 Anybody that doesn't know me, I'm Laura Hansen. I'm working with the neurophthalmologist. So I'm going to talk about a 69-year-old guy that I saw in clinic a couple of months ago now. He presented with vision changes that have been going on for one month in the right eye. His description was a light show and cloudiness that seemed to be present constantly, but wasn't bad enough that he was paying attention to it all the time. And over the past week or two, he'd noticed some missing areas of vision. And he really liked to play golf, and he was having a harder time finding the ball after he would hit it. He didn't have any pain and had no headache and no symptoms at all of jaw claudication. He had had a couple of episodes of what probably would be described as a transient visual obscuration in that eye, but no other symptoms of elevated intracurneal pressure. He did snore, but had recently been evaluated with a sleep study and did not have sleep apnea. So this is his past medical history. He did have significant coronary artery disease and had an urgent three-vessel cabbage about 10 years ago and then had a few pre-cancerous lesions removed from his skin. He was married. He's the retired director of engineering for a hospital. He would have a couple of beers per week, but no recreational drug use. Those are his medications there. At the bottom, he was on prednisone 60 milligrams daily when I saw him, and I'll talk a little bit more about that. So he had been seen by a regular eye doctor about two weeks prior to presentation. His family doctor had ordered an ESR and CRP for the vision changes. The ESR was 45, the CRP was 6.2. He had an MRI of the brain done with contrast. In the interest of time, I'm not going to post it, but you'll just have to believe me that it was normal. He was started on steroids, the prednisone 60 milligrams, and scheduled for a temporal artery biopsy and then sent to neuroethymology. So his acuity was 20-20 in both eyes. I could not find an afferent pupillary defect, but his pupils were minimally reactive, so do with that what you will. His motility was full and he was orthophoric. Color vision was full, excuse me, confrontational fields were full. Color vision was slightly decreased in the right eye. Pressures were normal. So his slutlamp and dilated fundus examination were unremarkable other than what I called stage one to two optic discidema in the right eye. There were no disc hemorrhages. These are disc photographs of the right and left eye, so you can kind of appreciate it. It's relatively mild discidema there. The disc is a little bit hybremic. These are his visual fields. This is a fluorescein angiogram. Again, I'm not gonna go through all of the images because I don't have enough time, but this is at 22 seconds. He did have normal arm to retina time, normal AB transit. I picked this image because I thought it kind of nicely showed some delayed filling of the optic nerve head there. That's at 32 seconds, there's a little bit more filling. That's after a couple of minutes, so it was really all I found on the fluorescein. So just ask everybody to think for a second about what your differential would be for someone with discidema who still has very preserved visual function. And I put up a list here. So these are the things that we typically think about at the top, I put diabetic papillitis because it's probably the most common hypertension. You can do the same thing. Papillodema, patients will usually have preserved function, but I would expect it to be in both eyes, although it's pretty mild, so it could be early. That's so much the rest of the list there. But what about the high ESR and CRP? So I used a trick that I learned during residency. If you don't really know what's going on, then you ask the patient, how's the rest of you? Have to do the hand motion, and I think it is a good trick and it does work. So then he told me, well, you know, actually back in May I did have this weird rash and there were these small, flat red spots and then there were some itchy pimples. So he saw dermatology, they did a biopsy, and it came back purocaritosis, which is a benign lesion that's kind of like a hyperkeratotic thing. And so the dermatologist's assessment was that she had just kind of inadvertently biopsied this lesion within the rest of the rash, and it wasn't really giving an answer, but she thought it was pediarysis. So she did do some lab work up. His creatinine was elevated and apparently has been that way for years, and he didn't really know why and wasn't really aware of it. His ESR back then was 73 and 23.3, and then she also did an RPR, which was non-reactive. And then he said, also I have this lesion on my tongue back in January and the gum next to the lesion receded significantly, but his dentist didn't really know what it was and then it went