Lecture: Electroretinography (ERG): When Do We Need It?

DR KHAN: Greetings from Abu Dhabi. My name is Arif Khan. I’m a pediatric ophthalmologist at Cleveland Clinic, Abu Dhabi. And it’s my pleasure to be participating in this Orbis webinar, regarding full field ERG. Let me just move this so it’s out of my way. Okay. I don’t think it’s any exaggeration to say that electrophysiology is one of the most misunderstood tests in ophthalmology. In fact, many people feel that it’s obsolete, with the multimodal imaging we have these days, autofluorescence, near-infrared and short wave optical coherence tomography, OCT, OCTA, adaptive optics, and advanced genetic testing… Why do we need electrophysiology anymore? Well, I would argue that actually we need it more than ever, because electrophysiology is the only way to objectively measure visual function. Sure, we have subjective ways of measuring visual function, like visual acuity and visual fields. But electrophysiology remains the only way currently and for the foreseeable future, of objectively quantitating visual function. For this talk today, what I would like to speak about is one of the most common and the major electrophysiology tests, full field ERG. There’s certainly much more to electrophysiology than full field ERG, but full field ERG is the granddaddy of electrophysiology. It’s the major test that we do, when we need electrophysiology. And my goal in this talk is not to make you understand how to perform electrophysiology. That is, full field ERG. It’s not my goal to make you understand how to read full field electrophysiology. Full field ERG, that is. My goal is to make you understand: When do we need it? When is it indicated? And this is something all eyecare practitioners should be aware of. When do we need full field ERG? Let me just close this box and move it out of my way. And we’ll get started. I do serve as a consultant regarding retinal dystrophies, but not relevant to the contents of this talk. So the way I’ve divided things is: First I’m gonna speak about the basics of retina, and of full field ERG, so we’re all on the same page. Then we’ll dive into full field ERG indications. And then towards the end, I have some interactive cases, where I want you to consider, for the cases that I show, do we need full field ERG? Is it needed or not? Some of them do need it. Some of them don’t. For the basics that I’m gonna cover, the two major references are listed here. So we know that light focuses through the anterior segment of the eye. Onto the back of the eye. The retina. The neurosensory retina. And it’s in the photoreceptors, where light is transformed into electricity, to start the process of vision. There are about ten layers of the retina. And really all of those layers of the retina, other than the photoreceptor layer, are supporting the photoreceptor layer. Interestingly, the photoreceptors are the outermost layer of the retina. So for most of the retina, when the light is passing to get to the photoreceptors, it has to get to every other layer before it gets there. The retina can be simplified as a three-neuron circuit. Photoreceptor, bipolar cell, and ganglion cell. The one exception, where light actually strikes the photoreceptors directly, is at the fovea. Of course, the fovea is what we use when we want to fixate on something. It’s where we have our central vision, our visual acuity. And at the fovea, the inner retinal layers move apart, and the light strikes directly on the photoreceptors, more or less, allowing us to have better acuity — achieve better acuity in that area of the retina. So again, the retina has multiple layers. The photoreceptors are the outermost layer. Other than — adjacent to the retinal pigment epithelium. And the photoreceptors can be divided into rods and cones. Rods are responsible for our dim vision. Gross vision. Cones are responsible for our visual acuity, our color vision, our central vision. And at the fovea, the inner retinal layers move apart, and light comes directly on the fovea. Another thing about the fovea: It’s very cone-dense. As a matter of fact, there are no rods in the fovea. Cones allow us to have our sharpest vision. You can think of the retina as really, you know, when we want to look at an object of interest, we’re using our fovea, and the rest of the retina is just gross motion detection. It detects something that is of interest. We move our eye. So that the fovea trains on that object. I’d like to share with you some facts about the photoreceptors. And think about this, while I go through it. What are the total number of cones in the retina? Think of a number. Is it 1 million? 100 million? 1,000? 100,000? There are about 6 million cones in the retina. Now… Knowing that there are 6 million cones in the retina… How many rods do you think there are in the retina? About the same? Less? More? In fact, there are 20 times more rods in the retina than cones. There are about 120 million rods in the retina. The retina is a rod-rich structure. Cones are only a minority of the photoreceptors in the retina. Even though it’s cones that we think about, when we’re using our daytime vision for reading and color vision. The retina is a rod-dominated structure. Now, you now know how many cones are in the retina. You know how many rods are in the retina. How many cones do you think there are in the fovea? This is something I find people get confused. And you might logically think that most of the cones are in the fovea. Given the fact that we use the fovea to concentrate on things, to really focus on objects of interest. But in fact, there are only about 200,000 cones in the fovea. The vast majority of cones are outside the fovea. So although the fovea is very cone-dense, the absolute number of cones is higher in the rest of the retina. The fovea is not fully developed at birth. It doesn’t develop until about four years of age. And the rods