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Glaucoma and OCT Are Macula Scans More Valuable than Disc Scans?Jason Higginbotham Bsc (Hons) MCOptom FBDO

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Glaucoma and OCT Are Macula Scans More Valuable than Disc Scans?Glaucoma clinic lets go back 25 years!

Look for the following:Raised Intra Ocular Pressure (IOP)Glaucomatous Field LossHigh CD Ratio, disc Pallor, deep cups, nasal shift of vessels, bayonetting and so onPx symptoms and family historyNarrow anglesSecondary markers (E.g. Krukenbergs spindles)

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A Classic View?Open angle glaucoma

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Do we measure IOP?IOP is still considered the biggest risk factor for Glaucoma.

Do we measure it?NO!? We estimate it. Often we are a long way off. Only two devices measure actual IOP The Reichert Ocular Response Analyser and the Oculus Corvis ST. OCT has shown a much higher rate of normal and low tension glaucoma cases. IOP is important still, but how relevant?

IOP would be seen as the key risk factor and there would be two potential causes of damage from that IOP Mechanical and Vascular. Everything would be disc centred in terms of investigations and ultimately consultants in the clinic of the past would have been thinking about the health or otherwise of the patients RNFL at the ONH (Optic Nerve Head). But, what is the RNFL? How much RNFL can we lose before it manifests as a field loss?If mechanical were the only cause, why would there be cases of NTG (normal tension glaucoma) and LTG (low tension glaucoma).5

Oculus Corvis

At 4300 frames per second, the high speed Scheimpflug camera on the Corvis allows for full understanding of the Corneal hysteresis as well as size and structure. This allows for pneumo tonometry to provide full analysis of the real IOP as well as better prediction of ectactic disease and follow up of treatments like CXL (Corneal Cross Linking). 6

Are Fields reliable?Id like to say yes, but the subjective nature of these tests and the affects of tilted discs and optic disc drusen (for example) can possibly affect the results as can happen on OCT disc scans.What about pre-perimetric glaucoma?What are RNFL fibres?

In glaucoma, up to 50% of retinal nerve fibres are lost before a visual field defect becomes manifest with full threshold automated static perimetry (Quigley et al 1989)

Of course visual fields are important and reducing IOP is aimed solely at reducing the speed and extent of visual field loss progression. The Early Manifest Glaucoma Trial showed that there is a 10% decrease in the risk of worsening visual field loss (visual field progression) for every 1 mmHg reduction in IOP.7

Definition of GlaucomaGlaucoma: a group of diseases of the optic nerve which result in a loss of retinal ganglion cells in a characteristic pattern of optic neuropathyGlaucoma is a group of eye diseases that cause progressive damage of the optic nerve at the point where it leaves the eye to carry visual information to the brain. - World Glaucoma AssociationThe American Academy of Ophthalmology now defines glaucoma as a group of diseases with certain features including an intraocular pressure that is too high for the continued health of the eye.

The definition seems to have changed back and forth slightly over recent decades. Ultimately, Glaucoma is an Optic Neuropathy. How and why that occurs is certainly not yet fully known.According to World Health Organisation data (2002), worldwide glaucoma accounts for 12% of cases of blindness which makes it the second leading cause of blindness after cataract (48%).8

What actually occurs in Glaucoma and where?Studies have shown that the actual process at play is RGC (Retinal Ganglion Cell) body shrinkage followed by RGC body death taking place. This has been shown to be due to cellular apoptosis caused either by ischaemia or by excitotoxicity (glutamate in the vitreous). IOP may cause release of glutamate as a traumatic response and glutamate is toxic to RGCs. However, papers also suggest bringing down the IOP in normal tension glaucoma patients is effective at slowing progress of the disease.

It is important to remember that apoptosis is often a useful mechanism in the body. For example, 50% of the RGCs naturally die off during the visual systems development by apoptosis and it is clear that some mechanism of insult and subsequent secondary neuro toxin release leads to the unnecessary programmed cell death encountered in glaucoma.9

Theories of DamageWhat actually occurs in Glaucoma and where?

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What actually occurs in Glaucoma and where?We now have two main theories:

Selective Damage Theory versusReduced Redundancy Theory

Its probable that a bit of both are at play!

However, its the RGC that dies off in all cases. But the axonal death may bring about the RGC death, or does it?

