 I didn't know the answer to this question at the start. And that's supposed to say next stiffness on the flyer, sorry. So it was a cute unilateral vision loss with next stiffness that our patient presented with. So this is another case presentation and I saw this patient on call on a Friday night. So without further ado, this was a nine-year-old girl who came into the ER at Primary Children's Hospital and she was there with her mother and the story was that she woke up four days prior to coming in with decreased vision in her left eye, just sort of spontaneously. This stayed the same for two days and then it decreased again. So it was kind of a step-wise vision loss with two steps, if you will. And her description of it was that it was like she only had one eye. So she thought it was a pretty severe loss of vision. She also had pain with eye movement, but the pain wasn't there unless she was moving her eye. And from her perspective, her right eye was totally normal. According to the mom, the patient had had decreased energy for the past one and a half months. She was pretty confident in this because the patient had a twin sister with whom she was always running around the house. But for the past one and a half months, the sister was running around and the patient was just sitting on the couch. The patient had also had next stiffness for five days, but this was actually improving. This was not on the downswing, so that was good news as well. And the mom had measured a temperature of up to 102 degrees Fahrenheit the week leading up to the presentation. So according to the mom, the patient was healthy otherwise. Mother thinks that the patient had a history of maybe a lazy eye. She wasn't really sure. But for this reason, the patient was followed by an ophthalmologist every couple of years. And nine months previously, she'd had an eye examined that according to the mother was completely normal. So whatever had happened seemed to have resolved. She also had a right anguinal hernia repair at age four. Family history was significant for diabetes, macular degeneration, unfortunately glioblastoma. And she had a 16-year-old brother who had walking pneumonia three months prior to her presentation. Social history was significant for multiple siblings. She lives with her parents and siblings locally. She started the fourth grade four days prior to coming in. She doesn't have any cats or dogs, but she does play with the neighborhood dogs, so she is around at least one animal. And she went camping in the Rocky Mountains the week prior to presentation. It was bitten by a lot of mosquitoes, but as far as I know it was not bitten by any ticks. She does take multivitamins, not allergic to anything, and she's never left the country. So on physical exam, on near-card uncorrected, she was 20-20 in the right eye and hand motion at five feet in the left eye. And she had a very significant APD of 2.4 log units. So at this point I was thinking, oh boy, Friday night starting off well. She had normal intraocular pressures, hexaocular motility was normal, visual field was full to confrontation in the right eye, and color vision was normal in the right eye, but she was unable to really do those tests in the left eye. Her tail was normal as well. So on slit lamp, her anterior segments were normal, and her dilated fundus exam was normal, with the exception of stage three discodema in the left eye, but also stage two discodema in the right eye, in spite of her not claiming to have any problems with her right eye. So she didn't have any hemorrhages or cotton wool spots around her nerves in either eye. So she'd actually been in to see her pediatrician the day prior for this myriad of symptoms, and that pediatrician worked through primary children so he had access to some of the labs that he had ordered. She had a leukocytosis that was predominantly neutrophils. Her CMP was normal, and he ordered a number of other tests, including Epstein-Barr virus serology, for which the early antigen IgG came back negative, nuclear IgG came back negative, and I'll go through what these tests mean. Viral capsid antigen IgM was negative, and the VCA IgG was positive. That stays positive for life, so it doesn't necessarily mean an acute infection. And her ANA, TSH-T4 were all normal, as was her anti-scriptolycin O. So we ordered an MRI with and without contrast. It showed enhancement of the left optic nerve from the post-ball bar area all the way back to the chiasm, and also enhancement of the right optic nerve at the annulus of the ZIN. So this also argued for bilateral involvement of whatever this process was. It showed no other abnormalities of her brain, which was good news. So these are just a couple of slides. You can see some enhancement of the nerve through here, and then on a coronal image, the left nerve is obviously enhanced when compared to the right. So the question is, what do you do in this situation? An infectious etiology was higher on her list, given her systemic complaints. Sorry, I didn't mention she did have neck stiffness on exam, and she was not federal in the emergency department. But given the mother's history, the patient's general exam, her malaise recently, we thought a systemic infectious process was probably at work. But we also thought that she had an optic neuritis, which we wanted to treat with steroids, but we didn't want to make whatever this process was worse for fear of really bad consequences in the end. So in the end, a lumbar puncture was performed, and she was admitted to the neurology