 Welcome to Grand Rounds this morning. So this morning, Dr. Byrd, she's one of our interns who's going to present a case. So she's just wrapping up her time with us. She's done a phenomenal job or we're really happy that she's in our program. Unfortunately for her, the recurring nightmare that I still have and wake up from every few weeks of being on medicine rounds is coming true for her this next week. So she's going to leave us for four months and then she'll be back and be ready to go. So she's going to present ocular manifestations of arthropod vector-borne diseases. Thanks, Trent. So this case was one that was seen in continuity clinic with Dr. Petty and Jim Bell. They're both not here today, but we'll get started. So the patient first came to ophthalmology from an ER consult. She is a 30-year-old female and her chief complaint at the time were these spots in her superior temporal field of vision in the right eye. She didn't say that they were floating. They stayed in the same place, moved with her vision and were new. She hadn't had any flashes, hadn't had these symptoms before. Her HPI, so significant, was that she had just returned from a trip to Bali. She had been there for two weeks. She had been home for about a week and two days after returning home, developed these kind of nonspecific symptoms, fevers, night sweats, diarrhea, nausea, vomiting, had severe headaches. She had this rash that started as a red papule with some, a slight dome shape on her arm, myalgias, arthralgias. She had right upper quadrant pain. Her primary care doctor and infectious disease had already seen her and worked her up and she was found to have thrombocytopenia, elevated ALT, elevated AST. While she was there in talking to her about her exposures, she had gotten scratched by a dog, didn't bite her, but she thought it looked ill. It wasn't acting aggressive. She wasn't really traveling in an area where she needed malaria prophylaxis, so she wasn't taking any. She had remembered getting four insect bites, but that was it. And then she did say she was involved in a native ceremony that involved drinking some fresh water. I don't know the details about that though. So, her past medical history, she's really otherwise pretty healthy, has some anxiety, hyperlipidemia. She's on citalopram, lives in Salt Lake City. Nothing, you know, she's pretty healthy, 30-year-old female, no past ocular history. So, on her visual exam in the emergency room, her vision, 2020, things looked pretty normal, normal pressure, and really the only abnormal finding at this time was mild inflammation in the interior chamber in bullfies. Hadn't had this before, like I said, no systemic diseases that we were aware of. Fund this exam was normal to some rare cell in the vitreous. And so, at this time, infectious disease, as I mentioned, had already seen her and her primary care doctor, and their leading diagnosis was Dengue. They felt like her symptoms and the area that she had traveled to would be most consistent with Dengue. They had gotten the antibodies for Dengue, IgM, and IgG, and they had come back slightly elevated, but inconclusive given the time frame, and I'll talk a little bit more about that. But the other diseases that were kind of on their differential are listed here as well, and they had started to get a kind of a fairly large lab work out to determine what she had. But at this time, from ophthalmology standpoint, mild inflammation in the anterior chamber didn't seem very likely to be from Dengue. Wanted to rule out some other uveic entities. She was started on pred forte and instructed to return to continuity clinic in about a week for follow up. So when she returned, she was still having the same symptoms, these spots, non-moving, not floating, no flashes. She was still systemically ill, having fevers, night sweats, abdominal pain, all the GI symptoms. She, an infectious disease, everyone thought she had Dengue. She basically said, I have basically been diagnosed with Dengue. So no changes in kind of the leading diagnosis at that time. But when she came back, she had a little bit of cell after being on pred forte, and then in her fundus exam, it was noted that she had these small, flat, white retinal lesions, prominent in the midperforal retina, and they were found in both eyes. So you can see a picture, and they're subtle, but you can, there's the, you know, you can see here these kind of, there's white, flat retinal lesions. We got fundus auto fluorescence and just showed some hypo fluorescence in the corresponding areas. Again, it's very subtle, nothing too drastic on fundus exam. The other eye also had the same white, small, flat, hypo-pigmented lesions in the periphery. So at this point, and then, sorry, and an OCT showed some thickening in the nerve fiber layer in the areas associated with retinal whitening. So in looking back at all of her work up this far, she had gotten fairly large work up and things had all been negative. The two kind of remaining diagnoses