Working Toward a Common Treatment Algorithm
Dr. Hariprasad: CME is the main cause of vision loss in many ocular disorders. CME has many causes (See "Potential Causes of Cystoid Macular Edema" below.) What is the mechanism by which pseudophakic CME occurs? During cataract surgery, the capsular bag is moving back and forth and perhaps that mechanical movement is transferred to the macula through the vitreous. On the other hand, a photochemical reaction may cause CME. Or is it prostaglandin mediated? Is it a simple pathway or is it complex with multiple causes?
Dr. Warren: I believe multiple pathways lead to pseudophakic CME. Many patients develop a posterior vitreous detachment after cataract surgery. Could that mechanism cause edema? Certainly. In addition to the scenarios you mentioned, the vasculature may be affected by sudden changes in chamber depth and intraocular pressure. Retained lens fragments can be a cause as can trauma itself. When we make an incision, the body's natural reaction is to start the inflammatory cascade. Therefore, I think chemical mediators play a role, too.
Dr. Hariprasad: The mediator pathway is important. The cyclooxygenase enzymes are a key factor. This is where nonsteroidal anti-inflammatory drugs (NSAIDs) come into play. Some NSAIDs block COX-1 preferably compared to COX-2. The new-generation NSAIDs block COX-2 preferably to COX-1. This is an important pathway that can be inhibited with proper prophylaxis. Another is the thromboxane and leukotriene pathway, which is where corticosteroids work. The combination of NSAIDs and steroids is a powerful way for cataract surgeons to modulate rates of CME.
Dr. Lindstrom, what do cataract surgeons believe is the incidence of pseudophakic CME?
Dr. Lindstrom: First, let me go back a step. The original research on pseudophakic CME, in rabbits, showed it to be prostaglandin-mediated inflammation. It does not take much trauma to the eye — just a paracentesis — to initiate a huge prostaglandin-mediated inflammatory process. It is possible that inflammatory cells could play a role later, but I think it is primarily prostaglandin-mediated, which is why we get such a good result treating with NSAIDs.
|The new-generation NSAIDs block COX-2 preferably to COX-1. This is an important pathway that can be inhibited with proper prophylaxis. Another is the thromboxane and leukotriene pathway, which is where corticosteroids work. The combination of NSAIDs and steroids is a powerful way for cataract surgeons to modulate rates of CME.|
— Seenu M. Hariprasad, MD
As far as the incidence of pseudophakic CME, the earliest studies indicated 1% to 3% of patients were affected with visually significant CME, which was defined as 20/40 or worse visual acuity and macular edema observable with a direct ophthalmoscope or contact lens or ruby lens exam. As I said earlier, I think that is the wrong definition. A study by McColgin and Raizman1 suggested the rate of CME without NSAID prophylaxis is 12%, although they were using a tighter visual acuity standard.
|Potential Causes of Cystoid Macular Edema|
|Cystoid macular edema (CME) can be caused by the following conditions and medications.|
■ Retinal vascular disorders
– diabetic retinopathy
– vein occlusion
– radiation retinopathy
– Irvine-Gass Syndrome
– retained lens fragments after cataract surgery
■ Mechanical causes
– epiretinal membrane
– vitreomacular traction
– retinitis pigmentosa
– age-related macular degeneration
– nicotinic acid
– prostaglandin analogues
If we were to define CME as a 10% increase in macular or perimacular thickening caused by edema, most patients would have it. It may be everybody.
Dr. Ober: By that definition, virtually everybody has impairment of their macular function following cataract surgery. That may or may not be the case. It remains to be seen whether having a low level of inflammation and possibly a temporary increase in retinal thickness has any clinical significance in the long run.
Dr. Lindstrom: I was not saying that it does. All patients have at least mild flare and cell after cataract surgery, but not all of them have trabecular meshwork damage or endothelial damage from that mild flare and cell. I do not think a small amount of edema for a short time necessarily causes an impact on long-term visual function.
