 All right, so for those who don't know me, my name is Jim Bell, and we can go on and get started with the second part of today, and I was going to present a young boy that I saw as a consult on the pediatric ophthalmology service, so we'll go on and dive right in. This was an eight-year-old, previously healthy boy who came to the primary children's ER with complaints of malaise, fever, sore throat, and a stiff neck. He just wasn't feeling good in general. He had been seen by his pediatrician a few days before. We don't have too much in the way of records of what happened that day, but he did have a rapid strep test that day and ended up being diagnosed with otitis media with a cephalosporin started. Needless to say, he did end up in the ER, so he didn't feel completely better. He started feeling a lot worse. His main symptom was fatigue, and even when I saw him, which wasn't for a few days, this was still the main thing that he was complaining of. He just kept talking about how tired he was. But he also had vomiting, decreased appetite, decreased fluid intake, and urine output. He had a mild cough that his parents noted that wasn't really of too much concern to him. He also had this rash that his parents talked about that a couple days before had started on his torso and spread to his extremities and face within hours, so it moved pretty quickly. It did involve his palms of his hands and soles of his feet, and by the time he was actually admitted, it had mostly resolved, so it had moved quickly and started going away pretty quickly as well. In addition to everything that I just mentioned, his parents said that the first day of his symptoms, the day that he went to his pediatrician, he had some red eyes. The next day, he actually complained of some eye discomfort and some photophobia, although he didn't think at any point that his actual visual acuity had changed. He didn't think that he had any color vision abnormalities. And he also was pretty articulate and pretty forthcoming with his symptoms. And he said that this eye pain really was worst on the second day of his illness and had slowly been getting better ever since. Other history for him, he had some asthma and really not too much else. Never had surgery, no eye problems. His family history didn't reveal any childhood illnesses for anyone else in the family. He lived locally with his family. They have a few pets, including a bird at home. Both of his parents smoke, no known sick contacts. He just started third grade. He'd never traveled outside the country and there were no known tick bites or insect bites or anything of that sort. Doesn't take any home medications and no known drug allergies. Review systems brought up a few other things. I think I mentioned before he had a sore throat and a sore neck at the start of his illness. He'd also had diarrhea and chest pain and his parents thought he looked jaundiced up until the point of admission. And by the time I saw him, that had also started to resolve. But the notes indicated that he was in fact jaundiced at the time of his admission. So day one when he came into the ER, his first set of vital signs included a temperature of 37.6. That actually wasn't the best example for me to include. I just went with the first temperature they recorded. But the truth was most of his temperatures that were recorded the first few days of his admission were over 38. So he was running a consistent fever at admission. He also had a heart rate of 109 and a blood pressure of 80 over 43, which for an eight year old, those are abnormal. I know that the normal range tends to vary for different age groups. But those are certainly abnormal and were concerning enough that he was actually sent to the unit. He didn't actually go to the floor. He also was extremely drowsy, but still responsive to questions. He had cracked lips, a strawberry tongue. And then the description of his rash was a generalized erythematous, coalescing rash, most prominent on the trunk and inguinal region with involvement of both arms and both legs. And this was the rash that the parents thought was much better than it was a couple days before he came in. So the differential at this point, when you type in differential diagnosis to Google images, house MD comes up. And so I thought I should include him. The differential at this point includes strep and staff toxin mediated diseases like scarlet fever and toxic shock syndrome, Kawasaki diseases on the list, viral etiologies such as adenovirus and enterovirus and even measles were considered. A drug reaction would fit the description, but he wasn't taking any medicines at home, so it's bumped pretty far down the list. And then a lot of autoimmune diseases and inflammatory diseases like Ryder syndrome, inflammatory bowel disease, et cetera. Interestingly, I recently learned that Dr. Ryder, people are sort of looking into his past now. I guess he was potentially involved in some inhumane experimentation in Nazi Germany. So there's a movement to take his name away from reactive arthritis. So I threw both names up there just because I don't think the verdict's quite out on that story yet, but a little side note there. So out of these, the highest on the differential for this patient were scarlet fever, toxic shock syndrome, and Kawasaki disease. Like I mentioned, drug reaction would have been up there, but he wasn't taking any drugs. So that doesn't really make any sense. But the other two really fit with all of his physical exam findings. And there wasn't a great way to distinguish between them. And labs were still trickling back, so they didn't have a perfect picture of what was going on yet. To give you an idea of what he was being treated with, it started with Cephtriaxone, clindamycin, and naphthalene. This treatment regimen changed throughout the course of his admission. But consistent for most of the admission was that he was on clindamycin with the thought that that would treat any toxins that he might have been exposed to. And usually