Hi, everyone.

Welcome to Febrile, a cultured podcast about all things infectious disease.

We use consult questions to dive into ID clinical reasoning, diagnostics, and antimicrobial management.

I'm Sara Dong, your host and a MedPeds ID doc.

Today, we have another State of the Art Review or StAR episode talking about ocular infections.

So let me start by introducing our guest stars.

We'll start with Dr.

Miriam Barshak, who completed her medical internship and residency at Brigham and Women's Hospital, followed by I.

D.

fellowship in the combined Massachusetts General Hospital Brigham and Women's Hospital I.

D.

fellowship program.

She then devoted 10 years to basic research in streptococcal pathogenesis before transitioning to a primarily clinical role at Massachusetts General Hospital and Massachusetts Eye and Ear.

There she serves as a primary I.

D.

consultant for Mass.

Eye and Ear.

Hi, thanks so much for having us.

Our other guest star today is Dr.

Akash Gupta.

He was Dr.

Barshak's ID clinic fellow at Massachusetts General Hospital, and she taught him everything he knows about ocular infections.

Prior to fellowship, he was an internal medicine pediatrics resident at Massachusetts General.

After fellowship, Akash practiced ID in northern Massachusetts, and since August 2024, he joined the University of Pittsburgh Medical Center, where he is a clinical assistant professor.

Uh, hey, this is Akash.

Happy to be here.

All right, as everyone's favorite cultured podcast, we love to ask our guests to share a little piece of culture, just something that you have enjoyed recently or that has brought you joy.

Yeah, I'll go first.

So, on a family vacation over the recent December holiday break, we went to this amazing place in St.

Augustine, Florida called the Museum of Tiny Art.

So, instead of looking at bacteria under microscopes, you can go from scope to scope to look at these miniature paintings that all fit inside the head of a needle.

Sculptures and paintings and all kinds of other incredible things that people do with microscopes that are unrelated to what we usually think of them for.

That sounds so delightful.

Yes.

One of them was a carving on a strand of hair that you can look at under the microscope.

It's kind of incredible to imagine how much effort must have gone into doing that.

Yeah, that's awesome.

What about you, Akash?

Um, do hobbies count as culture?

Mm hmm.

Um, so I'd say, like, the main thing I have gotten totally obsessed with over the last couple years is birding.

Following many in our ID department, I, um, kind of took a plunge.

I had a passive interest for years, and then two years ago, my brother in law kind of got me hooked on a trip to Costa Rica that we took as a family.

Um, and then I've just kind of gotten completely insane, and it's been a really fun part of my life.

Um, I recently moved to Colorado where, where the birding has been great.

Um, but I had to link it to like more conventional cultures, I guess I would say, there's a book or a series of books by Jen Ackerman, who writes a lot about like sort of bird behavior and bird intelligence, um, and like migration and stuff.

And they're just super fascinating.

Um, and there's a feel good movie that I think a lot of us need right now called The Big Year, which I watched a couple of weeks ago.

Um, that, uh, that was delightful.

Lovely.

I like that you had a couple different picks for us.

Um, well, thank you guys so much for creating this article.

We're going to be talking about ocular or eyeball infections today.

You address and highlight a lot of the common challenges we have in ID when we're co managing these patients, whether that is, you know, the exam and anatomy of the eyeball, the infections or the treatment options that we have, or even if it's just deciphering the ophthalmology note.

We're gonna have a couple rapid fire cases today, but before we start, I thought it might be helpful to have you share maybe just a little bit about creating the article, what you guys were thinking about and or some of your experiences treating ocular infections.

Yeah, so, um, I was very excited to be asked to write this article recognizing that there is a, uh, great amount of need for something that kind of bridges the language and the concepts of ophthalmology to ID doctors who individually probably don't see that many infections in the course of a career, unless they work at a location like ours, where I am at Mass Eye and Ear, where we are incredibly privileged to work really closely with amazing and thoughtful ophthalmologists and be able to access their notes and the photos that they take of the eyes that they're taking care of and to see all of the work up and be able to collaborate in managing this area of infections that is in some cases a world of its own.

But in other cases, it's very intimately connected with the rest of the body and the rest of the infections that we see, so it's been a really incredible professional experience for me.

And certainly there have been some really memorable cases in which the first inkling that there was something systemic going on was in the eye or the first opportunity to make a diagnosis of a systemic process that was otherwise undiagnosed was through taking advantage of that opportunity to have ocular sampling done.

It's very rewarding.

I guess I can add just a little bit.

I mean, a lot of my experience just comes through working with Miriam.

I was, um, lucky enough to have her as my clinic preceptor.

And so that was just kind of a step into this like, um, wild world of eye infections that I think I would have had a lot less familiarity with otherwise.

And I think what maybe stood out is just the really, really positive collaborative relationships that Miriam had with the ophthalmologist and, um, the ongoing discussions and, like, how much exam really matters.

And, and it's exams that we can't typically do ourselves.

And so it's just really like a full partnership.

And I think the stronger that partnership is, the easier it is to manage these.

Great.

