 I'll get started, so this must be a less popular topic, and it's also called miscellaneous. But this is kind of more of an OCAP or review type of a talk, just because it's kind of a lot of esoteric things to kind of go over, so kind of no way around it. So systemic disorders with corneal changes, and so I've organized this into inherited systemic disorders, congenital non-hereditary systemic disorders, and other acquired classes, and I'll show lots of pictures. Okay, so these are inherited systemic conditions, and most of these are pretty rare, not all of them. So Wilson's disease is a autosomal recessive disorder with a decreased production of ceruloplasm, which is a copper transfer protein, and so you get copper accumulation of liver, and also other organs, and that leads to just overall toxicity. Usually starts earlier on in life, ocular manifestations, as you know, the Kaiser Fleischer ring, that's actually deposited in decimates membrane, and it first appears superiorly, and then it spreads 360 degrees. You can also see a sunflower cataract, and the treatment is with systemic copper accumulating agents such as penicillin, yeah. What's the earliest you've actually seen Kaiser Fleischer ring? The earliest? Yeah. I don't know. I can't say I've seen many. I may have seen my kid or two. I had a console for a kid one time and I wanted me to come rule out Kaiser Fleischer ring. Yeah, they always want to rule out Kaiser Fleischer ring. I feel like, I mean, 99% of the time when they want that console, there's not one. So you look at, you look and you say it's normal. I'm just curious though, certainly, if you say yes, you could see it. Yeah, it doesn't tell you that they're not going to take you out of a big, orange and yellow image. Right, exactly. So, yeah, there's a lot of concepts for this, for inpatients. And I think today I have a patient on my schedule that's ruled out, Kaiser Fleischer ring. So it happens all the time. But this is what it looks like. So it's kind of a dark brown or a golden ring. It does not, there's no clear zone at the limbis. So it goes all the way to the limbis. And then if you look on slip beam, you can tell that the deposition is deep. So it's that decimates memory there. Yeah. So if a patient was older, like older or not, would you see the Kaiser Fleischer ring through the orange? I can't say. Again, this is rare. I can't say I've had that combination. I'm sure. I mean, this looks different than the orange. So I think on slip beam, you'd be able to tell. Yeah, it'd be kind of brownish. So kind of different. Sunflower cataract here is kind of an anterior subcapsular type of cataract with this particular look. So that's pretty, I guess it's something that can be seen in Wilson's disease. Next is spagary disease. This is an excellent lysosome storage disorder. Pretty rare. Incidents is 1 in 40,000 to 1 in 117,000 in males. It's a deficiency in alpha-galactosidase. And that leads to an inability to metabolize glycolibid ceramide trihexaside. And so that leads to deposition in the lysosomes, which impairs cellular function. I can't see it on my screen. Okay. Treatment is with enzyme replacement infusion therapy. And you can reduce the pain that they can have in risk of kidney failure and myosome strokes with treatment. Corneomanifestations. They're usually not visually significant. Porniovergicilata are the most common. You can also see vergicilata in hemizygous males and heterozygous females. Other signs are dilated in torturous condress levels. You can see PSE cataracts. The differential does include medication that cause corneovergicilata, which is going to be far more common in various diseases. So this is what corneovergicilata looks like. So it looks like ricicilata that you would see with amyogorhenosate. And this is deposition. These are some dilated condentival vessels. And so there's a deposition in the vascular endothelium. And that produces these dilated condensate vessels. Okay, cystinosis. This is another autosomal recessive myosome storage disease. It's 1 in 100,000 to 1 in 200,000. And there's widespread deposition of cysteine crystals throughout the body, especially the kidneys. There are infantile, juvenile, and adult onset forms. The adult onset form usually does not have kidney involvement. The treatment is with a cysteamine or a land or a topical. Aco-finding symptoms include recurrent erosions. On exam, you'll see these really, really fine corneal crystals. You might see peripheral, a new vascularization, band, keratopathy, iris and condentival crystals, and retinal degeneration. The differential includes multiple myeloma. Usually the crystals are not visually significant. But over time they, I guess they could be. So this is showing some condentival crystal