Ogul Uner (00:20):
Welcome to Pupil Pod, where we use clinical cases to guide discussions on board review topics. I'm your host, Ogul Uner, and my guest today is Dr. Maura Di Nicola. Dr. Di Nicola is a board-certified ophthalmologist and a uveitis and ocular oncology specialist at Bascom Palmer Eye Institute and an assistant professor of clinical ophthalmology at the University of Miami Miller School of Medicine. Dr. Di Nicola, thank you for joining me.
Maura Di Nicola (00:46):
Thank you so much for having me. It's a pleasure.
Ogul Uner (00:49):
So let's delve directly into the case. We have a 32-year-old woman who presents to your clinic with blurry vision in the right eye for two weeks. She reports new onset floaters with mild eye pain and photophobia. She's otherwise healthy, no history of autoimmune disease or recent infections. Visual acuity is 20 / 50 in the right, 20 / 25 in the left eye. There's low one plus anterior chamber cell in the right eye, the anterior segment in the left eye is quiet. There’s two plus vitreous cells in both eyes. You do a dilated exam which shows multiple small yellow white chorioretinal lesions in the posterior pole and in the mid-periphery of both eyes, some of which appear punched out. There are no hemorrhages. You perform an OCT through the macula, which shows RPE elevation with a deposit in the sub-RPE space of the right macula. Dr. Di Nicola, what are your thoughts about this case and what additional questions would you like to ask this patient?
Maura Di Nicola (01:46):
Yeah, so whenever we approach uveitis cases in general, we always want to get a little bit of an overview as to what we're dealing with. So I always like to approach this as this is a unilateral process versus a bilateral process. So in this case, we have a bilateral uveitis. This technically qualifies as a panuveitis as we have some interior chamber involvement, even though it doesn't seem to be very prominent or at least in one eye. We have vitreous involvement in both eyes, and we have chorioretinal lesions in both eyes. So of course, given this kind of presentation, we want to keep a broad differential and we know that uveitis always can be categorized in big buckets. We can think about infection. We can think about an autoimmune inflammatory process and we always have to keep neoplastic in the back of our minds. So, this is a phenotype with this hypopigmented lesions, panuveitis kind of presentation that we can see in a number of situations such as, for instance, in a tuberculosis as well as syphilis, that can always look like everything.
(02:59):
So those are definitely things that I would keep in my differential, but also some other autoimmune condition in the space of the white dot syndrome. So, things I would want to know from the patient is if they've had any sort of exposure that can be concerning for some sort of infection such as TB or if they work in high-risk settings for TB.
(03:25):
As you've had especially, we often end up asking our patients if they're sexually active. Patients in my clinic always end up getting tested for syphilis no matter what, but that's always an important piece of information to have. I would also like to know about any preceding illnesses, potentially any sort of viral illnesses, any precipitating conditions such as some sort of previous infection or vaccination. And I know you've mentioned that the patient doesn't really have any past medical history, but also knowing if there's a predisposition to an autoimmune condition can always be helpful. So those are the things I would be thinking of when I approach the patient.
Ogul Uner (04:04):
Yeah, that's great. I think you outlined it really well that we're dealing with this bilateral panuveitis, a phenotype of maybe multifocal choroiditis and panuveitis. And in the setting of a lot of infectious and inflammatory etiologies, it's important to just keep a broad differential, like you said. So you ask those questions. She's monogamous, denies any relevant past medical history, no high-risk TB exposures, no recent vaccines. How does this information help you?
Maura Di Nicola (04:40):
Yeah. So as I mentioned before, this is all helpful information that we collect because as uveitis specialists, we're always on the lookout for clues. We're little Sherlock Holmes’s in the making. We're always looking for clues and things that can help us get to the right answer. But nonetheless, even though she's monogamous and she doesn't have high-risk exposure for TB, I would still test for those two things. So syphilis and TB always get tested in my clinic. And we talked about exposure to recent vaccines or preceding illnesses. When we think about white dot syndrome such as multifocal choroiditis or PIC or NIU or other in this category, we know that some of this can be precipitated by preceding infections, but not all of them have to. So even though those things, she does not report any of this history, I would still keep that in my differential.
Ogul Uner (05:41):
You mentioned that there are several white dot syndromes, which we define as idiopathic inflammatory chorioretinopathies. And for part 2 of this white dot series, we'll touch on a few. So let's start with multifocal choroiditis. What is a typical demographic in history patients with MFC provide?
