 All right, guys, we're going to get started. So I think, first of all, we want to sort of reintroduce our newest faculty member. Annie Kuow has returned to be a faculty member in pediatric ophthalmology. Annie, would you stand up? She did a residency here. This is her first Grand Rounds back. Welcome back to Annie. And then today, we're going to have our presentation by Zachary Jost, one of our stellar first year residents. Something that you might not know about Zach is that he is a car aficionado. He has a real interest in antique cars and has worked on restoring cars with his dad. And he was just telling me that his favorite car that he's worked on was an original Fiat 500 that he restored with his dad. And what color did you paint it? Bright red, of course. All right. Thanks, Derek. So before I get started this morning, I just wanted to go over a brief clarification. Some of you might have seen the newest issue of Moran Focus magazine that came out this month. And as you might have seen, it has our typical list of current residents and fellows, including our three female pathos that we have this year. And you'll see this picture here. And I just wanted to clarify that I'm in fact not Shannon Stallings. I don't know if Shannon's here today. I don't see her, but I wanted to make sure Shannon got credit for who she really is. And I don't think this picture really does her justice. All right. Let's get started. So I'm going to present a case that I happened to be involved with while I was an intern on the inpatient neurology service. Patient was originally seen here at the Moran, and then I was involved in his care over at the University Hospital. So patient DS, 20-year-old Caucasian right-handed male presented to the Moran here with one month of black spot in his left eye is what he noticed. He described it as a sudden onset happened after work one day. He works as a loader at Walmart. He was seen by an outside optometrist with a quote, normal exam, was later sent to the triage clinic where he presented with these complaints. Denied any dyplopia, flashes, floaters, headache, any pain. Also had some. He was answering his questions very vaguely and kind of evasive in his answers, acting a little bit strangely. And then multiple occasions he was requesting a note for his recent work absences. His past ocular history, he had a flash burn to his eyes in 2007, never had eye surgery. Past medical history, he was admitted to the hospital after having a seizure. He had a drug overdose, GHB, which is commonly known on the street as the date rape drug. However, this was not the mechanism of which he took the drug. Also had a concussion after a motor vehicle accident. Shortly before presentation, about five, six months, history of alcohol dependence, depression. Family history is significant for depression and a mother's cousin with muscular dystrophy, no other neurologic diseases in the family, strokes, demyelinating things like that. Surgical history, he's never had surgery. Social history is quite complicated. He's a current smoker. He drinks to excess many days a week. Multiple street drugs here, meth, cocaine, ecstasy. We mentioned GHB, abuse of prescription pain medication. Also, huffing compressed air cans. However, he does deny history of IV drug use ever. And he did report the four month abstinence from drugs prior to his presentation. One other, tidbit, he's living in an aunt's house in town with several cats, do not use litter boxes. He says there's a lot of cat feces kind of lying around the house and things like that. Sexual history, multiple female partners, no male partners, no history of STDs. Doesn't take any medications, no allergies. And on review of systems, he had a non-specific upper respiratory-like infection three weeks or so prior to presentation. So, his initial exam, he was in no acute distress. He was alert and oriented times four. However, he was noted to be somewhat restless on the presentation, kind of moving around a lot and pretty fidgety. Visual QT was 2070 and 2080 in the left eye. This, he had been dilated at the optometrist's office. Therefore, we weren't able to check for apnea or pupillary defect. No improvement on pinhole in the left eye and the slight improvement on the right eye. His color vision was mildly decreased in both eyes. Notility was full, he had noted to have some fine and gauze in his stagnus. On confrontational visual fields, his fields were diminished in multiple quadrants from all sides, however, most markedly in the supertemporal quadrants in both eyes. Silt lamp exam was actually unremarkable, however, he was noted to have some anterior vitreous cell in both eyes. Was pretty mild, however. Flat cupless discs and no other retinal pathology. So, we got a visual field here on the patient. As you can see that in both eyes, the fields are restricted, especially in the left eye. It's kind of diffuse restriction, more so on the left side of his visual field. The technician didn't note here that the patient was moving around a ton during the exam, fidgety and moving his eyes side to side. There is about 12 out of 15 fixation losses here on the right eye and some fixation losses also on the left eye. Therefore, the reliability of this visual field was somewhat in question, however, you can see that there is somewhat of a drop off here respecting the vertical meridian in both eyes. So, early differential diagnosis for this patient was this patient malingering. He came in, kind of vague complaints, asking for a work excuse, kind of non-specific, he was acting strangely. The fellow who saw him was actually thinking maybe he was intoxicated