What is AMD?
Age-related macular degeneration (AMD) is a disabling eye condition that causes gradual decline of central vision.1 AMD affects a central area of the retina known as the macula, which is responsible for sharp central vision required for everyday activities such as reading, watching television, driving and facial recognition. Although AMD does not usually lead to complete blindness (peripheral vision is maintained), loss of central vision may have a major impact on a person’s independence and quality of life.2
AMD is a complex disease and is thought to have several different causes. A number of genetic and environmental risk factors have been associated with the development of AMD. Non-modifiable risk factors are age (increasing), race (white European), sex (female), family history & genetics (first degree relative). Modifiable risk factors are smoking, diet (several eye health cookbooks have been written by professionals in the field), physical activity and hypertension.
Symptoms of AMD
Early and Intermediate AMD
People with early and intermediate stages of AMD do not usually experience symptoms. Therefore, it is very important that regular eye examinations are performed in order to detect the early signs of AMD. These examinations also allow the detection of other eye diseases, many of which may also be painless and without obvious symptoms in their early stages (e.g. glaucoma).
Common symptoms relating to vision deterioration reported by people with late-stage AMD, either geographic atrophy (GA) or neovascular AMD (nvAMD) include:
Blurring of central vision/Loss of visual acuity (gradual or rapid onset) – reduced ability to see in detail (e.g. greater difficulty reading small print in newspaper or a reduction in reading rate). Tends to occur gradually in persons with GA, but can be rapid in people with nvAMD; this can affect one or both eyes. GA and nvAMD may occur alone, separately in each eye or simultaneously in the same eye.
Metamorphopsia – A type of distorted vision where straight lines in a grid appear wavy; this is a common symptom among people who have neovascular AMD. (The Amsler Grid is a useful tool for monitoring your central visual field and testing metamorphopsia.)
Blind spots (scotomas) in the central field of vision – an area of partial alteration in the field of vision consisting of a partially diminished or entirely degenerated visual acuity that is surrounded by a field of normal – or relatively well-preserved vision.
Reduced contrast sensitivity – difficulty seeing an image against a ‘similar’ background.
Delayed dark adaptation – difficulty adjusting when moving from bright to dimly lit environments.
The symptoms associated with AMD vary widely between patients. In a recent study3 researchers found that images commonly used to represent AMD (a patch of distortion or blackness in central vision surrounded by a clear periphery) did not provide a realistic representation of people’s experiences. The findings have significant ramifications for individuals, as it may lead them to misunderstand the severity of their own condition and may in turn affect how people monitor their own disease progression. Additionally images used to educate the public about vision loss due to AMD are potentially misleading as they do not represent the lived experience.
There is a need to develop more realistic images of the visual symptoms of AMD for both patient and public education.
AMD is a painless condition and people with the early and intermediate stages of the condition do not usually experience any symptoms. Regular (annual/biennial) eye examinations are recommended in order to detect the early signs of AMD. These examinations also allow the detection of other eye diseases, many of which may also be painless and without obvious symptoms in their early stages (e.g. glaucoma).
Definitive diagnosis of AMD relies on a dilated eye examination using imaging techniques typically undertaken in specialist ophthalmology clinics. It is important to note that visual acuity tests alone are not sufficient for the detection of AMD. This is because sight measured by the visual acuity test can remain unaffected, even in the presence of nvAMD or GA, if the central part of the retina is not affected by the condition. Therefore, it is essential that any person suspected of having AMD is referred to a specialist clinic for accurate diagnosis and follow-up.
Several retinal imaging techniques may be used by the ophthalmologist to diagnose and monitor patients with AMD in clinical practice. These non-invasive imaging techniques include Colour Fundus Photography (CFP), Fundus Auto-Fluorescence (FAF), Fluorescein Angiography, Optical Coherence Tomography (OCT) and a very new technique called OCT angiography.
FOR PATIENTS & FAMILIES
To help you to manage your own care it is helpful to have an understanding of what you should expect in terms of care at each stage of the disease.
Several retinal imaging techniques may be used by the ophthalmologist to diagnose and monitor patients with AMD in clinical practice.