there was something that would treat grand positives like stab and strep. He also, with the thought of Kawasaki disease, was put on IVIG and high-dose aspirin because people just weren't sure exactly what was causing his problems yet. He was sent to the unit and was put on pressers and given fluid boluses because his pressures just kept staying too low for him. And he was having evidence of end organ damage. But eventually he did respond to them while he was on this thorough treatment regimen and was sent back to the floor because he was doing a little bit better. Once he was sent to the floor, ophthalmology was consulted because he was a little more with it and communicative. Said that he was still having some of this eye pain. So they wanted our input. They also wanted our input because they thought maybe we could help them making a final diagnosis and differentiating between these diseases on the differential. So he was a real trooper and actually came to clinic. So I could look at him at the Slotlamp exam even though he didn't feel good. And I'm glad he did because I think we got a lot more information from this visit than I would have at the bedside. Visual acuity was excellent in both eyes about 2015. Both color vision was five out of seven in the right, six out of seven in the left. His pressures, extracular motility, visual fields were all normal. He didn't have an apparent pupillary defect. But then when we took a closer look, he actually had no congenitival injection. He had a little bit of icturus consistent with the previous jaundice that had been described. But he also had two plus cell in his interior chambers in both eyes. His cornea showed no subapithelial infiltrates. Iris showed no posterior synechia, and he did not have cataracts. But there was cell in the interior chamber. He was dilated, and he actually had stage two dyscadema in both eyes. The right eye looked a little more affected than the left, but they were both stage two. Macula, vessels, and periphery all looked normal. And he had about half plus cell in the vitreous in both eyes. So before I get down to what this implies for his diagnosis, labs had been trickling back throughout the course of his admission. So I'm not going to go through each and every single one of these, but the general gist of it is he did have an impressive leukocytosis. A number of viral cultures and PCRs had come back, including Epstein-Barr virus influenza, lots of them. They were all negative. His CSF showed an elevated white count, but really the other parameters in that were normal. So it was sort of a non-specific inflammatory picture. Blood cultures for bacteria didn't grow anything. Again, a number of more viruses here that all came back negative. He also had an elevated ESR on day one of his admission at 45, which jumped up to 107 by the time he was on the last day of his unit stay. But at that point he started feeling better, like I mentioned, so they sent him to the floor. So at any rate, with all of that information, we go back to our differential, the top things on the list of the differential, and out of Kawasaki disease, scarlet fever and toxic shock syndrome, only Kawasaki disease is known to be associated with the uveitis, so that really helped with the diagnosis and the primary team kind of honed in on it at that point, so that was kind of neat. As far as what to do with his eyes, we started prednisolone eight times a day in both eyes, and he was to follow Dr. Vitale in a week. So during this stay, the first couple days, he did have an echocardiogram, because as a lot of you know, Kawasaki disease is associated with coronary artery aneurysms, and this didn't show anything, which doesn't rule out Kawasaki disease, but it doesn't help make the diagnosis either. And then, like I said, he was started on IVIG and high-dose aspirin, this was continued after I had seen him in the clinic, but eight days after the first one, he did develop coronary artery aneurysms that were seen on a repeat echo, so this happened while he was in the hospital, unfortunately, and the entire purpose of giving those drugs is to keep these artery aneurysms from forming, so I'll talk a little bit about that later in the talk. So he came back to see Dr. Vitale, he'd been taking the prednisolone as requested. Vision was still great, the interior chamber cell had improved, but not completely resolved, and the same was true with the vitreous cell and the dysphedema, so he was moving in the right direction, but not totally back to normal yet. He said that his eyes felt normal, and he was happy with where he was. The plan at that point was to taper the prednisolone and have him come back in a month or two to see how he was doing. So a little bit about Kawasaki disease now, it's a vasculitis mediated by IGA, and it affects small and medium-sized vessels by causing fibrinoid necrosis in the vessel wall, so this doesn't limit it to just the coronary arteries, but that's where the most common and most serious complications of the disease occur, which is why that's what we always think about, but it happens in vessels throughout the entire body. The coronary, like I said, the coronary arteries are most commonly affected. It happens more commonly in boys than girls, and more commonly in young kids under five years old, which is partly what the hangup was with our patient, because eight years old is a little old on the spectrum of people who get this disease and they just didn't want to miss something like a toxic shock syndrome that could be potentially fatal. So how do you make the diagnosis? All these children, in theory, should have a fever for five days. I think that they sort of trusted that the parents felt that he had a fever for all those days prior to his admission, because his fever actually did continue after he was admitted for over five days, now that I think about it. You also need peripheral extremity, perineal area changes, like swelling, scaling, palmar sole erythema, our patient did have that. He had