deposition. And then on the sublamp exam on the cornea, you'll see these tiny, tiny little refractile crystals in the cornea. And they are polychromatic, so you can see the different colors there. Okay, so next is a set of diseases that our bucopelicycoridose sees. These are rare, inherited myosomal storage diseases. And they're an absence of enzymes that metabolize glycosaminoglycans. And that includes dermatan, sulfate, heparin sulfate, and keratin sulfate. And all of these diseases are autosomal recessive, except for Hunter's syndrome, which is X-linked recessive. And the way I remember this is that you imagine like a Hunter kind of spotting, kind of shooting an X, X-linked recessive. So that's my silly little mnemonic, which actually saves me, because this tends to come up on bucopelicycoridose sometimes, I think. So the other autosomal recessive diseases are hurlers, shays, marto lemay, and sand. So you'll see corneal clouding, a little bit less so in Hunter's. It usually involves the whole cornea starting in the periphery and then progressing centrally. You can also see retinopathy and optiatrophy. You can consider corneal transplant, but they can recur. Enzyme replacement therapy is used in shay and hurler syndromes, and gene replacement therapy is currently being investigated. So here are some pictures of shay syndrome, marto lemay, and hurler syndrome. So corneal clouding starting in the periphery and then spread centrally in here. Next category are hypo... Oh, this talk is uploaded on the MEDHA, so you guys can access the whole thing. That knows a lot of information to kind of take in. Hypo-lipoprotonemia. So this is an abnormal reduction in serum lipoprotein levels. There's LCAT deficiency, which is Luthacin-cholesterol acryltransferase deficiency, Tangier's disease for shy disease, familiohypoveta-lipoprotonemia, and Basin-to-corn-lite syndrome. Only the first three of these cause corneal disease. So the corneal affecting ones are rare. They're autosomal recessive. LCAT facilitates removal of excess cholesterol in the peripheral tissues and the liver. So deficiency leads to cholesterol accumulation everywhere. And so you'll see early corneal orcus and also kind of a nebular seromal haze that starts in childhood. And a lab will show low HDL. So this is LCAT deficiency. Pretty cloudy. They're labeling Olympus right here. Fischi disease and Tangier's disease. Next is tyrosinenium. This is autosomal recessive. This is another enzyme defect of tyrosine immunotransferase leading to excess tyrosine in the blood and urine. And so patients will have hyperkeratotic lesions on their palms, soles, and elbows, and then eventual mental retardation. Symptoms will include market, photophobia, tearing, conical injection, tarsal, papillary hypertrophy, pseudo-dendrites that do not stain well, and then recurrences will lead to corneal or new vascular issues starring could consider in a young child with recurrent HSC keratitis. Could, problem is HSC keratitis is way more common than tyrosinemia. But this would, tyrosinemia would be bilateral. HSC keratitis, more rare to be bilateral. So this is what this looks like. See, kind of central corneal clouding there. Central corneal clouding. Patchy with some peripheral new vascularization. So, yeah, this could look like HSC keratitis. Lab work to diagnose it. You'll see high tyrosine in the blood and urine with normal phenylalanine levels. And the biopsy will be showing soluble tyrosine immunotransferase deficiency. Treatment will be restricting the dietary intake of tyrosine and phenylalanine, and that can reduce the corneal and systemic changes, including mental status, and lead to mental retardation over time. Alcaptanuria is another autosomal recessive deficiency where there's a deficient enzyme that degrades tyrosine and phenylalanine. There's accumulation of a homogenic acid that oxidizes and polymerizes into Alcaptan, which is a ground black material similar to melanin. And you can get ochronosis, which is deposition of Alcaptan into the connective tissues. Clinical findings are arthropathy, renal-calculated pigmentation of the cartilaginous structures. On the eye, there'll be pigmentation of the medial rectus and lateral rectus tendons and of the sclero adjacent to the tendon insertions. And there'll be darkly pigmented dots in the corneal epithelium or bonans near the limbus. Lab work. There's urine that turns dark on standing and alkalinization and homogenic, gen-tistic acid oxidase deficiency. And gene therapy is being investigated, so I'll give some pictures here. A picture of the pigment deposition around the tendon, rectus tendon insertion. And you can also see the deposition at Omen's layer at the limbus. Ehlers-Danlos. This is a little bit more