And even though there are a lot of people who might be multitasking while they listen to Febrile, maybe they're in the car or they're walking their dog, um, I do want to direct everyone to the awesome figures that are in the paper, thinking about anatomy.

And so even without us having that visual in front of us, could you give us an overview of the way that you think about the anatomy of the eye and infection?

So I can take the first stab at this, um, and I will say, you know, for everything I, I take the first pass on, um, I'll, I'll let Miriam comment just cause she has vastly more expertise than I do, but the way she taught me to think about it and the way I've kind of tried to think about it before, so I, I guess, you know, one thing is that actually often when I have eye infection cases, I will actually look at the anatomy again, like I'll pull it up on Google or whatever.

Now I'm pulling it up on this review article because it's a little more specific, but there's kind of two ways that I think about it.

One is outside in, and then the other is sort of anterior, posterior, or front and back.

So the layers going outside in, and if you guys do have, if listeners do have the paper pulled up, it would be Figure one.

So from the outside, we have this layer called the sclera, and that's kind of the white part of the eyeball that you see.

And the sclera is continuous in the front with cornea, where It's kind of an opening that lets you, uh, lets light in.

And so that outer layer, uh, sclera, if it gets inflamed is called scleritis, which is kind of intuitive.

Um, what is less intuitive is that if you inflame the cornea, it's called keratitis.

And then, uh, there is a layer called the conjunctiva, which is probably the the area that most people are familiar with because they you know, see it in common practice, but the conjunctiva is basically a mucous membrane that covers part of the sclera up to its junction with the cornea and then reflects onto the inner eyelid, and we call inflammation of that conjunctivitis, which is again intuitive.

Um, so the next layer inside is called the uvea.

And we call inflammation of anything in this layer and sort of the areas around it, um, uveitis, and it's actually three different structures that form it.

Um, the iris is in the front, which controls the size of the pupil, and a lot of people are familiar with, and when that's inflamed, it's called the iritis, and then behind it is the choroid in the posterior part of the eyeball, and the inflammation of that is called a choroiditis, and that can end up being a pretty important finding for a few different infections, and then in between you have the ciliary body, which connects them together, and that is called cyclitis if it is inflamed.

And then finally, the medial layer we get is the retina, which many of us are familiar with, and that's how we get light perception.

And if you inflame that area, it's called retinitis.

It also has a blood eye barrier at the retina that's kind of similar to the blood brain barrier, which ends up being relevant.

So that's kind of the inner to outer dimension, and then we can think about the front and back dimension.

So in the, um, anterior part of the eye, we have something called the anterior segment, which is everything from the lens forward, basically, between the cornea and the lens, and it's filled with something called the aqueous humor.

And then in the back of the eye, we have the posterior segment, which is between the, uh, lens and sort of back of the eye, and it's filled with the vitreous humor.

So, uh, we call that vitritis if it gets inflamed, and then, um, inflammation of aqueous humor is, uh, little more complicated.

But if you do see inflammatory cells there, that's often what we call anterior uveitis or as a sign of anterior uveitis.

Miriam, anything to add?

No, I think that was a really great summary.

I was going to jump in with a couple of specific terms in the glossary that can be confusing for people that don't see them regularly.

And just to start by way of background, I think all of, all of us are familiar with the Snellen eye chart where there were a whole bunch of letters at the top, starting with a big letter E.

So people who can see that big letter E, but nothing smaller than that have 20 over 200 vision, um, but the ophthalmologists have more specialized ways of distinguishing lower levels of vision.

And those are things that are really important for us to know about because often that's kind of one of the eye vital signs is what the vision itself is like.

And it gives you a sense about how severe a vision threatening infection might be.

So for people that can't see the big E, but can count fingers that you'll hold up in front of their face, that's called count fingers vision, which would be designated as CF.

The next level down, if they can't count fingers, would be to determine whether they can see motion.

So moving your hand in front of their face, if they can tell when it's moving and when it's not, then that's hand motion vision.

If they can't see hand motion, then you can test for light perception with a pen light and see if they can localize the light in different areas or tell whether the light is on or off.

If they can, then they have light perception vision, and if they can't, then they have no light perception NLP.

And as you might imagine, NLP is not only the most undesirable of all those vision options, but it is also the most ominous, because often once there's no light perception, there's a lot less hope for regaining the vision.

As long as there's some vision, even if it's only light perception, there are a lot of reasons why the vision may be that poor, many of which may be reversible.

It may be that there's a lot of edema or a lot of inflammation that's, um, treatable, and so definitely they tend not to give up on eyes as long as there's light perception, but once there's no light perception and they don't think there's visual prognosis for the eye, then the, um, options that are used for trying to treat infections are a bit different in level of aggressiveness.

So those are the abbreviations for visual acuity.

Some of the helpful abbreviations related to the anterior eye exam that you may see.

So in describing the cornea, um, you may see something that's designated as PK.

That's a common one and it stands for penetrating keratoplasty.

So that is the ophthalmologic term for a corneal transplant.

So the cornea, that's the native cornea has been removed and a new cornea has been placed, whether it's a natural cornea or an artificial cornea, those get designated the same way as PK.