peak in their density about 20 degrees from the center of the fovea, in a ring. Again, there are no rods in the fovea itself. I like this diagram. It illustrates what I just said. Point zero is the fovea. And you can see it’s very highly densely populated by cones. However, as you go eccentric from the fovea to the peripheral retina, the density of cones is much less. But the absolute number of cones is much greater in total than the number of cones in the fovea. And the rods, again, no rods in the center, at point zero. But as you get about 20 degrees out, that’s where the rods peak. And the density declines slightly, as you go further and further peripheral. I like this electron micrograph of a peripheral retina. Those squiggly yellow lines are the rods, and you can see the retina is really a sea of rods. And those plum greenish things, scattered among them — those are the cones. Again, this is extrafoveal retina. If it was in the fovea, it’s all cones. The purple represents the retinal pigment epithelium. Now, cones only represent 5% of the photoreceptors, but it’s what gives us our color vision. And there are actually three types of cones. S cones, M cones, and L cones. And they are encoded by genes on the X chromosome and on chromosome 7. I’m not gonna get into this. I just want to mention it. These different types of cones, these three different types of cones, have different sensitivities to light. And depending upon how a particular wavelength of light stimulates these three different cone pigments, in its absorption spectrum, the retina starts computing and calculating color vision for us. So, for example, here is the spectral sensitivity of the three cone pigments. S, M, and L cones. You can see they have different peak sensitivities. And if something comes in that’s about 450 nanometers, only a little bit strongly stimulates the S cone. M cone also gets stimulated, but not as much. L cone also, but not as much. And the computation of the differential stimulation is what allows us color vision. It’s really a fascinating topic. It starts in the retina and it goes on, of course, in the brain. I’m not gonna go into details of this. I just wanted to mention it. Now, let’s move on to the ERG. What is the ERG? The full field electroretinogram? Basically it’s a measurement of the electrical activity generated by the retina under certain standardized conditions of light intensity and light adaptation. So we have certain standards of light adaptation and certain standards of stimuli. We stimulate the retina. We have a wire there, to measure the electrical activity. And that measurement is the electroretinogram. The full field electroretinogram. It’s important to realize that the full field electroretinogram is a measure of the retinal activity as a whole. It’s a measure of panretinal activity. So remember, the fovea, which is cone-dense, it only represents a minority of the retina. If someone has a macular hole and hand motion vision, they’ll have a normal full field ERG, because it’s a minor contribution to the ERG. The ERG is measuring panretinal function. Conversely, if somebody has total retinal wipeout, except for the macula, the ERG would be very low intensity, but the patient could have 20/20 vision. So the ERG doesn’t really tell you what the visual acuity is. When we do a full field ERG, we have to send the stimulus of light through the anterior segment to get to the retina. So anything in the anterior segment that might obstruct the standard stimulus that we give can affect the ERG recording. For example, if someone has a dense cataract, when we give the standard stimulus of light, not all of the expected light is gonna get to the retina. The ERG will be abnormal. This is why ERG cannot be done without being in the context of a good clinical exam. ERG technique is critical. And I really can’t stress that enough. Again, I’m not gonna talk about how to do an ERG here. Or even how to read it. But let me say that the electrodes have to be placed properly. There has to be minimal movement. The conditions have to be as per standard ISCEV conditions. That is International Society for Clinical Electrophysiology of Vision. The person performing the ERG has to be very skilled. It can be a PhD, MD, OD, CO, a highly, highly trained technician. But it’s not a hobby. It’s something that someone needs to be trained into doing. It’s a serious commitment to do ERGs properly. And once we do a proper ERG, it lets us electrically dissect the retina. We can dissect inner retina from outer retina, and we can dissect rods from cones. This is what the ERG does for us. The full field ERG. We have such fantastic multimodal imaging these days. I can’t imagine looking at a patient with a retinal problem without looking at multimodal imaging, in addition to that. But the multimodal imaging tells us structure. It doesn’t tell us function. The only way to objectively measure retinal function is with electrophysiology, such as the full field ERG. And the full field ERG — it’s worthwhile to highlight this — it’s the gross electrical response of certain retinal cells to certain protocols. And it isolates rods from cones and inner from outer retina. Let me stress what the ERG does not do. The ERG does not tell us anything about ganglion cell function. So someone has an optic neuropathy, the full field ERG is theoretically normal. The full field ERG doesn’t tell us anything about foveal function, because the fovea is a small part of the retina. When we’re talking about panretinal function. So the full field ERG does not tell us anything about the visual acuity of a patient. It doesn’t add information if there are no photoreceptors. If you can see clinically that the patient has complete photoreceptor wipeout or extremely advanced retinitis pigmentosa, there’s no point in getting an ERG. And finally, I always say this: The ERG is really meaningless without a good