Age-related macular degeneration (AMD)
Over the course of your life, the number of cells in the retinal pigment epithelium decreases.
If too many cells are destroyed in the retinal pigment epithelium (preliminary stage of AMD), the retinal pigment epithelium can no longer transport sufficient oxygen and nutrients into the macula, sufficient toxic metabolic end products are no longer transported away, the cells of the macula “starvation” and are "poisoned", and (dry) AMD starts. The earlier the corresponding therapy (see below) is started, i.e. the fewer sensory cells have perished at the start of treatment, the more likely AMD and hence deterioration of vision (with usually significant consequences with regard to quality of life) can be stemmed or delayed.
As already mentioned, since AMD cannot be healed, but can frequently be stemmed, early diagnosis and therapy is particularly important.
Cause of AMD
The exact cause of AMD is not yet known. Probably several factors need to converge for AMD to develop. From the age of 50, the probability of developing AMD increases.
Decisive for the dying off of macula sensory cells is the decreasing supply of oxygen and nutrients and the accumulation of toxic metabolic end products. The cause of this is the destruction of the retinal pigment epithelium as a result of increased oxidative stress (increased formation of free radicals). If a correspondingly large number of cells of the retinal pigment epithelium have been destroyed, this cell layer can no longer adequately transport oxygen and nutrients into the macula, and no longer completely remove the waste products from macular metabolism. This results in the depositing of these waste products under the retinal pigment epithelium in the area of the macula (drusen), the nutrient situation in the macula increasingly deteriorates, the macula cells "starve", are "poisoned" and die off, and (dry) AMD starts.
Dry AMD starts with the loss of the retinal pigment epithelium, which precedes the restriction of vision. Gradually, deposits under the retina, the so-called drusen, increase in number and size, and blood vessels supplying the macula perish (microcirculatory disorder). As a consequence, the sensory cells of the macula die off. When cell loss and deposits reach a critical limit, vision noticeably deteriorates. The final stage is so-called geographic atrophy with a massive loss of vision.
Left: Schematic representation of the retinal changes in an eye with dry (non-neovascular) AMD. Drusen (unremoved yellowish waste products from macular metabolism as a result of dying off (oxidative stress due to nutrient-deficiency-induced increased formation of free radicals) of the retinal pigment epithelium under the macula. Right: Fundus image of an eye with dry (non-neovascular) AMD with drusen
Even if the disease initially only affects one eye, there is a risk that the other eye is also likely to become diseased within a few years.
Dry AMD can go on to become a wet form in 20 - 30% of affected patients. Accordingly, regular check-ups in agreement with your ophthalmologist are important (at least once or twice a year).
The transition from dry to wet AMD is characterised by the onset of uncontrollably growing, abnormal choroidal neovascularisation (CNV – images 5 & 6). The basic process, whereby new blood vessels form, is called angiogenesis.
Angiogenesis is a regulated process, whereby new blood vessels are formed by the branching and extension of existing blood vessels. Angiogenesis plays an important role in many normal (physiological) processes such as wound healing, oxygen- deficiency-induced (hypoxic) damage and reproduction. With some diseases, for instance, cancer, arthritis, diabetes mellitus, and eye diseases such as wet (neovascular, i.e. with vascularisation) AMD, however, there is persistent and impaired (deregulated) angiogenesis.
Angiogenesis is characterised by a cascade of events. Local degradation of extracellular tissue is followed by blood vessel dilation and increased blood vessel permeability. This allows activated and proliferating endothelial cells to migrate (migration) and form tubes. It is assumed that these “sprouting” blood vessels are supported by a network of sophisticated periendothelial cells and extracellular matrix, before maturation and remodelling of the new blood vessels occurs (Carmeliet et al, 1996; Folkman & Shing, 1992).
The initial factor for angiogenesis in the eye is oxidative stress (nutrient-deficiency-induced increased formation of free radicals), which stimulates the upregulation and expression of vascular endothelial growth factor A (VEGF-A) and other angiogenic factors. This results in proliferation and migration of the endothelial cells, proteolysis and penetration of the basal membrane, followed by penetration of the blood vessels into the macula. Vascular endothelial growth factor A (VEGF-A) is an essential component of the angiogenic cascade and hence an important target for the treatment of certain stages of wet AMD (Das & McGuire, 2003; Witmer et al, 2003).