Not to be confused with PK as KP, keratic precipitates, so those are kind of clumps of inflammation from the aqueous that are walled up against the back of the cornea.

And that indicates the inflammatory process going on in what's called the anterior chamber, the space between the cornea and the iris.

Um, the AC is the designation for the anterior chamber.

And again, that's between the cornea and the iris.

And when they describe the exam of the AC, they refer to, um, flare, which is protein, and cells, which is white blood cells.

And those get scaled on a scale from one to four, depending on how much flare and how much cells being seen there.

Um, moving further back, there's a, um, abbreviation.

PC IOL that you might see.

So that's a lens.

And the PCIOL stands for posterior chamber intraocular lens.

And that refers to a lens that's been placed during a cataract surgery.

So if someone has one of those lenses, it means by definition, their eye has been surgically operated on.

And, you know, from the infection standpoint, it means there's an opportunity for having introduced infection and also a site perhaps for a nidus of infection to hang out.

So something specific about it.

And then the posterior eye exam.

They often describe cells in the vitreous if it's inflamed.

There's an abbreviation PPV, pars plana vitrectomy, so that's the descriptor that's given to the, um, removal of the vitreous, which is something that's done sometimes for diagnostic and sometimes for therapeutic reasons.

Um, in the retina, there's often a description of the macula, so, um, the macula gives central and sharp and color vision, and the peripheral areas of the retina are more important for low light and peripheral vision, and that is important because infection involving different areas of the retina may lead to different, um, degrees of symptoms and types of visual symptoms.

And then lastly, in the, in the glossary, I wanted to highlight the imaging studies that the ophthalmologists commonly use to work out various processes.

The most common one you'll see described is called a B scan.

B stands for brightness, little counterintuitively.

Um, but that's an ultrasound, so it's basically an ultrasound of the eye.

And on a B scan you can see inflammation in the vitreous or areas they may not be able to see into directly with the regular eye exam, particularly if there's a lot of inflammation in the front part of the eye, the ultrasound may be better at visualizing that.

And it can also help identify retinal detachment.

And then lastly, there are some angiography procedures that are used in ophthalmology for elucidating whether there's inflammation going on in the blood vessels.

And those studies get referred to as FA, fluorescence angiography, or ICG, which is a different kind of angiography that looks at the cord and retinal vasculature, which can be helpful in making various diagnoses on exam.

Great.

Yeah, I was going to show my vulnerability and just say that when I see these abbreviations, even if I feel, uh, pretty certain that I know what they are for things like OD (oculus dester, right eye), OS (oculus sinister, left eye), I often will go and double check and Google it to make sure I'm not misinterpreting information.

Um, so now everyone has a resource in Table 1 that summarizes all these terms into the reference glossary.

Can I make one additional plug?

Um, there was a website that I found while I was Miriam's fellow that I used to help prep for clinic, and it's called, um, eyeguru.org and simply eyeguru.org/translater, and it's literally an ophtho note translator.

Um, so you can put in, like, terms or strings of terms or phrases that you see in an ophtho exam or something, and it will turn it into, like, understandable prose for you.

Um, so I, that is something I've used a lot.

I don't know if, you know, as AI develops, that will become less specifically relevant, but for now it's still been very useful.

Excellent.

Yeah, I will put a link to it in our consult notes.

Um, all right.

Well, you guys are up today to talk us through a couple different rapid fire ocular infection cases so we can get some pearls, some learning.

All right.

And so I'll get us started.

We have a 73 year old woman who presents with two days of left eye watery drainage, redness, pain, and visual changes.

She also has five days of a vesicular rash on the left forehead.

On gross examination, there is conjunctival injection, and the slit lamp exam shows corneal edema with pseudodendritic lesions and fluorescein staining.

So what are we dealing with here?

Right, so whenever we hear about redness of the eye, um, many non specialists initially think of conjunctivitis because that is certainly the most common infectious cause of redness of the eye, but conjunctivitis doesn't usually come along with pain and definitely doesn't come along with visual changes.

Those are things that make you need to think about something else.

And especially knowing that there's a vesicular rash on the forehead.

That's kind of the, um, the strong suggestion that there may be a viral process going on, probably zoster, dermatomal zoster, which in the V1 distribution has an associated risk of involving various structures of the eye.

Classically with that, um, we advise that patients should get an eye exam, even if they don't have ocular symptoms, but if they do have ocular symptoms, then they should have a very prompt eye exam.

The treatment of ocular involvement with herpes zoster requires more than just systemic antiviral therapy.

So the most common, um, eye involvement that does get seen in these types of patients is some combination of conjunctivitis and keratitis.

And when you put this together, you get keratoconjunctivitis.

Just in, in general, when we think about conjunctivitis, there are other much more common viral causes of conjunctivitis, the most common one being adenovirus, and conjunctivitis in adults in general is most commonly viral.

So adeno is often at the top of the list, not in this case, but in most otherwise healthy patients.

Again, that's not usually vision threatening.

And diagnostically, it's often a clinical diagnosis.

Think about watery drainage, but really that doesn't necessarily have the greatest sensitivity or specificity and in better careful studies, there are other factors that can help you be more confident about that diagnosis.

