This lecture provides important updates on two public health topics:
Update on Malaria Retinopathy (Dr. Susan Lewallen)
- Be able to describe the 3 retinal features of malarial retinopathy;
- Know the significance of malaria retinopathy in the diagnosis of cerebral malaria.
Update on Global Elimination of Trachoma (Dr. Paul Courtright)
- Understand the SAFE strategy for the elimination of trachoma;
- Appreciate the magnitude of the Global Trachoma Mapping Project (largest infectious disease mapping exercise ever completed in the world;
- Understand that the global elimination of trachoma as a public health problem will be achieved in many countries of the world by the year 2020.
Lecturers: Dr. Paul Courtright & Dr. Susan Lewallen, co-founders of the Kilimanjaro Centre for Community Ophthalmology (KCCO)
(To translate please select your language to the right of this page)
DR LEWALLEN: Thank you for having us here today. I always love to talk about retinal and cerebral malaria. And I’m gonna give you a bit of an update. I don’t know how many of you are aware of the fact that there are retinal findings in cerebral malaria, which are actually rather important, I think. But I’m gonna try to… I may have talked about this in the past here, at UBC, but I’m gonna try to give an update anyway. I guess I just… Yeah. Okay. Before I start, I want to acknowledge many people who have made this work possible. Because what I’m gonna describe to you today actually has taken place over more than 25 years. And several of these people are actually from UBC. Their names are underlined up there. And I forgot to put Peter Nash’s name on there. And I see him glowering in the back. So Peter was also involved in this. And we couldn’t have done this work without lots of people. So why is malaria important? Well, there’s still 200 to 500 million cases a year. And it kills over a million people a year. Most of those are children in Sub-Saharan Africa. That’s where 90% of the deaths take place. Economically, it’s estimated it costs about $2 billion a year, the burden for malaria to the African economy. Only plasmodium falciparum causes life threatening infection. There’s other plasmodia that cause different types of malaria. But it’s only the P falciparum that causes the life threatening infection. And the way it does this is it invades red cells, and they become sticky and adhere to the walls of the vessels. Especially in the brain. So cerebral malaria is actually quite a difficult — or can be difficult to diagnose. Cerebral malaria is the most severe syndrome of malaria. And the diagnosis is difficult, because the clinical features of cerebral malaria are really variable, and they’re non-specific. Fever, lethargy, so there’s a broad differential diagnosis. And other diseases of course can coexist with malaria. And what really makes this difficult is that in endemic areas, at any time, if you went through and measured, 25% to 75% of the population might have asymptomatic infection. So a kid becomes comatose, goes into the hospital, they see has malaria parasites, and it’s assumed to be cerebral malaria, and it isn’t, necessarily. So before I talk to you about what’s new in cerebral malaria retinopathy, I think I’d better review what’s old in malaria retinopathy, in case you’ve missed out on this information. We lived in Malawi from 1990 to ’94. And one night, I was having dinner with Dr. Terry Taylor, who runs a really first class research project on malaria. And I asked her about cerebral malaria, and she was telling me about it, and I said: What do you see if you look in the fundus of these kids, the ocular fundus, of course. And she said… Well, nothing much. And I sort of cynically thought… Well, yeah? That’s what internists usually see when they try to look at the fundus. So I said… Could I look? Would you mind if I came in? I’ll bring my indirect ophthalmoscope and I’ll take a look and see what’s in there. So I started going in, and seeing these patients, these comatose kids, and I was absolutely gob smacked at what I found in the fundus. And it hadn’t ever been described before. So I wasn’t sure what the heck I was looking at. So I’m gonna run through… Well, this is 25, almost 30 years later. What we’ve done in those areas is we documented the findings — and this was very difficult. Because this started before there were such things as digital cameras. So getting photographs of this was really a challenge. We’ve described the histopathologic correlates of the findings. Demonstrated their clinical significance. And now what we still have to work hard on is changing the thinking of malaria researchers to use these findings effectively in their projects. So running through what we find in the retina… Is there a pointer up here? Oh. Okay. So the first finding is these white-centered hemorrhages, which are really common. About 60% of kids will have these. Second thing is what we call retinal whitening. If you look at this sort of fluffy appearance, this is perifoveal. And this is a mild case. There’s also a hemorrhage in there. But ignore that. And we just call this whitening. But it can occur in a wide spectrum of severity. Here’s a severe case, where you see a lot of this whitening around the fovea. And it’s always in a mosaic sort of pattern. It disappears completely if the child survives and wakes up. Here it is in the periphery. It’s not always in the macular area. You can see it outside the macula. And you can see those white sort of mosaic patterns