clinical exam. It doesn’t substitute for clinical exam. And a good ophthalmologist is better than excellent electrophysiology. Electrophysiology cannot be done without having a specific clinical question after a good clinical exam. Now, let me just show you the four recordings of an ERG, just briefly. I’m not gonna go into detail about this. We have an isolated rod response. And it looks like this. This is the scotopic ERG rod response. We have a combined-mixed response. And this is the wave form that most people associate with an ERG. We have an A wave and a B wave. It’s giving us reflection of both rod and cone function. The A wave is reflecting the photoreceptors and the B wave is the inner retina. And then we have two cone responses. The flash cone response and the cone flicker. These are the four standard minimum wave forms of a full field ERG. Now… Now that we’ve gone through the background, I’d like to go through: What are the indications for ERG? And the first indication — and I’ve divided this into five arbitrarily. This is my own way of thinking about it. The first classification, the first indication, that is, is if you have a patient with pigmentary or fibrotic changes, when you wonder if there’s a question of global retinal dysfunction. So here’s a 50-year-old asymptomatic woman who came in for a blepharoplasty. And before blepharoplasty, she had an eye exam, and she has these findings. She has pigmentary changes. She’s asymptomatic. This is picked up incidentally. Both eyes are the same. Is this the sign of a retinal disease? Of panretinal dysfunction? Only way to know is full field ERG. And when we do a full field ERG on her, she does have rod-cone dysfunction. She actually had a mild case of retinitis pigmentosa. Didn’t even know it. The only way to diagnose this is with full field ERG. Here’s a child who came in with refractive accommodative esotropia. And when we examined him, he’s got these strange fibrotic lesions on the retina. He also has some subtle mottling on the retina as well. This again is an indication for a full field ERG. Because we’re not sure what’s going on here. This could be — these could be signs of panretinal dysfunction. And when we do an ERG on this child — this is just a normal tracing for reference — he has abnormalities that are actually pathognomonic for a certain disease. Most of the time, when we do ERG, it gives us a general idea of the retinal dysfunction. But it’s not pathognomonic for something specific. But there are instances where it is. And in this particular case, this pattern with no rod function, the dull mixed rod-cone response, the dull cone response, and the abnormal flicker, this is pathognomonic for the enhanced S-cone/Goldmann-Favre syndrome. That’s what this patient had. In this case, we’re able to make a genetic diagnosis without doing any genetic testing, based on their ERG. Again, most of the time when you do an ERG, you can’t make a specific diagnosis, such as the enhanced S-cone syndrome. But there are exceptions, and the enhanced S-cone syndrome is one of them. The next indication for full field ERG is maculopathy. Now, when you have a patient who presents with maculopathy, very often I see these patients labeled as macular dystrophy. But you cannot classify whether a patient with a maculopathy has a macular dystrophy or panretinal dysfunction unless you do full field ERG. There’s no way. So anyone who comes in with maculopathy, full field ERG is indicated to know whether or not you’re dealing with a panretinal dysfunction or a localized macular dystrophy. So here’s a boy who comes in with decreasing vision, and you can see that he’s got a maculopathy. Both eyes are similar. Only the right eye is shown. Is this a macular dystrophy? Is this a panretinal dysfunction? The only way to know is to do a full field ERG. And when we do a full field ERG on him — again, this is the normal tracing — he has got cone-rod dysfunction. This is progressive. He’s got a cone-rod dystrophy. We can only make that diagnosis by doing a full field ERG. There’s no other way. He happens to have ABCA4 mutations. The most common cause of maculopathy in children, from genetic cause. And a full field ERG reveals what’s going on in ABCA4 retinopathy. It can cause macular disease only. When it’s only macular disease, classically, it’s known as Stargardt disease. And it can also cause cone-rod dystrophy, as in the patient I just showed you. There are clinical signs that suggest ABCA4 retinopathy. Genetic testing confirms it. But whether or not you’re dealing with a macular dystrophy or a cone-rod dystrophy, the only way to know is an ERG. ERG also informs prognosis in these patients. Patients who have cone-rod dystrophy by ERG have a much worse prognosis than those who have maculopathy only. Those with maculopathy only would have a normal ERG, because the macula is a small component of the full retinal function. Here’s another boy who came in with decreasing vision. And he’s another boy with maculopathy. And again, you know now that we have to do an ERG to understand if this is isolated to the macula, or is it panretinal dysfunction? And when we do the ERG on this boy, we have a very interesting pattern. He’s got a poor rod response. And he’s got a poor cone response. But paradoxically, the combined response seems to be supernormal. This is another one of those pathognomonic ERGs. This patient has cone dystrophy with supranormal rod response. The ERG signature is pathognomonic for KCNV2 mutations. Again, we just did a genetic diagnosis without any genetic testing. These patients don’t actually have supranormal rod response. It’s a glitch in the electrical signaling from the gene mutation that causes the flash combined response to seem supranormal. It’s not really supranormal. These patients can have a variety of clinical presentations, but the ERG is pathognomonic. Again, maculopathy — ERG can be very useful. It