Dr. Warren: The presence of inflammatory cells and flare indicates inflammation in the eye. Whether it is subclinical or not, we would suspect a chemical mediator is involved.
DEFINING AND DIFFERENTIATING BETWEEN ACUTE AND CHRONIC RECALCITRANT CME
Dr. Hariprasad: What about acute vs. chronic recalcitrant CME?
Dr. Ober: We have no strict definitions. In my opinion, CME is considered chronic or recalcitrant if it has not responded to the standard of care, which is treatment with topical steroids and NSAIDs.
Dr. Warren: Many people consider acute CME to be what Dr. Lindstrom described — the situation following cataract surgery in which all patients have some degree of retinal thickening and/or inflammation in the eye. I think it becomes chronic once it is refractory to treatment with a topical steroid and NSAID.
Dr. Benz: It is not a black and white issue. It is easy to say a patient who has CME 6–8 weeks after cataract surgery has acute CME. At what point it becomes chronic, whether that is 1 month or 2 months after treatment, is open for interpretation.
Dr. Hariprasad: It has been suggested that when CME extends beyond 6 months, only 25% of patients with appropriate treatment will achieve 20/40 or better vision. No matter how we define chronic or acute CME, the bottom line seems to be that it kills photoreceptors. The longer it is there, the more damage occurs. Therefore, it should be identified early and treated appropriately.
Dr. Warren: I think once the patient has long-standing edema a number of things occur, including architectural changes. Even if we dry the retina, it has had fluid-filled spaces for so long that photoreceptors are permanently rearranged to a new configuration. I think photoreceptor cells are lost because of the chronic architectural changes that occur.
Dr. Lindstrom: While this is not a perfect definition, we as ophthalmologists define the global treatment period for cataract surgery as 90 days. By that measure, everything is supposed to be back to "normal" in 90 days. If a patient has a problem past 90 days, I consider that a chronic problem.
|If we were to define CME as a 10% increase in macular or perimacular thickening caused by edema, most patients would have it. It may be everybody.|
— Richard L. Lindstrom, MD
If a patient is not seeing well a month after surgery, I look at the media and the macula. I look at the ocular surface, the capsule and the macula. If edema is present, I initiate therapy. If therapy does not resolve the edema in 4–8 weeks, I refer the patient to a vitreoretinal specialist.
IMPROVING COMMUNICATION BETWEEN SPECIALISTS
Dr. Hariprasad: This is a good time to ask Dr. Lindstrom several questions. First, how do anterior segment surgeons diagnose CME? When do they refer the patient? Do they refer to certain retinal specialists? What are patients told in your offices? What is your experience dealing with the retina subspecialty? Do you find us helpful? What can we do to make the patients' and your experience more positive?
Dr. Lindstrom: A broad range of practice patterns exist among anterior segment surgeons. Generally speaking, we refract patients for eyeglasses a month after cataract surgery. Even though we have a 90-day global treatment period, many of us are willing to have the patient come back in a year if everything looks good. If the patient does not refract to 20/20 or better, there is a reason and we want to identify it.
We use a differential diagnosis. As I said, I refer to that as "media and macula." If a patient has an afferent pupillary defect, we look at the disc, but we always look carefully at the macula and media. We rule out ocular surface and capsule problems. It is crucial to examine the macula before opening the capsule. Those of us who have been around a long time are fairly proficient at recognizing problems even with a direct ophthalmoscope. Obviously, we also can use a ruby lens or a contact lens.
I now use OCT, as well. If a patient is not seeing as well as I want them to and the macula is thicker than it was preoperatively or thicker than I believe it should be, or they have the patterns consistent with macular edema, I change my therapy. I do not immediately refer to a retinal specialist. I make sure the patient continues using the nonsteroidal drops, and I usually increase the dose of steroids. It is acceptable if the intraocular pressure increases a little bit. I might discontinue a prostaglandin. I try to reduce medicines that may be toxic, such as drops containing the preservative benzalkonium chloride.