VEGF-A is a growth factor with different characteristics; it promotes cell division of endothelial cells, it is crucial for the survival of newly-formed blood vessels and it is a chemotactic factor for inflammatory cells. In addition, it is still known under a different name - vascular permeability factor (VPF), since VEGF-A regulates the permeability of blood vessels.
VEGF-A has an affinity for two VEGF-A receptors (VEGFR) located on the surface of endothelial cells: VEGFR-1 and VEGFR-2 (Keyt et al., 1996; Ferrara and Davis-Smyth, 1997). The binding of VEGF-A to these receptors leads to the growth of endothelial cells and to changes in the connections between endothelial cells (so-called "tight junctions", Aiello et al, 1995; Ozaki et al., 2000), thereby further reducing the impermeability of the blood vessels (Antonetti et al, 1999).
If these processes are not regulated, abnormal blood vessels grow through the retinal pigment epithelium from the choroid. These abnormal new blood vessels secrete fluid and / or blood, thereby detaching the retinal pigment epithelium. This can in turn manifest as a distorted view (metamorphopsia), a central blind spot (central scotoma) or inability to read with the diseased eye.
As a consequence of the leakage of blood and fluid from choroidal neovascularisation under the macula, a scar forms and thereby extensive and irreversible loss of function in the affected tissue (loss of vision).
Left: Schematic representation of retinal changes and fundus image of an eye with wet (neovascular, exudative) AMD. Characteristic of wet AMD is uncontrolled growth of abnormal choroid blood vessels under and into the macula.
Right: Fundus image of an eye with wet (neovascular, exudative) AMD with blood and fluid discharge from abnormal choroid blood vessels
Development of AMD
The development of AMD depends on whether the AMD is dry or wet.
Wet AMD is the form that threatens our sight more severely. Development is more rapid and more aggressive. However, this form is also much rarer: approx. 5% of those aged over 60 are affected by wet AMD.
Dry AMD usually develops more slowly, sometimes over years. Dry AMD can go on to become wet AMD.
The progression of AMD is complex and can lead include transition from dry (non-neovascular) to wet (neovascular, exudative) AMD with the occurrence of choroidal neovascularisation (CNV) and the associated anatomical changes in the retina and retinal pigment epithelium.
The formation of a disc-shaped scar is the result of the leakage of blood and fluid from choroidal neovascularisation under and into the macula (Figures 7 & 8). This scar usually manifests as a white or yellowish-white, fibrous, generally round, raised lesion. Fresh bleeding at the edge of the scar indicate recurrent or persistent choroidal neovascularisation.
The progression of AMD can be rapid. In clinical trials, 2.9% of untreated patients were unable to read at the start, after 3 months the number increased to 13.4%, and after 24 months to 46.3% (Macular Photocoagulation Study Group, 1991).
During the development of AMD, the visual impression becomes increasingly distorted and blurred in the central field of vision.
In around 40% of patients with wet AMD in one eye, this disease is likely to develop in the other eye over a period of 5 years (Macular Photocoagulation Study Group, 1993).
Reading, recognising faces and everyday tasks such as shopping or driving can no longer be handled with advanced AMD, and capacity for self-determination is reduced.
Vision survives in the outer area of the field of vision, as the disease does not lead to complete blindness.
Regular check-ups are important in order to detect AMD early on, ideally before the onset of any functional restriction, but also for timely detection of any deterioration or transition from dry to wet AMD.
Early signs of AMD
Initially, the patient usually does not notice anything, as AMD develops in a painless manner. Visual acuity of the affected eye is initially only slightly limited or not at all, although there may already be a significant and advanced loss of the retinal pigment epithelium (AMD precursor). Even if vision is reduced, that is, if the disease is already noticeable through functional loss in one eye, the healthy eye often compensates for the loss in the diseased eye, so affected patients often only notice AMD at a late stage.