The overriding premise still in existence is that intra ocular pressure (IOP) is the main cause of glaucoma (Cioffi and Van Buskirk 1994; see other references at the end of the lecture). Most sources suggest a mechanical and a vascular element to how the IOP causes physical damage to tissue and may lead to the release of neuro toxins.Basically, Selective Damage Theory states that the larger retinal nerve fibres are most affected by raised IOP (whether mechanical or vascular mechanisms). All RNFL fibres are affected to some extent, but it appears that the larger fibres are affected the most and at a greater rate. There is some damage to the RGC axonal flow.Reduced redundancy depends on the number, spread and commonality of different RGCs. There are more Red ON RGCs than there are Blue ON RGCs. In glaucoma, all RGCs reduce in number, but the proportion of blue RGCs lost is much higher; this leads to blue on yellow defects occurring earlier in many cases. Note SWAP programme on the Humphrey field analyser.11

The Ganglion Cell ComplexThe Ganglion Cell Complex (GCC) is the innermost five layers of the retina (ILM, RNFL, GCL, IPL and INL). Easier to measure as a whole than just the GCL or GCL and IPL. GCC tends to shrink before obvious change at the disc, but there are cases where this doesnt occur.Lots of evidence to suggest that ganglion cell body shrinkage takes place first. Does axonal damage occur later if so, the RNFL may be intact or appear so for longer and might not manifest on eye examination.

In either case, a patient can lose 50% of their superior and inferior nerve fibre bundles or GCC before this manifests as a field loss and up to 40% of their papillo macular region of nerve fibres or GCC before this manifests as a field loss. So, until the patient has perimetric glaucoma (if normal tension), they may not be referred and we could be sending them to the eye department to rescue whats left of their retinal/optic nerve neural tissue. So, is glaucoma a disease of the optic nerve or the retina or essentially both?12

Normal GCCGCC thinner in Glaucoma

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The Ganglion Cell ComplexWith the added G Chart, Ganglion Cell Complex thickness can be assessed against the normative data. Notice that now the scale only represents half a bell curve. Where the GCC is thicker, this is represented in white as there is no known pathology of GCC hyperplasia.

G Chart

The Ganglion Cell Complex is a clinically recognised layer of the Retina. It represents the innermost five layers of the Retina. These are the ILM (Inner Limiting Membrane), the RNFL (Retinal Nerve Fibre Layer), the GCL (Ganglion Cell Layer), the IPL (Inner Plexiform Layer) and the INL (Inner Nuclear Layer). The GCC has been clinically proven to be the only layers of the Retina affected by Glaucoma and so some devices measure this against Normative data. Other OCTs try to measure the GCL alone or the GCL and IPL together to assess Glaucoma risk. Note also the Superior / Inferior comparison. This is useful as no RNFL fibres cross the midline, and usually, the inferior GCC is thicker than the superior. This also allows us to assess symmetry WITHIN the eye. If there is a considerable asymmetry between superior and inferior areas, this can be a sign of pathology. Symmetry is an important differential diagnostic tool on many occasions.It is important to remember that the IPL, GCL and RNFL are in fact all part of the same large cells, whose Nuclei lie within the Ganglion Cell Layer. Damage to the cell body tends to occur first and thus the GCC starts to reduce in thickness at the Macula first. Often, the axons of the Ganglion Cells (the RNFL) remain intact within the RNFL at the disc for some time after the cell body has started to die/shrink within the GCL. Hence, the RNFL at the disc can take longer to show loss of tissue than found within the GCC at the Macula.

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The Ganglion Cell Complex

Normative Scales

Imagine a Bell curve coming out of the page / screen based on the colour scale above. The top of the bell is the centre of the Green on the Normative Database Scale. It is important to note that even if the map is all red, it could still be normal for that patient. However, it is less likely that it is normal where the map is all red. Of course, there may be cases where despite being all green, the patient is still abnormal as well.

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Disc scans RNFL measurementDisc RNFL Analysis

As well as comparing Retinal thickness and GCC with a normative database, OCTs also compare RNFL thickness with normative data. There are several ways in which this can be assessed. On the right we have what is often referred to as a Disc Circle Scan. This is a 360 degree panoramic scan around a 3.4 mm circumference circle around the ONH (Optic Nerve Head). The OCT compares the RNFL thickness at all points around this circle to normative data and produces what is often called a TSNIT or ONH Profile map. The black line represents the patients RNFL ONH profile and this is overlaid over normative profiles. The same normal distribution and standard deviations apply and once again, there is no known condition where there is too much RNFL, so we only have colours for thinning of RNFL and white for anything thicker. We can also measure average RNFL thickness across the whole Optic Disc compared to normative data or to the Superior and Inferior Bundles, the ISNT rule (TSNIT) or even Clock hour for more refined analysis (for notching for example). OCTs will always measure the CD ratios higher than clinicians do. This is because the OCT can see where Bruchs Membrane ends and we cannot. We see the cup the same size as the OCT generally, but because we see the disc as being larger, we get a smaller CD ratio.16

Macula Scans versus Disc ScansIt is well known that Macula scans are more repeatable, accurate and reliable than Disc scans. Macula scans are easier to repeat and compare due to greater fixation stability and ease of scan overlay.Disc scans are more prone to subtle positioning errors, fixation loss and opto-kinetic nystagmus.Disc Drusen, Tilted Disc, Peripapillary ERMs and papilloedema all affect the accuracy and repeatability of disc scans.