Maura Di Nicola (06:03):
Yeah. So I think the case that you described is pretty typical for multifocal choroiditis in many ways. In terms of demographics, you mentioned this as a young woman. So this tends to be a little bit more often in women in their usually third decade of life. Oftentimes they are myopic as well. So myopia is something else that we can ask for or look in the chart for. Their refraction is a helpful clue in these cases. Yeah. So those are the main things I would be thinking about in this specific situation.
Ogul Uner (06:34):
And what are some clinical and multimodal imaging findings that you may see in a patient with MFC? So you kind of painted a young myopic female, but is there pretty significant anterior segment inflammation and how large are the lesions?
Maura Di Nicola (06:54):
Yeah, so that's an excellent question because one of the clues in multifocal choroiditis is exactly what you mentioned, the presence of inflammation. So, you will definitely see vitritis and that's why patients will often report floaters or other inflammatory symptoms such as pain, photophobia that are not necessarily seen in other conditions that might simulate multifocal choroiditis. For instance, PIC doesn't necessarily have lots of vitritis. Neither does presumed ocular histoplasmosis syndrome, which can definitely simulate MFC, but there is no inflammation in the vitreous oftentimes in those situations. The anterior chamber reaction can be present in multifocal choroiditis. It's not necessarily very robust, but it's definitely a clue in that sense. The other thing that you mentioned is the presence of these chorioretinal lesions that are not only confined to the posterior bulb, but pretty diffuse. So, typically the lesions in multifocal choroiditis would look yellow-white in color with fluffy ill-defined borders in their active phase.
(08:01):
As they become more inactive, they can change in color. They can become a little bit more grayish or more pigmented and more crisp, better defined with sharper borders and more atrophic and punched out over time. You can also see different lesions in different stages in the space of multifocal choroiditis. But the clue really is that these lesions are medium to large in size. They can go up to 450 microns in size and again, the distribution, not just the posterior bulb, but the periphery as well. Multimodal imaging can be very helpful. So fundus photography can help document the presence of these lesions. Another very important imaging modality that I love when it comes to white dot syndrome is fundus autofluorescence. The reason being is that the pathologic process in a lot of this condition is at the level of the RPE and choriocapillaris. And we know that fundus autofluorescence is particularly helpful in letting us know about the health and the status of the RPE.
(09:03):
So, for lesions that are active, you will notice hyper-autofluorescence while those lesions that are inactive will look hypo-autofluorescent. Then of course, the imaging modality that everybody walking through a retina clinic or uveitis clinic gets is OCT. OCT is helpful not only to detect anything that might be going on in the macula, for instance, you could even detect CME—cystic macular edema—and multifocal choroiditis that can happen in up to 40% of cases, so it can be a quite significant number. Not just this, you can detect the presence of the inflammatory material if you get a scan through one of the chorioretinal lesions. So you will see the accumulation of inflammatory cells and inflammatory material at the level of the RPE, sub-RPE, or subretinal space. When the lesions become punched out, you will notice outer retina atrophy and increased signal transmission corresponding to this OCT area.
(10:02):
Now, one thing I have not yet mentioned is that one of the complications that you can get in multifocal choroiditis is the presence of a choroidal neovascular membrane, which is due to this disruption at the level of Bruch’s membrane RPE and sub-RPE space, oftentimes type 2. So, it's a subretinal CNV, but certainly type 1 sub-RPE CMV can be possible as well. And so in those cases, you will see the typical signs that you see on OCT. You can see, again, subretinal sub-RPE hyperreflective material and the presence of subretinal and intraretinal fluid are important clues to the presence of a CNV as opposed to just an inflammatory lesion. When it comes to FA and ICG in FA, the lesions appear faintly hyperfluorescent in the early phases and they stay hyper in the late phases as well. While the ICG shows hypo-lesions both early and late, and sometimes the extent of this can be even more prominent than what we see clinically.
(11:07):
I think the combination of your clinical exam, the presence of the inflammatory reaction, as well as the combination of the information that you get from multimodal imaging can really help you reach the correct diagnosis. Once again, I do want to highlight it as a diagnosis of exclusion, so you should be sure to have excluded other etiology, especially infectious etiology or potentially even neoplastic etiology such as vitreoretinal lymphoma that can present some similar features but tend to occur definitely more in older people than the typical demographics for MFC.
Ogul Uner (11:40):
I think that was a phenomenal overview of the different imaging modalities and I think it segues well into our next question. So what systemic tests or imaging would you like to order for these patients? You mentioned that you have other inflammatory and neoplastic etiologies in your differential diagnosis. How do you approach your algorithm in testing for the workup?