Recommendations relating to the eye disease screening vary between countries. The American Academy of Ophthalmology recommends that everyone gets a baseline eye examination at age 40, the time when early signs of disease or changes in vision may occur. A baseline eye exam at 40 is a reminder to adults as they age to be aware of their eye health. It can help identify signs of eye disease at an early stage when many treatments can have the greatest impact on preserving vision. Follow-up eye examinations will be dependent upon overall health and results of the baseline examination. People 65 or older should have their eyes checked every year or two.
Stages of AMD
AMD is a progressive disease that primarily affects an area of the central retina called the macula, which is responsible for sharp focus central visual acuity.
AMD pathology is characterized by degenerative changes in the outer portion of the retina, photoreceptors, retinal pigment epithelium (RPE), Bruch’s membrane, and the choriocapillaris, which ultimately lead to central vision loss in the later stages of the disease. The earliest visible sign of AMD during an eye exam is the appearance of yellowish deposits of an extracellular lipoprotein, called drusen, which accumulate underneath the retina, between the retinal pigment epithelium (RPE) and Bruch’s membrane.1
Early AMD is diagnosed based on the presence of medium-sized drusen (>63 and ≤125 μm), but is not usually associated with any loss of visual function or other symptoms. (Small drusen particles (≤63 μm) can appear in the retina as part of the normal aging process, and are not associated with an increased risk of progression to late-stage AMD.)
Intermediate AMD is characterised by the presence of large drusen (>125 μm), abnormalities in the retinal pigment, or both. Intermediate AMD also tends to be asymptomatic. People who develop intermediate AMD are at an increased risk of developing late-stage AMD.
Late-AMD, associated with central vision loss that occurs as a result of damage to the macula, can be classified into two types: 4
Geographic atrophy (GA) (also known as ‘dry’ or ‘non-exudative’ AMD) ) is characterised by the progressive, irreversible loss of the retinal pigment epithelium (RPE), photoreceptor cells, and underlying choriocapillaris layer of the macula, resulting in a decline in visual function.
Neovascular AMD (also known as ‘wet’ or ‘exudative’ AMD) is defined by growth and invasion of immature blood vessels from the underlying choroid into the retina. Leakage from these fragile blood vessels can cause build-up of blood and fluid under the retina leading to detachment of the RPE or retina and scarring.
Progression from early/intermediate- to late- AMD (GA and/or neovascular AMD) is a complex process. Some people progress quickly to late-stage AMD (either GA or neovascular AMD), whereas others may progress slowly over several years.5 The underlying mechanisms that cause an eye to develop GA versus neovascular AMD are not fully understood. No reliable genetic or environmental risk factors have been identified to predict whether a patient will develop one form or the other.6 Both types can occur simultaneously in the same eye, or simultaneously in different eyes; it has in fact been suggested that GA and neovascular AMD are not mutually exclusive diseases, but that they lie on the same disease continuum.7 Eyes developing both types may in fact be at a more advanced stage than either GA or neovascular AMD alone.
Depiction of the progression from an intact retina through development of drusen (early/intermediate AMD) to GA & nvAMD.
Recent work has been undertaken to standardised terms and descriptions relating to staging of AMD – The Beckman Initiative for Macular Research Committee: AMD classification.4 Consensus was achieved in generating a basic clinical classiﬁcation system based on fundus lesions assessed within 2 disc diameters of the fovea in persons older than 55 years. The committee agreed that a single term, age-related macular degeneration, should be used for the disease.
In the early stages of vision loss many patients with AMD can manage very adequately with visual tasks. However, as sight worsens some adaptation is required. Patients should be referred to professionals such as rehabilitation specialists as early as possible. This allows individuals to be assessed for their needs and given practical support and advice. Low vision is strongly associated with a higher risk of falling, and patients benefit from guidance on orientation techniques and mobility training to help reduce this risk. Daily living skills can help people with a range of things including communication, safe food preparation, personal appearance, and handling medication. Appropriate support can help an individual to maintain their confidence and independence.
As sight worsens assistive devices may be necessary. Assistive devices can be as simple as a black felt tipped pen or as complicated as a voice recognition computer programme. Some devices are optical, using lenses and prisms, while others use the latest computer technology to enhance print or convert it into audio text. It is important to realise that no one assistive device can replace vision – to see objects in the distance as well as those up close, to see colours and in the dark, to detect depth, contrast and movement. For an assistive device to be successful three important steps need to be followed: accurate assessment, good choice of device and training in use of the device.