are dengue and rickettsia typhi. Dengue, IgM, IgG were slightly elevated. It's too soon for them to be significantly elevated in the course of dengue. So that's what I was saying, eye infectious disease still thought that that was highly likely. Rickettsia typhi, they had gotten this lab a little bit later in their work up, so it's still pending. And it was also thought that since dengue could, is in the flavivirus family, that it could, the slight elevation could indicate another flavivirus infection, such as West Nile virus. From the ophthalmology standpoint, those white retinal lesions, we thought maybe they could be cotton wool spots she'd been throwing beside a penis and had fevers. Didn't really, you know, they weren't, like I said, very drastic findings. And given her history, birdshot retinocoroid orthopathy was less likely, but just something that could have been, hadn't she not had this extensive travel history in this bilateral presentation? So right now I'm gonna go through kind of the differential of dengue, typhoid, and West Nile virus and talk about some ocular findings that have been discussed and kind of relate it back to our patients and see what we can come up with. So West Nile virus is a single-stranded RNA flavivirus. It's transmitted by mosquito. It has a wide distribution in Africa, Europe, Australia, and Asia. It's gotten some publicity recently for arriving in the U.S. No one's really sure exactly how it got here. They think they found the same strain, I think, in Israel, but the first case in the U.S. was in 1999. The transmission cycle is from the host, the hosts are birds. Mosquitoes are the maintenance vectors and so in the bird mosquito cycle until an infected mosquito infects an incidental host and they actually infect horses a lot. They're most common and then humans. Once a human gets West Nile, they can do direct transmission from human to human. Lots of different modalities for this have been described, blood transfusions, organ transplants, transplacental transmission. There was one case of conjunctival transmission. Systemic disease in West Nile virus, non-severe is very non-specific. Fever, headaches, nausea, vomiting, diarrhea, weakness, arthritis, the severe neurologic disease can be seen and elderly diabetics seem to be more at risk and have encephalitis, meningitis, altered mental status. So systemic findings aren't really that helpful because they are non-specific and similar to all these kind of viral diseases. So some of the ocular manifestations of West Nile virus that have been described are choreo-retinitis, the anterior ubiitis, vasculitis, optic neuritis, not commonly, but there's been cases of congenital, choreo-retinal scarring. So lots of these. What do you mean by congenital? So if it's transmitted transplantally and then they'll have what they think is from West Nile? Yeah, exactly. And most cases that are reported are single cases or a collection of cases, but there are a few larger studies and kind of interesting to look at. So the group in Tunisia did a prospective study with 29 serologically confirmed West Nile cases with neurological symptoms, which could be anywhere from a headache to meningitis. These patients didn't have ocular symptoms to be included in this study, which is an interesting difference in all these studies because they do find very different ocular findings based on symptoms, which isn't surprising, but the most kind of specific and common finding is this multifocal choreo-retinitis. It was seen in 69% of the cases. Intra-retinal hemorrhages are very common as well, and here was just the list of other things that they found, but retinal disease or retinal vascular disease, vascular leakage, a few cases of optic disswelling, but in the 29 cases, 20% didn't have findings. So the majority did have some findings when you did a full exam. Another group that did a retrospective case study on 14 eyes with patients who had known ocular involvement, so symptomatic, and they had presented with that. Again, these multifocal choreo-retinal target lesions were most commonly seen in 85% of the cases. It can present in many different ways as we see. There's a huge range of cases that have been reported with various ocular findings, and of note, in these 14 eyes, 71% of them were diabetic, and throughout the literature, it does seem that diabetic patients are much more at risk for having complications from West Nile. This was another interesting study just in the inclusion criteria. 