The inflection point of visual restoration occurred with the introduction of anti-VEGF drugs. Despite this success, the fact that the drug had to be injected into the vitreous or back part of the eye, proved to be a problem, ranging from a high level of treatment burden, i.e. multiple injections, as well as the risk for complications.

Here is the list of the anti-VEGF drugs that have been used since 2006:

1. Macugen (first drug but no longer used)
2. Avastin (most common drug used but not FDA approved for Exudative ARMD)
3. Lucentis
4. Eylea
5. Beovu (infrequently used in the USA due to inflammatory complications)
6. Vabysmo ( only drug that blocks both VEGF as well as Angiopoietin 2, another protein that stimulates abnormal blood vessel growth).

We use the term monotherapy to describe the use of one of these drugs at a time. We used the term combination therapy when more than one type of drug is used at the same time. More about this later.

The injections are given on a fixed frequency ( every 4 weeks) or a variable frequency ( as needed or treat and extend protocol where the time between injections is extended if the leakage remains stable). The original studies all included the use of every 4 week injections. Since then, we recognize that many patients do not need these drugs as often.

All the clinical studies have shown the safety and effectiveness of Lucentis, Eylea, Beovu, and Vabysmo. There is no proof that these drugs have specific risks unless a patient has had a heart attack or stroke within 6 weeks of the proposed injection. The injection, itself, has the most risk for injections, the worse been endophthalmitis, or infection in the eye, which can be quite serious and vision threatening. Thankfully, this only occurs infrequently. Recent advertisements for Vabysmo talk about elevated eye pressure after the injection. This occurs if the doctor does not drain the fluid out of the eye before or after an injection. Only 1% of doctors do this. Failure to do this does place the patient at risk for the development of glaucoma which can occur in up to 9% of patients.

Let's start with a few facts:

90% of patient who receive these drugs respond - i.e. resolution of neovascularization (abnormal vessels) and/or exudation (leakage) after the induction phase, i.e. two or three injections. If they do not, I call this a Primary AVF (Anti-VEGF Failure) - which comprises 10% of the patient population. Most doctors start treatment with a series of 2-3 monthly (fixed) injection (induction) and if they respond, the treatment frequency is decreased to a variable frequency. When this occurs, 30% of patients will start to leak again and/or the neovascularization might increase in size. This is called a Secondary AVF (Anti-VEGF Failure).

How does the doctor deal with this recurrent leakage which by all accounts represents a failure? Several choice are available:

1. Change the anti-VEGF drug - this is not that easy as insurance often dictates which drugs can be used - your doctor will help with this change.
2. Change the dosage of the anti-VEGF drug - this is now possible as Eylea is now available at a strength four times the standard dose (8 mg vs. 2 mg).
3. Change the frequency of the anti-VEGF drug - if the doctor tried to extend your treatment from 4 to 8 weeks and if leakage recurs, the doctor can go back to 4 weeks again, i.e. inject you more frequently.
4. Change the strategy with combination therapy, i.e. using different types of drugs to see if they work together better. Vabysmo is still considered a monotherapy however has two different proteins are being suppressed so by definition it is a combination therapy. Additionally, Photodynamic Therapy (PDT) can be combined with anti-VEGF therapy to create a true combination therapy. More on this later.

Let's start the discussion on how one can see if a drug works by giving an example - in the next blog post we'll talk more about the AVFs. In the photo below, the patient on the left has an early neovascularization - white arrow. These vessels regress or become smaller with subsequent injections (middle left and lower left). The same is true in the patient on the right. She has subretinal fluid (white arrow) and a retinal pigment epithelial detachment. Subsequent pictures shows the resolution of the subretinal fluid and the diminution of the RPE detachment.

Your doctor should be able to tell if the drug protocol is working or not working. Again, if the drug is not working, then one of the four steps above need to be entertained.

