 All right everybody, I think we're going to get started. So our presenter today is going to be Dr. Ruben Valenzuela, so a little bit about Ruben. He was born and raised in the Philippines. He finished his neurology training at the University of Illinois. He's currently a fellow here in neuro-ophthalmology and he's actually one of my favorite fellows because of his patience and his willingness to teach. But after he's done here, he's actually going to go and do a second fellowship in multiple sclerosis after which he has a job lined up at the University of Illinois in the neurology department. So without further ado, here's Dr. Valenzuela. So I'm going to do a short lecture on the neuro-ophthalmic manifestations of sarcoidosis. And so we'll start with the case. So I have a 40-year-old Caucasian man who we saw in consultation in September because of blurred vision in the left eye. And so he was previously healthy. In August, he awoke with painless loss of vision in the left eye and he described his vision as almost like a frosted glass appearance with like a fishnet over his left eye and it was constant. And he described it was associated with intermittent episodes of transient visual obscuration that would happen at least four to five times per day. Although he denies any eye pain, he said that his left eye feels tired all the time. So he denies headache. He has no shortness of breath, no cough. He has very mild fatigue. And he has this rush in his anal area that's been going on for the last three years. And he has a rash in his left knee that has not been evaluated by his primary care physician or a dermatologist. And so on examination, his visual acuity was 15 in the right eye and 20, 50 minus one in the left. His pupils were symmetric with a 0.9 log unit relative afferent popular defect in the left. His visual fields and extra-ocular motilities are normal. His anterior segment examination is normal specifically as no-cells in the anterior chamber. He has a 2-millimeter left preptosis. On dilated examination, his right optic nerve is normal. But he has a plus-3 disc swelling in the left eye and some retinal striate in the left eye. His neurologic and physical examination were otherwise unremarkable except for this small rash in his left knee. So his MRI actually showed enhancement proximal to the left optic nerve. And also there's evidence of obstruction of the CSF flow in the optic nerve sheet distal to the lesion. And you'll see there's minimal extension of the lesion into the optic canal. The right optic nerve seemed normal and there's no evidence of tumor or metastasis elsewhere in the brain. And when you look at the coronal section, you'll see that the left optic nerve is also actually enlarged. Yes, sir? Correct. So my impression is if you have increased flow of a CSF and increased pressure, the fluid would just go through the sides of the nerve sheet from pressure itself. And then we also requested the CT of the orbit to check for any abnormal calcification. We didn't find any abnormal calcification in the CT of the orbit. And we also requested the chest x-ray specifically to look for any pulmonary infiltrates or by hyalurlyphadenopathy, but the chest x-ray was normal. And so in summary, we have a 40-year-old Caucasian man with a painless loss of vision in the left eye in the setting of a left optic neuropathy and severe swelling actually of the left optic nerve. He had an abnormal MRI and we gave him a trial of steroids and he was responsive to steroids. The visual acuity actually improved in the left and there was also some improvement of the left proptosis. And so for this particular patient, we considered the following differential diagnosis. So we considered meningioma, glioma, lymphoma, infectious and any inflammatory condition and autoimmune and demyelinating disease. Although the CT of the orbit did not show any abnormal calcification, we still considered meningioma in the differential diagnosis because only 30-40% of patients with meningioma would show abnormal calcification in the CT scan. And so what do you want to do next for this patient? Any suggestions? Labs? Imaging? Observe? Yeah, so we talked about a number of differential diagnosis. So what specific lab do you want to get for this patient? Very good. So all those were requested. So because of the high suspicion for infection and inflammatory process, we got a CBCN and ESR, they were both normal. We also did an extensive infectious workup. So we did a quantiferent TB test for syphilis, a viral panel. They were all negative. Liver enzymes were all within normal. Serum angiotensin converting enzyme was within normal. I think it was 9. And then the only thing that came out positive was an elevated serum lysozyme, 27 nanograms per mil. I think the normal is, I think about 17. We also got a serum aquapoint for it to rule out neuromyelitis optica. You had the lumbar puncture and the CSF profile was normal. You had no cells, sugar and protein were both within normal. And so we did not really have, based on the labs and the presentation of the patient, we really did not have a definitive diagnosis. So we