can even give you a genetic diagnosis without even doing genetic testing. Let’s move on now to indication number three. Non-traumatic optic nerve pallor, particularly in children. Why do we need to do an ERG if a child has optic nerve pallor? If it’s optic nerve pallor, doesn’t that mean that it’s an optic neuropathy? No, actually, it doesn’t. Because sometimes retinal dysfunction can cause secondary optic nerve pallor. And the only way to know whether or not you really have panretinal disease or not is by doing the full field ERG. So here is an 8-year-old boy with poor vision since he’s 2 years old. He was previously diagnosed with optic neuropathy. You can see he has optic nerve pallor. He had MRI before. It was normal. His OCT is normal. His autofluorescence is normal. Even though his OCT is normal and autofluorescence is normal, it doesn’t mean his retina is normal. The only way to know whether or not his retina is normal is by doing a full field ERG. And when we do the ERG on him, he also has a very interesting signature. You know, abnormal rod and cone. With what we call an electronegative wave form, where there’s only the B wave is much smaller than the A wave. This is highly suggestive for a particular condition. And indeed, he has it. He’s got this condition known as congenital cone-rod synaptic disorder. It’s a form of retinal dysfunction that sometimes characterizes a form of incomplete general stationary night blindness. The point is not a specific diagnosis. The point is: A child comes in with optic nerve pallor, it doesn’t automatically mean he has optic neuropathy. You need to do ERG to rule out whether or not there’s retinal dysfunction, even if the multimodal imaging of the retina is normal. And here’s a 9-year-old girl who had decreased vision noted over the last year in school. Diagnosed with diabetes before. She’s got optic nerve pallor. Her ERG is normal. We ruled out retinal disease. We can see the OCT shows loss of inner retina. She actually has optic neuropathy. She has a genetic optic neuropathy. The ERG helped us to prove that it’s optic nerve disease alone. Not something more than that. The next indication is something I punched together. And it’s a major indication for ERG. Unexplained abnormal vision and infantile nystagmus. What do I mean by unexplained abnormal vision? Decreased visual acuity, and we’re not sure what the reason is. Photophobia, and we’re not sure what the reason is. Poor night vision. We’re not sure what the reason is. These are classic indications for ERG. Also infantile nystagmus. Because very often children with infantile nystagmus who have a normal appearing retina often have a panretinal dysfunction. So a big indication for full field ERG is the child who doesn’t seem to see well, or has nystagmus and doesn’t seem to see well. And has a normal-looking retina. Even if they have nystagmus and do seem to see well, this is also an indication for ERG, to understand what is the cause of nystagmus. Many causes of nystagmus in children are from retinal dysfunction. And I’m not gonna go through this. But there are some classic diagnoses for children with a normal fundus appearance and decreased vision. Just keep this in mind. It’s a major indication for full field ERG. Now, here’s a six-year-old girl who was referred to me for strabismus. She has esotropia, myopia, mom complains her daughter has poor night vision, and was told all was normal by retinal specialists. She wasn’t referred to me because of the retina. She was referred to me for strabismus. And she has esotropia, myopia, slight nystagmus, as we sometimes see in strabismus, and the multimodal imaging is normal. But we can’t stop there. You have to listen to the mother. The mother says she has poor night vision. Poor night vision, unexplained, we have to investigate it. How? Full field ERG is the only way. And her imaging is normal. Here is the normal tracings, and for her, she’s got no rod response. She’s got no night vision. And she has an electronegative combined response. That is — the A wave is normal, but there’s no B wave. That means inner retinal dysfunction. And she has normal cone response. This is a classic signature for congenital stationary night blindness. I can’t tell you how many patients I see who have congenital stationary night blindness and go undiagnosed for many, many years. Because the retina looks normal and the multimodal imaging looks normal. Someone is complaining of poor night vision, the only way to investigate that complaint properly is with full field ERG. Multimodal imaging is not enough. Very often the multimodal imaging is normal in congenital stationary night blindness. The last indication that I wanted to share with you — I’m not gonna give you any examples. I’m gonna just mention it. Another reason we do full field ERG is when we want to quantitate or monitor panretinal function or dysfunction. For example, someone with a known retinal disease, we want to follow them longitudinally, to see how they’re progressing. Perhaps there’s an intervention, like gene therapy, to see if that has done anything. Although there are other tests that are more sophisticated. Again, full field ERG is a panretinal test. So it’s only a gross measure. Can follow patients who are on medications that might be toxic to the retina. Patients with autoimmune disease, patients with inflammatory disease. Any condition where you want to follow or monitor panretinal function or panretinal dysfunction, this is another indication for the full field ERG. So these are the indications. This is the way I’d like to think of it. I like to divide it into five categories. And now… Good timing. I want to go into some cases. And what we’re gonna do is we’re actually gonna go into the ERG clinic. And see the patients that are referred to the ERG clinic, and decide whether or not we actually should do full field ERG or not. This is the standard