The number of people in Australia with AMD has been predicted to double in the next 20 years. However, new diagnostic devices for early AMD detection, recently devised treatments and ongoing research, are helping reverse the process of this devastating eye disease.
Age related macular degeneration (AMD), a degenerative condition of the retina, usually occurs in patients older than 50 years and results in central field visual loss. This common condition is more prevalent with increasing age and is the leading cause of severe visual loss in older adults in industrialised countries.
AMD is classified as either the dry/non-exudative type, or the wet/exudative/neovascular type.
Dry AMD
All patients with AMD initially have the dry form. Early AMD is characterised by the appearance of yellow or white waxy deposits between the basement membrane of the retinal pigment epithelium (RPE) and Bruch’s membrane. These deposits of cellular debris, called drusen, are comprised of lipids, glycoproteins and trace elements. The precise source is unclear but is thought to be degenerative products of RPE cells. Depending on type and severity, drusen can vary in size, colour and segregation.
The presence of a few drusen, small in size (hard type) is not unusual with advancing age and alone does not necessarily lead to AMD. However the presence of large drusen (soft type) greater than 64 µm, especially if confluent and presence of focal hyperpigmentation, is a high risk factor for more advanced AMD.
The presence of a few drusen, small in size (hard type) is not unusual with advancing age and alone does not necessarily lead to AMD. However the presence of large drusen (soft type) greater than 64 µm, especially if confluent and presence of focal hyperpigmentation, is a high risk factor for more advanced AMD. Advanced dry AMD is characterised by RPE disruption and atrophy of the overlying photoreceptors resulting, in vision loss. About 15 per cent of these progress to the end stages of dry AMD, termed geographic atrophy, having a sharply circumscribed area of atrophy of the choriocapillaris, photoreceptors and RPE with visible underlying choroidal vessels and complete central vision loss.
No medical or surgical treatment is currently available for dry AMD. However the results of the Age-Related Eye Disease Study (AREDS) conducted by the National Eye Institute in America found that taking high levels of antioxidants and zinc, while not a cure can reduce the risk of developing advanced AMD (refer to images 1, 2, 3 and 4).
Wet AMD
Approximately 15 per cent of AMD patients transition to the severely destructive wet form, which accounts for the majority of legally blind patients with AMD (90 per cent). Abnormal blood vessel growth from the choriocapillaris, termed Choroidal Neovascularisation (CNV), penetrate Bruch’s membrane and proliferate. The precise mechanism of CNV is unknown. Retinal cells deprived of nutrients and oxygen may secrete endothelial growth factors and other enzymes to stimulate vascular-ingrowth through disruptions in Bruch’s membrane to replenish oxygen and nutrient supply, although several other theories have been proposed.
1.Normal Anatomy
2. Drusen
3. Soft Drusen
4. Optovue RTVue Line Scan (same eye) showing detached RPE. RPE profile follows cross sectional profile of the large drusen. Bruch’s membrane visible below elevated RPE.
5. Submacular Hemorrhage
6. Optovue OCT Line Scan of wet AMD showing a hyper-reflective neovascular membrane and hypo-reflective subretinal fluid above the RPE.
7. Exudative CNV
Initially these patients may notice some metamorphosia (distortion of vision) due to fluid leakage from the choroid leading to RPE detachment and elevation with altered positioning of the overlying photoreceptors. If untreated CNV usually leads to rapid irreversible dysfunction of the photoreceptors resulting in severe vision loss.
In addition to the features associated with non-exudative AMD, neovascular AMD can also include, subretinal fluid, macular oedema, retinal or subretinal exudates, retinal or subretinal hemorrhage, RPE detachment or tear, and subretinal fibrosis. The end stages of exudative AMD ultimately lead to the formation of a blinding disciform scar, varying in size and extent of fibrotic submacular scarring. (Refer to images 5, 6, 7).
The World Health Organisation (WHO) has identified AMD as the leading cause of vision loss for people over the age of 50 in developed countries, affecting 25 to 30 million people globally1. Macular Degeneration affects one in seven Australians over the age of 50, with the incidence increasing with age2. Patients with CNV in one eye have a 43 per cent probability of progression to the fellow eye within five years3. Prevalence of AMD is three times that of glaucoma4.
New Treatments for Wet AMD
Until recently, no effective treatments were known for wet macular degeneration. New drugs, called anti-VEGF (anti-Vascular Endothelial Growth Factor) agents such as ranibizumab (trade name Lucentis) and bevacizumab (trade name Avastin), are being used to regress the abnormal blood vessels and improve vision when injected directly into the vitreous humour of the eye.