A practical application of common sense and imagination will also help maintain independence, including:
Illumination – spotlight work areas, use brighter bulbs.
Contrast – use coloured coasters or backgrounds.
Size – use larger and bolder text.
Tactile – use nail polish or hard setting putty to mark dials and devices.
Join your local vision loss group to keep up-to-date on developments with services and technologies. As technology develops it is expected that many more tools will become available in the years ahead to help you to maintain your independence.
FOR PATIENTS & FAMILIES
Rehabilitation services vary between countries and even within countries. What is universally true however is that it is important that rehabilitation services are identified and accessed as early as possible, before significant deterioration in sight is experienced. While some service providers offer a comprehensive service, in other cases more than one provider will be needed. Services may be made available via hospitals, universities, charitable organisations (NGOs) and state or commercial specialist service providers. Sources of information on local services include healthcare providers, NGOs (including blind organisations and Retina International), internet.
VIAOPTA is a recently developed suite of mobile applications that have been developed to assist visually impaired people with their daily lives. These apps allow individuals to maintain their independence by assisting with daily activities, navigating your local region and recognising people and places using image analysis technology.
Early & Intermediate AMD
No therapy has been developed to treat early and/or intermediate AMD. Antioxidant and mineral supplementation has been shown to reduce the risk of progression of early & intermediate AMD to late AMD (AREDS & AREDS2).8 Supplements containing vitamins C & E, zinc & copper and lutein & zeaxanthin are recommended.
Geographic Atrophy (GA) – No specific therapy has been developed to treat GA. The best available treatment for GA is provision of support and rehabilitation services to enable the individual to prolong their quality of life. Several potential therapies are being investigated for their suitability to treat Geographic Atrophy.
Neovascular AMD – Photodynamic Therapy and Laser photocoagulation for neovascular AMD have been available since the 1990s. However, more recently anti-vascular endothelial growth factor (anti-VEGF) therapy has revolutionized the treatment of neovascular AMD. Anti-VEGF treatments are a group of medicines which reduce new blood vessel growth or oedema (swelling). There are a number of licensed anti-VEGF treatments on the market.
- Beovu (Brolucizumab) is an anti-VEGF treatment which was approved by the FDA for treating wet AMD and is also approved in all 27 European Union Member states, as well as the UK, Iceland, Norway and Liechtenstein. Beovu administration achieves significant improvements in visual acuity, while also reducing fluid accumulation in participants. Additionally, Beovu has the potential to maintain visual function in eligible participants through quarterly dosing intervals, which is a big step in improving patient adherence to therapy.
Screening for Neuro-retinal Conditions.
Studies have highlighted that changes in the structural and functional features of the eyes are linked with neurodegenerative disease including Alzheimer’s disease, Multiple Sclerosis, Parkinson’s disease and Schizophrenia. This suggests that eye examinations may be useful for the early detection and diagnosis of these conditions 9,10.
Alzheimer’s disease is the most common form of dementia and it is characterized by destroyed and damaged connections between neural cells, due to abnormal accumulations of β-amyloid protein in the form of amyloid plaques and neurofibrillary tangles. It is difficult to diagnose and to treat 10. Ocular degeneration in Alzheimer’s disease (AD) is thought to arise as the retinal nerve fibre layer thins. Many researchers are looking at the eye as a promising new tool that may be useful for the early detection of AD.
Researchers used optical coherence tomographic angiography (OCTA), to look at retinal microvascular alterations in patients, with high levels of amyloid-beta but who do not yet exhibit the symptoms of Alzheimer’s disease compared patients without Alzheimer’s disease.
Results revealed that the foveal avascular zone of the retina, was about one-third larger, on average, in people with elevated amyloid-β. Also, the mean inner foveal thickness was decreased in people with elevated amyloid-β 10, 11.
This shows that cognitively healthy individuals with preclinical Alzheimer’s disease have retinal microvascular abnormalities in addition to architectural alterations and that these changes occur at earlier stages of Alzheimer’s disease than has previously been demonstrated. OCTA analysis of the foveal avascular zone may offer a non-invasive, cost-efficient, and rapid screen to identify preclinical Alzheimer disease. This highlights the potential benefit of screening the ageing eye.