considered there was a discussion about getting an orbital biopsy because of a risk to its vision. We were kind of thinking of getting a less invasive procedure. So we ended up getting a biopsy of the skin lesion. So a skin-punched biopsy of the left knee. Remember in this physical examination, there's this skin-rash in this left knee. So we got a skin-punched biopsy that showed granuloma. And still with the granuloma, you have to consider either inflammatory or infectious process, but the non-cascading nature of the lesion made sarcoidosis a primary diagnosis. And so this patient was diagnosed with ocular sarcoidosis without pulmonary involvement. And so sarcoidosis was first described by Dr. Jonathan Hutchinson. He's a dermatologist and he described this diffuse-raced red lesions in one of his patients, but he did not really use any term for this lesion. In 1888, Dr. Ernest Bestner coined the term lupus perinio to describe this diffused skin lesions. And then in 1909, a Danish ophthalmologist named Dr. Christensen described a triad of symptoms consisting of fever, paratitis, and uveitis. And from then on, you know, they were describing a condition called sarcoidosis. But in 1915, Dr. Schoeman actually emphasized that sarcoidosis is a systemic condition. And so he made a lot of research on this disease and because of all his work in describing this condition, pathologists described this calcification and this protein deposits in the Lankhans giant cells as Schoeman or asteroid bodies. In 1937, uvral parotid fever was first described. And then the first international conference on sarcoidosis was held in London. And interestingly, we had the first convention on sarcoidosis in Washington, DC in 1961. And so sarcoidosis usually occurs in the third or fourth decades of life and the prevalence is estimated at around 10 to 40 per 100,000. But the incidence is actually higher in African Americans, at least 10 to 17 times higher. And in Caucasians, around 15 to 20 per 100,000, it's sporadic and there's no gender predominance, although ocular sarcoidosis is more commonly seen in women. And then the etiology is unknown, so it's largely a diagnosis of exclusion. A lot of studies were done on genetic and environmental factors, and it revealed really little about sarcoidosis. But currently, there are studies on association between HLA DRB1 and mycobacterium tuberculosis DNA in relation to sarcoidosis. So histologically, they would present with a non-casiating granulomas in the affected tissue with some asteroid and Schoeman bodies. And so half of the patients with sarcoidosis would be asymptomatic, and the rest would present with different symptoms. And the most common would be respiratory symptoms. So some patients would present with cough, shortness of breath, and some would have skin lesions as my patient. And skin lesions would vary from having like almost like an erythema, nadosum, lupus perineus, scars or plaques. And then lacrimal and salivary gland involvement is relatively common. And then I'm just going to point out that ocular sarcoidosis is very common presentation. It's found in 30 to 50 percent of patients with sarcoidosis. And in fact, it's more common than neuropsycho- sarcoidosis, around 10 to 15 percent. And in fact, some literatures reported only 5 percent of neuropsychoidosis. 90 percent of patients with sarcoidosis would have pulmonary involvement. And so a very important test would be getting a chest x-ray or chest CT. And there's a pulmonary staging for sarcoidosis if there's pulmonary involvement, of course. And so the staging are based on four, you know, different stages. So stage one would be bihiler lymphadenopathy and chest x-ray. And 67 percent of these patients with bihiler lymphadenopathies would have spontaneous resolution of symptoms within one to two years. And then stage two are patients who percent with reticulonodulin infiltrates. Around 46 percent of patients would have a spontaneous resolution of symptoms within one to two years. And then stage three are patients with pulmonary infiltrates. And unfortunately, less than 10 percent, around 10 percent would have resolution of symptoms in two years. And then, of course, the worst would be patients percenting with fibrocystic changes and bulus changes in the chest x-ray. As you can see in this table, so sarcoidosis would be basically systemic manifestations of, you know, different organs can be involved. If you note the cardiac involvement is very rare. These five are less than 5 percent. But it's the most clinically challenging and the most fatal involvement in sarcoidosis. And so, again, I would mention that it's very common. Ocular involvement is 30 to 50 percent versus 10 to 50 percent in oerosarcoidosis. So what are the neuro-othalamic manifestations of sarcoidosis? So you can have anterior uveitis. And in fact, it's the most common of talmic manifestation of ocular sarcoidosis. So 40 to 70 percent of patients with percent with anterior uveitis and 80 percent of the time, it's bilateral involvement. And typically, they would percent with acute ireitis or eridocyclitis. And then posterior uveitis would