there. Here it is, where the whitening has actually coalesced in some spots. So that’s a severe case. Sometimes all you have is one little point of it. So what is it? Well, over the years, we managed — the team managed to get fluorescein angiograms done. And so here’s the fluorescein that goes along with this. And you can see what it is. This is areas of capillary dropout and hypoxic retina. So it causes this white opacification, which disappears completely, as I said, with no visual sequelae that we’ve ever been able to demonstrate, if the child survives and wakes up, and then we can measure it later. And of course, the same process is going on in the brain. So then the second finding — or the third finding — is these abnormal vessels. And that’s all we call them, still, is abnormal vessels or discolored vessels. And you can see how bizarre this looks. Kind of a funny lamellar sort of flow pattern, looking in this vessel kind of orange. Here’s another one. This vessel is relatively normal, and all of a sudden it turns chalk white. And you can also see the capillary bed is delineated. So this is very bizarre. I mean, there’s nothing else that looks like this. I thought I was losing my mind when I was seeing it in these kids all the time. Because there were no descriptions of it at the time. Here’s another one. This is odd. You get white along the edge of the vessel, and you can also see — here’s white vessel. And again, the capillary bed is somewhat delineated. Here’s another one. Very strange. I mean, I wasn’t even paying attention to the hemorrhages anymore. I was so fascinated by vessels that looked like this. And these vessels here are sort of orange, when they shouldn’t be. Here’s another one. The abnormalities often just occur in segments of the vessel. Here it is red, and yet here it is white. So what is this? Now, this is work that Val White did, when I managed to get the eyes of these kids and bring them back. And this is a lovely flat mount that Val made, and then did a stain for hemoglobin. And what you can see here is: All those little brown dots, by the way, are the malaria parasites. Malaria parasites eat the hemoglobin in the red cells. So what you have here, for example, is a bunch of malaria parasites in this segment, but almost no hemoglobin. Here next to it is a segment that’s relatively well hemoglobinized. Here there’s hemoglobin along in the central core of the vessel, but along the edges of the vessel, where, remember, I said that the parasitized red cells tend to stick… There’s relatively less hemoglobin. So I think that that is a very good explanation for why you could get a vessel looking like this. Because it’s of course the red column of hemoglobin that makes the vessels look the way they do normally. Here’s another one of Val’s nice stains. And you can see here a central core of well hemoglobinized red cells, which are not parasitized, and then around the periphery, you’ve got these late stage schizonts, which have devoured all the hemoglobin. And again, I think that that — a vessel like that is a good explanation for this kind of clinical picture. So that was really satisfying to me, to be able to finally figure out what it was that we were looking at. In terms of the clinical significance of this, that required that we develop a grading scale for the severity. Because each of these signs — the hemorrhages, the whitening, and the abnormal vessels can occur in a wide spectrum of severity. So we developed a grading scale for each of the features of the malaria retinopathy. And were able to show that the retinal signs were associated with a risk of death. Now, when we could do this, then the malaria researchers actually started believing me. Because none of them could see what I was seeing. There weren’t any other ophthalmologists in Malawi at that time. But being able to show that these were associated with death was very important. Furthermore, the more severe each of these signs was, the higher is the risk of death in the children. And the retinal signs are also associated with some specific and laboratory indicators, like hematocrit and platelets. So if we look at the case fatality rates, and this is a group of children, all of whom would have been said to have cerebral malaria by the pediatricians and the internists. They’re all comatose. They’ve all got parasites, and are thought not to have any other causes of their coma. But if we divide them up according to their fundus signs, the kids with the normal fundus have a 7% fatality rate. This is over 15 years that we collected this data. So we have 900 children with cerebral malaria in this study. The children with malarial retinopathy that did not include papilledema, because some of the kids with malarial retinopathy also have papilledema… Their case fatality rate, 15%. 