Then I see the patient again, every 2 to 4 weeks. I am starting to monitor progress with OCT much like I monitor corneal edema with pachymetry. If 2 to 4 weeks pass and I see no progress, I inject subconjunctival steroids and observe again. At 6 to 8 weeks after the 1-month visit — so now we have reached 10 to 12 weeks post surgery — if the CME has not resolved, I request a retinal consultation. Depending on where I refer, the next steps vary. Some retinal physicians inject intravitreal steroids and others use intravitreal anti-VEGF agents. Some repeat the subconjunctival injection.
|In my opinion, CME is considered chronic or recalcitrant if it has not responded to the standard of care, which is treatment with topical steroids and NSAIDs.|
— Michael D. Ober, MD
|It is not a black and white issue. It is easy to say a patient who has CME 6–8 weeks after cataract surgery has acute CME. At what point it becomes chronic, whether that is 1 month or 2 months after treatment, is open for interpretation.|
— Matthew S. Benz, MD
|Many people consider acute CME to be what Dr. Lindstrom described — the situation following cataract surgery in which all patients have some degree of retinal thickening and/or inflammation in the eye. I think it becomes chronic once it is refractory to treatment with a topical steroid and NSAID.|
— Keith A. Warren, MD
EXPLAINING CME DIAGNOSIS AND TREATMENT TO PATIENTS
Dr. Hariprasad: When do you tell patients they have CME, and how do you present the diagnosis?
|Strong or Weak: Analyzing the Connection Between Prostaglandin Analogues and CME|
|Dr. Hariprasad: CME can have many causes (See Table 1). What are your thoughts about discontinuing prostaglandin analogues before cataract surgery?|
Dr. Lindstrom: Some cataract surgeons may stop them. I do not routinely stop them in my clinical practice.
Dr. Benz: No one has ever asked me that question. If IOP was controlled with a prostaglandin analogue, I would most likely recommend it be continued.
Dr. Warren: I do not recommend discontinuation before surgery. We have not seen any problems using a nonsteroidal anti-inflammatory drug (NSAID) to treat patients who develop secondary CME.
Dr. Ober: I do not recommend discontinuation of prostaglandin analogues before cataract surgery. However, I routinely have them stopped in patients who develop postoperative CME.
Dr. Hariprasad: In general, prostaglandins are not stopped unless the patient has recalcitrant CME. I have not seen it personally, but in a situation where the CME is not resolved and the patient is on a prostaglandin analogue, the drug may be stopped to see if it is preventing the resolution of the CME.
Dr. Lindstrom: Clinically, it seems to me if IOP increases slightly, it helps the CME. So it may be reasonable to allow the pressure to increase temporarily if the disc is not at too much risk for glaucoma damage. We also can note that a large body of research suggests that the preservative benzalkonium chloride (BAK), which is in most glaucoma medications, is more toxic to the ocular surface than the glaucoma drugs.1-4 Often, ocular surface problems are the reason for suboptimal vision after cataract surgery. In addition, BAK has been implicated as a potential cause of CME.5
Dr. Warren: Has discontinuing the prostaglandin analogue made a difference in the response to treatment for CME?
Dr. Hariprasad: Not in my experience. I think it is a very weak association.
Dr. Ober: I have seen patients get better when the only change made was discontinuation of the prostaglandin. I think it is more important in a vitrectomized eye.
Dr. Warren: As I said, I do not discontinue prostaglandin analogues in patients who are having cataract surgery. If we assume that an NSAID inhibits the prostaglandins, we would expect the patient would not have the same responsiveness to that drug. However, I have not seen any changes in IOP in patients treated with both a prostaglandin analogue and an NSAID. That is just my observation.
Dr. Hariprasad: With good NSAID prophylaxis, it is probably safe to continue prostaglandins before cataract surgery.
Dr. Lindstrom: I tell them as soon as I make the diagnosis. I tell them they have some swelling in the retina, which usually responds to anti-inflammatory medication, and that we will start with topical drops. But basically, they are no longer in the "normal, everything is perfect" group.
Dr. Hariprasad: What do you tell them when you reach the 12-week point and the edema has not responded and you want to send them to a retina specialist?