service. They were really helpful. We worked together on this patient for close observation until we had a little more information on what was going on. So some of the early results of her lumbar puncture, which was done that night, were a normal opening pressure, an increased white cell count of 100 in her CSF, which was 60% lymphocytes, and then normal glucose protein. So the next day, she was examined at the slant lamp, and she was 20-20 in her right eye and no light perception in her left eye. Well, this was not moving in the right direction. She was still not febrile. She didn't seem to be getting any worse from a systemic standpoint. So it was decided at that point, since she was under close observation, it would be best to start a steroid treatment to see if we could help with her optic neuritis, especially since the right nerve was involved as well, and we didn't know if that was going to start going downhill soon or not. She was started on three days of IV steroids with a plan of a 10-day steroid oral taper after that. And in the meantime, we waited for labs to come back, and we ordered quite a number of them. I won't list every one of them out loud, but these are a lot of them that came back negative. You missed the serum. Oh, excuse me. That was the key. So she had negative lots of things. Neurovirus, West Nile, Lyme disease, Cascratch disease. I didn't mention her. Pediatrician also ordered an ESR, which was elevated at 25, and that was still elevated at 17, but it was at least trending down. But one thing that did come back positive was the CSF Epstein-Bar virus PCR. So that is indicative of an active infection with Epstein-Bar virus. So we thought that was our answer at that point. I don't think that came back the next day. I think that took a couple days to come back. But when it did come back, it was really helpful for us as far as what was going on with this patient. So she was followed up three days later at the end of her IV steroid portion of her regimen. And her vision was still 2020 in the right eye, and it actually improved from no light perception to 2030 in the left eye. So that was a huge improvement for this patient. She still had an afferent pupillary defect. It had improved from about 2.4 to about 1. She still had dyscadema in both eyes, but it improved from 3 to 2 in the left and 2 to 1 in the right. And she actually, this was Monday at this point, so we got a visual field that showed a full field in the right eye and an enlarged blind spot with a supranasal scatoma in the left eye. So that was her initial visual field after three days of IV steroid treatment. So a little bit about some of the basics of the labs that I just mentioned, and then I'll go into more detail on what happened with our patient and Epstein-Barr virus induced optic neuritis. The most common lab finding for an Epstein-Barr virus infection is a lymphocytosis, or over half of a peripheral smear being lymphocytes, which actually wasn't the case in our patients. She had a predominantly neutrophilic leukocytosis. You can also find atypical lymphocytes in the smear, which a lot of times with an automated count, it'll mark atypical lymphocytes and flag it as something that should be counted manually. That also didn't happen with our patient. Heterophile antibodies can be helpful, although in one study I read, they're much, much less sensitive and specific for children. That study looked at patients under the age of four, so I'm not sure how applicable it is to our patient at the age of nine. I don't know if that's a spectrum or if there's sort of a cut-off at some age when they become more helpful. At any rate, I came across one case study where a patient came in with optic neuritis and his MHATP came back positive, and it was thought that he had syphilis and he was admitted for IV penicillin, and all of his other tests came coming back negative, like the RPR and FDA, ABS, and in the end it was a false positive because of reaction with the heterophile antibody, so that's something to keep in mind, because both of those diseases can cause optic neuritis, and if this is the only test coming back positive for syphilis, this could be the answer. Viral capsidantogen was one of the tests that our patient had. IgG and IgM are usually present at the start of clinical illness, but there is a long incubation period in the order of months, so it's usually not present during the clinical or during the incubation period. The IgM tends to disappear after a few months, and the IgG is present for life, which is what our patient had positive. The IgM can be present for other viruses as well. The nuclear antigen shows up a little bit later, six to 12 weeks after the onset of symptoms, so the argument in the paper that I was reading for this was that if you have a positive nuclear antigen right when a patient's symptoms start, it could be that this is from an old infection and you should be looking for a different ideology of their problems. This might not be the answer. At any rate, none of these antigen tests are necessarily present for all patients. In fact, a lot of patients will only have one or two come back positive, and that can have different prognostic indications as well as I'll go through later. Early antigens are also present at the start of clinical illness if they're present at all. IgA antibodies were not ordered on our patient. That's more of a new test. One study found that they were positive, and 15 out of 15 patients found to be infected with Epstein-Barr virus, but I don't think