36% for the group that has malarial retinopathy with papilledema. And I think you can imagine how, if that retinal whitening is caused by hypoxia and swelling, and that same process is going on in the brain, the kids with the worst retinal whitening are the ones that get the papilledema. That makes sense, because the same process in the brain is leading to the papilledema. And then finally there’s this group, which is really a small group, but they have papilledema alone, and they have the highest case fatality rate of all. So the way I understand this is that in this group of children, all of whom supposedly have cerebral malaria, we have a group which I call group R. Retinopathy positive, who have hemorrhages, abnormal vessels, and retinal whitening, plus or minus papilledema. The mortality rate is about 19%, overall. And when we’ve been able to do autopsies on these children, indeed we find cerebral sequestration of the parasitized red cells, hemorrhages, and fibrin thrombi, which is what’s causing those white-centered hemorrhages in the retina. They have a coagulopathy going on, and local areas of tissue hypoxia, secondary to hypoperfusion and anemia. Group N, as I call them, the group that are retinopathy negative, most of those kids actually survive and wake up very quickly. And we think maybe they have a… I’m gonna say mild case of cerebral malaria. Or maybe it’s just a prolonged postictal state. And they are being treated for malaria, but they invariably will do very well. Although there are 7% of those who die, as I said. Now, amongst those 7% with a normal fundus who die, of the ones we’ve been able to autopsy, they have always had a different cause of death. It wasn’t malaria at all that was causing them to have coma. They had incidental parasitemia. And what we’ve actually learned from the autopsy study is, amongst children who die with cerebral malaria, about 25% of them don’t have cerebral malaria when we can autopsy them. And that 25% can be identified because of the fundus signs. They should have been — if the fundus signs had been looked for, and people had realized this wasn’t cerebral malaria, perhaps they could have treated these children for something else, because it wasn’t cerebral malaria. The final group, group P, which is just papilledema, is false cerebral malaria too. They don’t have any malaria retinopathy. The mortality is very high in this group. It’s a small group, as I said, and they have multiple pathologies. When we’ve autopsied these children, they also have no sequestration of parasitized red cells. Just a bunch of different causes of death in these kids. Incidental parasitemia. So to summarize that, children with clinical “cerebral malaria” are actually a heterogeneous group, and they’re best differentiated by looking at the fundus. Now, this is important, because older studies of both treatment and pathophysiology of cerebral malaria didn’t take this into account. And there’s been a lot of conflicting and unreproducible results. Now requiring fundus signs as a criteria for a case definition allowed the team in 2015 to demonstrate that brain swelling is actually the key predictor of death in cerebral malaria. This is important, because 25 or 30 years ago, there was a big study in Kenya that, when they assumed brain swelling was the problem, and they were trying to treat it, and they had terrible results, and they quit doing it anymore… But that’s because they probably had a group of kids with a whole lot of different pathologies in their study. So right now, in Malawi, the current research that’s going on is focusing on treating brain swelling, but this time we’re only treating the kids who really have cerebral malaria. So a big question for me has always been: How are we gonna ensure that these fundus signs are used for accurate diagnosis, when we don’t have ophthalmologists in malaria research projects? And our experiences trying to teach the non-ophthalmologists to examine the fundus have really been very discouraging indeed. So what are we gonna do about that? This is the what’s new part. A small group in Albuquerque, New Mexico, has developed an algorithm now that can, with high quality photographs, specificity of 100%, sensitivity of 95%, at identifying malaria retinopathy, using photographs. So their first studies… Well, this is an example of what their algorithm — here’s a case with all the findings. And their algorithm will make a picture like this. I didn’t think they’d be able to do this, because even when you’re examining these kids clinically, it can be hard to tell the whitening from just reflections off the internal limiting membrane. I was amazed that they could do this with a computer and be as accurate as they were. But they are. They have done it. It’s a pretty impressive algorithm. Their first work was with a Topcon desktop camera, which is of course really expensive. And had to be modified in all sorts of ways, in order to accommodate a comatose child. Last year, they managed to do this using the Pictor Plus portable camera with the software. To get the picture of the fundus, and then it transmits the images to a tablet, and the software is in there, and it can generate a patient record and say whether there’s malaria retinopathy or not. And this next year, they’ll be working using the iNview camera, which can work with an Apple… Whatever it is, iPhone. So they’ll be integrating the software into the iPhone. Because this iNview camera is now around $1,000 or so. So that makes this possible to use in research projects, in Sub-Saharan Africa. So take home message here: Malaria retinopathy is a unique entity, consists of the three retinal signs that we’ve looked at. It’s the best way to accurately diagnose cerebral malaria, and the best predictor, actually, of outcome in patients with cerebral malaria. The new imaging techniques that are coming on will allow non-ophthalmologists now to identify it, and ought to enhance research that’s still being done to try to understand cerebral malaria and find better treatments for it. So that’s it. Thank you.
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Update on Malaria Retinopathy (Dr. Susan Lewallen)
May 4, 2018