away. He didn't have any genital ulcers. He was having night sweats and then he related that he actually did have an unprotected sexual encounter with another male in December. So this was the work up that I decided to do, and I thought we would repeat the sleep study and do a lumbar puncture if none of these provided an answer, and he was scheduled for the TA biopsy, so I thought, okay, go ahead and do it. But then this is how his labs came back. So the rest of the labs were fine. His RPR was reactive with a high titer. His FDA absorption test was reactive. His quantifier in gold was also positive, and it does look like he probably has diabetes. He did have a chest X-ray that was negative. So I canceled the TA biopsy and I had him do a lumbar puncture and he had slightly elevated white blood cells. His protein was okay. The glucose was actually maybe a little bit low. The CSF VDRL was negative and cytology was negative. So I had IDCM and they started him on two weeks of continuous penicillin, 24 million units a day for syphilis. I thought that he would need to stop the steroids immediately, but they actually continued him on the steroids for the first three days because they were worried about a Jerich-Herxheimer reaction, and they felt like the quantifier in gold was probably a false positive, and I guess they're gonna retest it in a month or two here. So I'm not gonna talk a lot about ocular and neuro-syphilis. I'll just talk a little bit about it, but what I really wanted to focus on was more of the details about laboratory testing because I think we don't really review that very often, and in this case it was kind of a critical piece of the puzzle, so. Syphilis is caused by the spirochete, trepanema pallidum. Ocular syphilis in particular is considered a secondary syphilis and also a neuro-syphilis. So apart from what you do for the eye itself, you do treat it the same as neuro-syphilis. The manifestations, as everybody knows, are many and varied. Specifically, with the optic nerve, you can have inflammatory edema, neural retinitis, atrophy, or an optic nerve gumma, so an actual lesion on the nerve head. Neuro-syphilis can occur during any stage of syphilis, not just tertiary, and it's kind of divided into early and late neuro-syphilis. So early neuro-syphilis is when the involvement happens within months to a few years after the primary infection. Late neuro-syphilis happens years to decades later, and they tend to have different manifestations. So in early neuro-syphilis, they usually affects the meninges and the blood vessels, and you often get cranial nerve abnormalities, especially with two, seven, and eight. You can get arthritis of the vessels of the brain and spinal cord, so they can end up with big strokes. Late neuro-syphilis is kind of the typical one that we think of. That is part of tertiary syphilis, and that's the syphilitic dementia, the tabi-storcellus, and often it'll mimic psychiatric issues. So the diagnosis of neuro-syphilis's diagnosis is based on your clinical judgment, the CSF findings in the serologic testing that you do. The typical CSF finding would be that you have elevated white blood cells, usually with a lymphocytic predominance, usually it's 10 or more. They may have increased protein, and the serologic testing that you do may or may not be positive, so it's a really non-specific test. This is a graph that I took from the Utah Health Department. So there's been increasing rates of syphilis in the U.S. since 2000, so the top line is the U.S., the bottom line is Utah. So although the rates are less here, it is still going up, and this shows the disparity of infection rates between males and females in Utah. So that's just kind of something to keep in mind when you're seeing patients. You cannot culture trepanema in vivo, and so you have to use either one of the direct diagnostic methods or the indirect diagnostic methods. The direct methods require a tissue sample, either fluid or scraping from a lesion. You can do dark field microscopy, you can do histologic analysis or PCR testing, but they have to have a lesion. First of all, usually it also has to be moist, and so for most people it's not diagnosed that way. Most people use the indirect diagnostic methods where you test for antibodies. The non-trepanema tests, the RPR, VDRL, and then a couple of others that are used less common, they measure the level of antifospholipid antibodies. So those are formed when the host cells are damaged by the syphilis, and sometimes it'll respond to the lipid on the surface of the trepaneme, which is pretty non-specific. The trepanema tests are the FTA-ABS, the fluorescent trepanema antibody absorption test, the TPPA, which is the trepanema pallidum, particle aglubination, and then the others I'll talk a little bit more about in a minute, but those measure antibodies