Things like having a lot of itching, having having contacts with other people or having other viral symptoms that may go along with having an adenovirus syndrome, having a runny nose or other sorts of, um, of symptoms.

Bacterial infections in adults of the conjunctiva are relatively uncommon, um, but in children, bacterial infections of the conjunctiva are much more common than the most common bacteria.

Bacteria wise conjunctivitis include pneumococcus, staph aureus, and H.

flu in adults.

As I mentioned, bacteria are much less common, but of course, the only way to get a clear diagnosis of what it is that you're treating as a bacterial infection would be to get a culture.

Keratitis, in general, is more commonly caused by bacteria than by viruses.

So our case is a viral infection, but to put that aside for a moment, most of the cases of keratitis you're likely to come across are bacterial and the primary risk factor for keratitis is contact lens use.

And when I say contact lens use, what I really mean is lapses in hygiene associated with contact lenses, which are really common.

Um, anyone who wears contact lenses may know how common it is to maybe not change the case as frequently as you should or just sleep in them, um, or not change them out as frequently as they're supposed to be changed.

So this aspects of hygiene may explain why the rates of keratitis are so strongly associated with contact lens use, but there are other risk factors as well.

And those are things like ocular trauma or dry eye or other surface eye disease, which provides a nidus by which bacteria can set in and cause infection.

They're most common symptoms of keratitis involved pain in the eyes.

So the idea that this patient's having pain certainly goes along with having corneal involvement.

Sometimes, often there's also redness and sometimes there's also visual changes because the cornea has such an important role in being transparent and refracting light.

Any pathology in the cornea can really seriously impact vision.

On exam, the easy part of the exam was a pen light that all of us can do.

You may see an opacity where there may be a defect in the cornea, and you may be able to see a hypopyon, which is a layer of pus in the anterior chamber that's spaced between the cornea and the iris.

In patients with keratitis, those collections are kind of sympathetic to what's going on in the cornea, and the collection itself is usually sterile.

You can see that better on a slit lamp exam if it's a very small collection.

And the slit lamp also allows you to see deeper into the eye to make sure that there's nothing going on more deeply than the anterior chamber.

The microbiology of keratitis when it's bacterial is most commonly things like Staph and Pseudomonas.

For viral infections, as I mentioned, keratitis in this particular case, is caused by herpes viruses, and those are the most common causes of viral keratitis that you see.

Fungal infection is a really important cause of keratitis, particularly in less developed places, where a lot of the risk for infections in the cornea are from trauma, and often trauma associated with agricultural work, for example, or other environmental exposures rather than contact lens use.

And then Acanthamoeba is an organism, parasite, that we see, um, particularly associated with having unclean water in contact lens cases.

Usually treatment for keratitis is topical therapy.

Empirical treatment for bacteria usually is trying to cover the bases of staph and pseudomonas.

So usually things like quinolone or vancomycin in combination with tobramycin.

Um, if there's concern for fungal infection, then topical antifungals and natamycin is a frequent choice that the ophthalmologist will make.

Acanthamoeba has its own, uh, planned regimen, and typically these types of infections do get better with topical therapy, but if they don't, then there are a whole series of maneuvers that the ophthalmologist can do, including various types of light therapy and including cross linking.

And, um, ultimately, if those things don't work out well, then patients sometimes wind up needing a corneal transplant in order to debulk the infection.

And then they can get it into a cornea placed, um, and once the infection has settled down.

For viral cases like this one, the treatment involves systemic antiviral therapy for the forehead involvement with the zoster and topical antiviral therapy, um, for the eye involvement, although it depends a bit on how deep the corneal involvement is.

Cornea has a surface component, the epithelium, but it also has a stromal component, and so depending on how deep the involvement is with the, um, with the cornea, the appropriate treatment for the eye itself may include topical antivirals or oral antivirals.

Um, and then for stromal infiltrates, they usually also include topical steroids for trying to control the inflammation in the cornea that's impacting the vision so much.

The prognosis for viral infections of the cornea like this one is not great.

So, um, 50 to 60 percent of people will wind up with corneal scarring after an episode of corneal involvement with VZV.

And along with the scarring often comes anesthesia, which means that they can't necessarily feel that next episode of bacterial superinfection that may follow at some point.

So these patients have an elevated risk of subsequent corneal infections that can lead to ulceration and ultimately perforation if they don't recognize what's going on and aren't able to present for care fast enough.

So understandably, um, one of the biggest goals from the corneal infection standpoint is to try to prevent these episodes, um, using vaccination for VZV, uh, and using chronic acyclovir for recurrent episodes of HSV.

Um, and then obviously contact lens hygiene strategies to try to minimize the risks of other types of non viral keratitis.

Great.

And just to orient people again and summarize, we've just talked about conjunctivitis and keratitis.

If you think back to when Akash was talking through those layers, he mentioned the sclera, the cornea, and the conjunctiva.

Alright, well, we will jump into our second case now.

We have a 25 year old woman with a history of injection drug use.

She presents with pain and deteriorating right eye vision over the past month.

She's had no fever, sweats, or other systemic symptoms.

