Macular degeneration is a progressive, painless deterioration of the macula which leads to visual impairment (blindness). It is a common disorder in elderly people, and is the most common cause of visual impairment in the UK. The cause is unknown.
There are two forms of macular degeneration: dry and wet.
In dry macular degeneration, cells within and just beneath the macula die.
In wet macular degeneration, fragile new blood vessels grow beneath the macula; and these vessels may easily leak blood or other fluid, which damages the cells.
Both forms of macular degeneration produce a roughly circular area of blindness that increases in size. It does not cause total blindness because the vision is retained around the edges of the visual fields.
Diagnosis is by ophthalmoscopy and vision tests. If wet macular degeneration is suspected, fluorescein angiography (imaging of the blood vessels in the retina) may be performed to detect abnormal blood vessels.
Wet macular degeneration is usually remedied by laser treatment.
There is no treatment for the dry form of the condition, although the affected individual may benefit from visual aids such as magnifying instruments.
Brief medical technical summary
The central retina around the fovea has an extraordinarily high metabolic turnover. In some patients, the efficiency of recycling metabolic products fails, abnormal material is deposited in the retina, and tissue integrity breaks down. Drusen may form around the fovea, which do not themselves impair vision but they may herald formation of aberrant new vessels which grow into the fovea from the choroid beneath. Leakage and bleeding create a scar with an irregular ‘disciform’ shape. This permanently damages the fovea and the patient loses detailed central vision, though peripheral vision allows independent navigation. Only a few patients at an early stage of the ‘wet’ type of degeneration are ever likely to benefit from laser coagulation, even with the advent of specific photodynamic therapy.
Macular degeneration in more detail - technical
Age-Related Macular Degeneration
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. It is a complex multifactorial progressive disease with genetic and environmental influences. It occurs in people aged over 55. Current evidence suggests genetic susceptibility involving the complement pathway and environmental risk factors, including increasing age, white race, and smoking. The 10-year incidence among the white population is approximately 11.5% for early AMD and 1.5% for late AMD.
The pathogenesis is still poorly understood; however, degeneration of the retinal pigment epithelium, linked to oxidative stress, seems to be a crucial component. Changes in the adjacent extracellular matrix of Bruch's membrane and the formation of subretinal deposits are central to disease progression. Progressive diffuse thickening of Bruch's membrane reduces the ability of oxygen to diffuse through to the retinal pigment epithelium and photoreceptors. The resulting hypoxia results in release of growth factors and cytokines, which stimulate growth of choroidal new vessels. Development of single or multiple areas of weakness in Bruch's membrane allows the new vessels to grow through into the subretinal space, between the retinal pigment epithelium and the retina, to form a choroidal neovascular membrane. The new vessels leak serous fluid and/or blood, resulting in distortion and reduction of clarity of central vision. Alternatively, visual loss results from progression of the degenerative process to cell death and atrophy of the retinal pigment epithelium.
Classification of AMD is controversial. It is most simply classified as early and late, the latter being subdivided into geographic atrophy and neovascular disease. The Age-Related Eye Disease Study (AREDS) devised a grading system based on fundal features, of which a simplified form is also useful clinically.
Early Age-Related Macular Degeneration
Early age-related macular degeneration is characterized by limited drusen, pigmentary change, or retinal pigment epithelial atrophy. The level of associated visual impairment is variable and may be minimal. Fluorescein angiography demonstrates irregular patterns of retinal pigment epithelial hyperplasia and atrophy. Drusen are visualized clinically as yellow deposits, which are situated within Bruch's membrane. They vary in size and shape. They may be discrete or confluent (Figure 10–1). Histopathologically, drusen may also be detected as diffuse subretinal deposits, either basal laminar deposits, formed mainly of collagen-based material and situated between the plasma and basement membranes of the retinal pigment epithelium, or basal linear deposits, consisting of granular lipid-rich material located within Bruch's membrane. Pigmentary change may be due to focal clumps of pigmented cells in the subretinal space and outer retina or attenuated areas of hypopigmented retinal pigment epithelium progressing to atrophy.
Late Age-Related Macular Degeneration
Geographic atrophy ("dry age-related macular degeneration") manifests as well-demarcated areas, larger than two disc diameters, of atrophy of the retinal pigment epithelium and photoreceptor cells, allowing direct visualization of the underlying choroidal vessels. Visual loss occurs once the fovea is affected.