common. There are greater than 20 types. These are defects in collagen synthesis, so there's joint hyperaccessibility and easy crucibility. Ehlers-Danlos type 6 has ocular involvement. It is also more recessive. There's moderate joint hand-skin involvement. They have brittle corneas that are easily ruptured, blue sclera, keratoconus, keratoglobis, and severe scoliosis. So this is type 6 with keratoglobis and you can see blue sclera there. And this is severe sclerothenine in a patient that was seen after astrophysic surgery. Marfan syndrome, more common. This is autosomal dominant. And this occurs from defects in the fibrillin synthesis in the extracellular matrix, and that leads to a lot of other systemic findings. Aortic root dilatation in aortic aneurysms, mectis excavato and kyphoscoleosis, sclerothenine, ectopia lentis. Usually the subluxation is superotemporal. One subluxation. Corneal flattening is seen, so this is kind of in contrast to Ehlers-Danlos where you see steepening. In 20% of patients, the average corneal thickness, or corneal steepness will be actually less than 35 diopters. Megalocomy and megalocornia and keratconis are uncommon. So this is ectopia lentis and Marfan syndrome, so you can see the edge of the dislocated lens, and so it's dislocating superotemporal. You can see that more here. And so there's another syndrome, which I don't think I talk about here, which is homocystinuria, where the lens dislocates in front of nasal, which is kind of the opposite. So the way I think of it is like Marfan's is totally tall, so they're like this, and it's like up and out. That's how I think of it. It's just silly little things I use to remember during tests. So up and out, Marfan syndrome, and then homocystinuria is the other one, it's like the opposite, it's down and in. Congenital systemic conditions. So they're moving away from the inherited systemic conditions. So these are genetic, but they're not necessarily inherited. Down syndrome, congenital syphilis, wiger syndrome, and golden heart syndrome. So Down syndrome is trisomy 21, as we all know, so up to 30% will have keratoconus, and they actually may present with acute corneal high drops, and there's a big correlation with eye rubbing. Collagen cross thinking may be the best treatment, and with keratoconus that's kind of a whole nother talk, so I'm not really going to get into keratoconus quite so much, but just know that there's a high association with Down syndrome. So this is showing what sign? Monson sign. Yes, monson sign. So a monson sign, you have steeping of the cornea that's so steep that it indents the lower lid when they look down. And this is corneal high drops, where keratoconus gets so bad that decimates, it gets so steep that the decimates membrane actually ruptures, and so all the aqueous comes rushing into the corneal stroma, and that's what all this haziness is. Next, congenital syphilis. Signs can be present at birth, but it usually manifests later on in life, five to 20 years old, and the most common finding is interstitial keratitis. So interstitial keratitis symptoms include pain, tearing, redness, and photosensitivity. You'll see stroma infiltrates and edema. Late findings will include progressive vascularization into the central cornea that regress into ghost vessels, and this will be typically bilateral. There are many other causes of interstitial keratitis, like Cogan syndrome, EBV, HSV, leprosy, lubus, Lyme disease, and TB. So here's some examples of interstitial keratitis. So this is active interstitial keratitis of Cogan's disease. You see kind of stromal haziness and lots of neurovascularization, and this is congenital syphilis. That's inactive interstitial keratitis. You can see these ghost vessels without any blood. Waggar syndrome, so this stands for Wilms tumor, which is niproblastoma, aniridia, genitomy, urinary abnormalities, and mental retardation. So this occurs from a deletion of a short arm of chromosome 11, which often includes the PAC-6 gene, and the size of the deletion varies. It's pretty uncommon. The incidence is 1 in 500,000, 2 about 1 in a million. With the aniridia, I mean, the name is a little bit... I mean, the name suggests no iris, but there's always some deletion of the iris present. And with aniridia, it's associated with the most stem cell deficiency, macular and optic nerve hyperplasia, glaucoma and cataracts. So this is a picture of aniridia, so it looks like dilated pupils, but this is a patient who's not dilated, so you can just see remnants of iris tissue in the periphery. Next is golden horror syndromes. This is also known as ocular auricular vertebral syndrome. This is an anomalous development of the first and second brachial arches. It's an unknown cause and maybe genetic