Her visual acuity is 20/400 OD and 20/20 OS.

The fundoscopic exam reveals a white lesion in the vitreous, and she's diagnosed with endogenous endophthlamitis.

Intravitreal injections of vancomycin, ceftazidime, and voriconazole are given, and blood cultures are drawn.

So what organisms are you thinking about and most worried about here?

I think in this patient I would be most concerned about a fungal etiology for a few different reasons.

One is that it's a sort of a community acquired infection with the main risk factor being injection drug use, which does increase the likelihood of a candidal etiology.

And then there's also a subacute course of symptoms rather than over a few days.

It seems like it's been over a week to a month, and that also increases the likelihood of candida.

And I think just taking a step back to kind of how we think about endophthalmitis.

So endophthalmitis basically refers to any intraocular infection, but we kind of colloquially or generally use it to refer to a bacterial or fungal infection that involves either the vitreous or the aqueous humor.

And there's two types of endophthalmitis.

The most common by far actually is exogenous endophthalmitis, where pathogens get introduced from the ocular surface, like basically from trauma, bringing pathogens outside in.

That can either be due to direct ocular trauma, which is more common in non U.

S.

countries, or it could be as a complication of some type of eye procedure or surgery.

These are actually the ones that we have a lot less familiarity with because the vast majority of these are managed without infectious disease input and are just entirely managed by the ophthalmologist.

And so the other type is endogenous endophthalmitis, where the, the etiology is likely hematogenous spread without any sort of ocular trauma that would bring the pathogen inside.

These are actually only about 15 percent of endophthlamitis cases, but they're the ones that we see as ID practitioners far more and get called to help treat primarily because they're often associated with a systemic infection.

In addition to the direct eye symptoms, which would include eye pain and decreased vision, you can get systemic symptoms, which are more common in endogenous than exogenous.

But even in endogenous, they don't happen in everyone, and, you know, this, uh, young woman, despite having three, maybe four weeks of symptoms, actually didn't have systemic symptoms, um, uh, despite probably seeding from a hematogenous source.

So there are a variety of common bacterial pathogens that we see, including Staph aureus, Strep, um, we also see some gram negatives such as E.

coli, and then there have been, um, a fair amount of cases of the hypermucoid viscous klebsiella seeding the eye in addition to the other abscesses that it forms throughout the body.

Um, and in these, uh, bacterial etiologies, usually the symptoms are pretty acute between one and a few days.

And then in contrast, candida is more subacute, as I mentioned, and has a higher risk of intraocular seeding, um, if you have candidemia, then bacteremia.

And the risk factors for inpatients are kind of similar to what you think for of candidemia: people in the ICU for a long time with lines, maybe immunocompromised, um, but among outpatients, the major risk factor is injection drug use, which fits this case.

Among people with injection drug use related endophthalmitis in one series in Boston, 59 percent were candidal etiology.

So it is the majority of these kinds of cases.

In summary, for this case, I would say that she has subacute onset of ocular symptoms, absence of systemic symptoms, and evidence of endogenous, uh, endophthalmitis on exam with involvement of her, uh, vitreous and major risk factor being injection drug use.

So Candida would probably be the highest on my differential, but like they did in this case, you'd kind of treat for everything until you know what you're treating.

Got it.

So, she was started on systemic high dose fluconazole on admission.

Vitreous aspirate culture and blood cultures were negative, and by day three, the vitritis had worsened.

So, she ultimately undergoes a vitrectomy, so surgical debridement of the vitreous, um, and those cultures grew a fluconazole resistant Candida species.

Any other thoughts on this case and endophthalmitis in general?

So, I think what's reflected in terms of how they approach the initial empiric treatment is that the mainstay of therapy, at least for the eyeball, is intravitreal injections of antimicrobials.

And so this patient was given that empirically by ophthalmology.

And then when you think it's endogenous and you think it's hematogenously spread, you also provide systemic antimicrobials, although those probably do more for the systemic infection than they do for the eye infection itself.

They're just kind of supplementary for the eye infection.

We typically do use a long course of antifungals if we do suspect candida and it's important to think about intraocular penetration for your antimicrobials.

So I mentioned that there's a sort of like blood eye barrier formed at the retina.

A lot of us have probably been in this scenario where we suspect eye involvement, we have a patient empirically on micafungin and then we're kind of trying to decide what to do because micafungin and echinocandins penetrate the vitreous a lot less than azoles.

And so I think in this case, azoles are a very reasonable way to go and fluconazole was a reasonable empiric treatment.

It was unfortunately resistant, although it's unclear that if that's the reason that she actually failed the initial attempt at management because she actually got voriconazole intraocularly.

But sometimes even just despite getting intravitreal antibiotics, even sometimes multiple times, and systemic therapy.

Um, It fails and they ultimately do need a vitrectomy for further management.

And if the initial infection is bad enough, sometimes we'll just jump to vitrectomy immediately.

I guess I just have one additional point where if you do have someone with injection drug use who's being managed on methadone, it's just one thing to make sure that you're monitoring QTC if you're going to use methadone and nasal at the same time.

That was a great description.