Maura Di Nicola (12:06):
Yeah. So when I'm thinking about infectious etiologies, the two main ones I want to exclude, as I said, are TB and syphilis. So, I would obtain QuantiFERON. If that's not available, a PPD and syphilis testing. Other things you might want to think about are sarcoidosis. So sarcoidosis is an autoimmune inflammatory disease. Most people would get an ACE, lysozyme and chest x-ray to rule out sarcoidosis, so that's something you can think about. When it comes to other white dot syndromes that can stimulate this condition such as PIC or POHS, as I mentioned, there are no other specific tests really that you should get. In that case, what's going to help you is the clinical manifestations, the symptoms, the presence of, as I said, vitritis, anterior chamber reaction that is more commonly associated with multifocal choroiditis. Now, if you have a demographic of an older person, especially if they're experiencing neurological symptoms, this is something that can happen in older patients with vitreoretinal lymphoma.
(13:12):
Not all patients with vitreoretinal lymphoma have to be old and have to have neurologic symptoms. So that's always something to keep in the back of your mind, but what you will see, again, the imaging features in vitreoretinal lymphoma are a little bit different. Oftentimes you will see a sub-RPE deposit, subretinal deposits. You'll notice a granular kind of appearance on OCT. But again, you can have a larger hypopigmented or yellow lesions that are an accumulation of lymphoma cells in the case of vitreoretinal lymphoma as opposed to inflammatory material. So if that's a real concern, then in that case, an MRI of the brain might be warranted as well as potentially a diagnostic vitrectomy. Again, if the clinical suspicion is high.
Ogul Uner (13:57):
And what is the visual prognosis of patients with MFC? Do these require treatment? How do you approach your treatment algorithm?
Maura Di Nicola (14:07):
So a lot of it depends on how much the patient is symptomatic. So, if the patient is very symptomatic with significant inflammatory symptoms, if you notice a high level of inflammation, if there are associated complications—vision-threatening complications such as CME or the presence of a CMVM—then you want to act and you want to act quickly and you know that in order to act quickly, we need steroids. Topical steroids are not going to be enough for this condition. So you have to think about either oral steroids or potentially a steroid injection. Of course, if you're going to do a steroid injection, you really want to make sure you have ruled out an infection and you want to counsel the patient about the risks of potential progression of cataract or increased intraocular pressure. Now, if the inflammation subsides with steroids and you're able to successfully taper the patient off steroids, then in some cases you can just monitor the patient periodically.
(15:04):
If the patient is steroid dependent, meaning that you notice a reactivation of the lesions or a recurrence or a flareup of the inflammation of steroids, you might need to consider immunomodulatory therapy for long-term control of this condition and you can do this with antimetabolites and potentially escalate to other agents as well. If there is the presence of a choroidal neovascular membrane, then you want to consider injecting anti-VEGF.
Ogul Uner (15:30):
Great. I think that was a great overview of MFC. So now let's switch gears to another white dot syndrome you mentioned, which is punctate inner choroidopathy or PIC. Could you talk about how these patients may present?
Maura Di Nicola (15:45):
Yeah. So again, it can be a challenging differential sometimes because the demographic is pretty similar. Again, you will mostly be dealing with young myopic women. Again, it's not a hundred percent kind of rule, but the demographic is pretty similar. However, in this situation, your clinical manifestations and the symptoms are going to be a little bit different. We mentioned there's often no vitritis in PIC, so you won't necessarily have patients that complain about floaters or your typical inflammatory symptoms such as pain and photophobia, but they might complain about scotomas, paracentral or central scotomas or even metamorphopsia if CMVM is associated with PIC. When it comes to your clinical manifestation, you'll notice similar lesions as to what we described for MFC. So hypopigmented yellowish whiteish lesions that tend to be fluffier in the active phase. They tend to be a little bit smaller than the ones that you see in MFC, and they're mostly localized at the level of the posterior pole, so not so much in the periphery.
(16:54):
The multimodal imaging is pretty similar. So if you get an OCT through the lesion, again, you will see this accumulation of material. If the lesion progresses to a punched out lesion, you will see your outer retinal atrophy and increased signal transmission. The findings on FA and ICG are pretty similar. So again, hyper-fluorescence early and late, hypo-fluorescence on ICG early and late as well.
(17:21):
The other thing to mention for FA is if you have punched out lesions, you will notice window defects. So, these lesions will look hyper-fluorescent, but mostly due to the presence of window defects. The complication of choroidal neovascularization in PIC is more common than in MFC. So that can happen up to even 70% of cases sometimes. And so, these are young patients that can be very symptomatic with scotomas, and metamorphopsia if the CMVM occurs close to the fovea. So again, certainly you want to get an OCT through this lesion. Sometimes it can be hard to distinguish between an inflammatory lesion and a CMVM. And so this is one of those situations where I think OCT angiography is particularly helpful because in this situation you can distinguish between an accumulation of inflammatory cells, which will not have intrinsic flow when you look at an OCTA as opposed to a small choroidal neovascular network that can show that.