A regular check of the back of the eye (fundus oculi) by a macula specialist is therefore particularly important from the age of 50. The medical skill consists of early detection of the slightest changes in the retinal pigment epithelium, exclusion of possible other causes, diseases and / or degeneration, and carrying out the best possible therapy in the affected patients at an early stage, preferably before the onset of functional impairment, i.e. before a decrease in visual capacity, so as to prevent progressive loss of vision. The sooner AMD is detected, the better the chances of stemming the progression of this disease by means of a suitable individual form and stage-dependent therapy with or without only slight visual impairment.
Onset of loss of vision is usually irreversible, since by this stage of the disease the sensory cells necessary for the visual process have already died off.
Signs of advanced (clinically manifest) AMD
Blurred, unsharp vision
Distorted images (so-called metamorphopsia)
Straight lines appear curved
Increasing problems reading and adjusting to darkness
Colours appear weaker
Restricted visual perception (grey spot) or lack of visual perception (blind spot) in the centre of the field of vision (so-called scotoma)
Risk factors for AMD
The prevalence of AMD increases rapidly with age (Framingham-Study, Beaver Dam Eye Study, Netherlands Rotterdam Eye Study).
From the age of 60, approximately one in four people suffers from dry AMD. Around 18% of people between the ages of 70 and 74 have a form of AMD. 47% of people over the age of 85 have AMD. In approximately 90% of cases, dry AMD is present. In the case of people aged between 55-64, 0.1% has a wet AMD, and this figure increases to 7% from the age of 85 (Ferris et al, 1984; Klein et al, 1992; Vingerling et al, 1995).
AMD is, at least partially, an inherited condition, as studies with an increased rate of disease in first-degree relatives of AMD patients showed (Klein et al, 1992). If a first-degree relative suffers from AMD, the other family members also have an increased risk of developing AMD.
Considering all forms of AMD, men and women are affected more or less equally, but the wet form of AMD is more common in women, especially over the age of 75 (Klein et al, 1997).
Depending on the dose, cigarette smoke increases the risk of developing AMD.
Smokers currently smoking around 20 or more cigarettes a day have a 23-fold increased risk of developing AMD with vision loss compared to people who have never smoked (AREDS Study Research Group, 2000).
AMD is more common in Caucasians than in Asians or African Americans (Klein et al, 2003).
There is evidence that people with a light-coloured iris are more prone to developing.
Nutrition with few antioxidants
The prevalence rate of AMD is about twice as high in patients who only consume small amounts of antioxidants and lutein compared to patients who consume a high proportion of antioxidants and lutein (Oshinskie, 1996; AREDS Study Research Group, 2001 – active ingredients, see above).
High cholesterol values (Vingerling et al, 1995)
Hypertension (AREDS Study Research Group, 2000)
Cardiovascular disease (AREDS Study Research Group, 2000)
UV light (Nilsson et al, 2003; Rezai et al, 2008)
Quality of life with AMD
Although AMD rarely causes complete blindness when it occurs in both eyes, the ability of patients to deal with normal visual requirements such as reading, handling money, reading the time, recognising faces and driving, is severely impaired or no longer possible. As a result, the quality of life of the affected patients is also significantly reduced. Loss of vision that leads to a loss of independence (visual impairment can reduce mobility and increase the risk of injuries, e.g. caused by a fall) and lower self-esteem, limits patients very much and can cause depression.
Estimations indicate that slight AMD causes a 17% reduction in quality of life. For moderately severe and severe forms of AMD, the quality of life is reduced to 40% or by more than 60% (Brown et al, 2005).
AMD is described by patients as just as restrictive as other chronic obstructive diseases such as arthritis, chronic obstructive pulmonary disease and AIDS (Acquired Immune Deficiency Syndrome) (Williams et al, 1998; Brody et al, 2001).
Investigations with AMD
With suspected AMD, an examination of the macula is necessary. These painfree examinations are carried out after dilation of the pupil (eye droplets) with certain equipment (slit lamp, magnifying glasses, ophthalmoscope). If certain changes (Figures 3 - 8) are displayed, e.g., pathological deposits of typically yellowish fat-containing degradation products (drusen), pathological blood vessel sprouting or the leakage of blood and / or fluid, i.e. indications of AMD, further investigations may be necessary as follows:
Optical coherence tomography (OCT, to determine the retinal condition and retinal thickness)
Fundus diagnostic documentation (photography)
Vascular imaging (with fluorescein or indocyanine green angiography to highlight the blood vessels).