at the time, given his social history. Was this an infectious process that he had something going on in his brain? Either neoplastic, demyelinating issue. Was this trauma-related? With his drug use, he could have been involved in some type of altercation and he was just being kind of elusive with his history. Also other things, drug-induced visual disturbance, toxic nutritional, optic neuropathy. So, also because of those anterior vitreous cells that were seeing the initial workup for UVitis was undertaken with a test for any type of immunocompromise, basic labs. All these came back normal, by the way. Yeah, yeah, 28, I think what we did initially after the visual field, we started them on multivitamin just because it was a potentially malnutrition state and prolonged alcohol use. Asked him to come back to clinic the following week so we could repeat a visual field. On his return visit to the neuroophthalmology clinic, his mother accompanied him this time, which was actually very, very useful in our history taking. She noticed that the patient had become increasingly confused over the past several weeks. He was no longer able to speak clearly as he usually is, he's usually very articulate, the mother said. Also, he wasn't really understanding common words that he would normally understand. She had to explain to him things like, what does fatigue mean, he would ask, and just common words that he would normally know. His vision had slightly improved. Color vision also slightly improved. He had no afferent pupillary defect. And then on retest of his confrontational visual fields, it does correlate with the prior visual field of the left monomous superior quadrant deficit and less so in the inferior visual field that was tested just grossly. Movements were full, cranial nerves intact. No cells noted on this exam on repeat. And his dilated exam, his discs were still flat and coupless. Rest of his neurologic exam was also repeat visual field. We can see here that the, the scatoma that maybe we saw before is kind of less over the, the vertical meridian here. And then the rest of this visual field is much more reliable, less fixation errors. And you can see clearly that it respects this vertical meridian consistent with the left monomous immunopia. So what's the next step in the management of this patient? It might be pretty obvious, but we're not gonna send this patient home after these complaints of confusion, visual loss, and now with a much more reliable visual field. So here's a T2 axial scan of the patient's brain. You can see here, there's multiple hyper intense lesions here even in the cerebellum. And as we go upwards, multiple hyper intense lesions in the white matter of his brain. Mostly in the white matter, also kind of at the gray matter, white matter junction. Asymmetric pattern, diffuse, patchy. Also to note here is that his optic nerves looked relatively normal. Flair sequence, you can see the same thing, basically hyper intense patchy white lesions in the white matter. And the T1 images of the patient. A little bit different appearance here, some ring type lesions, which can broaden our differential. So something to think about. So revised differential diagnosis. Number one on the differential is demyelinating issues such as acute dissemination cephalomyelitis. Other things such as infectious. I mentioned the ring lesions, which broaden the differential to all these different, either bacterial, fungal, vasculitides, things like that. Other things like multiple sclerosis. Subtypes of multiple sclerosis like bellow concentric sclerosis, vasculitis, lupus, neurosarcoidosis, and some other more rare things down here at the bottom of the list. Back to the ring enhancing lesions that we saw, the differential is quite long. But just to keep in mind that there's many bacterial fungal, parasitic, neoplastic, inflammatory diseases that can cause lesions that look like this. And these are mostly can be teased out on MRI for different patterns of enhancement, which can help aid therapy. So another list here, based on the MRI findings, our patient would be in this category of multifocal discrete lesions. Also some bilateral and diffuse large lesions of the white matter, which may help narrow our differential to some of these things, multiple sclerosis. So our workup included the patient was sent to the university for this MRI. And then this is when I started becoming involved in his care while I was on the neurology service. Patient had a lumbar puncture, his serum, and CSF was sent for numerous different infectious pathogens, toxoplasmosis, multiple virus, HSV, VZV, CMV. The only things that came back positive on this, he did have a CSF, IgM, was elevated for varicella zoster. However, repeat PCR of that fluid showed a negative, it was negative for VZV. His blood cultures, fungal cultures, AFB cultures also came back negative. His lumbar puncture of note was pretty unremarkable. I mean, he did have a few higher white blood cells than normal, zero percent neutrophils, but normal glucose, normal protein. So pretty unimpressive CSF. Also noted in the CSF, he had seven oligoclonal bands, which is a marker for demyelinating diseases such as multiple sclerosis. Also had a chest X-ray, which was normal. And he's initially treated with IV methylprednisolone. 