(18:23):
If you don't have that and you want to confirm the presence of a CMVM, it's not done so commonly anymore, but you can certainly always get an FA and ICG and you will notice that kind of lazy pattern with hyper-fluorescence early and leakage and potentially staining in the late phases. Again, the CMVMs in PIC tend to be more often type 2, but type 1 is also possible.
Ogul Uner (18:51):
I think that was a great overview and I definitely agree on the importance of obtaining OCTs in these patients and getting OCTAs. I think it can be very challenging to differentiate a choroidal neovascular membrane from an active inflammatory lesion, like you said. And not infrequently will people either inject both anti-VEGF or steroids or inject anti-VEGF and start oral prednisone to just cover for both. But I think you brought up a great point on the use of OCTA. And now that we've covered these two entities, let's talk about the third entity called presumed ocular histoplasmosis syndrome or POHS. Let's talk about some similarities and differences. How do you put this disorder among PIC and MFC?
Maura Di Nicola (19:46):
This is a very interesting entity and I have to admit for a long time when I was studying it and I trained in Italy and I was practicing in Italy, I thought it was a legend. I was like, "I've never seen any case of this. This does not really exist.” Then I practiced in Cincinnati for a while and I can tell you the vast majority of our patients have findings that were compatible with POHS. So that lets you know that I was very naive to think that the world began and ended where I practiced, but of course, this gives us one important piece of information. So this is endemic in certain specific regions and in the United States specifically, this is found in the Ohio and Mississippi River Valley. Now the etiology of this condition is a little bit debated. We use the term “presumed” because we presume it's related to an infection from the yeast form of the histoplasma capsulatum.
(20:42):
However, there might be an autoimmune or immune mediated component. So it might not necessarily be just a pure infection, but there might be some sort of genetically determined predisposition to develop this phenotype given the pretty endemic exposure to this pathogen in certain areas of the country, as I mentioned. So, things that are going to be close to this are again, living or coming from or having lived a certain period of your life in these areas. Demographics are a little bit different because this can occur really in any ages. So you can see in older patients as well. It tends to be a pretty silent condition unless one of the, or the most common complication of this happens, which is the, again, the presence of a choroidal neovascular membrane. Other than that, patients are asymptomatic, they will typically present. So they don't experience any floaters, any inflammatory symptoms, no pain, no photophobia, none of that.
(21:48):
They will have metamorphopsia if they have a choroidal neovascular membrane, but other than that, they'll be asymptomatic. When you examine them, you will see a pretty typical triad of findings, which are the hypopigmented punched up lesions, the peripapillary atrophy and absence of vitritis. And then they can have, if they've developed a cordial neovascular membrane, they can have a macular scar or disciform scar of some sort. Now, the occurrence of choroidal neovascular membrane in POHS is even less than what we have described for multifocal choroiditis and PIC. It tends to be about, it's been estimated to be about 4 or 5% in those patients that have the peripapillary atrophy and up to 25% in those patients that have multiple punched out lesions close to the macula. So I think the clues here really to distinguish would be, again, the clinical presentation, presence or absence of inflammation, vitritis anterior chamber reaction, which can help you distinguish from multifocal choroiditis.
(22:56):
Similar to multifocal choroiditis, though different from PIC, the hypopigmented punched out lesions can be found not only in the posterior pole but also beyond the posterior pole, so in the periphery as well. And again, I think a big clue is the geographic kind of distribution. Now another thing that we always, one of the many funny questions that we ask when we are interviewing our uveitis patients is, do you go spelunking? So do you end up going in caves and have you been in any places where there could be bats because bats can also be carriers of this disease. So, it is a funny question to ask, but it could be a helpful one for those few patients that might end up doing that or have had experiences that way. So that's another clue to POHS.
Ogul Uner (23:47):
I think that was a great overview that you provided and I think it's very common to confuse POHS with MFC, but like you said, I think the absence of vitritis is very important and the lesions technically should not progress unless we're seeing a CNV that is maybe worsening and causing a scar, like you said, it's rare for more and more lesions to crop up, especially at a rate with MFC and PIC, for example. So in most cases we don't reach for immunomodulatory therapy in this case. I really appreciated how you also discussed the nuance of the diagnosis. I think it was mainly termed by Dr. Robert Watsky, who's one of our former faculty members and he used to say that it is endemic to the region. They think it is from histoplasmosis, but no one unfortunately is able to identify histoplasmosis as any of the samples.