As a rule, first of all fundus diagnostic documentation is gathered with a special image (optical coherence tomography, OCT), then fluorescence angiography is carried out. Fluorescence angiography, a special dye examination, helps in distinguishing the AMD (form and stage), and abnormal vascular growth can be detected and assessed. If a specific form of wet AMD is suspected, vascular imaging with another dye, indocyanine green, may be helpful.
Optical coherence tomography, a painless, three-dimensional laser method for contactless, high-resolution layer examination, allows microstructural changes in the macula to be detected. By combining angiography and optical coherence tomography, the macula specialist can identify certain diseased structures in the living eye and hence precisely calculate and analyse the type and extent of the diseased deposits of metabolic end products. This allows the individual progression of AMD to be estimated and the therapeutic success to be checked.
Treatment of AMD
AMD is so far incurable, and there is no guaranteed protection against it.
The most important aim in the treatment of AMD is to stem the natural progression of the disease (early, ideally before the onset of visual loss, i.e. at the start of changes in the retinal pigment epithelium) and to preserve as much visual faculty as possible.
The intake of specific, high-quality non-heat-stabilised active ingredients with high bioavailability (DL-alpha-lipoic acid, zeaxanthin, lutein, levocarnitine, pantothenic acid, pyridine-3-carbamide, thiamine, riboflavin, 3-hydroxy-2-methylpyridine, vitamin B6, pteroyl-glutamic acid, biotin, cyanocobalamin) has proved effective here in non-smokers (Age-Related Eye Disease Study Research Group, 2007; Briganti et al, 2008; Feher et al, 2005; Kim et al, 2008; Johnson et al, 2008; Parisi et al, 2008; Zulkhairi et al, 2008)
In addition, the treatment of AMD depends on the existing form (dry or wet AMD) and the stage of disease.
Treatment of dry AMD
In the case of dry AMD, the microcirculation of the retina, inter alia, is impaired, (see above). This leads to an insufficient supply of oxygen and nutrients to the macula. In order to maintain the functional capacity of the macula and hence central vision, the lifelong supply of specific nutrients and active ingredients (see above) as well as a sufficient blood flow in the fine blood vessels under the macula are necessary. In the case of dry AMD, progressive loss of the retinal pigment epithelium and a marked worsening of macular blood flow occur as duration of the disease increases. Directly below the macula, deposits of metabolic degradation products (so-called drusen) occur due to loss of function in the retinal pigment epithelium, nutrient supply and hence the function of the macula is further restricted, central vision worsens increasingly. In the late stage of dry AMD, the sensory cells in the macula perish irretrievably as a result of the dying off of the retinal pigment epithelium (so-called geographic atrophy), and central vision deteriorates considerably.
With certain early forms of dry AMD, rheopheresis may be helpful in addition to the intake of the above-mentioned active ingredients.
Rheopheresis with AMD
Scientific studies have shown that improving the flow characteristics of blood can help patients with dry AMD over and beyond therapy with specific active ingredients (see above) (Brunner et al, 2000; Kirchhof 2004; Klingel et al, 2003; Klingel et al, 2006; Pulido et al, 2005).
This therapy is known as rheopheresis. The goal of rheopheresis is to stabilise and / or improve central vision.
Rheopheresis is treatment of the blood outside the body. The blood treatment corresponds to a filtration process which removes certain blood components, for example, some fats and proteins, which have an adverse effect on the blood flow characteristics. The patient then receives his own "purified" blood back. Foreign blood components are not used. There are a number of similar processes for blood treatment outside the body that have been routinely used in the context of renal and metabolic diseases for decades.
Rheopheresis treatment takes about 2-3 hours. During this time, the patient lies comfortably in bed. Two veins are punctured in the arms to create access to the bloodstream. The blood is piped from a vein through two filters into a tube system (see Figure 9). There is always only a limited amount of blood outside the body in the closed circuit. Tube system and filters are sterile disposable products. The purified blood is returned to the body via the second vein.
