 Good morning, everyone. It's an honor to have you all at Grand Rounds. We'll be in exciting Grand Rounds. Abigail Gibrush will be our moderator for today and we'll let Randy take it away and then over to Abigail. So I just wanted to let everybody know what we're planning in regards to this tragic loss of our colleague, friend, mentor, you know, Alan Crandall. About two o'clock last Friday he passed away. I know, I'm sure most of the details are out, but he had a horrendous dissecting, or aneurysm, vascular surgeons all commented it's the worst, most difficult repair they'd ever been engaged in. It was a 12-hour repair and Alan's the toughest guy I know. I kind of thought anybody was going to beat it, he would, but there was just too much damage and association with that. So it leaves a huge hole. I want people to know that we are going to have a memorial service, mainly a celebration on Friday at 5.15 and there will be several of us who will discuss our personal contacts and information about Alan. Again, I'm going to pull out the best videos with Alan and then I'll have some comments. There's an interactive service that we have where people can, you know, go on and make their comments and, you know, discuss their thoughts about Alan. And so that's available on online and that was part of the announcement. They're not yesterday. People have been engaged in that and then we're going to wait to where we can really get together. It's going to be hard. It's so hard to do a thing like this without an audience to respond to that mutual sense of, you know, both mourning together and celebrating together, but we'll have that celebration. So our gala that we had to put off will come. I don't know exactly when, but when we can, hopefully in the spring, early summer, and this year it's going to be a celebration of Alan, his life and how he represents. So stay tuned. I know a lot of people are suffering. I know what a hard blow this is. Hearts have to go out to Julie and family. I can tell you that I was with them on Friday and this is very, very devastating. So just have that announcement and he will not be forgotten. Jeff, I turn it back to you. You're muted. All right. Thank you, Dr. Olson, for your words about Dr. Crandall. His loss is certainly felt by the residents as well. And he will always be remembered in our hearts as well. This morning, my name is Abigail Jabaraj. I'm one of the PGY2 residents. It is my pleasure to introduce this grand round today from our pathology fellows. First up, we have Philip Q. He is from the University, oh, sorry, due to technical difficulties, we're kind of switching up the order here, I think. First, we'll have Catherine Culp. She comes just from the Ohio State University College of Medicine. I asked the pathologist what their favorite activity they've done in Utah so far has been and her favorite activity has been visiting Bryce Canyon and also the Zion National Park, especially the Colob canyons in Zion. She will be presenting to us a case of ocular pathology of a patient with autoimmune polyendocrinopathy syndrome. As we have her present, if you have any questions or comments, please put that in the chat box. When she is completed, if we have time for some questions, we'll do that at that point. And if you'd like to be unmuted to ask a question, please say so in the chat box so you can be unmuted. Catherine, please take it away. Thanks, Abby. First, I'd just like to thank Dr. Manless and Warner for the amazing opportunity to work in their lab this past five months. And then I'd also like to thank Dr. Hagueman and his lab for helping us with this and finding the donor eyes that I'll be presenting on. Start off with, I just wanted to do a brief background of what autoimmune polyendocrinopathy syndrome or APS is. So this syndrome is a rare disease defined by the autoimmune failure of two or more endocrine glands. And it's been divided into two different types. Type one is an autosomal recessive syndrome caused by mutations in the AIRE gene, which encodes a transcription factor that is responsible for negative selection of auto reactive immune cells. It typically has a juvenile onset and is characterized by a combination of hypoparathyroidism, mucocotaneous candidiasis and or adrenal failure, which is also known as Addison's disease. And then type two consists of syndromes that are have a multifactorial cause and usually onset in adulthood between ages 40 to 60 years old. And as with most autoimmune diseases, this type of syndrome is more common in women than men. Here we go. Sorry, this is a busy slide, but I just wanted to use it to show that while juvenile type of APS is well characterized and has just one gene that it's associated with, adult type, which has been split into three different categories by this author based on which type of endocrine disease is present, is much more diverse in its manifestation, and there are quite a lot of genutations that have been associated with it. Moving on to our patient. So she was a 23-year-old female with a history of APS, which included acid disease or autoimmune endocrine failure and hypoparathyroidism. She also had a history of migraines, IVS, NASH, and hypercholesterolemia. She presented to Dr. Barlow in South Jordan complaining of blurry vision and dry eye. He had a history of bilateral cataracts associated with her acid disease and chronic steroid use to treat that disease. For a visual acuity, it was significant for decreased vision in her right eye compared to her left eye, and her visual field showed a super nasal defect in her right eye. On exam, it was notable for bilateral corneal erosions consistent with her history of dry eye, as well as bilateral cataracts. On fundus exam, Dr. Barlow saw two-plus optic edema in the right