(24:55):
And so I think that was an important point you brought up that there may be an autoimmune trigger to the inflammation and that we cannot detect the organism itself in ocular tissues in patients with POHS. So I thought that was interesting.
Maura Di Nicola (25:10):
Yeah, you're 100% right. It is fascinating. And the question is also in these regions that we mentioned, maybe 60 to 70% of the population even has had exposure to histoplasma, but not all of them have ocular manifestations of POHS. So again, what determines what that kind of phenotype in those patients is probably some sort of HLA type or genetic predisposition that we've been looking at. And I also agree with you completely, Ogul, you bring up an excellent point. These lesions tend to not be progressive. So oftentimes these patients do not require treatment unless it is for choroidal neovascularization. And in that case, again, anti- VEGF would be our mainstay of treatment.
Ogul Uner (25:54):
Great. So let's summarize what we've learned from Dr. Di Nicola. Multifocal choroiditis and panuveitis is a phenotype. So we talked about it being characterized by these bilateral medium-sized yellow to gray chorioretinal lesions. There's vitreous inflammation and occasionally anterior segment inflammation. It's seen most commonly in young myopic women. It's always important to rule out sarcoidosis, tuberculosis and syphilis in these patients as multifocal choroiditis can be a phenotype of any of these entities and always consider neoplastic etiology such as vitreoretinal lymphoma in older patients. Choroidal neovascularization can be present in up to 50% of patients in CME or cystoid macular edema and up to 40%. So treatment with systemic or local injectable steroids with or without immunomodulatory therapy is important to prevent vision loss. We talked about PIC, which is similar to MFC and it's also seen most commonly in young myopic women. However, it differs in that the lesions are predominantly in the posterior pole.
(27:03):
There's no vitritis or very, very minimal vitritis and the rate of CNV is much higher at up to 70%. Immunomodulatory therapy is needed for lesions threatening the fovea or if they become recurrent after steroid discontinuation. And we talked about POHS or presumed ocular histoplasmosis syndrome, which can also have a similar appearance to MFC, but it's different in that there's no vitritis and has the triad of peripapillary atrophy, the histo spots in the mid-periphery, and the disc forms scars that may form centrally from a choroidal neovascular membrane. So, PIC and POHS don't have vitritis and both MFC and POHS have lesions outside the posterior pole. These are important to remember when you're evaluating these patients or when you're taking exams that test these etiologies as they tend to like differentiating these entities. CNV risk and POHS is much less compared to the other two entities and the punched out lesions like we talked about should not progress and this differentiates POHS from active inflammatory chorioretinopathies like MFC and PIC.
(28:15):
Dr. Di Nicola, anything else you would like to add?
Maura Di Nicola (28:18):
No, I think that was a fantastic summary that you gave us all, and I hope this was helpful to our listeners to just keep the differential in mind and try to distinguish these entities when the time comes.
Ogul Uner (28:32):
Yeah. I learned a lot just talking about the different multimodal imaging. So thank you so much again. Dr. Di Nicola, before we end the episode, I ask all of my guests a question. My question for you is if you could go back in time and give your younger self one piece of advice, what would it be?
Maura Di Nicola (28:50):
Yeah, so that's an excellent question, Ogul. I love that question. So as you and I know each other and in a way have had similar paths and you know that I was internationally trained for medical school and residency. And so my path to eventually practicing in the United States has not necessarily always been a linear one. So one piece of advice I would give myself is just have faith in the process. Sometimes it feels like the process is overwhelming, it's overly complicated, it's too stressful. And if I could go back in time, I would just tell myself to take it easy, approach it with really faith that things will work out for the best and really take any chance that you can and take any opportunity and maybe what feels like a challenge in that moment as an opportunity for growth so that you get to enjoy the process as you get to reach your goal.
Ogul Uner (29:55):
I love that. I really resonate with that. Like you said, I think coming to the U.S. as an immigrant is always very challenging and there are a lot of barriers that people need to jump through, but I think people do very well and they contribute a lot to the community and to ophthalmology in general. So I'm very grateful that you brought that very insightful comment and response. So thank you.
Maura Di Nicola (30:29):
Thank you so much.
Ogul Uner (30:30):
And Dr. Di Nicola, thank you for joining us on this episode of The Pupil Pod.
Maura Di Nicola (30:35):
Thanks again for having me. It was truly a pleasure. Thanks so much.
Ogul Uner (30:39):
And thank you to our listeners. See you next time on The Pupil Pod.