Although there are also sources of error for Macula scans, these are fewer in number and severity. This means that repeatability of disc scans is lower than that of macula scans and as such, if you can measure RNFL via the GCC at the macula, you are more likely to get an accurate result that can be repeatably and reliably measured time and again.

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Progression analysisSpotting Glaucoma early is one of the most important uses of OCT and is certainly one area where Optometrists come into their own within Primary care and also in Community Ophthalmology and Secondary care.We can use the software to analyse if there is any progression in loss of Ganglion Cell Complex (GCC) at the Macula or Retinal Near Fibre Layer (RNFL) thickness at the Optic Nerve Head (ONH).Superior / Inferior step analysis as well as R/L comparison are always important too.

Such analysis is also useful for assessing if there is any progressive loss or increase in overall Retinal thickness at the posterior pole. This may help in assessing the rate of progress of Ischaemic Retinopathies, Macula Oedema or the effect of Lucentis treatment for example. Most software for OCTs allows complex analysis over time of tissue thickness change. Most software carries out statistical analysis over time to measure if change is due to pathology, age or isnt significant at all (i.e. within the normal repeatability limits of the device).

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GCC Progression R Eye

Glaucoma Progression Macula. Notice the progressive loss of Ganglion Cell Layer / GCC in this patients Right Eye. The graph produced by the OCT helps us determine if change is occurring and there is obvious loss of tissue. Notice the very evident Inferior / Superior difference. This progression may help us to decide upon a correct course of referral if this were only over a short period. In this particular case, this is from a Px already under Treatment and the progression will help the Ophthalmologist direct a more aggressive treatment protocol to try and prevent further tissue loss.

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RNFL Progression R Eye ONH

Glaucoma Progression Disc. This is the same eye! Notice there is less dramatic loss of RNFL tissue initially, but latterly the same Superior / Inferior difference can be seen. This is because recent studies have shown that loss of the Ganglion Cell Complex (ILM, RNFL, GCL, IPL and INL) can pre-date ONH RNFL loss and can be an excellent pre-clinical sign of Glaucomatous change and can help us to avoid field loss by starting Glaucoma treatment prior to this taking place. GCL / RNFL loss can help identify Glaucoma up to eight years before clinical signs such as field loss manifest. A Px can lose 50% of the GCC Superiorly and Inferiorly and 40% of the Papillo-Macula Bundle before this might manifest as a field loss!Diagnosing Glaucoma via field screening means we are often rescuing what is left of the Optic Nerve when we start treatment, where as with OCT, we can help to prevent or slow the field loss from occurring.

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This 44 year old patient attended a clinic. They had evident disc cupping in both eyes with some palour. Our suspicions would already be aroused by the discs, but the IOPs were not raised.A Late Stage Example. Case 1.

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The right visual field shows an arcuate scotoma, with blind spot enlargement in the left eye.

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The field loss becomes more obvious when we look at the RNFL layer thickness deviation maps against the normative data. You can see the evidence of loss of RNFL particularly in the Right Eye which corresponds perfectly with the field plot on the previous page.

RL

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The ETDRS chart shows minor thinning of the retina inferior to the Macula in the right eye.The G Chart, however, shows considerable inferior thinning and loss of the Ganglion Cell Complex across the inferior Macula. The shape from the deviation map is typically arcuate and matches the field loss very closely. Note the nasal step and the horizontal mid line.

Notice the Asymmetry WITHIN the eye, showing loss inferiorly only. With Glaucoma, we can see that only the GCC is affected initially. The overall Retinal thickness, even in later stages of GCC loss is relatively unchanged in thickness as outer layers are unaffected. Thus, if a patient has considerable loss of total Retinal thickness, the pathology may be less likely to be linked to Glaucoma or Optic Neuropathy. However, note that two conditions may co exist in some cases and there may be loss of total Retinal thickness as well as independent loss of GCC thickness in the same eye.24

Example Case 284 Year Old FemaleDrop in vision RE. Family history of Glaucoma.IOPs RE 17 mmHg LE 20 mmHg. CCT 512 microns. Visual Fields inconclusive, poor compliance.VA RE 6/24 distorted. LE 6/9 .OH Bilat IOLs. FOH Mother Glaucoma. GH Good. Arthritis. Meds Anti inflammatories. FMH Nil.No headaches or other Sx. Driver. Retired, but does voluntary work part time!

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Example Case 361 Year Old MaleNo visual complaints.IOPs RE 19 mmHg LE 18 mmHg. Corrected IOPs. Visual Fields show minor initial loss of sensitivity RE.VA RE 6/6 LE 6/6 OH No Ops. FOH NoneGH Good. Meds None. FMH Nil.No headaches or other Sx. Driver. Accountant.Uses PC a lot. Plays golf and goes to the gym.