that we use at Cleveland Clinic Abu Dhabi. When a patient is referred for full field ERG, we don’t do it unless we know that we have a good clinical exam beforehand. Because again, as I said, a full field ERG is meaningless unless you have a good clinical exam. So let’s go through some cases, and now I want your input, to know whether or not these patients should have full field ERG or not. So here’s a patient who’s referred because of difficulty seeing, especially at night. This is a 14-year-old male. Longstanding history of decreased seeing at night. Retina appears normal. And multimodal imaging appears normal. He’s got intermittent exotropia, everything looks normal. He’s myopic. Myopic patients can have decreased night vision. So this is the referral. Do we do a full field ERG or not? So Lawrence, can we have the question? Do we do a full field ERG or not on this patient? Yes or no? Yes or no? This patient gets a full field ERG or not? Okay. And we see that most of the people say yes. 86% said yes. 14% said no. And that’s great. Thanks for listening. You need to do a full field ERG to investigate a complaint of poor night vision. It doesn’t matter if the retina looks normal. The retina can look normal in congenital stationary night blindness and some other retinal dysfunctions. So this child — everything looks normal. His full field ERG — there’s no rod response. He’s got a prominent A wave, which means the photoreceptors are functioning, but he’s got no B wave, because the inner retina is not working. The cones are normal. This is congenital stationary night blindness. And he went the first 14 years of his life without the diagnosis. You can’t diagnose congenital stationary night blindness without doing an ERG. You have to know when it’s indicated. Very common for highly myopic males. Who are complaining of poor night vision. To have undiagnosed congenital stationary night blindness. We don’t diagnose it, who’s gonna diagnose it? We really need to be attuned to this diagnosis. It’s not uncommon. Let’s gone to the next case now. And again, I’m gonna ask you: Do we do an ERG or not? This is an infant with shaking eyes. And he’s improving. With time. So he’s a 12 month old male. The parents have noticed his eyes have been shaking, but it’s been improving. He puts his chin down, and he’s got some light sensitivity. He’s lighter pigmented than his siblings, and he was previously diagnosed with albinism, based on his pigmentation and his light sensitivity. He doesn’t have good fixation. He has nystagmus. His retina looks normal. We can’t do multimodal imaging because of his age. We’re not gonna sedate him for this. But the retina looks normal, and he doesn’t have any significant refractive error. So Lawrence, can we have the question again? Do we do an ERG or not? Again, he had some eye shaking, but it’s improving. The parents think he’s getting better. He’s got a presumptive diagnosis of albinism because of skin pigmentation. Everything in the retina looks normal when you look at it. Does he need an ERG or not? Do we need an ERG on a child with nystagmus if the nystagmus is getting better? And the retina looks normal? Just waiting for the questions to come. Okay. 70% said yes and 30% said no. Okay. Let’s take a look at him here. Here he is. You know, he has a chin-down position, he’s got nystagmus, he’s got a null point there. This patient needs an ERG to understand what’s going on. And when we do an ERG on him, these are normal tracings — when we do an ERG on him, basically he has no cone response. The rod response is normal. He’s got no cone response. We do genetic testing, guided by the ERG, he has biallelic CNAG3 mutations. This boy has achromatopsia. Achromatopsia. Now, it’s important to pick these patients up early these days, because there are gene therapy trials ongoing for achromatopsia. And there’s likely gonna be gene therapy soon. And these patients benefit the most when they’re detected early. So it’s not just academic to pick these patients up. The only way you can pick these patients up is by doing ERG. Very often, the achromatopsia patients, the retina looks normal. It’s actually very common. So a child who comes in with photophobia and nystagmus — retina looks normal — you need to do an ERG. Especially these days, when there are gene therapy trials for achromatopsia. If we don’t pick up these patients, they’re not gonna benefit the way they could, without being picked up early. Okay. Let’s see… What do we have next? And how is the time? The time is good. Okay. Let’s see here. Here’s a patient… An interesting one. Worsening vision and a history for breast cancer. Referred for ERG. This is a 38-year-old female. Recent worsening vision. Doesn’t improve with manifest refraction. She had a history of treatment for breast cancer. The retina is normal by report. She’s referred to rule out cancer-associated retinopathy. There is this phenomenon of cancer-associated retinopathy — patients who have had cancer sometimes develop an autoimmune retinopathy, and the ERG is very helpful in diagnosing those patients. The retina can look normal. So she’s got 20/40 vision. She’s got small angle esotropia. And all of the imaging is normal. Do we do an ERG on this referral? Can we have the poll question, please? 