 Good morning everybody we're going to go ahead and get started here in the interest of time. Welcome this morning to Grand Rounds we have three great topics that we're going to hear about today so I'm just going to go ahead and introduce all three of our speakers and then let them roll and we'll minimize the interruption. So first we'll be hearing from our UVitis fellow Lynn Hassmann. She's going to speak to us about an update on autoimmune retinopathy. Afterwards we'll hear from Ashley Brundrette one of our cornea fellows about desmetorexists without endothelial keratoplasty and other possible treatment options for corneal endothelial dysfunction and then finally we'll hear from one of our senior neurology residents who's been rotating through our neuro-ophthalmology rotation Jonathan Galli he'll talk to us about differential diagnosis for a painful horners syndrome. Thanks Lynn. Alright I'm Lynn Hassmann the UVitis fellow I'm going to talk I like Mike said about autoimmune retinopathy. So the story starts in 1976 when William Hoyt described three patients with blindness in the setting of metastatic cancer and he made an interesting observation visual disturbances associated with cancer are ordinarily caused by metastasis to the brain meninges optic nerve orbit coridoretina. This report documents blindness caused by retinal degeneration of obscure pathogenesis in three patients with cancer. So that kind of started the story about a decade later a 23 kilodalton protein was discovered that the patients with cancer associated retinopathy serum reacted to and a few years later it was revealed that that that protein was recovering a protein that is sometimes apparently expressed in cancer cells. Another decade later this group showed that the patients serum would react to the photoreceptor layer and that you could block that reaction with purified recovering so indicating that that probably was that the pathogenic antibody in this case and then the group further showed that if you immunize a mouse with recombinant recovering you could get a photoreceptor disruption that was immune mediated so sort of a cox postulate. So fast forward to now autoimmune retinopathy is comprised of perineoplastic retinopathy so cancer associate associate retinopathy is a spectrum of disorders that was sort of first described melanoma associated retinopathy is a little bit of a different beast with some characteristic antibodies that target more the bipolar cells and cause sort of a characteristic electronegative ERG and then nonperineoplastic autoimmune retinopathy in cases which there's no associated cancer discovered. So I'm going to present a few recent cases of non perineoplastic autoimmune retinopathy. The first is a 69 year old man who's complaining of progressive difficulty with night driving. So upon further questioning he actually says he's noticing some tunnel vision he's having problems with depth perception and intermittent double vision. His past ocular history is significant for myopia astute of fakia and he's been treated for normal tension glaucoma for the last five or ten years with lumigan and laser trapeculoplasty. He's had a he has coronary artery disease and he's had a heart attack also interstitial cystitis but no other significant past medical history. On review systems interestingly he endorses some fatigue a 30 pound unexplained weight loss over the last three years and tinnitus. It's a little concerning. So on exam his vision in the right eye is 2040 the left eye sees 2050 there's a very mild vitritus in both eyes and when you look at the fundus you can see peripapillary atrophy and sort of a myopic appearance to the fundus but the arterial the vessels particularly the arterioles are attenuated in the 69 year old and the the foveal reflex is sort of blunted and the optic nerves are not extremely glaucoma. So his visual field though is notable for very severe constriction. This is actually progressive compared to the information that he was referred with. So his auto fluorescence shows some hypo auto fluorescence around the nerve possibly just myopic some other myopic changes but then this dark hypo auto fluorescence around the macula and then actually a ring of hypo auto fluorescence right around the fovea and his fluorescein sort of shows hyper fluorescence that's likely window defect around the macula and nasal and then some changes around the nerve as well that may be myopic. The most striking feature of his imaging is this OCT in which if you look just beneath the fovea you see that the photoreceptor layer that ellipsoid zone is intact but then peripheral in the parafoval area it's gone and the outer retina is also attenuated and this is seen in both eyes so probably causing that constriction of vision and his tunnel vision that he noticed and his ERG is flat in scotopic and photopic parameters. So he had got a basic workup in which we ruled out usual inflammatory suspects and then actually ended up having enol anti enolase anti retinal antibodies detected on both western blot and immunohistochemistry a little more about that later. So we presumed autoimmune retinopathy the next step was to rule out malignancy in this patient with a 30-pound weight loss and his workup for malignancy was negative he had chestin abdomen CT he had a putt scan CA 125 colonoscopy prostate seromanogen and dermatology evaluation and a bladder biopsy because he had had a bladder mass but there was no malignancy found. He was treated with prednisone cell sept and eventually required psychosporin to stabilize his photoreceptor degeneration. The second case is a 47 year old female with progressive blurring for two years. When pressed she did endorse poor night vision difficulty adjusting to changing in lighting conditions and some contrast sensitivity issues no significant past medical or ocular history should a family history of autoimmune thyroiditis. On review system she also noted a 15 pound weight loss some joint pain chronic cough and a little bit of gait unsteadiness. So this patient on exam her vision the right is 2020 the left eye is 2025 there's a very trace of atritis in the left eye. If you compare the two eyes you can see that the vessels in the left eye are a little more attenuated maybe there's some mild blunting of the foveal reflex the nerves the rest of the exam is pretty normal there was some hypopigmented spots kind of in the periphery on her OCT the right eye looks pretty normal and the left eye you can see actually some macular edema the photoreceptor layer here looks and looks at fairly intact lost my screen here. Fundus autofluorescence is not very remarkable some subtle changes here in the left fovea that are probably related to the macular edema and on fluorescein you can see that the left eye there's a little bit of disc staining and maybe some parity vascular