Treatment for wet AMD
In the past, wet AMD was treated with laser photocoagulation, radiotherapy or surgical procedures. The results of these methods were often unsatisfactory. Newer pharmacological approaches, such as verteporfin (Visudyne®) within the context of photodynamic therapy (PDT) or pegaptanib sodium (Macugen®), an anti-VEGF-A165 RNA aptamer, resulted in more constant results; frequently, stabilisation of vision was achieved, which is defined as a loss of less than 15 letters on the ETDRS (Early Treatment Diabetic Retinopathy Study) panel.
Newer VEGF antagonists (e.g. monoclonal antibody Fab fragments) specifically inhibit impaired (deregulated) angiogenesis, i.e. the basic mechanism for the growth of diseased blood vessels in the choroid. Correspondingly, the leakage of blood and liquid in the retinal pigment epithelium and the sensory cells (photoreceptors) leading to damage, scarring and then to irreversible visual loss, can be stopped or inhibited.
The mechanism of action is based on blocking the receptors of the vascular endothelial growth factor A (VEGF-A) on the surface of the endothelial cells, which form the choroidal blood vessels of the choroid membrane. In the case of wet AMD, the VEGF-A values are increased. Regulating this growth factor prevents, among other things, the cascade of processes which lead to the formation of choroidal neovascularisation and fluid leakage.
Current, randomised, controlled phase III studies (MARINA and ANCHOR) showed improved mean visual acuity during the first three months of treatment, which was able to be sustained over the entire treatment period. The cause seems to be the rapid and sustained reduction of retinal swelling and fluid leakage.
The natural progression of wet AMD to blindness (within the meaning of the law) can usually be prevented by this therapy.
The therapy begins with a phase of saturation (upload) of three intravitreal injections of the antiproliferative substance (VEGF inhibitor) into the affected eye at monthly intervals, followed by a maintenance phase, in which the visual acuity of the patients is checked monthly. Depending on the findings, further injections may be necessary.
An advantage of the injection into the eye is that the active ingredient reaches the macula directly, i.e. the place where it is intended to be effective. If the patient takes the active ingredient in the form of tablets, a significantly higher dose would have to be taken, since the macula only absorbs small amounts of the substance from blood. In addition, the entire body would be exposed to the higher dose of active ingredient, which could lead to side effects.
The injection can be performed on an outpatient basis, but must be performed under controlled, sterile conditions (in the operating theatre), and the patient should use antibiotic eye drops 3 days before and after the injection. An appropriate ophthalmologic check tailored to the result should be carried out for a period of one week after the injection, even in the absence of symptoms.
Vision may be blurred following the injection into the eye. After the procedure, the patient should not drive vehicles or operate machines as long as this symptom of blurred vision persists.
With signs of inflammation (reddening of the eyes, pain, sensitivity to light, or change in vision), the patient should immediately contact the treating macula specialist.
Preventative approach to AMD
There is no perfect protection against AMD.
However, the following behaviour patterns may prevent AMD:
Sunglasses with 100% UV protection and wide side pieces so that no UV light can penetrate your eyes from the side
Regular inspection of your ocular fundus
Self-testing of your eyesight regularly with the so-called Amsler grid
The corresponding active ingredients, Including antioxidants (not for smokers)
Cessation of smoking
Balanced diet (fruit, vegetables, fish)
Check of your blood pressure by your family doctor, with possibly a blood pressure adjustment
Check of your blood lipid profile by your family doctor, with possibly a reduction in your blood lipid levels
Any changes in your vision should be detected as early as possible and treated where possible.
As already mentioned, AMD cannot be cured, but often stemmed or delayed. Therefore early diagnosis and therapy is particularly important. If a pre-stage of AMD or AMD is already manifest, a "healthy" diet alone is insufficient and therapy is usually required.
If you already have a clinically manifest AMD, it is important that the transition from dry to wet AMD is detected at an early stage in order to supplement or switch your treatment in good time.
Check-ups with AMD
You should arrange your check-ups with your treating macula specialist. As a rule, check-ups are required at least once or twice a year.
If you already have a wet form of AMD, you should usually go for a check-up every three to four months.
In the case of changes in your vision (Amsler test - see above), a prompt check-up should be carried out.