-tion of high resolution imaging devices to assess the retinalnerve fibre layer (RNFL) in vivo has given us potentially amore accurate means to document structural change, butthe structure/function relationship demonstrated by thesedevices has not been overwhelming. There are a number ofreasons for this, relating to variations in anatomy andfunction among the population, variations in methods ofassessment and the different measuring and scalingsystems used to quantify changes. In this issue, Malik et al.review in detail the factors that define this structure/function relationship and re-examine the literature toexplain why there are discrepancies. They go on to chal-lenge the very frequently quoted notion that at least 25%of ganglion cells are lost before any functional change isevident.
A major obstacle in defining the relationship is the hugevariety of optic disc sizes and shapes in the community,and this is associated with variations in the number andthe distribution of nerve fibres around the disc margin. Infact, even our ability to actually define the disc margin iscoming into question. Reis et al.1 and Strouthidis et al.2
have just reported that varying combinations of the termi-nation of Bruch’s membrane, border tissue or the anteriorscleral canal opening produce the two-dimensional discmargin we see and identify. Photographs and confocalscanning laser tomography examinations may even over-estimate the amount of remaining rim in regions where thefull extent of Bruch’s membrane is not detected clinically.Spectral domain optical coherence tomography can dem-
onstrate transparent overhanging Bruch in some areas, andthe angle of insertion of the nerve can make a significantdifference to the perceived neural canal opening. In addi-tion, when interpreting an obliquely inserting disc, thetypical double hump pattern characteristic of a ‘normaltemporal-superior-nasal-inferior-temporal (TSNIT)’ distri-bution gets displaced. The superotemporal and inferotem-poral bundles are still usually within normal limits interms of number of fibres but they will not fit the standarddistribution of sectors represented in the normative data-base for a particular imaging device. In fact, nerve fibrelayer studies show considerable variability for a givenvisual field location,3 with optic nerve head entry pointsvarying with a standard deviation of 8.8°, with some indi-vidual points being spread over a range of up to 30°.Furthermore, a small but significant number of individualsdo not have the anatomically well-defined horizontalraphé that we take for granted when interpreting fields,with some having overlaps that can produce variations inthe typical nasal step pattern.4 Ideally, we need to indi-vidualize our structure/function map for each subject,which would need to take into consideration the size andthree-dimensional shape of the disc, as well as relatedretinal anatomy, such as the fovea to disc angle, and posi-tion and/or overlap of the raphé.
There may be a variety of processes occurring in thespectrum of glaucomas, and evolution of the cuppingprocess may vary considerably between individuals. Afocally notched disc shows quite a different structuralchange from a more saucerized sclerotic type disc. It isassumed that the amount of nerve fibre loss should stillcorrelate with field loss, but measuring this could becomplex with factors such as lamina structure playing arole. Primate modelling of glaucoma has even shown someinitial thickening of pre-laminar tissue in early cases, priorto the deepening of the cup. There is also a residual non-neural component of tissue (around 30–60 mm) thatremains even in advanced glaucoma and will be includedin the RNFL measured by our imaging devices, confound-ing the relationship.
The different methods employed by our test strategiesfor perimetry and imaging provide an inherent problem incombining data from the two sources. The structure func-tion topographical map described by Garway-Heath et al.5
is the most commonly used, although more recently othergroups have devised alternate models with slightly differ-ent representations.6 Such maps provide a representationof areas of the visual field that correlate with sectors of the
bs_bs_banner
Clinical and Experimental Ophthalmology 2012; 40: 337–338 doi: 10.1111/j.1442-9071.2012.02803.x
© 2012 The AuthorClinical and Experimental Ophthalmology © 2012 Royal Australian and New Zealand College of Ophthalmologists
neuroretinal rim. However, as RNFL is measured on alinear scale and visual fields on a logarithmic scale, therelationship between the two will not be linear. A smalldB change in thresholds represents a much greater order ofmagnitude of change than the associated RNFL changesmeasured on a linear scale in microns.
Clinical trials have shown that there are many patientswho show structural change before functional loss, butequally there are other studies that show a large numberof converters on perimetry before disc end points aredetected. This can largely be explained by our lack ofability to reliably define and detect change and the par-ticular definitions used in these studies. Our field strate-gies use the same stimulus at all eccentricities eventhough we know that retinal cell distributions changewith eccentricity. Electrophysiology studies with themultifocal visual evoked potential (VEP) have shownamplitudes to have a linear relationship with RNFLthickness and this strategy uses different stimulus sizeswith increasing eccentricity (although mainly due to cor-tical magnification factors).
Typically, in early glaucoma, structural loss appearsgreater than functional loss, whereas in more advanceddisease, it appears as if function changes at a greater ratethan structure. However, if we could measure individualganglion cell counts and had more sensitive techniques toassess early functional loss, this might not be the case, andthe two would run in parallel. Ganglion cell dysfunctionprior to actual death of the cell may account for some caseswhere perimetric loss appears to occur first.
Recent studies have suggested that combining data, forexample using Bayesian hierarchical models,7 better pre-dicts future progression. It makes good sense to combineall information when diagnosing a patient, and it appearsthat technology is moving towards trying to help us, withnew printouts combining structural and functional data. Itwill probably take some time before we see the concor-dance we would like to be certain in our diagnostic
process, but in the mean time we should accept that therewill be some spurious and even confusing results that willrequire our clinical judgment to interpret.
Stuart Graham PhD FRANZCO
Level 1, Australian School of Advanced Medicine,2 Technology Pl, Macquarie University, Sydney,
New South Wales, Australia
REFERENCES
1. Reis ASC, Sharpe GP, Yang H et al. Optic disc marginanatomy in patients with glaucoma and normal controlswith spectral domain optical coherence tomography.Ophthalmology 2012; 119: 738–47.
2. Strouthidis N, Yang H, Reynaud JF et al. Comparison ofclinical and spectral domain optical coherence tomogra-phy optic disc margin. Invest Ophthalmol Vis Sci 2009; 50:4709–18.
3. Jansonius NM, Nevalainen J, Selig B et al. A mathemati-cal description of nerve fiber bundle trajectories andtheir variability in the human retina. Vision Res 2009; 49:2157–63.
4. Jeoung JW, Kim TW, Kang KB et al. Overlapping ofretinal nerve fibers in the horizontal plane. Invest Oph-thalmol Vis Sci 2008; 49: 1753–7.
5. Garway-Heath DF, Caprioli J, Fitzke FW et al. Scalingthe hill of vision: the physiological relationshipbetween light sensitivity and ganglion cell numbers.Invest Ophthalmol Vis Sci 2000; 41: 1774–82.
6. Kanamori A, Naka M, Nagai-Kusuhara A et al. Regionalrelationship between retinal nerve fiber layer thicknessand corresponding visual field sensitivity in glaucoma-tous eyes. Arch Ophthalmol 2008; 126: 1500–6.
7. Medeiros FA, Zangwill LM, Girkin CA et al. Combiningstructural and functional measurements to improve esti-mates of rates of glaucomatous progression. Am J Oph-thalmol 2012; 153: 1197–205. e1.
338 Editorial
© 2012 The AuthorClinical and Experimental Ophthalmology © 2012 Royal Australian and New Zealand College of Ophthalmologists