be seen in 14 to 20 percent of patients. And with posterior uveitis, it's very common to have cystoid macular edema. And then the other presentation would be orbital sarcoid. You can have involvement of the optic nerve, the optic chiasm, or the posterior chiasmal visual pathway. And oculomotor dysfunction and pupillary dysfunction have been reported in the literature but not very common. And so the signs in anterior uveitis can be, you know, mutton-fat-creatic precipitates. You have kepi nodules, you have bosacan nodules, you have anterior chamber or ciliary baddy inflammation. And so this is an example of your mutton-fat-creatic precipitates. So these are inflammatory cells that are found in the corneal and the filium. And most of the time it's associated with granulomatous inflammation and it's highly suggestive of sarcoidosis. And then you can have kepi nodules that are usually seen along the pupillary margins. And when you have kepi nodules, it can be an ireus for posterior sinike where there's a risk for developing cataract, glaucoma, and band keratopathy. And then you can also find bosacan nodules closer to the limbus, these brown arrows. And then mutton-fat-creatic precipitates are these whitish nodules right here, the corneal and the filium. And then in posterior uveitis, the signs would be from inflammation, obviously inflammation of your vitreous, your retinine, your chloride. The common signs would be your candle wax drippings. You can have branched retinal vein occlusions. You can have neovascularization and hemorrhage. You can have vasculitis. You can have corioretinal granulomas. So this patient is presented with coroidal vasculitis as evidenced by the white sub-retinal spots. So this particular patient is presented with cells in the anterior chamber in the vitreous. And so another sign in posterior uveitis would be candle wax drippings. So this would be your whitish and sometimes yellowish-white waxy retinal precipitates that are found along the retinal veins, usually in the inferior equatorial retina and sometimes in the posterior poles of your retina. And some literature suggests that 20 to 40% of patients with sarcoidosis would present with candle wax drippings. And histopathologically, candle wax drippings are actually represent periflebitis and corioretinal granuloma. So sometimes the candle wax drippings are called granuloma to periflebitis. And then this patient obviously had a branched retinal vein occlusion from ocular sarcoidosis. You see this inter-retinal, segmental inter-retinal hemorrhage. And then you can also have retinal vascular sheathing, as you can see in this colored photo in this angiogram. And then patients can have corioretinal granulomas. This can be associated with your candle wax drippings as well. So these are whitish lesions and they appear in clusters. So whitish lesions are usually associated with more active disease. And then more chronic disease usually presented like grayish appearance of the lesions with sharp margins. So they could be chronic or, you know, secretarial lesions. And so they can also have retinal macroanurysm, as you can see in this photo, and the intermediate and late stage of your fluorescent angiogram. But I think what's interesting is when they took an ICGA of this patient, it showed hypofluorescent areas that actually they said that were associated with occult granulomas. And so I think ICGA is very important, especially in patients that present with very minimal ocular signs and you want to prove that there's bilateral involvement. So ICGA is a good test. And so although not specific, you can see neovascularization and hemorrhage with ocular sarcoidosis. And so orbital sarcoids, the most common manifestation would be involvement of your lacrimal glands. And sometimes patients can also have tumors that appear in the eyelid so they can have eyelid mass. And then the signs and symptoms can mimic on orbital tumors so they can have optic neuropathy, they can have diplopia, exothermosin, proptosis, and signs of dry eyes. And this is an axial MRI showing bilateral lacrimal gland involvement in a patient with lacrimal sarcoidosis. So symmetric involvement of the lacrimal glands have been reported to be highly suggestive of ocular sarcoidosis. But you have to rule out other causes of bilateral lacrimal gland involvement. And you have to make sure that you rule out lymphoma, leukemia, and infection. And one literature suggests that a good way of differentiating sarcoid from lymphoma within your imaging is getting a DWI, diffusion weighted imaging, and ADC. And apparently lymphoma would have lower DWI and ADC compared to your sarcoidosis. And then there are certain imaging findings that can help you say whether this is lacrimal involvement in sarcoids. So usually they describe lacrimal involvement as diffuse, smooth, homogenous involvement on almost symmetric involvement of the lacrimal glands. And just, you know, at additional information, lacrimal glands thickness normally measure around four millimeters. And this particular patient is at full thickness. It's around 11 millimeters. So this patient was diagnosed