the rash that reached the palms and soles. He also, the day that I saw him develop swelling of his hands, and that's another point with this, is that not all these findings need to be present on day one, you can develop them as time goes on. So even though they don't quite qualify for Kawasaki disease right away, it should still be in the back of your mind because they might qualify in two or three days. A polymorphous exanthema, which our patient did have, bilateral conjunctival injection, our patient had that as well, and then a strawberry tongue. So our patient had this, and then the fifth one our patient didn't have actually. He didn't have cervical and fat anopathy, but he did have four out of the five in addition to the fever. So a little bit more about the conjunctival injection. It's extremely common in these patients. Over 90% of the patients do have it, and it is bilateral. So because it's so common, it's not something ophthalmology typically gets consulted for because it's a known finding in this disease. But if it is present, and you do see the patient, it should just be the bulbar region, the palpebral conjunctiva should not be involved, and there should not be chemosis papillae follicles or discharge. If any of those are present, you should start thinking about other illnesses such as, for instance, adenoviral conjunctivitis, with which I am very familiar, as some of you know. So that can make people feel awful. It can give them fevers. It can just make them feel terrible. It can give them a rash. It can give them cervical and fat anopathy. So that can cloud the picture too. And that's something that you can be of help to for a primary team. If the patient has this really nasty discharge from their conjunctivitis, you might want to steer them away from Kawasaki disease. It often resolves as well within days of IVIG treatment, which may be the reason that I didn't see any of this injection the day that I saw the patient, because he'd already been treated for a few days. So what about the interior uveitis that I saw? There were a few studies that I came across looking at a series of children with Kawasaki disease and the incidence of the uveitis. And one of the studies looked at 41 patients with Kawasaki disease. All of these patients were examined at the slit lamp, which I thought was impressive since you're talking about young children. And the timing of the exam was measured with respect to the onset of the fever. So the first day of a recorded fever was day one and so on. Exams were positive only if the patient had cell or flare in the anterior chamber. So out of these 41 patients, 27 were found to have interior uveitis. I thought that number was really high compared to what I anticipated seeing. Out of the 27, 25 had bilateral involvement. 24 of these patients had their first slit lamp exam within one week of the onset of fevers and 20 out of those 24 had a positive exam for anterior uveitis. If you looked at the rest of the patients, there's 17 patients left who weren't examined until after week one. Seven out of those 17 had a positive exam for anterior uveitis. So the p-value for the difference between those two groups was 0.004. That's a huge difference for finding cell in the interior chamber from week one to week two. So that would potentially imply that a lot of these patients have this reaction that's going right away and then it kind of resolves on its own. Especially since most of these patients didn't actually complain of any eye problems. They didn't have eye pain. They didn't have vision changes. They just were examined because it was part of this study. So it's kind of interesting. A lot of these patients might actually have these reactions and we just don't know about it. While the timing of the exam did seem to correlate with the rate of positive exam, gender, age, race, ESR, ESR value, and aneurysm formation didn't correlate at all with whether or not an exam for anterior uveitis was positive. So the only indicator of whether or not you were gonna find this seemed to just be the timing of the exam with respect to the onset of fever. So there was another study that was somewhat similar in setup. It looked at 115 Brazilian patients diagnosed with Kawasaki disease. This study was a little more general. They involved ophthalmologists to look for anterior uveitis but they were looking at other aspects of the disease as well. All of these patients were treated with IVIG right when the diagnosis was made and all of them received a slit-lamp exam and dilated fundus exam. These eye exams were performed in the acute and subacute phases of the disease and in this study, only 15 out of 115 patients actually had ocular manifestations of disease with 13 of those being anterior uveitis. All of these findings resolved within 30 days of the first eye exam. So this is a really different number than that first study and there were three things that I could come up with that were different between the two. These were the two largest studies I came across regarding uveitis and Kawasaki disease. One was this study was primarily Brazilian patients so there could be a difference in the manifestations of disease depending on the patient's ethnic background. Another was all of these patients were just received IVIG treatment whereas they didn't imply that in the other studies. So if not all those kids were getting IVIG treatment it might have affected whether or not they developed this uveitis. And finally, this study, all of the exams were done in the acute and subacute phases but they didn't really define what those were. So I don't know how early they were actually having their exams and if they were all having them week two, week three then that would imply from the first studies results that these numbers are gonna be a little bit lower. At any rate, I think the take home point from these two studies is that anterior uveitis is associated with Kawasaki disease and even if you go with this lower number of 13 out of 115 patients it's