eye, as well as pigmentary changes in both eyes. Due to the disc edema, he referred her to neuro ophthalmology, and she saw Dr. Crumb two months later. Dr. Crumb's exam was consistent with Dr. Barlow's, and she took these fundus photos, in which not only can you see the blurring of the optic disc in the right eye, you can also start to see these pigmentary changes that Dr. Barlow talked about. Due to concern for an intracranial mass, she ordered it outside MRI, which showed no mass or thrombosis, but mild dilation of the optic nerve sheath, as well as scleral flattening of the globes consistent with increased intracranial pressure. Due to this finding and no change in the patient's symptoms or exam two months later, she started the patient on dimox, and then saw her back 48 months later. At the four months follow-up, she had gotten cataract surgery in her right eye in the interim, and the patient stated that her vision had improved in both eyes, and the exam correlated with this showing what improved edema of the optic nerve and improvement in the right visual field defects. Here is the patient's OCT, showing that in February when she was started on dimox, and then improvement in June when she came back for a four month follow-up, although the improvement especially in the nasal OCT and edema is most likely exaggerated due to a difference in segmentation right here and here. And then this is the left nerve, which is relatively normal. Unfortunately, the patient was lost to follow-up and passed away 18 months later due to a cardiac arrest caused by electrolyte abnormalities from her Addison's disease. Her eyes were donated to the Lyons EyeBank, and here you can see their postmortem photographs that are taken by the EyeBank after they take off the cornea and then cut the globe into a flower petal shape. I've circled on these pictures areas where you can see this pigmentation that correlates to what Dr. Barlow and Dr. Krum saw on exam, and it's notable for having a bony specule appearance similar to what we see in retinitis pigmentosa. So we took the left eye and processed it in our lab and stained it with H&E, and here's one of those slides. I would just like to note that the detachment of the retina is just an artifact of processing, and you can see at the black arrow there is this pigmentation that has been deposited in the inner retina around a blood vessel, which is magnified on the right, and then between these orange arrows you can see that the retina, especially the outer retina, has been atrophied. In this picture you can once again see this deposition of pigment in the inner retina, but in the corresponding RPE there is a loss of pigmentation, and this is just a higher magnification showing that deposition of pigment, especially around this vessel. This slide is from Dr. Hagueman's lab. They stain with Richardson stain, and the way they process it, they can make the slides very thin and have better resolution. So in these pictures you can see at the black arrows there is this pigment deposition again, and then when we look closer you can see it's very nice resolution of the retina, and in addition to this pigmentation in the retina you can see this atrophy of the outer retina and loss of pigmentation, the RPE, very nicely. Based on what we saw on the histopathology I looked in the literature to see what's known about ocular manifestations of APS and the autoimmune diseases that make it up. So first, dry eye and cataract are unsurprisingly common in most of autoimmune diseases, and for APS-1 given it's a monogenetic disease it has also been well characterized as being associated with keratoconjunctivitis, optic atrophy and retinal detachment in addition to cataract, but for our patient for Addison's disease has been documented be associated with conjunctivitis as well as abladema, but in larger literature reviews there's no mention of the retinal pigmentation. So looking, so I looked further into the literature and I found three different case studies that spoke about retinal pigmentation in either APS or Addison's disease. The first case was from 1926 from my home state of Ohio where a 35-year-old man was admitted for an adrenal crisis and diagnosed for with Addison's disease. He had common Addison's disease symptoms in addition to the renal crisis such as bronze pigmentation of his skin and ocular dermal melanocytosis, sorry. He also had some optic nerve pallor temporarily, but what I found most interesting was they noted dark gray homogenous deposits of pigment around each macula on fundus exam. Unfortunately, this patient passed away but they were not able to do a postmortem exam. On the eyes and then the second paper I found was from 1991. It was a 39-year-old man with APS-1 who presented with six months of progressive loss in his left eye. He'd also had previous vision loss 20 years before in his other eye. He had bilateral arcuate visual field defects similar to the visual field defect our patient had and then they noted on exam they had optic nerve pallor attenuated arterioles and this bone spignant spicula pigmentation of his right eye similar to what our patient showed. And then the last paper I found was from 2015. It was a series of five cases of patients with APS-1. The authors found that all of these patients had peripheral retinal changes which went from isolated atrophy of the RP to more bone spicula pigmentation similar to RP just like we found in our patient. They also were able to do a CT on their patients and showed that four of them had macular atrophy which you can see is shown in the picture on the right and then they were also able to test for the patients for antibodies and found that all four of the ones tested had antiretinal antibodies correlating that the changes they found