1,000 milligrams daily for three days. And we'll see why we decided to treat him with that. So now, we have a narrow differential diagnosis. The first thing was to rule out infectious causes, because we don't wanna treat anybody with high-dose steroids if they have potential fungal infection or other types of infections. So we pretty much did that with all those tests that we did, all those did not come back very quickly. Because of his unimpressive lumbar puncture and his general state of being normal white count, we thought, and we could pretty much say, based on the radiographic evidence that this is not an infectious process that looked more like this. And to de-hear, acute dysentery and cephalomyelitis, or add them. So, just a brief discussion about ADEM. It's an immune-mediated inflammatory demyelining disorder of the central nervous system. It's commonly seen in young children, age range, five to eight years old, but it has been reported in all ages. Commonly preceded by an infection, used to be called post-infectious encephalomyelitis. Not specific to URI. It's typical history that patients can give, such as our patient. Lesions that are seen on MRI typically involve the white matter. Three bruhomospheres, brainstem, even optic nerves and spinal cord. Therefore, other diagnoses like clinically isolated syndromes like optic neuritis, transverse myelitis, neuromyelitis, optica, can kind of muddy the water in terms of what's the true diagnosis here. Multifocal involvement and encephalopathy are presenting signs. And then the disease is generally monophasic. However, patients have been shown to relapse and come back in within a three-month period, and then that's to consider the same episode of this disease. Diagnostic criteria for diagnosing ADEM. This can be acute or subacute. Patients usually have a shorter duration of symptoms than those who present with symptoms of multiple sclerosis. MRI shows multiple hyper-intense lesions, as we saw. A key point of the history is the patients are encephalopathic. One of the things that was not noticed on the first presentation to the Moran was how confused this patient truly was. It was tough to get a true baseline on the patient. Was he just acting his normal way? Was he intoxicated? But once the mother came in with him and really told us how he was acting so strangely, that was a key addition to the history. No evidence of previous white matter lesions. This is kind of tough to say on most patients. We don't have baseline MRIs on patients, but that's included in the diagnostic criteria, however this criteria is somewhat up for debate. Epidemiology, it's quite rare. Under 20 year old patients, the incidence is less than one in 100,000 per year. This is the incidence noted in California. I don't have data for the entire country. Mean age range, as I mentioned, is five to eight years old, however reported in all ages. Slight male predominance, and then in keeping with the thought that this is a post-infectious process, increase incidence in the winter and spring and decrease in the summer months. So presentation, our patient was pretty typical. Symptoms occur for a couple days, up to four weeks post-infection. He presented about a month, so he might have been a little bit further out than what's typically noted. 70 to 93% of patients report an antecedent infection. Typical symptoms include fever, headache, vomiting, meningesimus, and cephalopathy like this patient had. Up to a third of patients can have seizures, and if there's any involvement of the brainstem, patients can actually have respiratory compromise and require ventilation. Rash is also another non-specific finding seen in these patients in keeping with the viral illness. Other neurologic signs, hemiplegia is quite common. Ataxia cranial neuropathies, which include the third, fourth, and sixth cranial nerves can cause diplopia. Visual loss due to optic neuritis, seen less commonly. Spinal cord dysfunction, impaired speech like this patient had. And patients don't necessarily have to present like a typical infection with leukocytosis, elevated ESR, CRP. These are patients that are, for the most part, out of this infectious window. However, it's good to have baseline labs to make sure that they don't have something else going on, like underlying central nerve system infection. Some of the implicated pathogens, the list is very, very long, as you can see here. Some of the more common things like coronavirus, which cause common colds, influenza, measles, and little children that haven't been vaccinated, multiple bacterial infections, and then the more rare things that you might see in the developing world, malaria, dengue fever. Also, interestingly, some vaccines have been implicated in the development of this disease. Less than 5% of cases, however, most commonly the MMR vaccine has been linked to this. Other things that maybe you and I might have had recently was the 2009 H1N1 influenza vaccination has been linked to this as well. So, quick pathology, you can see here that this disease involves perivascular inflammation, edema, perivenular demyelination. You can see here there's lymphocytes and macrophages surrounding this venial here, and there's relative sparing of the arterial down here. These are some special stains for myelin, and there is a clear border here of demyelination around this venial, and the same thing is seen here. Proposed mechanism of this disease, although it's not known for sure, similar to multiple sclerosis, is a transient autoimmune response to myelin or other self antigens because of the activation of auto reactive T cell clones. Molecular memory is, mimicry is one of the most common hypotheses that's written in the literature. Basically, host pathogens and host cells have enough similarity to incite T cell activation and response, however, not enough similarity to induce T cell tolerance. That's how this mechanism works, basically. Another mechanism proposed, there's a direct