The MARINA study (New England Journal of Medicine Oct. 2006) reported monthly intraocular injections with 0.5 mg ranibizumab resulted in stable or improved visual acuity in 95 per cent of patients after one year and in 90 per cent of patients after two years. Improvement in visual acuity was evident one month after the first injection, the improvement continued through three months, and was sustained through two years. Overall, 34 per cent of the patients experienced a significant improvement in vision of three lines or more after one year and 33 per cent of patients after two years compared with only five per cent and three per cent of controls.
Early Detection Essential
Early detection in the transitional stages from dry is necessary for effective treatment of wet AMD. With the average lesion growing at an approximate rate of 20 microns/day or 3300 microns over a six month period, timely intervention is crucial.
Objective non-invasive means of detecting changes include fundus observation, digital photography, autofluorescence utilising a scanning laser ophthalmoscope (SLO) and Optical Coherence Tomography (OCT).
OCT scanning provides virtual cross sectional imaging of the internal microstructure of retinal tissue and quantitative analysis. Current Spectral/Fourier Domain OCT technology such as the Optovue RTVue and iVue models deliver 5µ axial resolution further enhanced by multiple frame capture and averaging algorithms with baseline registration to precisely monitor micron-scale changes of retinal structure. RTVue 3D En Face technology provides frontal analysis selectable to any depth and follows the curvature of the observed layer. En Face applications for AMD include observation and quantitative assessment of RPE disruption and visualisation of choroidal vasculature by non-invasive means.
Blue Laser SLO autofluorescence uses the natural occurring fluorescent properties of lipofuscin (a by product of retinal metabolism) accumulating in RPE cells to provide images for evaluating the health of the RPE without intravenous dye.
Invasive methods of diagnosing CNV by intravenous dye injection are fluorescein angiography to evaluate blood circulation in and just beneath the surface of the retina, and ICG angiography for photographing the deeper choroidal vessels.
Subjectively the current standard of care in the management of AMD is patient monitoring with an Amsler Grid to visualise distortion due to RPE elevation. However as the brain often ignores, suppresses or compensates for visual defects, patients with early AMD often do not notice any defects in their vision. As AMD is the leading cause of blindness in the industrialised world the current procedure for early transitional detection is probably inadequate and may not be sufficiently effective.
New Device for Functional Detection
A relatively new device, the Foresee PHP Preferential Hyperacuity Perimeter (PHP) from Reichert monitors macular function by measuring relative photoreceptor location of the central 14º visual field for detection of recent onset CNV. The PHP utilises the phenomenon of hyperacuity or vernier resolution, the ability to detect acute misalignment of an object’s location relative to other objects in space to within six seconds of arc, which is 10 times better than the resolution ability in the fovea (around 60 seconds of arc).
Hyperacuity is unaffected by a patient’s age and is highly resistant to retinal image degradation, and is therefore also suitable for assessing retinal function in patients with cataracts. PHP technology reveals distortions otherwise hidden by the brain’s innate ability to fill in scotomas and overcomes inherent problems associated with the Amsler Grid; completion, fixation, crowding and compliance.
Response patterns are compared to a normative database. The test report presents a Hyperacuity Deviation Map, reliability parameters and confidence level indicating the likelihood that the test results are consistent with CNV or with intermediate AMD. Produced results have been shown to have 82 per cent sensitivity and 88 per cent specificity5. Expectation of making a timely diagnosis and referral is well improved.
Therapies Hold Promise
The prevalence of AMD increases exponentially with age. Australian data from the Visual Impairment Project and the Blue Mountains Eye Study predicts that the number of people in Australia with AMD will double in the next 20 years6.
However, Retinal Regeneration Therapy holds great promise for treatment of retinal degeneration. The Ellex 2RT utilises an ultra-fast nanosecond green laser pulse applied to the melanin in RPE cells to produce a regenerative healing effect. Early clinical trials undertaken at the Victorian Eye and Ear Hospital confirm the potential to reverse the degenerative process causing AMD, with clinical results showing drusen reduction and improvement in visual function, with no evidence of collateral laser damage to photoreceptor cells yet detected.
Advances in stem cell research for regeneration of neural retinal and RPE are encouraging and may have potential to restore retinal function.
Conclusion
Until recently the only available options to help stabilise vision loss from wet AMD were laser photocoagulation but this thermal laser destroys healthy retinal tissue, and photodynamic laser therapy (PDT) which is rarely used as success is very restricted. The high success rate of anti VEGF agents has rapidly taken over as the standard treatment of choice. Ocular and systemic complications following anti -VEGF injections are reported to be very rare.
Advances in technology for structural and functional retinal evaluation allow for earliest detection of transitional wet AMD.
Timely diagnosis, prudent monitoring, referral, management and treatment are significantly helping to reverse the process of this debilitating disease.
Robin Lanesman is a qualified optometrist. He has worked in ophthalmic instrumentation / equipment as a product specialist and sales consultant for over 15 years and is currently with BOC instruments. His special interest is in Retinal and OCT imaging.