are possibly related to the auto-reactivity present in patients with autoimmune disease. In conclusion, autoimmune polyintercropathy syndrome is a rare disease defined by the presence of two or more autoendocrine diseases whereas type one is an auto-recessive disease caused by this mutation in the A-I-R-E. Same with very specific findings of hyperparathyroidism, mucocotaneous, candidiasis, and adrenal failure. Type two encompasses a spectrum of disease that's multifactorial in cause and usually begins in adulthood. The ocular manifestations of APS-1 have been well defined as well and include keratitis, dry eye, cataract, retinopathy, and apoptic atrophy. While in APS-2 the findings in each patient depend on the specific autoimmune disease that's present. And then finally based on the histopathology we found as well as in what I found in the literature, it appears that the retinal pigmentation changes in atrophy present in our patient appear to be a possible manifestation of Addison's disease and are also pathologically similar to those found in retinitis pigmentosa. I'd like to thank everyone in my lab or in my lab and in Dr. Hageman's lab that helped me including Dr. Mamelis, Dr. Hageman, Mark, Tosa, Mary, Mayfield, our histologist, and Phillip. I'd also like to thank the Lions EyeBank for providing the eyes that we used in this presentation. And here are my references. Finally I'm open to any questions. Thank you so much for your presentation, Catherine. You did an awesome job. At this time we will take any questions in the chat box or if you would like to be unmuted please let me know. So it's Dr. Olson. It's amazing how protean the presentation is that we call retinitis pigmentosa. There are what? Over a hundred and fifty now genetic mutations that will result in that presentation. And though some of them are certainly in related areas there are a lot of different drivers. And here we have one that would seem to be potentially directly not related to raw dystrophy resulting in this presentation as well. I think this is fascinating and I hope you're indeed going to put this out for publication. I think it's a nice correlate of which I'm not aware of anything that's been this complete with such great histopathology. Thank you. Hey this is Anayak. Am I unmuted? Yes. Okay excellent. What I found was really interesting on this case as Catherine presented is the fact that the retinal findings were very very similar to retinitis pigmentosa yet there was significant preservation of retinal function. And so even though the pigment was coming from the RPE and was going along the vessel similar to what we see in retinitis pigmentosa there was still a good preservation of retinal function where the findings were not found. So it's very interesting in that it looks a lot like RP but in a way behaves differently. Interesting. Fascinating shows you how you know morphology and function don't necessarily correlate completely but obviously there's something about any disruption having to do with that visual cycle that will result in the retina responding in this type of morphological fashion. Great presentation. If you wouldn't mind just stop sharing for a moment so Philip can get queued up. I actually don't have a question other than to say go Buckeyes welcome to you. That was a job well done. Great presentation. Wonderful. All right thank you Catherine. Next we have Philip Q. He comes to us from the University of Mississippi School of Medicine. Here in Utah so far he's enjoyed hiking as well as participating in the Navajo outreach trips. He will be presenting histopathology of Roth spots in a patient with anemic retinopathy. Philip take it away. Is this working now? Okay thank you. Good morning. Sorry about the technical difficulties. Abigail thank you for the introduction. My name is Philip as Abigail said and I'll be talking about the histopathology of Roth spots in a patient with anemic retinopathy. Before we get started I need to thank some instrumental people who were who made this project possible. I'd like to thank Dr. Mamois, Dr. Warner, Mary and Michelle, again Catherine as well and thank everyone for the opportunity of being here and also Dr. Hagenman for providing us with the donor eyes. This project would not have been possible without him. So for our patient we have a 41 year old male with a history of acute lymphocytic leukemia and myelodysplastic syndrome who is consulted due to changes in his vision in both eyes. During this admission he was undergoing infectious workup after admission for fever and abdominal pain. His past medical history included only the ALL and myelodysplastic syndrome. He did not have any history of diabetes or hypertension. The only surgery that he's ever had was an appendectomy. His family history reveal no history of any eye problems and his social history was unremarkable for any IV drug use. His review systems was positive for fever and bleeding and of note during this admission the patient's myelodysplastic syndrome was found to have transformed into an acute myeloid leukemia and the patient passed away from septic shock soon after his initial ophthalmology exam. On his exam his vitals were within normal limits. His base eye exam showed a severe vision loss in his right eye. Here we see that he has only count fingers in the right eye while 20, 30 in the left eye. The rest of the base exam is normal with pressures of 13 and 12. There's no apparent pupillary defect. His visual fields and extra ocular movements were full as well. His slit lamp exam was benign and on further investigation the fund has showed some striking exam findings. In the right eye we see 360 degrees of discadema with disc hemorrhages surrounding the nerves. In the macula of the right eye it was covered with