52 patients in India in the R-R-Vin UVitis Clinic who presented with inflammation, they included them if they had a history of a preceding fever, and out of 52 of those patients, 37 of them, when they did the serology for West Nile, were positive for West Nile virus, and they described the first cases of neural retinitis, and they saw retinal hemorrhages, arteritis, similar findings, but the new neural retinitis hadn't been described before. So here's a funnestoto of some of the deep active choreo-retinal lesions, and you can notice they're in this kind of linear pattern, and then you see the inactive focal choreo-retinitis, and on FA, when the lesions are inactive, they have the peripheral hyperfluorescence and central hypofluorescence, and the cases that have been reported all seem to have this linear distribution of the lesions appearing like they are spreading out or being spread contiguously along the nerve fiber layer. So looking at pathogenesis, how this is happening, not clearly understood, patients who are getting infected or have peripheral inoculation by the virus seems that the virus replicates in the skin longer-hunger dendritic cells that then migrate to lymph nodes, byremia occurred, and organ seeding, but how the virus gets to the CNS is unclear at this time. There's many ways that have been positive, but it does gain access, and then choreo-retinitis is thought to be from direct cell damage by the virus, and then a secondary damage from host inflammatory response to the virus, and it's also thought that this, the presence of the West Nile virus induces a multifocal granulominox choreo-retinitis, and in the patients, they all seem to, once they're presenting, they have these findings, so it's early in the course of the disease that they seem to develop the choreo-retinitis, and a lot of the times, by the time they were seen, they had the inactive lesions. A good news is that the ocular involvement was self-limited in most of the cases. If you have some of these complications, like a foveal scar, choroidoneovascularization, they're reported to have visual impairment, but for the most cases, they do resolve on their own, and treatment for West Nile is supportive at this time, so patients do fairly well. All right. The next disease that we're gonna talk about is Dengue fever. This is another virus that's transmitted by mosquito. It's in the Flavivirus family. This is a disease that's getting a lot of recognition currently just the epidemics are increasing exponentially, and mosquito control is becoming a large focus for a lot of international health movements. So the mosquito transmits it from primates in this cycle, primate to primate through mosquito, and then mosquito will go to a human, and once the human's infected, it's just human to human transmission via a mosquito vector, which demonstrates why when you have these epidemics, it's really important to have mosquito control, and the more mosquitoes, the more it can just spread. Symptoms for Dengue, again, these kind of non-specific fevers, headache, myalgias, arthralgias, and GI pain, or GI symptoms, a rash, the most severe form of Dengue would be Dengue hemorrhagic fever syndrome. This occurs with increased capillary permeability, and it can develop into Dengue shock syndrome, and can be really detrimental for the patients and have a high morbidity and mortality. Our patient definitely didn't have Dengue hemorrhagic fever syndrome, but certainly did fit in these symptoms, non-specific symptoms of viral infection. Incubations, three to 14 days, again, that seemed reasonable with her presentation. The most common ocular symptoms that patients have described is acute sudden decrease in vision, central scatoma, floaters, and usually the findings are bilateral and asymmetric. So, looking at some of the larger studies that have been done with Dengue, there was a prospective study with 134 patients who had known Dengue in East India, and they were hospitalized. So, they didn't necessarily have vision complaints, but out of, actually, none of them had vision complaints, and 40% of them still had ocular findings. Subconjunctival hemorrhage and retinal hemorrhages were common in these patients, but it's important to keep in mind that this was a group selected without real, there was a group that didn't have ocular findings and is a little different when you look at cases that did have visual complaints. So, this is another study retrospective with 13 cases, and they did have visual complaints, and most commonly found in these 13 cases was macular edema, but they saw macular hemorrhage, vasculitis, some continual spots. We can see here a picture of a patient with Dengue, and this patient presented with blurring in vision had intra-retinal hemorrhages, continual spots, macular edema. So, significant findings on fundus. There's also been reported foveolitis related to Dengue, not commonly, but you can see it in the left eye there, the yellow lesion surrounding the fovea and on OCT this would be thickening the retina and the RPA around the fovea. The pathogenesis for Dengue is also unknown, but there's a few theories in terms of the ocular manifestations. It's thought that the Dengue virus has this non-structural protein one and antibodies that we produce against it can cross-react with platelets and endothelial cells. So, problem with this theory is that the antibodies for NS1 would stay around in your body much longer than the actual symptoms and the presentation of the disease is