A large prospective cohort’s data; Adult Changes in Thought (ACT) was designed which included 3877 participants who were followed for over 31,142 person-years. In this study, participants were screened biennially with the Cognitive Abilities Screening Instrument, which is used in screening for dementia, monitoring disease progression, and providing profiles of cognitive impairment. Results showed that glaucoma, AMD, and diabetes-related retinopathy (DR) are associated with increased risk of AD 12.
Participants with AMD have a 20% higher risk of AD and there is 44% higher AD risk in patients with DR in comparison with those without AMD. AD risk in participants with recent and established AMD were 20% and 50% respectively. Participants with recent and established DR were at a higher AD risk by 67% and 50% compared with those living without the condition.
This suggests that retinal degeneration may be a risk factor for AD, therefore, it may be worthwhile checking patients with AMD and DR for possible dementia. It may also allow for early detection of AD and developing better treatments.
Multiple sclerosis (MS) is a chronic inflammatory disease characterized by central nervous system (CNS) lesions that can lead to severe physical or cognitive disability as well as neurological defects. 13 In this disorder, the immune system disrupts communication in the central nervous system by attacking myelin, a fatty substance that forms a protective layer around nerve fibres. This process damages several parts of the brain, including those involved in pathways that are responsible for vision and the optic nerve, which carries impulses between the eye and the brain 10. Visual dysfunction is one of the most common causes of disability in multiple sclerosis (MS).
By combining OCT (structural) tests with tests for low-contrast vision (functional), researchers have uncovered a correlation between a thinning retina and vision problems in multiple sclerosis. Retinal nerve fibre thinning in the eyes of patients with MS with or without prior history of acute optic neuritis (ON) have been studied. A study that involved 299 patients with MS who were tracked for 6 months to 4.5 years revealed that there is a significant association between visual loss and retinal nerve fibre layer thinning over time in both cases. RNFL thinning was also shown to correlate with MRI measure of lesion volume and normalised brain volumes. This suggests that the use of OCT may be a useful, non-invasive method for the early detection of MS and could be used to examine the progression of disease as well as testing the effectiveness of treatments.14
Using ophthalmologic evaluation for the detection of MS may lead to better and early diagnosis and treatment and potentially better outcomes for patients. It may also be used as an indicator of disease severity.
Parkinson’s disease (PD) is a multifactorial neurodegenerative disease that involves the progressive impairment of voluntary motor control due to the gradual loss of brain cells that produce dopamine, a substance that helps control movement15.
Symptoms of PD typically manifests only when more than 70% of dopaminergic cells are lost. Definitive diagnosis of PD can only be made histologically post-mortem.16 Finding ways for earlier diagnosis is important.
Ahn et al. recently identified a link between the thinning of the retina and the loss of the brain cells that produce dopamine. They found that the greater the retina thinning, the greater the severity of the disease. This suggests that a simple eye scan may be useful in detecting Parkinson’s disease early as well as following its progression.17
Schizophrenia is a chronic and severe disorder that affects how a person thinks, feels, and behaves. People with schizophrenia may seem like they have lost touch with reality. Although schizophrenia is not as common as other neuro degenerative disorders, symptoms can be very disabling.18 While there have been genetic, physiology and neuro-imaging studies that show changes in patients with schizophrenia, there is no established objective biomarker for the diagnosis of schizophrenia in clinical settings.
The potential to use abnormalities in the retina and other structures of the eye as a biomarker to predict for schizophrenia is under research. The retina and the brain develop from the same tissue, the neuroectoderm and it is the only part of the CNS that can be seen with the naked eyes. Therefore, it can be said that the retinal changes may mirror the integrity of the brain structure and therefore serve as a marker of progressive tissue loss. The strongest evidence of this involves findings of widened retinal venules, thinning of the retinal nerve fibre layer and abnormal ERG amplitudes19 .
Genetics of AMD
AMD results from a combination of environmental and genetic factors. Environmental factors associated with AMD include age, gender, smoking and diet. Evidence for genetic risk has also been supported by several family studies and twin studies. Results from these studies revealed that people with an affected parent have approximately twice the risk of getting AMD than someone whose parent does not have AMD.