Dr. Lindstrom: Typically, I already have told them that if they do not respond to the subconjunctival steroid, more aggressive treatments can be used, such as medicines inside the eye or surgery if necessary.
While most patients do respond to treatment in our practice, it would be useful to know how long we should wait to refer. How much swelling for how long is too much? Do patients respond better to intravitreal steroids if they are administered earlier, or does it not matter? I am very nervous if the patient is not better by 10 to 12 weeks. Other cataract surgeons may be sending the patients away as soon as they diagnose CME at 1 month.
Dr. Benz: In cases of suboptimal vision after cataract surgery, Dr. Lindstrom is looking at media and macula, which raises a good point for other anterior segment surgeons to remember: never forget the macula. At the same time, retinal specialists should not forget the media. Cataract patients are sent to us sometimes and the surgeon does not know exactly why the vision is not optimal. We tend to focus on the macula when there may be some other reason why vision is not 20/20, such as IOL placement, the capsule or the surface.
Dr. Warren: The majority of CME patients referred to me do not reach a complaint-free visual acuity outcome, partly because they have had the condition chronically and have not responded well to treatment. From an anterior segment perspective, how many of the patients that you treat with topical therapy end up complaint-free?
Dr. Lindstrom: My feeling is the less wet for the least amount of time is best for the macula. Therefore, I have gotten aggressive with prophylaxis and interventional therapy. If the vision is 20/20-1, which is not perfect, and OCT shows some macular thickening, I treat even though many patients may have been fine without the treatment.
Dr. Warren: How many reach the point where they say, "This is great, doctor"?
Dr. Lindstrom: I do not have a solid number for you. Not all of them reach that point. Not all of them come back, and sometimes they do not know they could have been better. Sometimes when I am following them, I am wondering whether they could have done better if I had been more aggressive.
It is important for anterior segment surgeons and retinal specialists to discuss therapy. It is incredibly awkward if a patient asks the retina doctor whether anything could have been done to prevent this and he or she replies, "Well, had you been started on this or that therapy …"
CONSIDERATIONS FOR THE TIMING OF PATIENT REFERRALS
Dr. Hariprasad: What else can retina specialists do to make the transition from the cataract surgeon to the retina office more beneficial for everyone?
Dr. Lindstrom: We need to communicate with one another. The only disconnect is whether you would do something earlier or differently than I would. If I treated my patient prophylactically with an NSAID and steroid and continued those therapies for the appropriate length of time, and then bumped up treatment at 1 month and followed that with a subconjunctival triamcinolone injection, and that is exactly what you would have done, we are fine. Once we reach the point where you would have done something different, it becomes awkward.
If a patient clearly has CME, when would you inject an intravitreal steroid? When would you inject a sub-Tenon's steroid, or would you not? That is what anterior segment doctors need to know because that is when we should send the patient to you.
Dr. Warren: Until recently, retinal specialists were not using NSAIDs in the treatment of CME because the previous generation of medications was not very effective. Now, we are seeing that the newer options can be effective. This benefits patients because all of us can become more consistent in our approach.
Dr. Ober: It is difficult for me to generalize how I treat CME patients because I personally do not treat all patients in exactly the same way. Not only do I look at the media and the macula but also whether the hyaloid is attached or detached, whether there is an epiretinal membrane, whether there is vitreomacular traction and so on. I may move faster to intravitreal injection when different components of macular disease or vitreous architecture are present.
Also, a sub-Tenon's steroid injection technique varies widely. Some physicians place it over the ciliary body; others put it directly behind the macula. This may be why Dr. Lindstrom finds some retinal specialists repeating his sub-Tenon's injection. They may believe a different technique or location makes a difference.
Dr. Warren: Yes, but I do think we should at least consider creating a common algorithm that would serve as a basis for treatment. RP
|1. McColgin AZ, Raizman MB. Efficacy of topical diclofenac in reducing the incidence of postoperative cystoid macular edema. Invest Ophthalmol Vis Sci. 1999;40:289.|