seen. So, clearly a piece missing, but the other thought is possible direct viral invasion, but when they've gotten pathology samples, there's no signs of viral invasion and no signs that there had been or any changes related to it. So, a lot is really unknown. They've shown that there's a lot of increase in cytokine production and inflammatory markers, but the actual pathway for why this is happening has not been shown yet. So, the diagnosis of Dengue is related to the timeframe in which the patient presents. There's two stages, stage one, the patient has fever and viremia and the NS1 antigen in the blood. And not unlike many other diseases, you can't detect the elevated IgM and IgG until a few weeks later when they're in stage two. And so in our patient, basically, she had been tested for IgM and IgG elevation for Dengue, but she was in stage one of the disease, had was acutely fibril with possible viremia, this is what she had. So, she had needed to wait a few weeks to have the elevated IgM and IgG detected. Treatment for Dengue, like these other viruses, is supportive, but again, it's a good prognosis for patients with ocular findings and the rare cases of patients who had optic neuritis and maculopathy did have some permanent impairment, but for the most part, the lesions all resolved and the patients had normal vision after the course of the disease. And the last group of diseases I'm gonna talk about are the rickettsias. This is a, the group has a wide range of various diseases, but they're small, aerobic, pleomorphic, gram-negative bacteria. They can be broken down into two groups, the spotted fever group, which we list, there's a lot of different varieties, but most well-known is Rocky Mountain spotted fever, and then the typhus group. So there's epidemic typhus, marine typhus, and scrub typhus. So, our patient was thought to possibly have marine typhus endemic, so rickettsia typhi. Most of these diseases are transmitted by ticks. There's a few exceptions. Rickettsia typhi is one of those exceptions. Please transmit it. So please transmit it from, or we'll get infected from rats with rickettsia typhi. They will, the fleas will then spread it to various hosts and it can be a wide variety, humans, cats, dogs, rats, and the cycle would continue. So humans are incidental hosts. The way that the fleas do infect people, when they are biting humans or any animals, they actually leave some feces, and so an open lesion that feces get in can infect people. Right now, it's pretty good for early morning. So don't, yeah, not a great way to get infected, but that's how the transmission does occur. Epidemiology is very hard to find specific incidence rates because a lot of these are pretty nonspecific and it's thought that this is underdiagnosed, but it's an urban setting, coastal ports with lots of rats, makes sense, with the increasing incidence of insecticides. It's been declining, but in other countries, it is common and most cases from the U.S. have been reported in Texas, California, and Hawaii, and just as an example for how much it's probably underdiagnosed, there was a group in Texas that took about 500 children and out of those 500 children, about 13% of them had positive IgM and IgG for rickettsia typhi. So that's just a small sampling of kids. It's likely that many people have had this as a just a nonspecific viral infection in the past, and it doesn't come to the attention of healthcare providers. Systemic symptoms, pretty much the same as all the others, but headaches, high-grade fevers, rash, predominantly on the trunk. Myalgias, arthralgias, somnazia, and vomiting. And there's been, for the various rickettsia diseases, there's been a lot of different, and a wide variety of ocular findings reported, and here's just a list of some of them, but anything ranging from AION to endogenous endophthalminus. That was only one case that I saw of endophthalminus, but wide variety. The rickettsia typhi is mostly reported in the literature as single case studies. There was one group that I found that did, and this group in Tunisia did a few of these vector-borne diseases studies, but they took nine patients, prospectively looked at them. They had serologically confirmed cases, and they underwent full examination. So out of the eight, or sorry, out of the nine patients, eight of them had ocular involvement related to marine typhus, so high amount. And three had symptoms, five didn't have symptoms. Vitreous inflammation was present in about half of the eyes, and these white retinal lesions were present in half of the eyes. The authors thought that the lesions they saw were from inner retinitis versus rickettsial duplication and deposition of immune complexes and inflammatory cells in the site of infection. The question again came up, if this is cotton wool spots versus another mechanism, but the distribution that the authors saw, they thought were less likely to be cotton wool spots. They saw a few retinal hemorrhages, and two eyes had optic disc