38-year-old woman. Worsening vision. History of breast cancer. Retina looks normal. Small angle esotropia. Multimodal imaging, normal. Does this need an ERG to assess for cancer-associated retinopathy? Just waiting for the numbers to come in. So we have overwhelming yes. We have 85% yes, 15% no. Now… Let me stop here for a second. And put on my other hat. I do… In addition to doing electrophysiology and genetics, I also am a pediatric ophthalmologist. I am a pediatric ophthalmologist, and I do strabismus. And let me stop for a minute and put on my strabismus hat. This patient has an esotropia. Any patient with esotropia — I don’t care what the age is — needs a cycloplegic refraction. This patient never had a cycloplegic refraction. We do a cycloplegic refraction on this patient. And she’s +4.00. What’s going on here? She’s a latent hyperope. She’s prepresbyopic. And this is the source of her visual complaints. Again, the ERG should not be done without a good clinical exam, first of all. And we give her the glasses, she becomes much more comfortable, she no longer has worsening vision and discomfort, and her eyes straighten. This woman has latent hyperopia. Again, very important to have a good clinical exam before going on to full field ERG. We don’t do full field ERG unless we’ve done a thorough clinical exam to rule out other things for complaints. These are all real cases, by the way. These are not made up cases. These are all cases that have come to the clinic. Now… Let’s look at this one. Decreased vision in school. Examined and maculopathy noted. Let’s take a look at this one. This is a five-year-old boy. Decreased vision noted in school over the last year. He’s examined. And he has a maculopathy. He doesn’t have any significant refractive error. There he is. That’s his right eye. His left eye is similar. You can see the maculopathy. So this patient has a maculopathy. Do we need to do an ERG? Can we have the question up, please? Why do we need to do it? We know he has a maculopathy. Do we need to do an ERG? It’s obvious from the multimodal imaging. He has a maculopathy. Do we need to do an ERG? Put him through this? Does it benefit him in any way? Yes or no? So overwhelming yes. 86%. And 14% no. Any patient who comes in with a maculopathy needs an ERG, because you don’t understand what’s going on in the retina unless you do an ERG. And the ERG is the only way to get that information. There’s no other way to get that information. There’s no other substitute for that test. And when we do the ERG on him… It was actually quite a surprising result. He’s got no rod response. He’s got no cone response. And this mixed response is low, but it’s electronegative. This is a very disturbing signature. Actually. Because it suggests inner retinal loss, in addition to photoreceptor loss. It suggests a storage disease. It suggests a lysosomal storage disease. And in fact, this child has Batten disease. This child has neuronal ceroid lipofuscinosis. This is a horrible disease, and it presents to ophthalmologists first, as visual decline, as maculopathy. These patients typically come in at 5 or 6 years old with bull’s eye maculopathy, and the ERG rapidly deteriorates to non-recordable. They go on to have progressive dementia, extrapyramidal signs, and premature death. Unfortunately, this was the first sign of this disease in this child. Now… Because we identified it so early in him, he was able to enroll in a gene therapy trial for Batten disease. Most patients who want to enroll in gene therapy trials are ineligible. Because by the time they’re diagnosed, a lot of damage has occurred already. And gene therapy trials traditionally — particularly for the eye — gene therapy trials are salvage operations. They’re rescue operations. They rescue tissue before it’s dead. Once tissue is dead, gene therapy cannot make it alive. This child, because he was diagnosed so early, was a good candidate for a gene therapy trial. So it is important to pick up these patients early. Not to mention preparing the family for the psychosocial needs that they’re gonna require, for the support that they’re gonna require, and to provide genetic counseling for the rest of the family, as they often do want. In bad situations like this. Again, it was the ERG that allowed us to make this early diagnosis. Maybe this is the last case, because of time. Here is a patient who came in because of photophobia and worsening vision. This is a 36-year-old female. She’s had bad headaches for three years. Worsening vision. Sometimes photophobic. Nystagmus since childhood. Her manifest refraction is hyperopic. And her multimodal imaging is normal by report. Does she need an ERG? Severe headache. Worsening vision. Photophobia. Do we need to do an ERG? So a majority say yes. But… Let me put on my strabismus hat again, and say: Any person who is hyperopic and has severe headaches, any adult who is hyperopic with severe headaches, needs to have a cycloplegic refraction. So we need to do a cycloplegic refraction on this patient first. What about the photophobia and nystagmus? Well, that could use an ERG. But let’s examine her a little bit more. The retina is normal by report. But when I see the images of this fundus, there are two things that strike me. One is: When you look at the vessels exiting from the disc, instead of exiting temporally, as they normally do, the vessels are exiting nasally. The other thing is: This patient has, for the area, doesn’t have as much retinal pigment epithelium pigmentation as we typically see in the region. But the way that the vessels are exiting from the disc gives me a clue about something. And maybe on this Optos image, you can see this hypopigmentation of the fundus a little bit better. Even though this was read as… This was considered normal previously. We do OCT. The OCT looks grossly normal. But actually, there is subtle foveal hypoplasia. Remember, at the fovea, there’s supposed to be no inner retinal layers. But there’s some persistence of inner retinal layers in this woman. She actually has two problems that we can diagnose clinically. One, she has latent hyperopia. We do a cycloplegic refraction, she’s much more hyperopic. The other thing is: She has albinism. This woman actually has albinism. And she has slight foveal hypoplasia related to the albinism. That’s why she’s had nystagmus all her life. We give her full hyperopic correction. She’s much more comfortable. Why is she photophobic? It’s because of the albinism. So actually, after this clinical exam, she doesn’t really need ERG. Now, let