Continuing Education

The diagnosis and monitoring of ocular disease presents considerable clinical difficulties due to the substantial physiological variation of anatomical structure of the visual pathway, writes Dr Helena Workman (C4508, one standard CET point). This is the fourth in our series developed with the Aston Academy of Life Sciences

As the retina is the principal anatomical site for damage associated with visual loss, objective measures of retinal thickness and retinal nerve fibre layer thickness are key to the detection of pathology.

Ocular disease may impact retinal tissue thickness and structure in a number of ways. Decreases in retinal thickness may accompany degenerative diseases through atrophy, in age-related macular degeneration, or through ganglion cell axon loss exhibited in glaucoma. Macular oedema, arising from complications of uveitis, diabetic retinopathy, or retinal vein occlusion will be exhibited as an increase in retinal thickness.

Optical coherence tomography (OCT) is a non-contact and non-invasive imaging modality which uses low coherence interferometry to obtain objective, quantitative  repeatable measurements of retinal thickness in normal and diseased eyes.1-8

Anatomy of the retinal layer
The retina comprises 10 distinct layers arranged from outer to inner portions as detailed below:

1 Retinal pigment epithelium (RPE)
2 Photoreceptor layer 
3 External limiting membrane 
4 Outer nuclear layer
5 Outer plexiform layer
6 Inner nuclear layer
7 Inner plexiform layer
8 Ganglion cell layer
9 Nerve fibre layer
10 Inner limiting membrane.

The RPE has several functions including light absorption, synthesis of photosensitive pigments and the formation of the blood retinal barrier as a consequence of the tight junctions between cells.

The photoreceptor layer consists of approximately 110 million rods and 6 million cones, the density of which varies according to retinal location. Briefly, light detected by the photoreceptors is converted into nerve impulses, processed by the neural retina and transmitted along the optic nerve via the visual pathway to the visual cortex.

The retinal nerve fibre layer (RNFL) is composed mainly of ganglion cell axons, together with neuroglial cells and astrocytes. Retinal ganglion cell axons curve sharply at the optic nerve margin and form the optic nerve, passing through the lamina cribrosa, and converge upon the optic chiasm to form the optic tract before reaching the lateral geniculate nucleus (LGN).

From the LGN, relay neurones projecting to the primary visual cortex make up the final part of the visual pathway. According to histological studies, the peripapillary retinal contour follows a double hump pattern whereby the retinal nerve fibre layer thickness is greatest at the inferior and superior poles of the optic disc and thinnest at the temporal and nasal disc margins.9,10 There appears to be a good correlation between measurements of retinal nerve fibre layer thickness using the optical coherence tomographer (OCT) compared with histological data.11,12

The RNFL is not easy to visualise but is best examined using red-free ophthalmoscopy or photography, preferably with a stereoscopic view. The normal retinal nerve fibre layer looks translucent, with fine pale striations.

Physiological variations of the retinal tissue
In a clinical situation where retinal tissue changes are observed, it is important to consider normal physiological variations in retinal tissue, prior to conclusions being drawn and diagnoses being made.

Age effects
There is some evidence to suggest that retinal and nerve fibre tissue may be affected by age, however results are largely inconsistent. Conclusive findings are complicated by the variety of imaging techniques and particular type of scan employed in each study. A number of studies have reported that age effects on retinal thickness and retinal nerve fibre layer thickness are regional, whereby only certain sectors or locations of scanned tissue are affected. Reduced retinal thickness with increasing age has been reported by several authors13-16 while others found no such effect.12,17-18

Foveolar thickness has been reported to increase with age, although to date this would appear to be a minority view.19 

The observed reduction in retinal thickness with age is thought to be the result of degeneration of the nerve fibre layer,20 a view which receives strong support.

Several authors have found that the RNFL decreases with age, a result confirmed by post-mortem studies. 21-27

More recently, studies using optical coherence tomography have demonstrated that RNFL significantly decreased with age,15 with the temporal quadrant appearing to be particularly susceptible.28

A reduction of RNFL with increasing age has been revealed using red-free photography in a number of studies,29 30 while histological studies have shown that the superonasal and inferotemporal RNFL thickness at the disc margin is inversely related to age. 9

The majority of studies using scanning laser polarimetry have shown a progressive reduction in RNFL thickness as age increases, with reported values of decay rates from 0.19μm,31 0.2μm32 and 0.38μm26 per year, although there are exceptions to these findings, with one report documenting no significant relationship between RNFL thickness and age.27

Gender effects
Several reports have investigated the effect of gender on the nerve fibre layer thickness of normal subjects. RNFL around the optic nerve head has been shown to be generally thinner in females compared to men but not to a significant degree.4 Differences in macular and peripapillary RNFL thickness between men and women have failed to reach statistical significance according to a number of studies.12, 16, 33

Race effects
Racial differences in RNFL thickness between Caucasians and Afro-Caribbeans as measured by scanning laser polarimetry have been documented.26

Axial length effects
The axial length of the globe in myopic eyes is associated with a subsequent thinning of the scleral tissue and since this may also result in stretching of the retinal tissue, it has been suggested that there may be consequential thinning of the retina in eyes with a greater volume.34,35 Such an association between retinal volume (and its correlates) and retinal thickness should be known prior to interpretation of OCT scans of diseased eyes.