subpilot hemorrhage and superiorly there is an area of widening. In the periphery of the right eye there are some nasal and inferior peripheral raw spots. In the left eye there is discadema nasally as well with some disc hemorrhages and closely arranged raw spots. The hemorrhage in the macula was significantly less than the left eye and there are also two temporal raw spots. Here we have the fundus photos from our photography department. They beautifully show the classic raw spots in both eyes. Raw spots are these areas of retinal hemorrhage that can be round or flame shaped. They are characterized by this area of central widening. In the right eye we see multiple raw spots scattered throughout the fundus and in the left eye as well. The fundus photo also shows the other exam finds of discadema, disc hemorrhages in both eyes and then also the marked macula subhyloid hemorrhage in the right eye. On the macula OCT we see subhyloid blood that is much greater in the right eye than the left and that's consistent with the previous fundus photos. Looking at the labs the CBC of this patient shows that he was pancytopenic but he had a severe anemia with a hemoglobin 6.5 and a hematocrit of 19.4. He's also severely thrombocytopenic with a platelet count of 10. We'll also see I think it's important to note that his white blood cell count is mildly low at 2.6. Given this patient's presentation the differential for the cause of this patient's raw spots includes subacute bacterial endocarditis leukemia and anemia and it was determined that the most likely cause was an anemic retinopathy. While subacute bacterial endocarditis leukemia and anemia are among the most common causes of raw spots is a thing is important that we keep in mind all these other causes as well and the differential upon seeing a raw spot should remain wide. So a little bit about the pathogenesis of raw spots. The studies have shown that the white centers of the raw spots result from a formation of this platelet fibrin thrombus that forms at the site of a capillary rupture. Intuitively this tends to affect patients with conditions characterized by capillary fragility or patients prone to bleeding. As we can see from the long list of of conditions that cause raw spots elevated venous pressure is a risk factor as well and that is seen in neonates with traumatic birth, shaken baby syndrome and also intracranial hemorrhage. And lastly there have been rare reports of raw spots occurring after a trabeculectomy which suggests that there's some component a mechanical trauma to the fragile retinal vessels that can cause the capillary rupture as well. These are the gross photos from from Dr. Haigman's lab. They confirm the diffuse hemorrhages that we saw on the fundus photos. These photos are taken after they were cut with this flowering technique that enables these globes to be nicely laid out flat. So the globe that we received in our lab was the right eye and we processed it like with our typical glove processing. This is the cut we we typically do in order to preserve the macula and in this case we're also able to preserve most of the the areas of interest as well. And we did our typical H&E stain which nicely shows the location of the hemorrhage. We see in the Roth spot itself this area of intra retinal hemorrhage and then there's also a small component small sub-hyloid component as well. A little bit higher magnification we see the the intra retinal hemorrhage and then we also see the central location of this platelet fibrin thrombus and then at the highest magnification this we see that the platelet fibrin thrombus is this pale staining acelular area in the center of the hemorrhage. We also see the the hemorrhage kind of disrupting the normal architecture of the retina. One important thing that we do not see here is we see there is a lack of any neoplastic leukemic cells which we would likely see in in a patient with leukemic infiltrates. So in the left eye these were processed by Dr. Hegman and in his lab and after these kind of punched out biopsies were taken they were able to stain it with this beautiful Richardson stain showing that nicely shows the location of the hemorrhage again. So upon observing a raw spot it's important to work up the patient with a thorough history and physical exam and then a further treatment will be directed with whatever is revealed. For patients with with findings suspicious for endocarditis such as the classic Janeway lesions, Osler nodes, splinter hemorrhages, CBC, ESR, CRP blood cultures, ECHO and starting antibiotic therapy would be would all be reasonable. In patients with a complaint of episodes of bleeding and a possible hematologic disorder CBC again and also peripheral blood smear patients at risk of HIV should get HIV testing. And then people with carbon monoxide poisoning should get a blood gas co-oxymetry and patients with possible diabetes should get a hemoglobin A1C and blood glucose as well. So a little background on raw spots these spots were described in 1872 by Maritz Roth who described these retinal hemorrhages with white centers and patients with bacteremia. A few years later Maritz Roth described these retinal hemorrhages with white centers A few years later Maritz Lytton actually coined the term raw spots and reported incidents of 80% in cases of subacute bacterial endocarditis. At this point in time these white centers were actually believed to be septic emboli that composed of actual bacteria and leukocytes but this was later found to be untrue and and these at this time these raw spots were also considered to be a very specific finding for endocarditis but that has also been shown to be not true as we saw. So for a literature view on raw spots in an anemic retinopathy in this case series retinopathy