in some cases. It's associated with limbo-dermoids, pre-aricular skin tags, strabismus, scoliosis and hearing loss. Incidence is 1 in 3,500 to 1 in 26,000. Slightly more males than females. And these are the pre-aricular skin tags, and this is a pretty classic limbo-dermoid vaccine. So the treatment of this, you can either leave it alone or you can kind of shave it down and then do a partial-thickness corneal patch graft with long-tailed. So this is a whole list of acquired systemic conditions. So a lot of these are going to be more common than things that you actually see in clinic and in hospitals. Yeah. So with limbo-dermoids, if you can shave it down. They typically don't. They can. But they typically don't. Yeah. Because they're actually not really progressive. They're usually just there at birth when they kind of stay there. Okay, so diabetes, corneosiculate, diabetes. You know, it's dry eye. You can also get neurotrophic corneas that leads to poor epithelial healing and neurotrophic keratitis. And this is showing a neurotrophic ulcer. And the classic look, it's kind of horizontally oval and it's got these kind of heat-up thickened gray-white edges. So this is very classic of the neurotrophic ulcer. Hypercholesterolemia can lead to lipid deposition in the peripheral corneal leading to arches. So early onset arches is suspicious for high cholesterol. There's dense arches. So on the SELAM exam, the arches is kind of in the more in the stroma. Whereas with the Kaiser Fleischer ring it was deep. It was at this amazing moment. So yeah, I think on SELAM exam, you should be able to tell if they're both. Gout, you get elevated uric acid levels in the blood and deposition of monosodium uric crystals throughout the body, including the eyes. The crystals occur in the corneal epithelial and the stroma, as well as you can get conductivitis episcleritis and scleritis. So these are uric crystals in the corneal stroma here. When this is nodular episcleritis, which you can engout us in the differential of episcleritis. Sleep apnea is associated with floppy eyelid syndrome and keratoconus. And this is a pretty classic floppy eyelid syndrome. So you just kind of try and raise the eyelid up and it moves way, way more than it should. So then you have to ask about sleep apnea symptoms, get them over to their PCP and get them tested for sleep apnea. Autoimmune conditions there are several. I'm just going to highlight some of them. Movertorn arthritis can lead to dry eye peripheral ulcerative keratitis or a central paracentral thinning which can actually lead to perforation. They can get scleromalacia perforance which is non-negrotizing or a negrotizing scleritis. Wegener's is associated with negrotizing scleritis. Pneudoderm dry eye is the most predominant disease seen. So these are examples of thinning that you can see with rheumatoid arthritis primarily. So this is kind of a small excavated area and it's usually paracentral and I tend to see thinning like this more than the classic PUK that you read about. I think it's more common to get actually negrotized and these perforate really quickly. Patients don't really have too much pain with it until they perforate. Then this is pretty severe peripheral sort of keratitis. This is advanced scleromalacia perforance in Movertorn arthritis. You can see uvea coming out to the sclera and notice that the eye is very relatively quiet. With negrotizing scleritis it's very angry, very inflamed and there you see thin, very very thin sclera. Here's a few medication related findings. So corneal verticillata which we read about earlier with Fabri's disease these are going to be the more common medication related causes of verticillata with amiodarone being the most common just because it's a lot more common of a medication but you could in theory also see it with chloroquine, chlorpoemazine and endomethacin. With corneal edema we can see with amantadine so anyone who is on, if you see bilateral corneal edema kind of look through their med list see what they're on and amantadine can be a cause. Amantadine's used for Parkinson's and dementia but I think it's also being used for epilepsy and psych issues too. Can you also see the hydroxychloride? I don't think so. Cataracts we all know about steroids causing cataracts. There's also a particular type of cataract that you can see with phenophyzine or thorazine. This is not really used commonly. So this is again corneal over just allata. This was with amiodarone. These are stellate thorazine deposits that are beneath the anterior lens capsule. This is a classic PSC cataract which you see with steroids. Hyperthyroidism so you can get proptosis leading to exposure keratopathy. You can also get superior limbic keratocontactivitis with