still a significant number of patients and it's still something to consider for these kids. So I talked a lot about the anterior uveitis but our patient had dyscadema so what to make of that? There was a case report that I came across of a six year old boy with Kawasaki disease. He was admitted and started on IVIG. Day two of admission he had eye pain so he had an ophthalmology consultation. This is actually a picture of his eye. They found punctate epithelial keratopathy endothelial precipitates, macular edema, periphoveal, stellate exudates, horizontal rednal folds along with cotton wool spots so they found a lot of stuff going on in the back of his eyes. These are his OCTs which revealed macular edema, sub-phovial detachment of the RPE and exudates in the outer nuclear layer that were consistent with that stellate pattern you saw in the color photograph. They started him on local and systemic steroids and his vision was excellent along with a normal OCT within two weeks of starting that treatment regimen. So he, like our patients, seemed to rebound quite well as far as his eyes were concerned once he was on some steroid treatment. They sort of reviewed the literature and I looked at a few of these papers and the general gist of posterior involvement in these uveitic processes is that they're not reported often but it's not entirely clear if they're not reported often because they don't occur often or if they're not reported often just because most kids don't have an exam. If you'll recall, most of these patients from the first studies that were done really don't have any ocular complaints and they all have red eyes but that's the known finding in the disease so there's no reason to have them at a slow end just for that reason. So this could happen more often than we think. This patient had an exam because he did have eye complaints but it's really hard to sort of tease out the frequency of these findings in these patients. So posterior segment findings listed in the literature include optic disc edema, vitritus, perivascular sheeting, optic disc vessel leakage, arterial or narrowing, stellate maculopathy, and macular edema. So those have all been recorded but like I said, the frequency is pretty much unknown. So I keep talking about these kids who have all these findings that get better and no problems really occur but that's not always the case. There was a nine-year-old girl in the literature who was admitted with Kawasaki disease. She was started on IVIG and P.O. aspirin. Day two of admission, she said that she went blind in her right eye on exam. She was found to be no light perception in the right eye with normal vision in the left. She had a large APD, the Expected Conjunctival Injection with just a little bit of cell in the interior chambers. Dilated exam showed a quiet vitrious in a normal left eye dilated exam but her right retina was white with a pale edematous disc, narrowed arterials and no cherry red spots. So with all of that, especially the no cherry red spot, you'd think of an ophthalmic artery occlusion which was in fact what her final diagnosis was and in spite of prolonged treatment she didn't improve at all. So I included this story just because I thought it was important to illustrate that if you have one of these kids, it's not necessarily that it's UVitis that's bothering them with their vision. This is at heart a vasculitis that affects the whole body and can certainly affect the eyes through the vasculated component and can lead to things like emboli and thrombi that would occlude arteries that are essential for the function of the eye. So keep lots of things in the back of your mind if you're examining a kid with Kawasaki disease who has ocular complaints because it might not be a benign finding like all of these other stories that I'm presenting today. So to sort of close with the final report there was an 18-year-old woman and I thought this was interesting. I don't have any statistics on this but all of these case reports involved children including the story that I gave who are older than that normal age range of five years older or younger. So I don't know if that means something or if those are just the kids who cooperated with the Slotlamp exam but the children who seem to have vision problems or eye pain all seem to be older than the normal age range for Kawasaki disease. This patient had decreased vision, fever for a week, strawberry tongue, erythematous macules. She qualified for Kawasaki disease but she also qualified perfectly well for scarlet fever and toxic shock syndrome. So it was really interesting. I included this because this differential was exactly the same one that we had for our patient. The only difference was they threw in a drug reaction because she had been taking medications at home. So I don't think that it's an isolated incident that we have this patient at Primary Children's who had that very list of diseases on his differential. This patient was given almost the same antibiotics along with IVIG and aspirin and ophthalmology was consulted to help out with making a diagnosis. So before I go through what they found at the Slotlamp, why do they care? What difference does it make? Well, there are serious implications with Kawasaki disease. The most common of which, like I mentioned, was coronary artery changes. They don't have to just be aneurysms. Stenosis can happen as well. 15 to 25% depending on which paper you look at develop these coronary artery changes and out of those patients there's a 2% mortality rate. So there's not a huge mortality rate but it's certainly there. And if you're talking about someone's child, I think that's something to really consider. It's been found that treating with aspirin and IVIG can help decrease the rate of the formation of these aneurysms and decrease the rate of death if these aneurysms are formed. The rate of coronary artery change decreases by three to 8% and out of those patients, mortality decreases to 0.2% if you give this treatment. That all