infection of the central nervous system which damages the blood-brain barrier, and there's leakage of these auto antigens into the serum and then an autoimmune reaction which occurs after that. High affinity antibodies to myelin basic protein which would lead to destruction of myelin and give you these characteristic findings on MRI. And then most recently there's this protein called myelin oligodendrocyte glycoprotein. There's assays for the IgG levels of this, and there's higher levels of this MOG, high DG in the serum of patients with Atom and also clinically isolated syndromes. So, workup as we did in the emergency room, a lumbar puncture patient already had an MRI, at least you'd go MRI first, then lumbar puncture, labs to rule out any infectious ideologies like we did, and then demyelinating markers. These are somewhat mixed in terms of how helpful these are. We typically see patients that are admitted with multiple sclerosis flares, they get oligoclonal band levels like this patient did, an IgG index. These are markers for demyelination. However, the studies that I've looked up did not show any statistical significant difference between patients with MS and patients with ADEM in terms of is this useful for characterizing one over the other. Lumbar puncture, like in our patient, may have a little bit of pleocytosis, increased protein concentration, but for the most part these patients can have normal CSF, unremarkable. This kind of helps you say oh, this might not be infectious and these lesions look characteristic of demyelination. I'm more comfortable starting steroids without completing my infectious workup. Neuroimaging, so this is really a diagnosis clinically and radiographically. T2 and flare are the best imaging sequences to show these demyelinating lesions, as I showed previously. Subcortical white matter, gray, white junction lesions, multifocal, asymmetric, patchy, white, hyper-intense lesions. Throughout the CNS we can see them not only in the cortex or subcortical areas or the cerebellum like our patient had, also in the thalamus, basal ganglia, which can lead to patients' ataxi and things like that. Paryventricular sparing, this is a variable sign on MRI. MRI on multiple sclerosis more typically shows this periventricular hyper-intensities. There isn't any statistical significant difference in between periventricular sparing in MS and ABEM, however. Also optic neuritis has been reported and CT is often normal and not helpful, so always go with MRI in these similar cases. Okay, here's some more typical images of patients with ADEM. You can see here maybe more so than in our patient is confluent, patchy, white, hyper-intense lesions in the white matter. Over here on the right, you can see lesions involving the thalamus. Here's an MRI of a patient, 18-month-old patient with similar lesions, can also involve the center of the brain here. Some of the ophthalmic manifestations that we wanna look out for as clinicians that we might have patients like this walking in just like we did here. Visual field deficits like our patient had. Optic neuritis is a presentation, cranial neuropathies causing double vision, ptosis. This is a case report of a patient taken from the University of Iowa who presented with white matter lesions on his MRI as well as grade two papillodema. Here's the MRI of that same patient, you can see enhancement of the right optic nerve here. I don't have any of the other cuts lower down but he did have characteristic lesions for this disease. Another patient presented with optic nerve swelling as well as peripapular hemorrhages. This is another rare presentation of this disease, however, something to keep in mind if this is seen on your fundoscopic exam. Now, a little distinction from multiple sclerosis. Many of you might be saying, oh, what's the difference between multiple sclerosis and how am I gonna differentiate this based on MRI? And of course, the neuroradiologists are the one to really say, oh, this is more characteristic of ADM versus multiple sclerosis. However, just briefly, some studies, one by Schwartz showed that patients had a significantly longer duration of symptoms than MS than the patients that present with ADM. Less likely to have prior infection in MS as well. Another study by Callum and his colleagues, radiographic criteria that they proposed, absence of diffuse bilateral lesions, presence of black holes on MRI, presence of two or more periventricular lesions. These are more suggestive of multiple sclerosis and a pretty high sensitivity specificity for differentiating these two entities. Another picture here, this is MRI that's typical of MS. So you can see some differences here. There's multiple ovoid lesions here, periventricularly. You can see here on the T2 and the flare images, then the sagittal section here, you can see periventricular around the corpus callosum. These are, I guess you could call these Dawson's fingers as they commonly call them in the radiology suite. And down here, these are showing some black holes. They're pretty hard to see here. These are small, but these are characters of findings of multiple sclerosis. So there is some overlap with MS. You mean on this image here? Yeah, so that's a, I think a T, that's that image, which shows this overlap with multiple sclerosis, the same study of the Schwartz. They did a pretty long-term follow-up of 38 months of these patients. These were adult patients now, and 35% of the patients that initially diagnosed with ADEM did progress to MS and all these were within one year. Just a pretty high and scary number if you think about it. The data in children is a little