I mean, when you think about what a fungal ball looks like, you can imagine it might be hard, even with intravitreal treatment, to get good diffusion of the drug into the place where the problem is.

It's just really a physics problem more than anything else.

The only other thing I wanted to add is we get asked quite a bit about whether fungal markers are helpful from the bloodstream and either making this diagnosis or following the treatment path.

And I would say for people like this, for whom their syndrome is probably related to transient fungemia and not ongoing fungemia that usually those fungal markers are negative.

So they're not, they're not useful in ruling out the diagnosis and don't let that dissuade you from thinking about endophthalmitis or otherwise.

Yeah, those are great reminders.

And just to pause and summarize again, we just talked through endophthalmitis, which is that term describing infection in the vitreous and or aqueous.

And you guys talked a little bit about exogenous versus endogenous as well.

Alright, so I'm going to move us forward to our next patient who's come into clinic.

We have a 55 year old male, previously healthy, who presents with five days of mild eye pain and progressively blurry vision and floaters OS.

The flashlight exam is normal, but visual acuity OS is 20/200.

The dilated fundoscopic exam reveals retinal necrosis and vasculitis with associated vitritis.

So he is diagnosed with acute retinal necrosis.

So we're going to hear a little bit more about this mini case, but I'm going to stop us here to see if you can talk about uveitis, and what infectious or non infectious causes you're considering at this point.

And I also think it's really easy for people to get confused by alphabet soup and maybe need clarification on terms like acute retinal necrosis versus progressive outer retinal necrosis.

So can you help us out here?

Sure.

When I think about uveitis, the first and kind of most important distinction is which part of the uvea is involved.

So as Akash mentioned, there's the anterior uvea, the iris and the ciliary body, and then there's the posterior uvea, which is the choroid that often is, uh, involves inflammation there, often involves the retina as well and is associated with vitritis.

The reason why that distinction between anterior and posterior is important is because anterior uveitis is most commonly non infectious.

So usually these are autoimmune conditions whether people have the ANA or the ANCA positive or whether they're sort of less well defined autoimmune conditions, more than 90 percent of anterior uveitis is non infectious, and we don't tend to get consulted so much for anterior uveitis.

That being said, the subset that is infectious is usually from HSV, and so often the ophthalmologists are managing that on their own as well with topical or systemic therapies.

Um, posterior uveitis is kind of a different story.

So usually posterior uveitis has kind of a broader differential.

Some of that is also noninfectious, but worldwide, the most common cause of posterior uveitis is actually toxoplasmosis and we refer to posterior uveitis.

Again, the definition of that is the choroid, but often there's involvement of the retina and the vitreous as well.

But, um, there's anterior uveitis, there's posterior uveitis, and then there's so called panuveitis, which means essentially both the anterior and the posterior parts of the uvea are involved.

In the U.

S., the most common cause of posterior uveitis that we tend to see is herpes virus.

Either HSV or VZV and that comes in two flavors, as you were alluding to.

So ARN, acute retinal necrosis, and PORN, progressive outer retinal necrosis.

I know someone once told me that, um, it's hard to explain the difference, but you'll know PORN when you see it, haha.

Um, to the ophthalmologist, there is a distinct exam associated with PORN though, um, both of these entities are associated with a vaso occlusive angiitis of the retinal vessels that can, um, proceed to blindness.

With PORN it tends to be much more rapidly progressive because it involves the macula sooner and faster.

And it tends to be in people who are terribly immunocompromised.

So people with advanced AIDS, people who are on terribly high amounts of chemotherapy, and they're really much more vulnerable.

Um, so usually the distinction between those two entities has to do with who the patient is and then what the exam looks like by the ophthalmologist.

These are both considered ophthalmologic emergencies though, because even though HSV and VZV ARN are less rapidly progressive than PORN, and they're both types of entities that can lead to blindness that could be reversed.

Yeah, and so the second half of this case, we learned that the vitreous aspirate was sent for PCR testing for HSV and VZV.

He receives an intravitreal injection of foscarnet and has started on high dose oral valacyclovir with close outpatient follow up.

Two days later, the retinitis has progressed and he ultimately requires admission for IV acyclovir.

Vitreous PCR testing shows VZV.

Yeah, so, um, acute retinal necrosis is most commonly caused by HSV VZV, and typically the way the diagnosis is confirmed is with those intraocular samples, although often it's a clinical exam by the ophthalmologist, and the treatment should not wait for the confirmation of the diagnosis, because it's important to start antiviral therapy early.

Most of the time, um, systemic antiviral therapy as well as intraocular antiviral therapy are used and the usual intraocular treatment these days is foscarnet so it isn't necessarily important to know which virus it is because that generally covers all of them.

Importantly, acute retinal necrosis usually impacts immunologically normal hosts.

So while it's always worth thinking about and looking for evidence of immune compromise and certainly offering HIV testing and thinking about decreasing any immune suppressing medicines that the patient might be on.

Usually don't find anything as an obvious cause, and so it isn't always clear why it is that someone has had this happen to them, which is always a bit disconcerting.