leakage but then there's just sort of this nasal hyper fluorescence you know in the a little bit later stages which which may just indicate a little bit of thinning and window defect there. For visual fields are remarkable the right eye is pretty full the left eye is dramatically constricted and then when we look at her ERG she has pretty flat scotopic responses and a really reduced B way especially in the left eye and so she had to also work up we included HLA A29 for bird shot because she had a few spots and some ERG changes that could be consistent. She also got spark genetic testing looking for any polymorphisms associated with retinal degeneration and that was all negative. Antiretinal antibodies she actually had four only one of them is actually associated with a known protein and then she had some staining on in immunosubchemistry at the photoreceptor layer as well. So she was treated with Ozardex which resolved her macular edema and she's going to undergoing a malignancy work up in coordination with her PCP and starting methotrexate. So autoimmune retinopathy the median age for patients with a cancer associated retinopathy and often this is or this can be the first presentation of a cancer actually is about 79 patients with autoimmune retinopathy tend to be around 51 and then interestingly patients who present with macular edema can be younger around age 36. There are more women than men affected and the reports vary on what the frequency is and there's often a family history of autoimmunity. So essential elements in the diagnosis of this disease. Number one there cannot be any evidence of malignancy after a thorough work up. There can't be any evidence of a retinal degenerative condition. They have to have some anti-retinal antibodies and there needs to be an ERG abnormality plus or minus a visual field abnormality. Supportive criteria are symptomatic photopsias, scutomas, nictalopoeia or photoeversion and discromatopsias. So how do we test for this? The screening Western blots are used to basically probe a blot created from human or porcine retinal lysates with human serum to detect any reactivity. Then this is validated with immunohistochemistry so tissue sections of retina either murine or human or porcine with the same serum and then it can also be validated with a Western blot against a purified protein like recovering or enolase or an ELISA against the same. So then how do we interpret this? So this is really where the field is struggling right now. So proteins targeted by anti-retinal antibodies in the car or cancer associate retinopathy there's a handful that have been described. Some of them have been actually found to be expressed in tumors and shown either in vitro or in vivo like the mouse photo that I showed you before to be pathogenic like recovering and many have not been. Similarly with mar or melanoma associated retinopathy these antibodies are usually targeting bipolar cells and we see an electronegative ERG so they're probably pathogenic we think. But then in autoimmune retinopathy there's an even longer list of antibodies that have been associated. The pathophysiologic significance of those is not really known. Very interestingly though if you look in some other patients with inflammation in their eye you find antibodies against retinal antigens. So in oncocerciasis greater than 90% of the patients that were looked at had an antibody against a 44 kilo Dalton RPE protein. In taxoplasmosis there's an antibody found in more than 90% of the patients against a photoreceptor protein. Patients with retinitis pigmentosa particularly those with cystoid macular edema in which there's breakdown of the blood retina barrier have antiretinal antibodies as do macular degeneration patients and other neurologic disease autoimmune neurologic diseases lupus and then 6 to 62% of normal people have antibodies as well. So how do we interpret this so there's few few of these antibodies with demonstrated pathologic role few with tumor expression that's known many of unknown significance and importantly the presence of antiretinal antibodies might just be an indication that there's some inflammation going on in the eye. So you you damage a portion of the eye you release cells that are not normally exposed to the immune system and the immune system recognizes those those proteins and mounts an immune response. So it may be just a marker for some people of something pathologic going on in the eye. So what else do we know about the pathophysiology? So the serum of these patients have a show elevated levels of TNF alpha and interfering gamma to sort of generic pro inflammatory markers but at levels much lower than other UV entities like posterior UV entities that we think of similarly much lower levels of IL-1 beta which is a very upstream pro inflammatory cytokine and then fewer circulating plasma blasts which are the antibody producing cells in an acute reaction. So whether or not these antibodies are pathogenic in every patient still definitely remains to be determined and also notably B cells are not the predominant of circulating immune cell in either autoimmune retinopathy or other UVitis diseases. So it may just be part of a global immune response. So the most important thing basically to do for these patients once we've identified them is to rule out cancer. As I said, cancer socio-retinopathy often presents before known diagnosis of cancer. So this is coordinated with a primary care physician. The patients need a chest CT of the chest out of abdomen and pelvis. Maybe they need a PET scan as well. They often get an MRI of the brain, Durham exam, colonoscopy, mammography when appropriate, and a gyne exam as well as when appropriate, prostate screening when appropriate. And then they're treated usually first line with steroids and then they almost always require something more anometabolites, cyclosporine, plasmus, phoresis and IVIG have been used and that makes intuitive sense if you're if you think that the antibodies are pathogenic, rotexamab and other immunomodulatory therapies have been used as well. And so if the disease is caught early, you can have some reversal of the photoreceptor damage and some improvement in vision. So what are the future directions for this disease? First of all, validation of antiretinal antibody pathogenesis is a big important move forward. Both for diagnostic purposes and for understanding the pathology of this disease and then characterizing the immunogenetic predisposition of these patients. Why are these patients getting this disease? Why do some normal people have these antiretinal antibodies and don't suffer any vision loss? So some of this can be done with epidemiology, perhaps with the Utah population database, HLA haplotyping, NK cell receptor analysis and even large scale screens like genome wide association studies.