bit less. You can see that the development of MS is around 28% in maximum. There's a range depending on what study you look at. The use of oligoclonal bands I mentioned before, is there an increased likelihood of relapse in ADEM or development of MS of patients that have elevated oligoclonal bands? Potentially, there's conflicting data. One study showed no statistical significant difference between patients that had ADEM and MS, and so it's not really a useful tool in differentiating. Another table here just showing some increased risk versus decreased risk of patients that could develop MS. If you're greater than 10 years old, 10 years old and develop this disease, you're at greater risk. Patients without encephalopathy, no precipitating infection, those with optic neuritis. They mentioned oligoclonal bands based on their data, but I just kind of refuted that on my last slide. Periventricular, perpendicular ovoid lesions, the Dawson's fingers that I showed you are patients that are increased risk of developing MS. The treatment. So before diagnosis, certainly you want to make sure to cover for infectious entities. Bacterial and viral pathogens can be covered with things like acyclovir and then antibiotics that are commonly used for bacterial meningitis. First line treatment, however, for these demyelinating lesions is high dose IV methylprednisolone. Our patient got the max dose for three days. After his three day course, he seemed to improve significantly. He was less confused. He said his vision was actually better, although we don't have any visual field to confirm that. After these three to five days, many authors propose using oral prednisone taper over several weeks. There's no randomized control trials to support the use of long-dose steroid taper. However, some studies have noticed that shorter steroid tapers showed higher incidence of relapse to this disease. Other things to keep in mind on an inpatient basis, anti-apileptic drugs for those that are experiencing seizures and up to a third of patients, respiratory support for those needing it if they have brainstem involvement. Even things like continuous pulse oximetry can be useful in patients that are at risk. Second line treatment, if IV steroids are not cutting it, you can also use IVIG as an adjuvant or by itself. Third line, there has been some anecdotal evidence that plasma pharesis has helped some of these patients that typically do six exchanges every other day and shown some promise with this treatment. Also some case reports with patients that fail IV steroids using cyclophosphine, interferon, beta, but no hard data to support use of this. Clinical course of this patient, actually for typical patients is slow recovery over three to 12 weeks could be longer. Many patients have complete resolution of their MRI findings up to 75% and I'd say a combination between patients that have complete resolution and partial resolution is the majority. Current recommendations are for two follow-up MRI studies after a first normal MRI. So if this patient would have come back six months after had a normal MRI, then we would have gotten two subsequent MRIs to make sure that he does not have any more active lesions and just keep a close eye on him. He's in the adult range. He is at significant risk for developing multiple sclerosis. Some early data on mortality rates of this disease is less than 5% and I think things have clearly gotten better now that we have more advanced diagnostic techniques, better imaging techniques and just better in hospital care. 38 month follow-up in that Schwartz study that I mentioned, 46% of patients were symptom free, 35% so up to a third of patients who had minor residual symptoms, whether that be mild hemiplegia, ataxia, speech deficits, visual field problems and then 12% of patients in the study actually had moderate deficits. None of them were incapacitated at the point where they needed long-term care. Our patient follow-up, he was actually originally from Las Vegas so he was kind of bouncing back between Salt Lake and Las Vegas. However, we did see him three weeks post-op in the neurology clinic with the follow-up MRI. Patients mother was with him this time. She thought his speech was much better but they did note that he did have some mild speech errors during the exam but nothing major. They recommended he go to speech therapy for these. MRI, I'll show you a picture on the next slide, did show interval decrease of the size of lesions, less intense so we do think that this is very, very consistent with ADEM. Unfortunately, we do not have a follow-up visual field or visual acuity on this patient. We also recommended a six-month follow-up MRI which none of these are in power charts so this patient was lost the follow-up, unfortunately. So here's a comparison of his MRI. This is a T-tube image here. This is on presentation. I showed you this before. Very, very large lesion here which was most likely accounting for his visual field deficit. And then here, three weeks later, decreased intensity on these white-mattered lesions here and also this lesion here also shrunk. So conclusions and observations that are important for ophthalmologists. Important to know this is in post-infectious etiology, demyelinating lesions, it's acute in onset, can affect your younger patients, not just in the elderly. Visual symptoms can be common like things that present as optic neuritis, visual field deficits, cranial neuropathies. This is a steroid-responsive disease and there is a connection with multiple sclerosis so the patients do need long-term follow-up for these. And that's it. Any questions? Thank you.