that are reacting to an antigen from the trepaneme itself. So you use the non-trepanema tests, like RPR and VDRL, for screening, monitoring how well they're responding to treatment, and detecting a reinfection. The VDRL is the only one that you can use to test the CSF because of its sensitivity and specificity profile, and even then the sensitivity is only 30 to 70%. So the primary limitations are that the sensitivity and specificity goes down by quite a bit in primary and late syphilis. You can also get a fair number of false positives. You know, you can imagine it's pretty, there's a lot of things that could give you that kind of reaction, and you can get false negatives from something called a pros and reaction. So that is something that happens when the antibody tighter in the plasma is really high. So the way that they do, like the RPR, they have a little card and they mix your serum, or plasma with like these antigens that are kind of bound with these little charcoal particles. And it forms this antibody antigen lattice, and then it kind of precipitates out and they see a color. But if you have really high antibody titers, then it kind of messes with the balance there and it looks like it's negative. This is a nice chart showing how the sensitivity changes in the different stages. So you can see that the VDRL and RPR drop significantly in primary and late. I put a list up of some and not even all of the things that can give you a false positive with the non-treponymol tests. So the treponymol tests like the FTA, ABS, they will remain reactive for years. There may be a lifetime, whether or not you have treatment, and so they correlate poorly with disease activity. So right now they're primarily used as confirmatory tests unless it's somebody for instance who has a negative RPR but you're suspicious for syphilis. They tend to be more expensive than the screening tests. The TPPA, the predecessor for that is the microheumagglutination assay, the MHATP, which isn't really used anymore. They took in the MHATP, they have the antigen bound to erythrocytes. In the TPPA they've changed it to gelatin particles so that there's kind of less abnormal reactions with the plasma to the erythrocytes. So this is the list of the ones that are out there right now. The newer ones are the enzyme immuno-assays, the trap check and trap shore, and the chemiluminescence immuno-assays. The advantage of those is that they're fully automated so in higher volume situations they offer higher throughput and less cost and because they're fully automated there is no manual pipetting by a technician so it kind of decreases the occupational hazard for them. But they do have a higher sensitivity but a lower specificity than the FTA and TPPA. This is from that same paper and kind of gives a nice way to interpret the test results when you do a non-treponemone or traponemol test. The traponemol test don't have any way to differentiate between syphilis and then the non-sexually transmitted or endemic types of spirochete or traponemol infections, the yazar pinta. If you have a positive RPR and a negative FTA then that was a false positive RPR. If the RPR is negative and the FTA is positive then it's either primary or latent syphilis or they've already been treated or you had a prozone reaction for that RPR and if they're both negative then it's either no syphilis or really early syphilis and you'd have to recheck. So I think my suspicion is that my patient had a prozone reaction with his RPR. That most commonly happens during the secondary stage of syphilis and most labs don't routinely test for that phenomenon so if you're suspicious for it you can ask them to dilute the sample down and retest and then it would come or should come back positive but I don't think anyone was aware of that so. There is a new paradigm of diagnostic testing that the CDC is endorsing and they're calling it reverse sequence testing so you use either the EIA or CIA test as the screening test and if that comes back positive you reflex to the RPR to confirm active infection so it's designed to catch more of those early late or latent syphilis cases and if there are any discordant results like if your EIA is positive but the RPR is negative then you do the confirmatory testing with the TPPA it has higher specificity than an FTA ABS so it must be that one but so they're kind of advocating that people change how they test for syphilis. Okay, that's all. Any questions? You mentioned HIV testing with Yamazi. Sorry, I did test him for that, it was negative. That's actually a really good point and you should test for HIV and anybody that you're suspicious about syphilis. That is the main reason for not testing all RPR and the EIA at the same time is simply a matter of not over testing. Mm-hmm, yep. Do we have EIA here? I don't know, do I need that?