hyperthyroidism. So it's a very, very severe form of proptosis and you can imagine that there's going to be chronic corneal exposure from this. With SLK it's associated with thyroid dysfunction 30% of the time. And you can see inflammation of the superior bulbarian to our subconjunctiva, thorazine staining of the superior corneal limbus and you can pretty commonly see filaments especially superiorly in the cornea. Typically people develop this later on in life, on the sixth decade. Usually more in females. The etiology is likely from eyelid laxity causing excessive friction. So here are some pictures here. You can see the injection of the conjuctiva superiorly. If you don't lift up the lid, you're not going to see SLK. And here's some listening green staining. You'll see some staining on superior bulbaric conge. And here are filaments superiorly. Treatment is typically with topical lubrication, multiple plugs or stasis. A bandage contact lens can be used. You can do argon laser cottery of the superior bulbaric conge. In the past there should be a nitrate was applied. Nitrate was applied. I don't think people typically do that so much anymore. A conjuctiva or resection is also performed. Exacerbations tend to be recurrent but also tend to diminish with time. So in our floppy eyelid patients should we also be looking out for SLK? I'm trying to think if there's a particular association. I don't know if those are typically associated. I can't really think of that. I think in theory it could be because of friction. I'm not sure if I've really seen it. Next is monoclonal gamemopathy or that includes multiple myeloma. So you'll see bilateral corneal crystalline deposits of immunoglobulin origin. Diagnosis is by aspeb and bone marrow biopsy. So here are some examples of crystalline keratopathy that you see with multiple myeloma. Pre and post treatment. So this is pre-treatment, post-treatment. I'm not sure if that's better but this one's definitely better. You can see pre and post. Next is hyperparathyroidism. You'll see banned keratopathy that results from the hypercalcemia and it looks like any other banned keratopathy. There's banned keratopathy going on and there's no cause for that, you know, chronic glaucoma or other chronic eye disease and how chronic inflammation might want to work up the patient for hyperparathyroidism. They have calcium deposits throughout the body. They can have decreased vision from their banned keratopathy, foreign body sensation and recurrent erosions. You want to treat the banned keratopathy with EDTA chelation. So here's some classic picture of banned keratopathy here. There's a lot of calcium kind of across the central or inferior portion of the cornea and with hyperparathyroidism you can see actually calcium deposits on the lid margin too. Next is amyloidosis. This is another systemic deposition. Pathology is going to be staining of the amyloid with congo red dye and with dichroism and birefringence. Primarily localized disease, primary systemic and then secondary localized and secondary systemic. So with primary localized disease it's the most common form of the ocular disease. This includes gelatinous drop-like dystrophy which is familial, platus dystrophy and polymorphic amyloid degeneration. Then there's primary systemic disease where they get kind of waxy, ecomotic eyelid papules. Secondary localized is the most common form of corneal disease and this occurs with long-standing chronic inflammatory disease. They can get a degenerative panacea yellowish-pink or yellow-gray lamella deposits in a deep stroma. With secondary systemic disease eye involvement is uncommon. So this is a picture of severe chemosis with amyloid deposition and associated subconch heme and these are amyloid deposits that are infiltrating the conjunctiva and cornea. Vitamin A deficiency so we suspect this in poor nutrition people have with poor nutrition such as alcoholics or post-gastric bypass patients. Night blindness is the first symptom and they get xerophthalmia which is severe dry eye with the toe spots which I'll show a picture of and keratinization of the cornea and these represent a squamous in severe forms that could lead to corneal melting from necrosis of collagen. So this is a picture of the bito spot. My silly way of kind of remembering that bito spots look like this is it looks like it looks like a bundle of spit so it's like bito, you're like spitting. So that's fine with that. Keratinization of the cornea here so you get with vitamin A deficiency you get mucin deficiency because it kind of destroys the goblet cells and that leads to decreased tear breakup time. Treatment obviously with vitamin A so that can be high dose oral supplementation or IM injections of vitamin A. And that's it.