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Example Case 465 Year Old FemaleNoticed poor vision LE. A few headaches. No eye ache. No haloes. Reading difficult.Corrected IOPs RE 22 mmHg LE 23 mmHg. Visual Fields RE: Full 26 dB, LE: Early inferior arcuate loss 24 dB. Slightly narrow angles OU.VA RE 6/6- LE 6/9 OH Good. No Ops. FOH Sister Glaucoma. GH Hypertension. Meds Anti hypertensives and statins. FMH Father heart attack.Driver. Retired.

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Example Case 572 Year Old FemaleNight driving difficult. No headaches. No pain or other ocular symptoms.IOPs RE 13 mmHg LE 13 mmHg. Visual Fields full right and left. 24-2 screening.VA RE 6/6- LE 6/6-OH Early lens opacities. No Ops. FOH Mother went blind; AMD. GH Arthritis and IBS Meds Anti inflammatories. FMH Nil. Driver. Retired. Uses PC and likes to read.

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Potential Errors with Macula ScansThere are circumstances where the reliability and accuracy of Macula scans is slightly reduced. These include:High myopes. Some cases show overall retinal thinning, whereas occasionally, the GCC alone seems thinned in some myopes.Epi retinal membranes (ERMs) can affect the overall retinal thickness and make accurate assessment of GCC difficult.Presence of over underlying pathology, particularly where a large regional increase in overall retinal thickness occurs, such as CSR (central serous retinopathy).

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Potential for the futureAs higher resolution devices become available with longer wavelength infra red lasers and greater tissue penetration, then it will be likely that better repeatability of scans will occur and more effective scan imaging even with dense lens opacities might become possible.As whole eye OCT is being developed, it may not be too long before such device can offer assessment of more eye parameters in one full glaucoma plot.Many devices have software which can or will incorporate visual field plots and other test results.

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Earliest Glaucoma detectionThere is no doubt that OCT can detect glaucomatous damage much earlier than visual fields and other older techniques. However, it is possible to detect even earlier changes that OCTs might not.Modern ERG / VEP tests can detect extremely subtle alterations in the speed of response in the visual system and the speed of depolarisation in the process of seeing.There is a new device which makes these tests much quicker and easier than before.

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The Diopsys Nova and Argos systems

Tabletop

Cart

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ERG and VEP for early glaucoma detectionStructureFundus Photograph(Subjective)

FunctionVisual Field(Subjective)

Currently, many practitioners still rely on subjective examinations of structure versus function. The inherent problems with subjective assessments and testing mean that these are not the most effective ways of diagnosing glaucoma. For instance, even with FDT (M theory / selective damage and reduced redundancy), a large amount of RGC / RNFL loss will have occurred before any clinically significant visual field loss will have manifested. Evaluation of disc photographs, even with red free and other manipulation is likely to only find active and established glaucomatous damage.57

ERG and VEP for early glaucoma detectionStructureFunctionOptical Coherence Tomography(Objective)ERG(Objective)

As previously mentioned, OCT offers a more objective and reliable early detection of glaucoma through tissue measurement and progression analysis for example. Add to this the even earlier detection sensitivity and specificity of ERG and VEP and practitioners should be able to correctly identify glaucoma suspects long before any subjective signs or patient symptoms arise (whether his be HTG high tension glaucoma, NTG normal tension glaucoma or LTG low tension glaucoma). Also, if a subject has IOH intra ocular hypertension, such devices should allow differential diagnosis from HTG and may assist the clinicians decision making on control of IOH.58

ERG and VEP for early glaucoma detectionElectrical activity of the retina

ERG

Pattern ERGFlash ERGObjective/functional assessment for early to moderate disease patientsFirst technology to assess cell sickness, not cell deathEarly diagnosis = early treatmentAdditional information to assist the doctor to make a more informed decision to either treat or follow the patientAssists the doctor in determining whether treatment is working or notLike OCT, Electrophysiology is a multi faceted technology which offers clinical benefits for glaucoma, retina, and anterior segment

Pattern ERG assesses RGC function / dysfunction. This is excellent for detection of glaucoma and maculopathies.Flash ERG is more suited to detection of AMD, DR, Diabetic macula oedema, CRVO and CRAO. Flash ERG can be done with fixed luminance flicker and multi luminance flicker.

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Glaucoma Multiple Sclerosis Ischemic Optic Neuropathy Traumatic Brain Injury Amblyopia Other NeuropathiesMAIN INDICATIONSVisual Evoked Potential (VEP)

ERG and VEP for early glaucoma detection

VEP helps to diagnose optic nerve and visual pathway pathologies as opposed to retinal. Again, glaucoma can be diagnosed this way.60

Age (years):75Gender:MaleComplaint:Blurry vision, OD