DNA is the chemical in our cells that gives our bodies instructions about how to grow, develop and function. DNA is a string of coded messages organised into specific instructions called genes. Humans have 30,000 different genes, arranged on a number of thread like structures, called chromosomes. We inherit our chromosomes from our parents, 23 from our mother and 23 from our father, so we have two sets of 23 chromosomes, or 23 ‘pairs’. A good description is If you think of genetics as the book of life, then the DNA are the letters, the genes are words, and the chromosomes are the chapters.
If you think of a mutation as a spelling mistake or a series of words changed in a sentence, then this causes a problem in the meaning and interpretation and it is just this that happens when there is a mistake or a mutations occurs in a gene – it can cause a condition like inherited AMD.
Sometimes a mutation will have no effect at all. This depends on environmental factors, an element of chance, or mutations in other genes. Mutations can cause problems if they stop the gene or chromosome communicating the correct instructions needed for the body to function properly. Genetic tests therefore aim to find mutations in a particular gene or chromosome. For information on genetic mutations (mistakes) or genetic testing please follow this link:
In the largest study of the complete set of human genes to date, it was reported that AMD is associated with a number of types of mutations, 45 common single nucleotide polymorphisms (SNPs) and 7 rare variants across 34 genetic loci, which explain 34% of AMD risk1. Many of these genetic variants reside in the complement factor H (CFH) gene on chromosome 1 and ARMS2/HTRA genes on chromosome 10. Other variants can be seen in and around genes involved in the cholesterol metabolism, collagen production and cell signalling. This suggests that AMD is a complex disease associated with multiple genetic risk factors2.
The link between the CFH gene and AMD has been studied intensively. The complement system is a part of the immune system that attacks invading bacteria. Although the liver is the major source of systemic complement, retinal cells make their own complement. As well as the genetic implication of CFH in AMD, raised systemic levels of complement have been reported in AMD patients. Complement proteins have also been detected in drusen, yellowish deposits of an extracellular lipoprotein, which are the earliest visible sign of AMD during an eye exam.
Genetic changes in and around several complement system genes are found to add to a person’s risk of developing AMD. Among the known complement genes, it has been found that the complement factor H (CFH) confers the greatest AMD risk.2,3,4
CFH usually has the amino acid tyrosine at position 402, but sometimes it has the amino acid histidine instead. This Tyr402His polymorphism seems to be associated with an increased risk of AMD. People who carry a copy of this polymorphism have a 2.5- fold increased risk of developing AMD than people who do not. People who carry two copies of the polymorphism have a six-fold increase, however, most people with these variant never develop the disorder4. Although It is suspected that changes in the CFH gene alters the production of CFH protein, how this abnormal protein is linked to the build-up of drusen and progressive vision loss is not well understood.
Researchers in the UK have recently identified a new protein linked to AMD. They found significantly higher levels of a protein called factor H-related protein 4 (FHR-4), a regulator of complement (mentioned above), in the blood of AMD patients in comparison with age-matched control samples. The higher blood FHR-4 levels were associated with changes to genes that code for proteins that belong to the factor H family. These changes also overlapped with genetic variants first found to increase the risk of AMD5.
This indicates FHR-4 as a key molecular player contributing to complement dysregulation in AMD and it demonstrate FHR-4’s prominent role in AMD pathogenesis. It can be presumed that inherited changes can lead to higher blood FHR-4 causes uncontrolled activation of the complement system withing the eye and drive AMD5.
Drugs that target the complement pathway
Since the discovery of the involvement of the complement system with AMD, pharmaceutical companies have developed therapies targeting the complement pathway to treat and prevent AMD.
A complement inhibitor, which inhibits the Complement 3 (C3) showed promising results in a phase two clinical trial and has now progressed into stage three trials2.
ARMS2 and HRTA1
Changes in the long (q) arm of chromosome 10 in a region known as 10q26 are also associated with an increased risk of AMD. This region contains two genes ARMS2 and HRTA1, changes in these genes are possible risk factors for AMD.
However, because these genes are so close together, it is difficult to tell which gene is associated with AMD risk, or whether increased risk results from variation in both genes. However, new data indicate that the genetic variants at ARMS2, but not HTRA1 are responsible for AMD risk6.