Neovascular ("wet") age-related macular degeneration is characterized by the development of choroidal neovascularization or serous retinal pigment epithelial detachment. Choroidal new vessels may grow in a flat cartwheel or sea-fan configuration away from their site of entry into the subretinal space to form a choroidal neovascular membrane. Hemorrhagic detachment of the retina may undergo fibrous metaplasia, resulting in an elevated subretinal mass called a disciform scar. Permanent loss of central vision ensues. OCT imaging identifies both subretinal and intraretinal fluid, along with the choroidal neovascular membrane. Fluorescein angiography should be performed on all patients with age-related macular degeneration, with new onset of reduced vision or distortion as the most sensitive method for detection of choroidal neovascularization. It can also guide treatment options. Choroidal neovascularization can be classified angiographically into either classic or occult, depending on the pattern of new vessel growth. Classic is characterized by early hyperfluorescence, which is usually well circumscribed and may have a lacy pattern (Figure 10–2). Occult is characterized by ill-defined and late hyperfluorescence. For research studies, choroidal neovascularization has been subdivided into predominantly classic, in which more than 50% of the lesion has the characteristics of classic choroidal neovascularization; minimally classic, in which less than 50% of the lesion has the characteristics of classic choroidal neovascularization; and pure occult, in which no classic component can be identified.
Retinal pigment epithelial detachment is included in the category of neovascular age-related macular degeneration because of its strong, although not absolute, association with choroidal neovascularization, to the extent that choroidal neovascularization should be assumed to be present until investigations or natural history have excluded it. Serous retinal pigment epithelial detachment may develop from influx of proteinaceous material through a plane of cleavage at the site of drusen. Focal retinal pigment epithelial detachment may also develop from leak of serous fluid from the choroid through small defects in Bruch's membrane. Retinal pigment epithelial detachments may spontaneously flatten, with variable visual results, but usually leaving an area of geographic atrophy.
It is uncertain whether retinal angiomatous proliferation (RAP) is a manifestation of age-related macular degeneration, but it usually presents in the same clinical setting. The cause is unknown. It manifests as superficial (inner retinal) hemorrhage with retinal pigment epithelial detachment and extensive exudation (Figure 10–3) and is characterized by anastomosis between the retinal and choroidal circulations.
Risk of Progression to Late Age-Related Macular Degeneration
The AREDS, which includes an interventional longitudinal study of progression of age-related macular degeneration, has identified pigmentary changes and large drusen (>250 microns) to be the most important fundal features predictive of progression to late age-related macular degeneration, from which a simple clinical scoring system to predict risk of progression has been devised. Points are assigned according to whether pigmentary changes or large drusen can be identified on fundoscopy. For patients with no late disease, 1 point is assigned for each eye with large drusen, for each eye with pigmentary abnormalities, and if neither eye has large drusen for intermediate-size drusen present in both eyes. For patients with late disease in one eye, 2 points are assigned for the eye with late disease and 1 point for each of large drusen or pigmentary abnormalities in the fellow eye. The 5-year risk of progression to late age-related macular degeneration is 0.5%, 3.0%, 12.0%, 25%, and 50%, respectively, as the cumulative score rises from 0 to 4.
Treatment with oral vitamins and antioxidants, comprising vitamin C (500 g), vitamin E (400 IU), betacarotene (15 mg), and zinc (80 mg) and copper (2 mg) daily, was found in the AREDS to reduce the 5-year risk of progression to late age-related macular degeneration from 28% to 20% in patients with cumulative score of 3 or 4 on the risk prediction score (see above) but did not show any benefit for those with lower cumulative score. In a separate study, smokers taking betacarotene have been shown to have an increased risk of development of lung cancer. Therefore, smokers and ex-smokers are advised to omit the betacarotene. Smoking is a proven risk factor for development of all forms of macular degeneration. Cessation of smoking is thought to reduce the rate of progression, although further trials are required to establish the extent of its effect. It is recommended that smoking be discontinued, together with change in lifestyle to incorporate gentle daily exercise, which lowers the risk of age-related macular degeneration. It takes about 20 years of smoking cessation to reduce the level of risk of development of age-related macular degeneration to that of a nonsmoker. Retinal laser photocoagulation reduces the extent of drusen but increases the rate of choroidal neovascularization and is not recommended outside a clinical trial.
Treatment of Neovascular Age-Related Macular Degeneration
Conventional retinal laser photocoagulation can achieve direct destruction of a choroidal neovascular membrane. It requires confluent high-energy burns over and around the whole membrane. The overlying retina is also destroyed, the laser scar may expand, leading to visual loss, and the rate of recurrence of the neovascular membrane is high. Laser photocoagulation is only used for choroidal neovascular membranes that are more than 200 microns from the center of the foveal avascular zone (extrafoveal).