me see. We have about 15 minutes left. Again, latent hyperopia and albinism. She has two problems. And it’s not a retinal dystrophy. Clinical exam has told us this. I think I’ll stop here and answer the questions. Because of time. Let me just see. Actually, I think I’ll do one more case, and then we’ll go to the questions. And the last case, I’ll just go through it, because I think we’ve been through it so many times now. This is a patient with idiopathic macula dystrophy, referred for further evaluation. This is a 15-year-old woman, referred for macular dystrophy, second opinion. She had genetic testing before, but it came back normal. And she has a maculopathy on fundus exam. Here it is. Hard to see. But you can see the outer retinal atrophy on the OCT here. There is a maculopathy here. She had a previous gene panel. And it was negative. A panel of many genes for retinal dystrophy. Does she need an ERG? Well, I think I’ve said it many times now, before. If you have a macular dystrophy, or supposed macular dystrophy, if you have a maculopathy, you need to have an ERG. When we do an ERG on her, actually she has a very interesting signature. She has a signature — one of those pathognomonic ERGs, KCNV2. But when she had genetic testing, it came back negative. We looked at the panel and the gene panel didn’t include KCNV2. So we called the lab back, they were able to test KCNV2, and when they did the test specifically, sure enough, she had the mutation. So here the genetic testing panel wasn’t able to make the diagnosis, but when we do the ERG, we know what the diagnosis is. It wasn’t even part of the panel that was tested. Again, the power of the ERG. Cone-rod dystrophy, with supranormal response. It’s one of those rare conditions where the ERG is pathognomonic for the diagnosis. So I think know I’ll stop here and just answer questions. In the last 10 minutes. But let me just go to the end. My summary slide. Full field ERG is time-consuming to perform, requires skill to perform, and needs careful interpretation. It’s not a hobby. So if you’re gonna be doing full field ERG, you have to have a commitment. The person who’s doing it has to have a commitment. It’s a team approach. It’s not just like… Taking a photograph. It requires skill and interpretation. The full field ERG should never be done unless you’ve had a good clinical exam beforehand. And you have a specific question from that clinical exam. And I’ll say it again. A good ophthalmologist is better than excellent electrophysiology. Full field ERG is an ancillary test to help the clinician. It’s not a substitute for the clinician. It’s meaningless without clinical exam. And the way I’ve divided — the way I look at it, there are five general indications. One is if you have suspicious pigmentary changes in the retina. When you’re considering panretinal disease. Maculopathy, as I’ve said several times before. Because you don’t know if it’s isolated maculopathy, or panretinal dysfunction. And the pattern of the ERG can direct what the potential specific diagnosis is. Non-traumatic optic nerve pallor. Especially in children. Because pallor of the nerve could be a secondary finding from retinal dysfunction. Even if the multimodal imaging is normal. Unexplained abnormal vision. That’s not only visual acuity, but also photophobia. Or nyctalopia. That cannot be explained by the clinical exam. As well as infantile nystagmus. These are major indications. And final, quantitating and monitoring panretinal function. So this is my summary slide. And now let me go through the questions. Let me see… What are the questions here? I’ll take it in order here. Can ERG be a useful investigation for patients with visual field loss, especially if we are suspecting a functional visual loss? Well, the answer is yes and no. If you have functional… If you’re suspecting functional visual loss, electrophysiology can be very helpful. But full field ERG is not enough. Because somebody can have decreased visual acuity from a real reason, with a normal full field ERG. So when you’re suspecting functional visual loss in a patient, electrophysiology can be helpful. But we’re talking about things like pattern ERG, pattern VEP. Full field ERG might be helpful, but alone it’s not helpful, because, as I’ve said in the beginning, because the fovea, the visual acuity is a small part of the retina, and because the full field ERG is assessing the entire retina, full field ERG alone cannot assess decreased visual acuity. You need some of these other electrophysiology tests, and you can do it. But you shouldn’t be doing this unless you’re doing it on a regular basis. This should be done at a place that normally does electrophysiology. To do the proper tests, to tease out, regarding the visual field loss. Let’s see. What else do we have? Can you quickly summarize the other types of ERG besides full field ERG? Yeah. Well… Full field ERG is the big one. There’s also something called pattern ERG. Pattern ERG is assessing macular function. And ganglion cell function. There’s also something called multifocal ERG. Multifocal ERG assesses sections of the retina. It’s sectors of the retina. The thing about multifocal ERG and pattern ERG — those are assessing cone function. The full field ERG assesses all the retinal function. And of course, the majority of the retina is rods. But pattern ERG and multifocal ERG assess cone function. And it can be helpful in patients where you’re looking at the macula specifically. Or the optic nerve specifically. Or sections of retina. The one thing about those tests, though — you have to have the patient fixate relatively well, usually. Otherwise, if they’re not fixating well, your results are not as easy to interpret. The good thing about full field ERG is that you don’t require patient fixation. So to really dissect the different parts of the visual pathway, you need to do these different visual field