was observed in 38% of patients with both severe anemia and severe thrombocytopenia. It was theorized that direct anoxia resulted in some endothelial dysfunction the role of platelets play is kind of twofold. The platelets themselves play an essential role in endothelial homeostasis and a low platelet count is conducive to bleeding episodes as well. Therefore this combination of a severe anemia and thrombocytopenia greatly increased the risk of retinal hemorrhages and raw spots. And then what I thought was interesting about this case was the patient's concurrent transformation of the myelodysplastic syndrome into a acute myeloid leukemia. So there have been reports of these leukemic infiltrates that appear to be kind of a pre-retinal white mass that can often be confused for the white centers and raw spots but in this case series Dr. Shachat differentiated between these leukemic infiltrates and raw spots and identified leukemic infiltrates in only 3% of patients who had been recently diagnosed with leukemia. The raw spots fell in the category of the other 39% of patients who had other ocular abnormalities related to their cancer. In an autopsy series they had reported leukemic infiltrates in 31% of patients who had passed away due to their leukemia. This kind of disparity in the incidence of these leukemic infiltrates can be attributed to possibly the more severe leukemia in the patients who passed away in the autopsy series. And then I thought it was interesting that they found a strong positive correlation between the presence of leukemic infiltrates and the agonal leukocyte count and if we can remember from this patient that his leukocyte count was actually low which may explain the lack of leukemic infiltrates. So as a summary some takeaway points I would like to emphasize that white centered hemorrhages are a nonspecific finding and especially in patients with severe anemia and severe thrombocytopenia and other blood dyscrasias. Remember that they are at risk for retinal hemorrhage and severe visual impairment. I'd also like to mention that the our histopathology shows that the raw spots are composed the white center is composed of a platelet of fibrin thrombus that is surrounded by the areas of extravaceated blood. And then here are my references and I would like to thank everyone in our lab as well as everyone in Dr. Hageman's lab at the Utah Eye Bank. Dr. Petty was one of the initial providers as well and I'd also like to thank my family. They they have been very supportive of me and I recently went to the living room on this hike and I told my family about it. My sister generously offered to send me a tent for to complete a bedroom to go with my living room and this is our puppy Rootby. He would like to ask if there are any questions out there. Thank you for your presentation Philip. We will take questions or comments at this time if you'd like to be in the chat box or be unmuted. Just briefly from a resident perspective Catherine and Philip have both been excellent in answering resident questions regarding pathology and getting back to us about different specimens so I would like to thank them both. Any questions or comments? Hi Philip it's Nick just a comment nicely done presentation. This is very nice in that the pathology really does answer the question of what is a Roth spot and I know you know even when I was a resident we were taught that it was probably gatherings of white blood cells or leukemic cells or part of a endophthalmide part of a you know infection from endocarditis and so this really nicely shows the area of the fibrin thrombus in the middle of the Roth spot and this case is particularly nice because it shows beautifully clinical pictures scans and then pathology and so nicely done. Yes sir thank you. Another question actually for both of you both can answer Catherine and Philip you know with all the advances in technology genetics diagnosis understanding of pathophysiology I'd really love to hear your perspective what you've learned about the role of pathology and what you see the future role of again plain old pathology in the future of medicine and understanding disease. Well I can start I think pathology has been I think there's a reason that you know in medical school we start pathology is one of the you know basic science courses that we study and I think kind of understanding different diseases from the microscopic standpoint has been very helpful personally for me understanding you know some of the clinical findings that I've seen you know during rotations and such. I agree with Philip I'd also say that even with all the advances that have been made in imaging and genetic testing there are still quite a few diseases that you might have suspect you know what the diagnosis is but the pathology is needed to actually confirm it or in cases like tumors you need the pathology to actually know whether or not you took the whole tumor hour or if more treatment is needed. Thank you both. Hi y'all I just wanted to make a comment and congratulate Catherine and Philip for a job very well done and just to comment how nice it is the Muranai Center that we have this opportunity through collaboration to actually have full clinical information and full histopathology on the same cases and in many instances for example we have a lot of studies with cadaver eyes and intraocular lenses but in the great majority of the cases we have almost no information clinically so through collaboration this is really great so congratulations. Are there any more questions or comments before we wrap up right with that thank you everyone for attending this grand rounds presentation thank you Catherine and Philip again for excellent presentations and we will see you next week for grand rounds thank you. Thank you.