Typically the treatment that gets started up front is oral valacyclovir and typically it's high dose and in a normal kidney function patient, high dose means 2 grams Q8 hours and that's almost the equivalent of what you can do with IV acyclovir, although IV acyclovir with weight based dosing, you can probably get slightly higher levels, so if people don't respond adequately to the oral within a couple of days, the usual practice here is they'll get admitted for intravenous IV acyclovir and then with the goal basically of halting the progression of their retinitis.

And then typically because the retinitis comes along with a lot of vitriol inflammation, 24 to 40 hours into antivirals, um, systemic therapy with steroids is often started in order to control that inflammation.

The eye is a relatively unforgiving place for having pressure built up from inflammatory response.

And so often people have a better chance of responding when steroids are started fairly early.

In general, the course of treatment is six weeks of antivirals.

Once people have responded to that IV therapy, usually the step down, uh, choices to go back on valacyclovir unless there's reason to suspect resistant virus.

Very occasionally, we've seen people who didn't clinically respond to IV acyclovir and not necessarily for obvious reasons, but there are a few case reports of patients who needed intravenous foscarnet in order to be able to halt their disease, um, which is obviously a much bigger deal in many ways.

And I'll just add that, um, my first patient that I admitted on my medicine clerkship as a third year student had concurrent PORN syndrome and varicella vasculopathy and I was like, wow, medicine is crazy.

And then I later on realized that that's become significantly more rare and that was the only case I've seen.

One last thing about treating acute retinal necrosis is that because many of these patients don't have an obvious reason for why this happened to them and because it's a vicious cycle.

We often, um, de escalate to long term suppressive antivirals in order to try to protect them from having a recurrence either in the one eye that was impacted or perhaps in the other eye.

This isn't always very well supported by insurance, um, in the, in the long term with an explicit description of the plan for long term antivirals.

So sometimes it's a, it's a less explicit plan for long term antivirals, but it's gonna be a long term.

Alright, so that was us talking through a case of VZV retinitis.

I'll move us to our next clinic patient, who is a 25 year old male who presents a blurry vision OD for the last several days.

He has had a similar but less severe episode about three years ago that self resolved.

He is otherwise well and is previously healthy.

He immigrated to the U.

S.

from Brazil five years ago.

And on eye exam, we see a creamy white lesion adjacent to the scar.

The view is hazy due to vitritis.

And so I'm just going to jump to the diagnosis and confirm that he is diagnosed with ocular toxoplasmosis.

He's placed on trimethoprim sulfamethoxazole, or Bactrim.

So I was hoping you could share some pearls about treating ocular toxo, and I would love to hear your opinion in particular about how you think about risk benefits of secondary prophylaxis for toxoplasmosis.

Absolutely.

So ocular toxo, although it's not something we necessarily see all that frequently here, um, and particularly in otherwise immunologically normal people, just to to highlight that this is often the only manifestation of toxo in people who are immunologically normal.

It doesn't require that people have HIV or low T cell counts or any other obvious immune deficiency.

This is sort of a typical course of ocular toxo for many people around the world and particularly in Brazil, where they seem to have a more virulent strain of Toxo than what we tend to see here.

These patients, as I mentioned, are typically not immunocompromised, so, you know, looking for CNS toxo or doing an extensive exhaustive workup for immune deficiency is usually not very rewarding.

Um, but certainly it's worth considering whether they may be immunocompromised.

Don't be surprised if they're not.

Usually the treatment in the old days was pyrimethamine and sulfadiazine, but as those medicines have become more difficult to access and more expensive, the TMP-SMX is really the new standard.

In general, most of the data about treating ocular toxo comes out of Brazil, where they have a lot more experience than we do.

Alternatives for people who can't take trimethoprim sulfa include things like atovaquone or azithromycin, although the amount of data for these treatments is much, much, much less than the sulfa based therapies.

Usually, for people that can't get sulfa based therapies, the first option for a pretty severe disease actually is intraocular clindamycin injections.

Systemic clindamycin can also be used, but there's not as much experience with that, and you can imagine the appeal of having clindamycin given directly in the eye.

As far as the secondary prophylaxis, I think there's a couple ways to look at that.

There's a group in Brazil that's been looking at this question pretty intensely over the course of the last few years, and the motivation for that is that most people who have an episode of ocular toxo will relapse.

More than half of them will if you follow for a long enough period of time.

So this group of Brazil most recently put out their last randomized control trial, um, in 2020, where they looked at people who were having an acute episode of toxo and they treated the acute episode with trimethoprim sulfa for a defined period of time.

And then they left people on alternating day trimethoprim sulfa for a year following the treatment of the acute episode.

And they found that 28 percent of the people in the placebo group versus 1.

4 percent of the people in the TMP-SMX group had a recurrence by six years, which is a pretty substantial difference.

Again, they only treated people for a year, but they followed them for five years thereafter.

There will be, I'm sure, some update subsequently about longer term follow up and whether a year is really enough to change the longer term course of their, of their infection.

But at this point, that's kind of considered the standard approach is to put people on this, this regimen that was studied for a year.

Great.

So, moving from ocular toxo, we will meet our next patient, who is a 35 year old with a history of sexually transmitted infections, who presents with four days of ocular injection and blurry vision in both eyes, without other symptoms.