tests, if you’re not sure what’s going on. The full field ERG is for assessing panretinal dysfunction. This is what we were concentrating on, in this talk. Could you reelaborate on the optic neuropathy? Well… I’ll just say that if a patient has optic nerve pallor, that does not automatically mean that it’s optic neuropathy. Because patients with retinal dysfunction can have secondary optic nerve pallor. And that may be — the multimodal imaging might be abnormal. But sometimes the multimodal imaging is normal. So that’s what I mean about the optic neuropathy. What I mean to say is that an optic nerve that looks pale seems to be from optic neuropathy. It often is. But it could be from panretinal dysfunction. The only way to know whether or not there’s panretinal dysfunction is by doing a full field ERG. Next question. Are full field ERG of different eye centers comparable? Well, this is the ISCEV standard. There is the International Society for Clinical Electrophysiology of Vision. ISCEV. You can find them on the internet. All of their protocols are available for free. And one of the major purposes of that organization is to set standards, so that across different centers and across different machines, results are comparable. If you don’t follow those standards, it becomes difficult to interpret from one center to the other. Are there any circadian changes in full field ERG findings? Great question. This is the purpose of the standards. Because we’ve put patients — we darkened our patients, and we use standardized flashes and everything like this… There’s no difference. Because we are standardizing everything. So the answer to the question is: When you follow the standards, no. There’s no difference. It’s all the same. That’s the purpose of the standards. To eliminate such variability. What are the normality values of amplitude and latency that you use in cones, rods, and mixed responses? This is something for the ERG lab to determine on their population. Every lab should have their own normal values. For their population. And use them when assessing new patients. So this is the job of the ERG lab, to standardize. Every lab should have their own values. Because there could be some differences from lab to lab. However, the wave forms should all be the same. Across all labs. And also the same question was asked about the flicker. Again, the normal values are to be standardized on the population of interest by the lab doing the test. How often can we use full field ERG for exams of progressive retinal diseases? Well, you know, the thing about the full field ERG is that it is a panretinal reading. So there are other tests that are better, when you’re looking for subtle findings. So in general, we’re not really using the full field ERG for follow-up of progressive retinal diseases, unless there’s a specific clinical question that’s looking to be answered. The reason we’re not — because once again, full field ERG is a gross reading of the retina. And there has to be significant panretinal change for there to be change in the reading. These patients also have absence of foveal pit or fovea plana? I’m not sure what that’s referring to. That might be referring to albinism. So… I’m not sure what that’s referring to. What is the best method to measure esophoria? Simple cover-alternate? Can the patient have dilated pupils? You shouldn’t be assessing it with dilated pupils. The best way to assess esophoria is with alternate cover tests. Alternate cover tests measures the complete latent and manifest strabismus. The cover-uncover test measures the manifest deviation. That’s a little bit off-topic. To summarize… Alternate cover test uncovers esophoria. Patients with headaches and esophoria should have a cycloplegic refraction to make sure they’re not latent hyperopes. Patients with macular problems in diabetes — do you consider doing an ERG? Well, we won’t do an ERG in patients with diabetes. You could probably get some interesting findings from oscillatory potentials. Something we didn’t discuss. But that’s more a research type thing. For clinical care of diabetic patients, there’s really no role in doing an ERG. In a non-traumatic optic nerve pallor, if you were allowed only one test, would you prefer ERG or VEP? Good question. The thing about the VEP, which we didn’t cover, is the VEP doesn’t localize. You could have foveal disease, macular disease, optic nerve disease, or theoretically even occipital disease, and affect the VEP. So in non-traumatic optic nerve pallor, I would prefer an ERG. Because that will tell me whether or not there’s a retinal contribution to the optic nerve pallor. If there’s no retinal contribution, typically you’re gonna have findings on multimodal imaging, showing loss of nerve fiber layer, that confirms you’re dealing with an optic neuropathy. Does wave form change with age? Could it improve? Wave form doesn’t really change that much with age. But it decreases, definitely. Latencies increase and wave forms decrease with time. You know, my wave forms are not the same wave forms that I had 20 years ago. It happens with time. And this is an important point, when you’re doing very young children. Because their wave forms and their amplitudes are less, to a certain point, until they reach a certain age. Then they’re normal, and then they decline again. So it is age dependent. I think we’re running out of time. I’m not sure how much more time we have. I’ll just answer this one. Do you operate strabismus with large angle in patients with stationary night blindness? Sure. I’ve done it many times. There’s no reason not to do strabismus surgery on these patients. And it is now 7:00. There are some more questions. But I think it’s time to end. Thank you very much. And maybe we can answer these questions — the remaining questions — in another way, online. Thanks again for your attention and the opportunity to participate in this webinar.