What is the retina and the macula?
The retina is tissue that lines the back of the eye and is analogous with film in a camera. Within the retina are photoreceptors, which are light reactive cells that send a signal to the brain, allowing us to visually perceive the world around us. There are two types of photoreceptors, rods and cones. Of the two, only cones are able to detect color and give us the ability to distinguish separate colors. The highest concentration of cones is found within the macula and becomes sparser towards the periphery, or outer portion of the retina. Anatomically, the macula is located in the middle of the retina and is where the eye naturally focuses the light onto. It is from the macula that we get our clear, detailed, central field of vision for both distance and reading.
What is the choroid and RPE?
Another important tissue involved in age-related macular degeneration is the choroid and the retinal pigment epithelial (RPE). The choroid is a thin blood vessel containing layer of connective tissue that is between the retina and the outer, white portion of the eye. It is responsible for supplying oxygen and nutrients to the photoreceptors in the retina. The layer that separates the retina and choroid is called the retinal pigment epithelial. It is responsible for destroying used photoreceptors and transporting waste from portions of the retina to the choroidal blood vessels. In macular degeneration, changes that can be seen occur in the RPE.
What is Macular Degeneration and What Causes it?
Age-related Macular Degeneration (AMD) is a condition affecting people over the age of 50 and is the leading cause of blindness in people over the age of 65. Damage to the macula in AMD occurs due to oxidative stress (oxygen free-radical molecules) and inflammation. Free radicals are created throughout life, typically from energy creation by cells and exposure to the sun, and are usually taken care of by antioxidants in the body. As the body ages, the choroid, RPE and retina become less efficient, allowing free radicals to build up in the retina. These free radicals cause damage (which leads to chronic inflammation) in the RPE and in turn the RPE becomes even less efficient. Since the RPE acts as the “pump” for the eye, digesting and excreting used up photoreceptors to the choroid, damage to this layer causes waste to build up under the retina. As this process occurs, yellow spots, known as drusen, form under the retina. “Hard drusen” form first and have a small, well defined shape. Hard drusen in the retina is not a sign of macular degeneration but rather is a part of the normal aging process (around 98.8% of those over the age of 49 have some small hard drusens). Studies have shown that a few small hard drusen is not a risk factor for developing AMD. In some cases, the RPE continues to degrade under hard drusen, causing waste material to “pool.” When this occurs, “soft drusen”, which are larger and less well defined then hard drusen, form. The presence of soft drusen is a high risk factor for developing AMD and once several medium sized soft drusen form, a diagnosis of macular degeneration is made. Sometimes fluid can build up under soft drusen, which leads to a pigment epithelial detachment (PED). A PED alone does not indicate wet AMD; however the risk of developing wet AMD is higher in patients who have one or more PED’s. It is important to get a fluorescein angiography and indocyanine green angiography to evaluate a PED.
What are the risk factors for developing Age-related Macular Degeneration?
Several risk factors that have been strongly correlated with the development of macular degeneration and/or the severity of macular degeneration include:
- Confluent soft drusen
- Having a family history of AMD (the gene coding for Complement Factor H has been shown to be associated with the development of AMD)
- Having blue or light colored eyes
- Long-term unprotected exposure to the sun.
Other possible risk factors may include:
- Hypertension (high blood pressure)
- High cholesterol
- Having a diet high in fat
Fundus photo of high risk soft
Fundus photo of a patient with wet macular degeneration
What is Wet Macular Degeneration?
In around 15% of cases, Dry Age-related Macular Degeneration progresses to the more vision threatening wet form of the disease. Though Wet AMD accounts for only a small percentage of total AMD cases, nearly 90% of all severe vision loss caused by AMD is attributed to this form. Wet AMD is characterized by the growth of abnormal blood vessels below the retina called Choroidal Neovascularization, or CNV for short. As the RPE becomes damaged and inflamed during dry AMD, ischemia (not enough blood) occurs. When this happens, cells within the RPE release a chemical called vascular endiothelial growth factor (VEGF), which causes new blood vessels to grow. These new vessels are very fragile and tend to leak blood and fluid under the retina, causing further damage and inflammation. Damage to the macula can occur rapidly and vision loss usually progresses much more quickly than dry AMD.
What are the Symptoms of Dry Age-related Macular Degeneration?
Common symptoms of wet macular degeneration include:
- Straight lines or edges appear distorted, crooked or wavy.
- Blurred or blind spot within your central vision.
- Rapid onset of vision loss, especially within your central vision.
- Increasing difficulty adapting to low light levels. For example, patient in clinic told us, “when walking into a dimly lit room from outside, it takes longer than it used to for my eyes to adapt.”
- Colors don’t look as bright or vivid.
- Need to constantly increase light levels when reading or performing close work.
One simple way to check for wet macular degeneration at home is by using an amsler grid like the one shown below. Test each eye individually and hold the chart about a 1 foot away. If you notice any distortions, waviness, or missing areas within the grid call us immediately!