swelling, and one patient did have optic neuritis. So I think it just demonstrates you can really see a lot of different and wide variety of findings, but here's one of the patients that they reported and has these kind of small white retinal lesions, flat, but not the most impressive and obvious. And here's another picture of the small white retinal lesions with the arrow. The similar lesions have been reported in a variety of the rickettsial diseases, Rocky Mountain spotted fever, Queensland typhus, and then marine typhus. In this study, the findings were all self-limited and they disappeared with eight weeks. The patients were treated with antibiotics, so they had gotten treatment, and rickettsia you do treat with tetracyclins versus the other viral diseases where there's really no specific therapy. So most of the patients had fever 10 days prior to their presentation when they were bound to have rickettsia typhi. Pathogenicity of rickettsia, rickettsial bacteria invade endothelial cells. Once they invade the cells, they escape the phagosomes and can replicate in the host site of plasma and kind of spread from there. They do specifically target endothelial cells with blood vessels, distract the adherence junctions between infected cells and can increase microvascular permeability. So back to our patients. She had follow-up in three weeks and in that time her lab results did come back and she was positive for IgM and IgEG, rickettsia typhi. She was started on her doxycycline course and when she came back her symptoms had completely resolved and her fundus photo had none of those white retinal lesions that had completely resolved. So, you know, in her it probably would have resolved without the treatment. She was just systemically sick for a while and infectious disease was late to actually even look for rickettsia typhi but I think it's in the case just shows even here in Salt Lake City in Utah there's still these kind of obscured other diseases that we can think about but looking at her fundus findings, initially her findings were consistent with rickettsia typhi from the beginning and not Dengue and not West Nile or the others but there are reports in literature. So, just another interesting one to keep in the back of our minds and it is in the U.S. barely prevalent especially in Coastal area. Thank you guys. Thank you. Thank you all with Dengue. Friends who've had it say that you're so sick. Devastating. Which is similar to horses, yeah. Yeah, right. And all of these are getting more looked at as their incidence is increasing and we're seeing it around the world more and people are looking for the serology markers whereas before you couldn't really look at them as well and find these collections of patients as well. Now we used to think of West Nile with the reaction. Right, right. And the elderly, diabetic, those have been the groups but it can be really devastating. So now that's right, now that's in bird. Watch out for it. That's what it appears to be. Yeah, I think so. Huh? Right. Right. And they resolved completely when she had resolved retinal findings. And the patients that they have reported with these white retinal lesions for the various rickettsial diseases, they have these, they say sometimes it seems to be that presentation and then resolution once their ocular findings are resolved. Yeah. So that was in our patient, the OCT findings. I didn't, yeah. The rickettsia typhi, yeah. And that was, unclear from our perspective at first with you know, cotton wool spots versus some we didn't know exactly what infection was going on in but they have found these inner retinal lesions in the case reports of it. Yeah. It seems that FA was used in a little, at least from West Nile versus the rickettsia typhi. FA seemed to be more helpful in differentiating but OCT could be used because you wouldn't really expect to see any nerve fibulae, I think. Yeah. It just was, at that time in the clinic, we just, I don't know. Just one of those things. We didn't do it at that time. And I think you're not, you're not powerful. I'm good. You've done a lot of it. I've had no problem with it. I didn't have any burning at the injection site and our nurses are very good. You extrapolate it. It's got a pH of eight. I would say anecdotes pay floors to your patients who are licensed to it. Patients who feel you can steal. Patients, some patients will walk in their room at their sleep as they walk in. It just doesn't bother them that much. But the nausea is real and there's nothing we can give. There's no way to treat it. It's the first time they hate it and it says it's time for it. But if a patient's very ill. If a patient was still sick. You know, and she wasn't, and she was convinced she had dengue and didn't, I don't know. She just wasn't really wanting to do that at that time. But probably would have been nice to have that information. Thank you guys. Thank you. I'm excited to come back in four months. Thank you. Yeah, thank you so much. Thank you. I'm excited.