To date, studies investigating the effect of myopia on retinal tissue have produced conflicting reports. Some report no evidence of a relationship between axial length and retinal thickness at either the temporal papillary retina36 or the fovea.37,38 However, a relationship between macular retinal thickness and degrees of myopia has been reported by a more recent OCT study of young myopes.39 In addition, Kremser and colleagues, using a prototype retinal thickness analyser (RTA) report retinal thinning at the posterior pole of myopic eyes.40

Pathological variations of the retinal layer

Retinal nerve fibre layer in glaucomatous eyes
That a reduction in RNFL occurs in glaucoma is widely acknowledged.  Photographs of the retinal nerve fibre layer showing glaucomatous fibre loss even in the absence of visual field defects and optic disc changes were observed as early as 1973.41 Several early studies by Sommer and colleagues demonstrated that visible atrophy of the nerve fibre layer preceded visual field loss by as much as five years and was at least as accurate in predicting further damage as optic disc examination.42, 43

RNFL abnormalities have been shown to accurately correspond with areas of visual field loss.44,45 Quigley and colleagues observed that RNFL defects in suspect glaucoma patients were more localised in comparison with diffuse atrophy found in eyes with established visual field loss. A combination of a general decline in fibres and more specific fibre loss often situated in the arcuate fibre bundle areas in the glaucomatous eye has been reported.46

Defects of the RNFL may be diffuse or localised in nature. Localised defects appear as dark, wedge-shaped areas within the supero-temporal and infero-temporal retinal arcades.47 They can be found in 20 per cent or more of all greater eyes and, in the same way as disc haemorrhages, vary in their frequency according to the stage in the disease process.48 Incidence is highest in normal-tension glaucoma, followed by POAG and lastly by secondary open-angle glaucoma. They exhibit a positive relationship with disc margin haemorrhages and show a high specificity to indicate optic nerve damage.49 Diffuse nerve fibre loss can also be found in eyes with optic nerve damage and is exhibited as a decreased visibility of the RNFL.

Retinal nerve fibre layer in ocular hypertension
While reports regarding retinal nerve fibre layer changes in glaucoma are generally consistent, retinal nerve fibre layer changes in ocular hypertension are less established. RNFL thickness has been shown to be significantly reduced in ocular hypertensives compared with normals.50 Reductions appear to be particularly marked in the nasal and inferior quadrant of the optic disc.51

Conversely, others have found no difference between the RNFL in normals and ocular hypertensives, but this may be the result of different imaging techniques, sample size and study group demographics.52,53

Considerable RNFL measurement overlap among normal, ocular hypertensive and glaucomatous eyes when examined with both OCT and scanning laser polarimetry have been documented. These techniques were capable of differentiating between glaucomatous eyes and non-glaucomatous eyes but were unable to distinguish normal from ocular hypertensives.54

Macular volume in glaucoma
Glaucoma leads to a loss of retinal ganglion cells and since these cell types make up 30-35 per cent of the retinal thickness in the macular region, it is likely that glaucomatous changes are apparent both here and at the optic nerve head.55 OCT macular volume is greater in normals compared to glaucomatous eyes.56 The authors conclude that volumetric analysis of macular thickness using OCT is a useful method of monitoring glaucomatous optic neuropathy. Similarly, macular thickness changes are well correlated with changes in visual function and RNFL structure in glaucoma and postulate macular thickness measurements may be a surrogate indicator of retinal ganglion cell loss.57

Diabetes

Diabetes is a major health concern in the UK and worldwide and diabetic retinopathy is a major cause of blindness in the working population.
Objective, quantitative measurements of retinal thickness, particularly at the macula, provide essential information regarding disease progression and the efficacy of treatment.

Diabetes and retinal nerve fibre layer thickness
Focal retinal nerve fibre layer defects in type 2 diabetic patients with no diabetic fundus changes have been reported.58, 59

A significant reduction in the RNFL thickness of the superior polar quadrant in type 1 diabetic patients without retinopathy compared to the aged-matched control group has been reported.60 The authors hypothesise that their findings suggest that neurodegeneration may be an event in the pathogenesis of diabetic retinopathy. The apparent asymmetry of nerve fibre loss mirrors evidence that retinal changes such as microaneurysms are twice as common in the superior than in the inferior retina.61

Diabetic macular oedema
Diabetic macular oedema is one of the main causes of visual loss in diabetic patients.62,63 It is the result of the breakdown of the blood-retinal barrier leading to the accumulation of abnormal fluid in the retinal tissue (see Figure 1). It is defined as an increase in retinal volume and is manifest as an increase in retinal thickness. The incidence of diabetic macular oedema after 10 years of follow-up has been reported to be 20.1 per cent in type 1 diabetics, 13.9 per cent in type 2 non-insulin diabetics and 25.4 per cent in type 2 insulin-dependent diabetics.62

A number of studies have been performed to determine whether clinical measurement of retinal thickness may be useful in the screening, and monitoring of diabetic patients. Foveal thickness measures greater than 180-185μm should be regarded as indicating abnormal macular thickening and careful follow up of such patients is recommended.6,64 

Likewise, Goebel and Kretzchmar-Gross found a high correlation between foveal thickness and average thickness across the OCT scan and suggested that measurements of foveal thickness alone may be sufficient for clinically significant macular oedema screening.37

The Early Treatment of Diabetic Retinopathy Study group demonstrated that focal or grid laser photocoagulation for CSMO reduced moderate visual loss by 50 per cent.65 However, even with treatment, visual outcomes for retinal thickening as a result of cystoid macular oedema or diffuse macular oedema are poor. Early detection of macular thickening will contribute to a better outcome for the diabetic patient.

Conclusion
In order to identify retinal changes associated with disease it is imperative that the diverse physiological traits of the normal healthy eye are understood. Technological advances in imaging devices, including optical coherence tomography and scanning laser polarimetry, aid the detection and monitoring of ocular disease.

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• Dr Helena Workman is a clinical and research optometrist at Aston Academy of Life Sciences.
  

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