In photodynamic therapy, a photosensitive dye, verteporfin (Visudyne, Novartis), which is believed to preferentially accumulate in active new vessels, is infused intravenously and then activated by a low-energy visible laser (689 nm). The resultant reaction produces localized thrombosis of the new vessels. Treatment is repeated every 3 months as required. Significant improvement in the proportion of patients with stable or improved vision at 2 years has been shown to occur in those with predominantly classic choroidal neovascularization (59% versus 31% in untreated controls), particularly in those with no occult features and in those with small pure occult choroidal neovascularization with evidence of recent progression (TAP trial). The addition of intravitreal or sub-Tenon triamcinolone reduces the inflammatory response, may reduce the retreatment rate, and may improve visual outcome.
Vascular endothelial growth factor (VEGF) plays a crucial role in the expansion of choroidal neovascular membranes. It induces both angiogenesis and increased permeability. Blocking vascular endothelial growth factor (anti-VEGF therapy) has been shown to be beneficial for treating choroidal neovascularization.
The oligonucleotide aptamer (chemically synthesized single-stranded nucleic acid), pegaptanib (Macugen, Eyetech), binds the major pathogenic isoform of vascular endothelial growth factor, VEGF165. It is administered by intravitreal injection every 6 weeks. Stabilization of vision has been demonstrated in 71% of patients, with improvement occurring in 6% (VISION trial).
Ranibizumab (Lucentis, Genentech) is a humanized Fab fragment of a murine monoclonal anti-VEGF antibody, which is able to bind all isoforms of VEGF. It is able to penetrate through all layers of the retina and is administered by monthly intravitreal injection. Stabilization of vision in 94% of eyes with minimally classic or occult lesions and improvement in 34% has been reported (MARINA trial). Similar results, with significant benefit over photodynamic therapy for predominantly classic lesions, have also been reported (ANCHOR trial). Currently, ranibizumab is the treatment of choice for all forms of neovascular age-related macular degeneration.
Bevacizumab (Avastin, Genentech) is a humanized full-length monoclonal antibody to VEGF. Initially it was thought not to be able to pass through the retina, but it has been widely used with good results. Its future role in neovascular age-related macular degeneration is likely to be small, but it might be useful in the treatment of macular edema.
Repeated intravitreal injections are very well tolerated with minimal side effects; however, the ideal treatment regimen is still under investigation. Monthly injections are probably not needed, but a loading phase of three treatments at monthly intervals followed by a maintenance phase of treatment as required might be required. Combination therapy with photodynamic therapy, steroids, or other agents is currently under investigation. Other agents being investigated include the VEGF trap, a designer molecule that binds to VEGF to prevent it binding to its receptor, and RNA interference (RNAi) technology to prevent transcription of VEGF or its receptors.
Surgery for late age-related macular degeneration continues to be studied with mixed results. Options include surgical removal of the choroidal neovascular membrane, macular translocation, and retinal pigment epithelial transplantation. Surgery is recommended only as part of a clinical trial.
Myopic Macular Degeneration
Pathologic myopia is one of the leading causes of blindness in the United States and is much more common in the Far East and Japan. It is characterized by progressive elongation of the eye with subsequent thinning and atrophy of the choroid and retinal pigment epithelium in the macula. By definition, there is greater than 8 diopters myopia. Peripapillary chorioretinal atrophy and linear breaks in Bruch's membrane ("lacquer cracks") are characteristic findings on fundoscopy (Figure 10–5). The degenerative changes of the macular pigment epithelium resemble those found in the older patient with age-related macular degeneration. A characteristic lesion of pathologic myopia is a raised, circular, pigmented macular lesion called a Fuchs spot. Most patients are in the fifth decade when the degenerative macular changes cause a slowly progressive loss of vision; rapid loss of visual acuity is usually caused by serous and hemorrhagic macular detachment overlying a choroidal neovascular membrane, which occurs in 5–10% of patients.
Fluorescein angiography shows delayed filling of choroidal and retinal blood vessel and is helpful in identifying and locating the site of subretinal neovascularization in eyes with serous or hemorrhagic detachment of the macula. Treatment of subfoveal choroidal neovascularization with photodynamic therapy results in stabilization of vision in 50–70% of patients. The visual benefit is maintained for up to 3 years, with better responses occurring in younger patients with better pretreatment visual acuity. Treatment failure is related to increasing retinal pigment epithelial atrophy, which is more likely in older patients. Anti-VEGF therapies (see above) seem to be effective, with fewer injections being required than for neovascular age-related macular degeneration, but studies are in progress.
The chorioretinal changes of pathologic myopia predispose to retinal breaks and thus to retinal detachment. Peripheral retinal findings may include paving-stone degeneration, pigmentary degeneration, and lattice degeneration. Retinal breaks usually occur in areas involved with chorioretinal lesions, but they also arise in areas of apparently normal retina. Some of these breaks, particularly those of the "horseshoe" and round retinal tear type, will progress to rhegmatogenous retinal detachment.