that it's as commonly used yet as the other studies. PCR is the only one of these that's truly indicative for sure of an active infection. It's more often positive and seronegative patients, interestingly, and if you get a quantitative PCR, you'll actually be indicative of other things going on, like lymphadenopathy, lymphocyte numbers, and aminotransferase levels. It correlates with those. So, with our patient, with her symptoms, lab values, family history, everything going on, we thought this all made sense. It matched up. She had what seemed like a mono prodrome followed by optic neuritis. Everyone was happy with how she was doing. She was discharged to complete her oral steroid follow-up and follow-up with Dr. Katz in a few weeks. And unfortunately, she got worse. So, she came back with hand motion vision in the left eye. She had finished her steroid taper six days prior, so it was decided to re-admit her, start her back on another three-day regimen of IV steroids, followed by a much more drawn-out oral steroid taper with the thought that maybe she didn't get enough of a taper the first time around. This time, she had no systemic signs of infection. Her malaise had gone away. She wasn't having fevers anymore. Her neck stiffness was gone. Infectious disease was consulted, and they decided to start IV-cancyclovir in case the active Epstein-Barr virus infection just wasn't getting better. So, while she was admitted this time around, we wanted to make sure we weren't missing anything else. She got a CT and L spine MRI, which all came back normal. Her brain MRI was done on the last visit, so we didn't repeat that. She had CSF and plasma Epstein-Barr virus PCR, which actually this time is not detectable. So, happily enough, it seems like her actual infectious process was over, which went along with her systemic signs, but she still had this optic neuritis. So, infectious disease was happy to stop the cancyclovir at that point. She only got one day of it. Those tests came back quickly. And her protein glucose were normal again. She elevated white count this time around still. It was a lot lower than last time, and it was still predominantly lymphocytic. So, there's not a huge amount. There were some large studies on the effects of Epstein-Barr virus on the central nervous system, and really they just mentioned that it can cause optic neuritis. So, the only detailed reports that I could come up, come across were case reports, and I was just going to go through some of my findings from those. Typically, this will present with a program of, well, not typically, a decent amount of the time from the case reports that I read. The patients will have a program of fatigue, fever, cough headache weeks to months prior to coming in. So, that can be a sign, as it was with our patient, that something more systemic is going on. The vision seemed to improve in these patients, although if other central nervous system problems are present, like paralysis or hearing loss, which some of the patients had, those problems don't seem to get better as frequently, unfortunately. IV steroids do tend to help patients to a more speedy recovery. As far as I could tell, there were no studies on this, but that was the impression I got from reading these reports. But some authors think that you run the risk of worsening an active infection. They don't. And I was going to talk about that a little bit. That's all theoretical, very much so. So, I was going to go through a few specific cases, partly to illustrate that question there. One group saw a 49-year-old man who had simultaneous Guillain-Barre syndrome with optic neuritis, and he came in with light perception vision in the right eye. So, all of these patients tend to have pretty dramatic vision decrease with this type of optic neuritis. He was initially treated with three days of IV steroids and the Guillain-Barre syndrome worsened. Unfortunately, they didn't give a visual acuity after those three days. He was then started on IVIG for a total of five days of treatment with that. His visual acuity only improved to count fingers vision at that point. And then, 35 days later, his visual acuity was about 20-30 and his Guillain-Barre syndrome had improved. They don't really give any information in the interim. And these authors argued that steroids and IVIG would be beneficial, but I'm not entirely sure. I agree with them here because, for one, the patient didn't seem to improve all that much with the steroids and IVIG. He seemed to improve, in my opinion, more on his own after the treatment regimen was stopped. And also, I don't know that the steroids, as far as his vision was concerned, were given the more standard treatment regimen, which is to include an oral steroid taper after the IVIG. And we don't know what his vision was after the first three days. So, that was their argument. It was the only time that I came across that IVIG was used, but I don't know that I would go that route from the other reports that I was reading. I don't think they were specific, so I think it was pulled. There was another report with a 32-year-old woman with neuromyelitis optica with initial hand motion vision in both eyes. She was treated with the more standard three days of IV steroids followed by an oral taper. Two weeks later, her vision was 20-30 in both eyes, and she had no improvement with her paraplegia after six weeks of follow-up. So, that was sort of what I was alluding to. A lot of these patients, their other problems don't improve as well as their vision does. These