with lacrimal gland sarcoidosis. So another example would be sarcoidosis involving the lower lead margins. Optic nerve involvement is very rare. But when they do happen, they can present with varying degrees of visual field defect and relative affluent popular defect. And they can present with poplidema. They can present with anterior or posterior optic neuropathy, optic atrophy or disc elevation. So this particular patient has this small nodule in the disc that resulted in disc elevation. And kind of dramatic elevation of the disc in someone with sarcoid populitis. Optic chiasum involvement, again, is a rare presentation in sarcoidosis. But when they happen, it's very difficult to differentiate from your pituitary tumor because they present similarly with patients with a pituitary micro-adenoma macrodot for that purpose. So they can have diabetes insipidus. They can have aminory, galacteria, hypogonadysm, or bitemporal hemianopia. So this T1 post-contrast sagittal and coronal section shows enhancement of the optic chiasum. So this was a pediatric patient who was initially misdiagnosed with optic chiasum glioma and ended up having optic chiasum sarcoidosis. He responded really well with steroids. And the involvement of the posterior chiasmal visual pathway can be symptomatic based on three different mechanisms. So they can have compressive effect. They can infiltrate, and they can have vascular changes. And sometimes they can have stroke-like lesions or stroke-like symptoms from angitis and from thrombosis. And then you can have oculomotor dysfunction. Basically, the most common would be isolated six-nerve function. Involvement of the third nerve is not very common. And if you have a gaze palsy, make sure you rule out supranuclear gaze palsy from neuropsychidosis. So pupillary dysfunction, they can present differently as severe as loss of vision or some minor changes in your pupil. For instance, you can have parasympathetic denervation and you can have tonic pupil. Sympathetic denervation, you can have Horner's syndrome and you can also have Argil Robertson pupil. And sometimes patients would come to you with bell palsy because facial nerve is the most common cranial nerve involved in sarcoidosis. And the second most common is your optic nerve. However, of course, patient can present with multiple cranial neuropathies. And so because ocular sarcoidosis is very common, so the international workshop on ocular sarcoidosis actually developed a diagnostic criteria for ocular sarcoidosis. And so it's universally accepted that to have a definitive diagnosis, you have a positive biopsy. But some patients would not agree to have intraocular biopsy because of risk to their vision. So the international workshop on sarcoidosis developed diagnostic criteria that may or may not involve biopsy findings based on seven ocular signs and five laboratory tests. So the seven ocular signs are the signs that we discuss in anterior UVID. So patients can have mutton fat, static precipitates, kepi or busaka nodules, trabecular meshwork nodules. They can have string of uproars, vitreous opacities. They can have multiple corioretinal lesions. You can have candle wax drippings, optic disc nodules, and very important with the bilateral involvement with sarcoidosis. And then the five laboratory tests would be very important to check for TB, check for a serum angiotensin-converting enzyme or a serum lysosine, check for chest x-ray. If chest x-ray is negative, do a chest CT, and then check for liver enzymes. And so this is not part of the diagnostic criteria, but I just want to make sure that when you work up a patient, you rule out all the mascarades or the mimickers of sarcoidosis. So make sure you rule out TB, ocular TB, lymphoma, viral infections. I forgot to add here, syphilis as well. You need to check those. Autoimmune demyelinating disease. Volcoionaga-harada syndrome. Not very common, but sometimes 10% like sarcoidosis. And so serum angiotensin-converting enzyme alone has 73% sensitivity and 83% specificity. It's a very good test to monitor disease activity. So higher ACE levels are usually associated with more active disease. And then 58 to 60% of biopsy-proven cases have elevated angiotensin-converting enzymes. But when I was doing my research on this topic, it was kind of interesting to note that they're saying that angiotensin-converting enzyme is not really very useful in two sets of populations. So children can have elevated angiotensin-converting enzyme above the normal values. And then watch out for hypertensive patients on ACE inhibitors and patients on the synopil. So patients on ACE inhibitors can have undetectable levels of angiotensin-converting enzymes despite having, you know, raging sarcoidosis. And so for this two population of the solution, they said, get a serum lysozyme. Although it's not as sensitive or as specific as your serum ACE, it has 60% sensitivity and 70% specificity. In our patient, he was not on, you know, any ACE inhibitor. ACE apparently, unfortunately, was negative within normal, but the lysozyme was elevated. And then since granulomas can form in the liver, you want