Here are the four reasons for vision loss:

1. Refractive errors, i.e. need glasses. We use the concept of Best Corrected Vision - BCVA. This is the best vision that can be obtained after having the eye checked for glasses. This obviously is the most common reason for 'vision loss' in young, health individuals. If this is the only problem you have, you do not wind up seeing a retinal specialist.
2. Media obstruction, i.e. something is blocking light from entering the eye and getting to the retina where light is transmitted to the brain for interpretation and creation of vision. The most common reason is a cataract or a cloudiness of the normally clear internal lens of the eye. If this is the only cause of vision loss, cataract surgery is the cure. Other reasons for media obstruction are cloudiness of the vitreous cavity (in the back part of the eye) typically due to blood which is a common complication of diabetic retinopathy. The simple rule is that the patient's vision out is equal to the doctors view in of the retina with examination lenses.
3. The third is damage to the optic nerve. We're not going to talk about this at this time, however, if there is damage to the optic nerve, the vision loss will be significant.
4. The fourth reason for vision loss is what retinal specialists are most focused (sorry) on - damage to the macula must be understood to get an appreciation of the quantity of vision loss, i.e. 20/20 versus 20/40, and the quality of vision loss, i.e. having blind spots and/or distortion.

We concentrate on the fovea or the central part of the macula which normally is depressed on the OCT. Here the fovea is swollen from exudation and represents an elevation (4). To assess the vision, we concentrate on the posterior two layers of the retina and RPE. The photoreceptors or cells that transmit light to the retina occupy this space. In the left side of the photo, these layers are relatively normal (1), however in the fovea, the layers are markedly disrupted (2) and even missing (3). GA is present when the RPE is missing (3).

The last concept is that vision loss can be from several reasons - the patient might need glasses, have cataracts, and mild macular damage. Or the cataracts might have been removed and all the vision loss is due to the macular degeneration. I use the concept of macular capability - what would the patient see if the glasses were updated, the cataract removed, and the absence of optic nerve disease. For example if the patient has a 20/100 cataract and I think that the macular capability is 20/40, the patient will not see better than 20/40 after cataract surgery. It's a calculated guess but one based on years of experience. With this assessment, there are no surprises after cataract surgery.

We're going to talk about Dry ARMD first and save the discussion on Exudative ARMD to the next blog. Dry ARMD may be mild, moderate or severe. The most important concept is that mild is mild and severe is severe and moderate can be on the way to becoming severe. You can see the progression on the OCT and photographs of the macula - this process takes years - be sure to look at 3-5 years of images. The Heidelberg OCT has the advantage of tracking the progress which makes the disease process easier to see.

Mild Dry ARMD consist of drusen or yellowish deposits under the retina. There are unfortunately many types of drusen and that discussion is a bit too complicated for this blog entry. Drusen are the hallmark of ARMD, i.e. a typical finding. Mild Dry ARMD is not usually associated with vision loss, however, if the druse (singular for drusen) is present in the center of the macula (foveal), i.e. subfoveal, then there might be some mild vision loss, either as a scotoma or blind spot or distortion or metamorphopsia. There is no need to treat at this point, however your eye doctor will start watching you more carefully, perhaps more often than yearly. Moderate ARMD usually involves enlargement and increased numbers of drusen and early visual disturbance can be present. This usually signals an increased risk of progression into severe Dry ARMD.

Severe Dry ARMD is typically associated with a phenomenon called Geographic Atrophy or GA for short. This phenomenon involves the destruction of the Retinal Pigment Epithelial layer and the adjacent retina. This destruction usually presents in a pattern that resembles a map, hence the term geographic atrophy. We'll talk more about the treatments in a future post but the most important concept is that the GA can be extrafoveal (outside the fovea) or subfoveal (beneath the fovea). With the former there is usually a mild amount of vision loss. In the latter, significant and permanent loss of reading vision, i.e. central vision, is present. Therefore the treatment hopes to limit the likely progression of an extrafoveal location to a subfoveal location. This treatment can not reverse the damage done by the GA.

The last comment is one I hear all the time."Dry ARMD is better than Exudative ARMD". That's not necessarily true as severe Dry ARMD is much worse than Mild Exudative ARMD. Neither one is better, however, Dry ARMD progresses slowly and Exudative ARMD progresses quickly, however, they both progress.