authors were some of the authors that speculated that CNS-induced problems by Epstein-Barr virus are of immune etiology rather than a direct effective infection. And I think our case is helpful in that regard because we finally have a case where we had an active infection and we're pretty confident that this was an Epstein-Barr virus-induced neuromyelitis. And then she came back with, I don't know if you would call it a relapse because I don't know that she ever completely recovered, but she certainly got worse. And we had evidence with a repeat PCR that the infection was no longer present. So, I think that's an argument toward the idea that this is an immune etiology, not direct infection of the central nervous system causing the Epstein-Barr virus infection. These authors were also some of the authors that highlighted that they might be more hesitant to just throw steroids at these patients because of the risk of worsening an active infection. This is only one case, but this is one case where she was treated with steroids and presumably while being treated her PCR went from positive to negative so it didn't seem to cause her harm in that area. Obviously it's a sample size of one, but it is an argument, I think, that steroids can be beneficial for these patients without necessarily causing them further harm. Another group, this patient was a little bit different. This was an eight-year-old girl who had ulcerative colitis and sclerosis and cholangitis who had a liver transplant for these reasons. Prior to the transplant she had serology that was positive for Epstein-Barr virus and the status of her donor was unknown. After the transplant she was immunosuppressed with cyclosporine, azathioprine, and prednisone. She was found to be positive for EBV a year after the transplant. She was started on fancyclovir for this reason and her PCR never did become negative. It just fluctuated up and down over the years. At the age of 13 she came in with worsening left eye pain. It was found to have an APD and 2065 vision in the left eye. She had an MRI done which showed left optic nerve enhancement along with multiple lesions along the corpus close to periventricular region. Similar to our patients she had a myriad of tests done. Everything came back negative other than the Epstein-Barr virus test which was already known to be positive. So she had been put on Ganscyclovir for fear of CMV. That was stopped. Her steroids were adjusted and her visual acuity resolved and she had a residual APD. Unfortunately she came back six months later with fever, fatigue, and cervical lymph adenopathy with similar lesions and no evidence of this time of optic neuritis. She had her lymph nodes biopsied and they came back positive for CD20 B cells and she was diagnosed with post-transplant lymph or proliferative disease. A year later she developed headache, tonic-clonic seizures. She came in with more lymph adenopathy throughout her body. She had patchy white matter lesions consistent with CNS lymphoma. She had bilateral optic discodema and pallor and she was started on chemotherapy and basically transitioned to more of a hospice type care and she passed away. So it's a sad story but the author's point is that this could have been, this optic neuritis could have been the initial presentation of this post-transplant lymph or proliferative disease. Obviously this patient is a different demographic than ours. She's immunosuppressed. She's had systemic problems before but they argue that in an immunosuppressed patient, particularly a patient who's had a transplant prior, it's important to keep other more malignant etiologies on the differential for these patients. I don't think that there was a high suspicion of anything like this in our patient but this was the first time they think that the optic neuritis was the first presenting sign of an Epstein-Barr virus induced post-transplant lymph or proliferative disease. And I also included her because she had a positive PCR which our patient did and there was only one other case that I came across that did. This was a 24-year-old man who had the positive PCR along with positive VCA antibodies. He had a number of other problems including altered mental status, facial peresis, left lateral rectus weakness, hearing loss, impaired finger to nose, neck stiffness as well. He was actually not started on steroids. He stayed in the hospital for three weeks essentially being observed as far as I can tell and his visual acuity returned to his baseline. He did have residual facial peresis and hearing loss but he was one of two cases that I came across who did not receive any form of steroid treatment or other treatment and both of those patients seemed to recover quite well as far as their vision is concerned but both of them did seem to take a little longer than the majority of the other patients to get back to their baseline. So a summary of the other cases, I won't go through all of them, I lost ten cases, nine plus the one that I saw. Eight out of the ten patients were male. Five of the cases had unilateral optic neuritis and five had other neurologic findings so there was no real trend there. When I say neurologic findings, I included things like deficits like paralysis or hearing loss. I didn't include things like neck stiffness. Six of the patients had prodromal symptoms so not a huge trend in that direction and three of the patients had a positive PCR. Eight out of ten had some form of steroid treatment. A lot of the regimens were different from one another and five had