When AMD is suspected, several tests are done to confirm the diagnosis and to determine if it is dry or wet. Optical Coherence Tomography scans are taken on all suspected and established AMD patients. If wet AMD is suspected, the doctor may order a fluorescein angiography and/or an indocyanine green angiography. Each of these tests has a specific role in the diagnosis and management of AMD.
OCT scans: Optical Coherence Tomography (OCT) is the best way to image the retina and quantitatively track changes that occur. We use a Carl Zeiss Stratus Spectral Domain OCT, which is one of the highest quality machines available on the market today. The OCT uses a harmless scanning laser to take around 65,000 images of the retina (a 6mm x 6mm area, with the fovea at the center) within a 3-5 second period and creates a high definition image of the different layers. The OCT is able to detect very small changes within the retina (up to 5µm, which is 0.000196 inches) and with the ability to compare scans from different visits, any new developments can be seen by the doctor . Each eye will normally have 2 scans and the procedure will take a total of 2-5 minutes. One of the biggest limitations of an OCT is that since photos are taken over a short period of time, leakage activity from a CNV cannot be determined.
Fluorescein Angiography (FA): When Wet AMD is suspected, or if you are at high risk of developing wet AMD, the doctor will order a fluorescein angiography (FA). This test is done in our clinic and you will not need to go to a separate testing facility to have it done. In order to perform the angiogram, the doctor will inject (using a very small butterfly needle) a mild vegetable based dye into one of your arm veins and the technician will take several pictures of your retina using a blue light over a 10 minute period. The dye is used to “light up” the arteries and veins of the retina and to detect any leakage and the rate of leakage that might be emanating from choroidal neovascularization. Both dry and wet AMD have specific patterns and will help the doctor make the correct diagnosis. Your doctor will explain the pictures to you in detail. One of the limitations of a fluorescein angiography is that the blue light used for imaging the retina is unable to penetrate the RPE significantly enough to image the choroid.
Indocyanine Green Angiography (ICG-A): Though not done as often as FA imaging, ICG-A is usually performed in conjunction with fluorescein angiography. This type of imaging allows the doctor to evaluate the vasculature in the choroid by using infrared light, which is better able to penetrate the RPE than the blue light used in fluorescein angiography. ICG-A is an important diagnostic tool in detecting CNV’s that may otherwise have been missed by other imaging techniques. Several studies have shown that ICG-A was able to detect CNV’s in over 10% of suspicious cases which showed only dry AMD changes on fluorescein angiography or OCT. ICG-A is also a useful tool in the management of wet AMD. Over 85% of wet AMD cases have areas of poorly defined leakage on fluorescein angiography; however on ICG-A, a “hot spot” defining exactly where the leakage is coming from can usually be discovered. By tracking changes on ICG-A, the physician can better determine how a choroidal neovascular network is responding to treatment.
OCT image showing wet macular degeneration
Fluorescein Angiography showing leakage
Treatments for Wet Age-Related Macular Degeneration
INJECTIONS INTO THE EYE (INTRAVITREAL INJECTIONS):
Stopping new blood vessel growth (anti-angiogenesis)
Since parts of the macula become damaged during AMD, the body, as a natural defense, begins to grow new blood vessels in the area. When tissue become damaged and does not get enough oxygen or nutrients, the cell releases a chemical called vascular endothelial growth factor (VEGF) to stimulate the growth of new vessels. Unfortunately these new blood vessels are leaky and do more harm than good in the eye. When wet AMD is active (leaky new blood vessels), an anti-VEGF treatment is given into the eye to prevent new blood vessels from continuing to grow. First the eye is numbed up with an anesthetic eye drop, and than an injection of lidocaine is given into the outer white portion of the eye. After around 10 minutes (allowing for the lidocaine to take effects), the doctor will than give you the injection of medication into the eye.
- Macugen (Pegaptanib): Macugen is the first generation of anti-VEGF treatments and was approved by the FDA for use against wet AMD in 2004. Macugen is rarely used today since more recent generations of anti-VEGF treatments have proven more effective. However, recent studies have come out showing that Macugen may be safer for patients with certain conditions (very high risk of stroke or heart problems).
- Avastin (Bevacizumab): Avastin was originally used as a treatment for colon cancer by preventing new blood vessel growth, thereby starving tumors of blood. Since wet AMD has a similar mechanism (VEGF expression, however AMD is NOT a form of cancer), ophthalmologists attempted using Avastin on AMD patients. The first study reporting use of Avastin injections into the eye for AMD was published in Ophthalmology in March 2006 and showed positive results. Since then, over 200 reports have been published in various journals around the world. Though the use of Avastin is off-label for AMD, it is used by many retina specialists as the first line of defense against AMD.
- Lucentis (Ranibizumab): Lucentis was approved by the FDA for use against wet AMD in 2006 and is similar in composition to Avastin. It has shown to be very effective against wet AMD in clinical trials, however it costs approximately $2,000 per dose.
- Avastin vs. Lucentis: Since Avastin and Lucentis are very similar structurally, most retina specialists use Avastin since it costs significantly less than Lucentis. This cost savings is realized by the patient in terms of either private insurance or medicare (if the patient does not have a supplemental) co-payments. Though there is no proof that one is better than the other, a large study is underway (sponsored by both the National Eye Institute and the National Health Institute) comparing Avastin vs. Lucentis in treating wet AMD. Either is an effective medication and your doctor will discuss which one is right for you.