Routine genetic testing for AMD is not currently advised in clinical practice. However, as there is a list of known AMD-associated genetic variants, genetic testing will allow for the prediction of a person’s risk of developing AMD, so that preventive measures can be taken in high risk individuals6.
Genetic testing will also be an important step towards personalised medicine. Furthermore, it will help to identify which AMD patients are most likely to benefit from certain treatments. For example, it can be expected that therapies modulating the complement system may be most effective in patients harbouring complement-related risk alleles. Lastly, genetic testing may help with the selection of patients for clinical trials.
Several rare genetic variants have been found to contribute to the development of AMD. Results from a large study of the complete set of human genes reveal possible rare variants associated with AMD. All variants found in this study were seen in/near the complement genes. One of the rare variants was in the CFH gene (Arg1210Cys)1. This highly penetrant rare variant is the strongest genetic risk factor for AMD identified to date. People with this mutation are 20 times higher risk of developing AMD compared with people without the mutation7. This mutation is also associated with earlier onset of advanced AMD6. Carriers of rare CFH variants tend to have increased drusen load and are more likely to have extramacular drusen and crystalline or calcified drusen.
Other rare genetic variants in and near the complement gene were seen in the CFI, C9, and C3 genes. These variants were more frequently observed in patients with geographic atrophy (GA) than those with wet-AMD.
Other studies have shown rare variants associated with non-complement genes. These variants were seen on the TIMP3 and SLC16A8 genes6.
The Action You Can Take Now.
In addition to avoiding smoking, and protecting your eyes from the sun, developing a healthy eating habit can help to maintain eye health. It is recommended to avoid artificial fats and processed food as much as possible. Adding foods that are rich in antioxidants such as lutein, zeaxanthin, omega-3 fatty acids, beta carotene, vitamin C/E and zinc to your diet, may help to reduce the risk of AMD, or slow down its progression.
Foods for Healthy Eyes include:
- Fruits and vegetables – most fruits and vegetables including strawberries, oranges, tomatoes, bell peppers and kale contain vitamin C
- Almonds, brazil nuts, pecans as well as from vegetable oils (corn oil and olive oil) are good sources of vitamin E.
- Dark green leafy vegetables such as spinach, kale, broccoli and asparagus are the primary sources of lutein and zeaxanthin.
- Leafy green vegetables, nuts, salmon, vegetable oils and flaxseeds are a good source of omega3 fatty acid.
- Deep orange or yellow fruits and vegetables such as carrots, sweet potatoes, peaches and apricots are good sources of beta-carotene.
- Beef, pork, lamb, eggs, milk, peanuts, wholegrain and wheat germ are good sources of zinc (However be aware that high meat intake is a risk factor for AMD)
- Avocados are one of the most nutrient-dense food that exists. They contain more lutein than any other fruit, which is important in the prevention of macular degeneration. They are also a great source of vitamin A, vitamin C, vitamin B6 and vitamin E.
For a list of healthy recipes that promote eye health, click on the links below.
AREDS /AREDS2 and Caution
Age-Related Eye Disease Study (AREDS) was a clinical trial that studied the benefits of a nutritional supplement containing high doses of antioxidants, vitamins and zinc in reducing the risk of developing late AMD. Results showed that the combination of antioxidant and zinc reduced the risk of developing advanced stages of AMD by about 25% and also it reduced the risk of central vision loss by 19%8.
A second study called AREDS2 was carried out to determine if the AREDS could be improved. In this study, beta-carotene was substituted for lutein and zeaxanthin, as beta-carotene was found to be linked to an increased risk of lung cancer in smokers. Therefore, AREDS2 is a safer combination for those who are smokers or former smokers. Results from this study showed that AREDS2 reduced the risk of AMD progression by 19% and of vision loss by 25%8, 9.
Some publications have recommended that the AREDS formula should be adjusted based on a patients’ genetic variants in CFH and ARMS2/HTRA. It was found that patients with high-risk CFH allele and no ARMS2 risk alleles have an increased progression into wet-AMD if treated with the AREDS formulation compared with placebo. Whereas, for patients with low CFH risk allele and high ARMS2 risk alleles, there was a significant beneficial effect from the AREDS formulation treatment10.
Genetic testing may be a useful method of showing of identifying who is likely to benefit from the AREDS formulation.
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