to make sure that you check your liver enzyme. So check for alkaline phosphatase. Check for ASTN-ALT. To be considered significant, your alkaline phosphatase should be at least three times above the normal value. And your ASTN-ALT should be twice above the normal value. And so, again, check for TB, very important. So I would prefer you do a quantiferent TB goal. So for example, never, ever do a tuberculin skin test in a patient like me who came from a third world who has a BCG because there will be a lot of, you know, maybe difficulty in interpretation depending on who's reading your skin test. So quantiferent TB goal is simple, it's easy, and it's very easy to interpret. So go with quantiferent TB goal. And then chest x-ray, at least 50% of patients would have pulmonary involvement. So always get a chest x-ray. If chest x-ray is negative, go ahead and get your CT of the chest. And then, based on the seven ocular signs and five tests, there are four levels of diagnostic certainty based on the synapsic work of the ocular symptoms. So you have a definite sarcoidosis if it's biopsy proven, whether it's a thin biopsy, a trans-branque-alung biopsy, a lacrimal-gran biopsy, and then you consider the ocular symptoms. So it's a presumed sarcoidosis if you have biognopathies. For any reason, you don't have the vial or adenopathies. You need three signs and two ocular signs and two lacrims. So this is a diagram of the international workshop on sarcoidosis. Sarcoidosis has a very high incidence. So they start with a very invasive and aggressive procedure. So they do trans-branque-alung biopsy. And the result, they go with the... So I think the way to go with being, you know, practical and being non-invasive and symptoms, you decide on whether you want to do a biopsy. And the biopsy would be any of the following. You can do skin, you can do a lymph node, salivary and lacrimal-gran biopsy, and then conjunctival and trans-branque-alung procedure so you can have false negative results depending on, you know, which area you biopsy. One of the diagnostic criteria is used by the Japanese Society of Sarcoidosis. And so they stain the fluid and they look at the pathology. And in addition, they look at the t-lymphocytes, the t-cell count. And an elevated CD4 and CD8 level is actually suggestive of sarcoidosis. I'm going to go back to the ICG. I think some clinics underuse ICGA in diagnosing sarcoidosis. So for a patient who has signs of anterior uveitis, signs and symptoms of anterior uveitis, but very limited ocular signs of sarcoidosis, ICGA is a very good test to show the clinical picture and the diagnosis of the patient because it confirms the path of the disease. And then it also detects ocular coronal lesions. And then they mention four ICGA signs for sarcoidosis, although I think it's nonspecific. So you look at hypochlorosin, the darkness of the large choroidal vessels. And then there's late diffuse choroidal hyperchlorosin. And then they said, very common, you see hyperchlorosin pinpoints in patients with ocular sarcoidosis. And so management of this, yes, both anterior and posterior. So for management, majority of the patients 75% would require symptomatic treatment with or without steroids. But then for patients with widespread disease, corticosteroids is the mainstay of treatment. So one that I reviewed mentioned using methylprednisolone at 20 milligrams per kilogram per day for three to five days followed by prednisone taper. And then for patients who are unresponsive to steroids or who cannot tolerate steroids, you can consider a steroid sparing agents. So the most studied drug, a non-steroid sparing agent for sarcoidosomethotrexate, there's a lot of pulmonary and hepatic toxicity around, I would say, 10 to 20%. So they recommend, of course, using acid when you treat patients with methotrexate. And then another drug would be esothiopin. So those bone marrow suppression with esothiopin. So one of the complications would be malignancy. But the most common side effect would be thrombocytopenia and elevated liver enzymes. There's some report of a success in using mycophenolate with UVL, sarcoidosis and encercoidosis. But I think what's commonly used now as a replacement for... And so in general, the patients can have... The UVs can remit spontaneously. But in some patients, you can have exacerbations and remissions. And the prognosis is less favorable in African Americans. And with cardiac involvement, it's really bad prognosis. For patients who have a chronic horse, the following can happen. They can have cancer in other areas that are affected by the sarcoidosis. There's a risk for lymphoma. There's a risk for lymphal proliferative disorder like a non-Hodgkin's lymphoma. So for this particular patient... This patient received methylprednisolone and prednisone taper. His vision actually improved from 2050 to 2020 and the prognosis actually improved as well. So he's being followed by pulmonology and rheumatology. And so far, he's been happy. He's not in a lesion, but he's happy with all what's going on with his life right now. Overall, much improved. Those are my references. Thank you.