sounds great but if you really look at the numbers that's not a huge change. You're growing from 2% of 20% of the patients to 0.2% of say 15% of patients which isn't, it's a pretty large number needed to treat when you really break it down. But it is a real difference and if it were my child I would probably want them to receive this treatment which is why all these kids get it. As you recall, our patient had IVIG and aspirin treatment and still developed the coronary artery aneurysms. So it didn't stop him from developing these changes but after a few more kids you might have actually prevented this from happening. As I mentioned before, these aneurysms can occur in other systems in the body including the GI system and the central nervous system. So it's not just the heart that you have to be worried about but that is the most common location for these changes to occur. So back to this 18-year-old girl she had numerous findings of UBI as conjunctival injection, keratic precipitates cell in the anterior chamber. She didn't have a visual acuity measured because like our patient she was extremely tired and it sounds like she couldn't sit up for more than just a slow length exam. Kawasaki disease was the diagnosis, aspirin and IVIG were given and she responded very well and was discharged and did well afterward. So back to our patient, the final bit of the story. He was started on three days of IV methylprednisolone followed by steroid taper. Rheumatology was working closely with him and felt that since he developed these aneurysms while on IVIG they wanted to be more aggressive with his treatment. He still had fevers throughout this whole time. I mean he really didn't feel good for a long time when he was in the hospital. So they gave him infliximab which seemed to have the fevers resolved so he was discharged and then unfortunately came back the very next day with a recurrent fever. So they still hadn't kicked this thing. He was admitted to rheumatology at that point and he got another round of high-dose steroids and he did quite well on those and went home afterward. So the plan is he's still supposed to follow with Dr. Vitale in the next couple of weeks I think. Dr. Vitale is out of town right now but I'm interested to hear how he's doing when he sees him again. So I think the take home points from this is that UVitis is pretty common for patients with Kalisaki disease and it seems to be fairly self-limited. Our patient and a number of the other patients that I talked about did have steroid treatment for the UVitis but if you think about it those series of patients, most of those kids would have developed UVitis and never had any treatment because they wouldn't have had an eye exam because they didn't have complaints. And most kids with UVitis don't end up with poor vision down the road. I would think that it doesn't really typically have long-term implications for patients' vision. It's often but not always limited to anterior UVitis and then serious sequelae of the disease are possible if you remember the nine-year-old girl with the ophthalmic artery occlusion. So just because I keep saying the UVitis seems to get better, their eye complaints might not be related to UVitis. This disease can manifest in different ways so they deserve an eye exam I think if they're having eye problems. The presence or absence of UVitis can also help the primary team clinch a diagnosis which seems to have happened before our case so that's something also to consider and it's kind of fun to be a part of that. So that was, or any questions? I don't think they actually measured that. Did I include, I don't think that they measured it. I don't think they measured it actually. I could go back and look but we interpreted that more as a breakdown of the endothelial barrier as part of the vascular process. That's a good question and maybe we should have considered that more but yeah, we interpreted it as more of a vascular process than a high intracranial pressure in part just because it had been reported a few times before and it seemed to fit with the rest of the picture. I don't think there is total conclusion on that. If anyone out there disagrees with me, please let me know but I didn't come across any real great evidence of the way that it did work. I think the thought is that it helps with the inflammation but I don't think people know for sure. They found that it helps. Does anyone know more about the mechanism there? I don't think they're limited as far as what they're allowed to do as a child but as far as what that means for when they're 50. So there are thoughts along with Dr. Cass's giant cell arthritis work. There are thoughts that this could be related to an infection and no one has proven that. They don't know what bug would cause it but they think that these children might be exposed to some sort of a pathogen and have a setup where they are susceptible to an inflammatory change related to that pathogen that people haven't isolated any specific disease to cause them that. That's the leading theory out there but it hasn't been proven. No, they're not standard of care. So they were given for this patient and I didn't come across them making things worse either so I don't know if that's true but they're definitely not standard of care. The standard is the IVIG and Aspen treatment. Our patient got that and continued to get worse and I think rheumatology was kind of reaching for things because it wasn't just that he developed these coronary artery aneurysms it was also that his ESR continued to be high. He continued to have fevers. Really the only thing that had improved was his rash and his blood pressure which blood pressure was obviously something that had to improve. But the other indicators that people were going by with him was that he just wasn't getting much better so I think they were reaching for things and giving treatments a little bit outside the box with him including the influx of mad that he eventually got. But no, it's not standard of care.