what I called a complete visual recovery including the two that did not have steroid treatment. When I say complete visual recovery, most of these patients didn't have things like color vision reported so I'm not sure if they had residual visual field deficits or color vision deficits but their visual acuity returned to their baseline. To be specific, that's what I meant by visual recovery. Our patient was seen most recently, five and a half months after her initial presentation and her vision at that visit was 2015 in both eyes with perfect color vision, perfect stereo vision, just a slight APD. Her disc showed a tiny bit of pallor temporally in the left eye and actually I don't think it was a tiny bit. I think I'm being too optimistic there. I think she did have temporal pallor in the left eye. Her visual fields were normal in each eye and she feels like she's doing great. She doesn't have any problems anymore. Partway through her visits, this is her RNFL OCT which is consistent with the temporal pallor in that left eye. So just a couple final comments on the prognosis for this patient. So optic neuritis in a child can have other prognostic implications. As most people here know, the optic neuritis treatment trial looked at prognosis for patients with optic neuritis in terms of whether their chances of developing multiple sclerosis down the road along with many other things. And the general trend there was that if you have findings on an MRI, in addition to findings of optic neuritis, you have a higher chance of developing multiple sclerosis. There have been some smaller studies that looked at children with the same sort of a question. One of them as an example was a study in 2009 that was a retrospective study of children with idiopathic optic neuritis which doesn't entirely apply to our patient because first it's not idiopathic but to dangerously extrapolate. Three out of 18 of these patients had multiple sclerosis after two years of follow-up. Three out of seven of them developed it if they had other findings on an MRI and only zero out of 11 developed multiple sclerosis with an otherwise normal MRI. And the trend was continued in a meta-analysis done a couple years later with similar studies. So not as many patients in these studies but the trend seems to be similar that if your MRI doesn't show other abnormalities then you stand less of a chance to develop multiple sclerosis. An interesting study that I came across looked at patients in northern Sweden which is an area where multiple sclerosis is much more common and they actually had a registry of patients' serum that they studied and they did a huge amount of tests. They probably did do the, was it the porphyrin test Dr. Olsen that I missed? They probably did that one as well. But they had a group of prospective cases and retrospective cases. Prospective cases were patients who did not have multiple sclerosis. Some of them went on to develop it. Some of them did not. The retrospective cases were patients who all had already developed multiple sclerosis and in both of these groups they found that a high eBNA1, one of the early nuclear antigen tests correlated with an increased risk for multiple sclerosis but interestingly if you have a positive viral capsid antigen antibody you have less of a chance of developing multiple sclerosis. So this also argues in our patients' favor she had the positive VCA with the negative eBNA. I think, I don't remember. I'm sorry. I do remember the difference for the eBNA was larger than the VCA but I'm sorry I don't remember the exact numbers. That's true. I'm sorry I don't remember the specific numbers. They did mention in their study that similar findings came about with rheumatoid arthritis in a study done in Germany but I don't have those numbers either. And they also showed a latency period between people who did develop multiple sclerosis who had previous Epstein-Barr virus infection. There was a latency period of years for the most part between those two disease processes. But Dr. Katzen, Dr. Keon along with the rest of the mineral ophthalmology department were very helpful with this patient. Any other questions? And I think that's a real key point in this series of patients because the truth is the people treated with steroids did a lot of them got better but there were two patients that I came across who had no steroid treatment and their visual acuity was great at the end of the day. And that was, like I said, it was a very small sample size but that was my impression of the trend looking at these 10 cases. But then you asked yourself. I was thinking about that too. Yeah, I'm not going to run the chance. That's exactly what we did with this patient too. You know, she went from Count Fingers Vision to NLP and we said, oh, let's do something. Yeah. Right. And I didn't come across, we talked with infectious disease about that and I didn't come across previous cases where the patient was treated with an active antiviral other than the immunosuppressed patient that I mentioned. And infectious disease at least thought the second time around because she got worse that it would be worth starting one the second time around. I didn't come across evidence for or against that when I was reading. I guess from what I read if you're confident that it's the Epstein-Barr virus that's causing the problem, I feel like it's probably okay to withhold the antiviral because 10 out of 10 of these patients didn't seem to have a worsening. I guess I take that back. Yeah, that's true. Sorry, I don't know.