If your doctor finds leakage, or exudation, under your retina and the diagnosis of Exudative Age-Related Macular Degeneration (ARMD) is made, he/she may inject an imaging dye into your vein and take photos of the macula/retina. This test is critical to determine what type of Exudative ARMD you have - there is no 'one size fits all'. There are many phenotypes, or different ways in which the disease presents. This is important because different phenotypes respond to anti-VEGF drugs differently (more later). OCT, OCT Angiography (OCTA), flourescein angiography (IVFA), and indocyanine green (ICG) are all used to best diagnose, treat and follow these diseases.

The image above shows how neovascularization can be appreciated on each modality. Below, a cross section of the retina shows neovascularization on OCT. The photo on the top right shows how this neovascularization is appreciated on OCTA, the middle photo by ICG and the top left photo on IVFA.

When we look at an OCT, we look at a cross section of the retina as shown in the left photo. The right photo is the cross section of the macula at the level of the bright green line shown on the left. (1) denotes a relatively normal retina. (2) represents retinal leakage (and thickening) within the retina or intraretinal edema (3) presents neovascularization or abnormal vessels below the retina that are the source of leakage, i.e. wet or exudative macular degeneration (ARMD) and (4) represents a different type of exudative macular degeneration with leakage under the retina. It is not important to understand the different layers of the retina and/or the degrees of leakage but to recognize that the OCT is the most critical test we do in order to diagnose, treat, and follow exudative macular degeneration.

This represents OCT Angiography or OCTA. It is a major advancement on the technology of OCT. Not only can you see the cross section of the macula (on the right) but it actually will show the abnormal neovascularization (vessels responsible for exudation in exudative ARMD) as seen on the left. Not every eye care professional has this device. It is currently not reimbursed by insurance but it adds valuable information in the management of Exudative ARMD especially in patients who have persistent leakage despite multiple injections of anti-VEGF agents.

The picture below shows the left macula of a patient with Age-Related Macular Degeneration (ARMD). The photo on the left is how the macula appears when the doctor examines the eye - the optic nerve is on the left edge - the macula is in the central part of the photo. The green line represents the specific area of the macula that is being examined. The corresponding image on the right is the cross sectional view of the retina. One can see irregular thickness and elevations in the center part of the photo. On part 2 of this blog, I will give more information on how to look at an OCT.

The OCT will be performed when you are first examined and then during each subsequent exam to see if the disease has progressed or improved. Ask the photographer or doctor to show your OCT .

Macular degeneration, also known as Age-Related Macular Degeneration (ARMD), is a degenerative disease of the macula, a part of the retina that is responsible for reading vision. There are two types: dry (nonexudative ARMD) and wet (exudative ARMD). The term wet refers to leakage of fluid and blood from abnormal vessels below the retina (neovascularization ) . Vision loss can occur from both nonexudative and exudative ARMD, however the latter is rapidly progressive and largely treatable. Vision loss begins with central vision, which mainly affects reading, but it can later spread into peripheral vision, and can lead to profound visual disability.
Signs and symptoms
Though ARMD has often been attributed to aging, many patients develop changes as soon as the fifth decade, especially if there is a family history. While early ARMD has no symptoms, more advanced ARMD has patterns of blind spots called scotomas, distortion called metamorphopsia, and varying degrees of vision loss. Very often, these changes affect the “quality” of vision, most commonly reading vision and is often manifested as complaints of missing words or “words jumping”.
An eye care professional will see drusen, or yellow spots under the retina, and/or areas of retinal damage in nonexudative ARMD, or leakage of fluid or blood in exudative ARMD. A referral to a retinal physician is common and might involve the use advanced imaging techniques, such as fluorescein angiography (IVFA), and/or indocyanine green (ICG) imaging where dyes are injected into the vein for visualization of damage, and/or Optical Coherent Tomography (OCT) Angiography, a new technique that allows for visualization of damage without the dye injection. The presence of early or intermediate ARMD can be monitored for progress and often this process can take years, and then, abruptly cause severe vision loss if unrecognized. To paraphrase Ernest Hemingway, vision loss from ARMD occurs, “in two ways … gradually and then suddenly”.