- Eylea (Aflibercept): Eylea was approved by the FDA for use against wet AMD in 2011. It is an anti-VEGF-A and placental growth factor (PlGF), which are members of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and vascular permeability factors for endothelial cells. it also costs approximately $2,000 per dose.
Since wet AMD has an inflammatory component that further aggravates the disease, giving an anti-inflammatory in conjunction with either Avastin or Lucentis acts as a way to further reduce the effects of wet AMD on the eye. The body’s natural response to tissue damage is inflammation (for example, reddening of the hand after getting it caught in a door), which promotes healing and is a good thing in most parts of the body. However, it only acts as a mechanism for causing more damage to the very fragile tissues of the eye.
- Kenalog (Triamcinolone): Kenalog is a long-acting steroid that was used in the past either by itself or in conjunction with PDT(Photodynamic Therapy or cold laser), Avastin or Lucentis. However, treatment with triamcinolone fell out of favor because by treating one problem (wet AMD), in 20% cases a new problem arose, high eye pressure. Kenalog is used less often today as a result.
- Dexamethasone: Dexamethasone is a short-acting steroid that is commonly used in our clinic in conjunction with either Avastin or Lucentis. Studies have shown that it does not increase eye pressure, yet as a steroid, it still acts to decrease local inflammation in the eye.
LASER PROCEDURES FOR AMD
Laser Photocoagulation: Laser photocoagulation was the first treatment for wet AMD and uses a “hot” laser to cauterize and destroy leaky blood vessels. A major side effect of laser photocoagulation is a permanent blind spot where the laser was used. With the advent of new treatments, laser photocoagulation is rarely used today.
Photodynamic Therapy : Photodynamic therapy (PDT) was approved by the FDA for the treatment of wet AMD in 2000. PDT is considered a “cold laser” because it uses a light-reactive chemical called Visudyne along with the laser to destroy the choroidal neovascularization (CNV). It is considered a cold laser because the type of laser used must react with the Visudyne to work; the laser by itself doesn’t do anything. Due to the characteristics of a CNV, Visudyne has a much higher concentration in the CNV than the surrounding tissue. During the treatment, the laser does not cause damage to the normal tissue around the CNV. In-order to perform the procedure, Visudyne will be infused into one of your arm veins over a 10 minute period. Your chin will then be placed in the chin rest and the doctor will focus on the portion of your retina that needs treatment. At 15 minutes, the doctor will initiate the laser portion of the treatment.
Since AMD has several components, it only makes sense that treatments for wet AMD targets these underlying causes. There are two main combination treatments used at Retina Eye Specialists
Avastin or Lucentis or Eylea + Dexamethasone combines the anti-VEGF aspects of Avastin/Lucentis/Eylea and the anti-inflammatory aspects of Dexamethasone. The two medications are mixed and injected together in one injection. Avastin or Lucentis or Eylea + Dexamethasone is the first line of treatment for wet AMD and in most cases stabilizes vision and in some cases improves vision. The doctor will evaluate your case and recommend how frequently you will need treatment.
Avastin or Lucentis or Eylea + Dexamethasone + PDT is used for CNV’s that are very aggressive or non-responsive to Avastin or Lucentis or Eylea + Dexamethasone treatments. First an injection of Avastin + Dexamethasone is given and then several days later the PDT procedure is performed. Studies have shown that PDT alone is effective at stabilizing vision in patients with aggressive types of CNV’s, and more recently, additional studies have shown that the combination of Avastin and Dexamethasone with PDT is an effective way to treat patients with these type of CNV’s.
NEW APPROACHES TO TREATING WET AMD
Telescopic Eye Implant: The telescopic eye implant was approved by the FDA for end-stage AMD in July 2010. The telescope magnifies images between 2.2x and 2.7x and projects the image onto areas of the retina that are not damaged. To qualify for the implant, the patient must have end stage macular degeneration (20/200 or worse) in both eyes and have no active leakage or have been treated for wet AMD within the last 6 months in the eye that will receive the implant. Also, the patient cannot have had cataract surgery in the eye receiving the implant. Since the technology is relatively recent, there have not been many studies done on the implant, though the few studies that have been done show very promising results. A gain of 2 or 3 lines during vision exam was shown for some patients and activities of daily life measurements increased for most patients.
Retinal Chip: For the past 10 years, researchers have been working on a way of implanting a CMOS chip (like that in a digital camera) in the back of the eye. With new breakthroughs in nanotechnology, progress on the chip has accelerated quickly and a third generation chip (the Argus III) is almost ready to be tested. While the first generation (the Argus I) chip only provided 16 pixels of resolution, the Argus III will provide over 200 pixels of resolution. It is projected that when developed, the Argus V will provide near 1000 pixels of resolution, which is the number of pixels required for face recognition. Though great strides are being made in retina chip technology, it will be many years before this treatment is available to the public.