ARMD vs. cataracts
Cataracts or the clouding of a normal clear ocular lens is a common cause of vision loss in the aging eye. It is essential to differentiate between the cataracts and ARMD because they have different treatments. Cataracts generally cause blurred vision, especially at night, and are easily removed with surgery. ARMD , on the other hand, causes changes in the quality of vision, with scotomas and metamorphopsia.

Family history
In recent years, it has been found that patients with family histories of ARMD may display imaging biomarkers, or measurable findings on imaging techniques, that may predict future progression. It is also clear that genetic predisposition increases the risk of developing ARMD and can predict future progression into the exudative form. Genetic tests are commercially available, but not entirely definitive on their own. Patients with a strong family history should be followed by eye care professionals and have OCTs done routinely as early as age 40 or 50.

Treatment options
The process that causes nonexudative ARMD to become exudative ARMD is unclear, but evidence strongly suggests that a collection of over the counter vitamins based on large clinical studies (AREDS and AREDS2) , can slow this progression.
The treatment of moderate to severe nonexudative ARMD has been elusive, but recent FDA approvals of two new drugs are encouraging. These include pegcetacoplan (Syfovre) and avacincaptad pegol intravitreal solution (Izervay).
The treatment of exudative ARMD comes from groundbreaking research to suppress abnormal vessel growth in solid cancers. In exudative ARMD, neovascularization grows in the choroid, or the tissue below the retina in response to an unknown injury or stimulus. This process is mediated by a chemical called a cytokine, specifically Vascular Endothelial Growth Factor (VEGF). While VEGF naturally repairs damaged blood vessels in patients with a heart attack or stroke, it promotes abnormal neovascularization in exudative ARMD. Treatment, then, uses drugs that block the production of VEGF by the diseased choroid. These anti-VEGF drugs are injected into the eye and have been found to lead to visual improvement and/or stability in a large majority of patients.
There are four anti-VEGF drugs that are the standard of care: ranibizumab (Lucentis) and aflibercept (Eylea) have been used for more than 10 years and are FDA approved. Bevacizumab (Avastin) is not FDA approved for ophthalmic use (it is for cancer), but it is widely used due to its affordability. A new entry, faricimab (Vabysmo) is now FDA approved and is becoming more commonly used due to its longevity and the need for fewer injections.
Originally, patients were given anti-VEGF injections monthly, but research has shown that some patients can be treated with fewer injections. We now know that every patient, and every eye, have different requirements for treatment. The goal is to reduce the number of treatments and have the best clinical effect.
The use of anti-VEGF drug therapy is an ongoing process that may continue for years. The treating ophthalmologist must monitor the response to treatment by testing visual acuity and OCT imaging. Treatment that is not working has to be modified, either by increasing the frequency of injections or by changing the drug. Faricimab (Vabysmo) represents a new class of drugs as it suppresses two specific cytokines simultaneously. Another treatment option is photodynamic therapy (PDT) which was largely abandoned after the start of the anti-VEGF era, but is again being investigated in combination with anti-VEGF agents.
Even though patients can progress from nonexudative to exudative stages, the nonexudative changes continue in a slowly progressive manner. Despite successful resolution of neovascularization and leakage with anti-VEGF drugs, vision loss may ensue over time. The next challenge for treatment will be integrating intraocular injections for both nonexudative and exudative ARMD together in a successful protocol.

The vision loss from ARMD is largely limited to the inability to read or drive, however the risk of severe vision loss is increased by the use of an anticoagulant drug. Despite this risk, it is imperative that a patient consult their primary care or specialist doctor on the discontinuance of anti-coagulation as this could cause serious consequences such as heart attack or stroke.
Treating exudative ARMD with anti-VEGF drugs can help most people maintain or improve vision. The challenges in the future involve the mitigation of treatment burden, improved treatment response, and the successful treatment of nonexudative ARMD.