The eye exam shows panuviitis, OD greater than OS.

Lab testing returned with an RPR of 1 to 256 and a positive FTA ABS.

The patient is admitted for IV penicillin and begins to improve.

We, of course, know that syphilis remains an issue and is going to play an increasing role in eye infections if we continue to have increasing cases.

So, can you give us a quick overview of some of the major take homes that you think about related to ocular syphilis?

You know, most, I think, listeners, ID practitioners are very comfortable with syphilis because it's been resurging, and so I won't get into like syphilis overall as a pathogen, but, um, I think just one of the major take homes is, uh, that ocular syphilis can be vision threatening, and so it's very important to think of in basically every case of, um, syphilis, and I actually did recently have a, a case where there was a very delayed diagnosis, um, mostly just because the patient, um, hadn't presented to care for a long time, and, um, And she did have a complete vision loss in one in one eye.

So just a reminder that it truly can be vision threatening.

And then the other major take home point.

And I try to emphasize this.

I think I.

D.

docs are often familiar with this, but I try to emphasize it with some of the PCPs and generalists that I work with that it really can happen at any stage.

It's most common in secondary syphilis, but but it can happen in any.

And so it should be kind of part of the routine reflex algorithm checklist that you go through when you see a case of syphilis is to ask about it, ocular, neurologic and otic symptoms.

Basically no matter what stage they're in, um, it can happen even with, uh, a negative RPR.

And that could either be due to a truly negative RPR, but with positive, um, treponemal testing, um, or it could be due to the prozone effect where if you have a super high titer of RPR, um, it can actually show up as a false negative.

And so some labs will auto dilute their samples to check for the prozone effect, but not every lab will.

So it's helpful to kind of know if your lab does and not use the absence of a positive RPR to sway you in either direction.

And then, uh, finally, and this is a little bit newer in the last few years, um, is that the 2021 CDC treatment guidelines no longer, uh, require an LP for CSF exam.

That's not because they don't think the CSF exam will be positive.

It's, it's actually as positive in up to 60 percent of patients who do have ocular syphilis, but the main reason being that it probably won't change management in most cases and, um, it's treated essentially similarly to neurosyphilis.

And so, um, if a patient has isolated ocular symptoms, no concurrent major concerns about neurologic involvement, a LP is not, uh, as strictly necessary.

Um, and then I'll let Miriam add any additional comments.

Yeah, no, officially what they say is, um, if there's no cranial neuropathy or other evidence of neurologic involvement and there's a compatible eye exam, uh, and positive RPR that you can assume that your treatment for ocular syphilis is appropriate and follow up accordingly without the lumbar puncture.

Great.

Yeah, I feel like this has been a common topic and learning points that I've gone over because I've had a lot of recent patients with questions related to syphilis.

Alright, while we are closing in, we are on our final clinic case for the day.

A 65 year old woman is referred to ID clinic after positive IGRA testing.

She has uveitis that has been incompletely responsive to variable doses of topical steroids over the past six months.

There is some ongoing conversation and consideration for systemic immunosuppression.

For other background, she's received the BCG vaccine as a child from a high TB burden country, but is not aware of any known TB exposures.

She immigrated to the U.

S.

12 years prior to presentation, and she currently has no symptoms other than the blurry vision.

So I can take point on this one too.

So these, um, honestly these were the hardest cases that I saw with Miriam in clinic and continue to be the hardest cases that I saw for ocular, um, symptoms in clinic when I started practicing independently.

And there's a couple of reasons.

So, you know, Miriam mentioned that for anterior uveitis, a lot of cases don't even necessarily get referred to I.

D.

because they are thought to be autoimmune and some other causes found or no causes found.

And they're sort of treated for sort of autoimmune syndrome.

N.

O.

S.

Um, but, uh, you know, part of the the workup they often do is to check for TB exposure and often will send an IGRA.

And, um, that IGRA positive, they'll often refer to I.

D.

to kind of discuss whether that is indicative of this being, um, tuberculosis in etiology.

And it's really, really hard to tell.

So uveitis can occur in about 1.

5 percent of patients with systemic TB.

But it's extraordinarily difficult to confirm.

And unlike many of these other infections we've talked about where ocular sampling can be super helpful, it's basically not helpful in this case, and it's extremely unlikely to be positive, and so often it's not even pursued or recommended.

So in the absence of that, you mostly kind of, uh, diagnose and treat presumptively, but, um, based on extremely incomplete evidence.

And so basically clinical approach to this infection is primarily based on expert opinion at this point.

And there is a lot of practice variation, but there's been groups that have been trying to come to some consensus, but that consensus is based on relatively minimal information that we have in the, in the literature.

So there are certain features that are thought to maybe be more consistent.

So one is certain findings on eye exam, um, and those particularly involve involvement of the choroid.

So that's that sort of posterior uvea layer, and there can be specific patterns that they might mention on exam, like serpiginous, like choroiditis, um, a choroid tuberculoma or tubercles, although those can sometimes look like other etiologies as well.

And then multifocal choroiditis.

Other features include recurrent episodes.

And so, you know, if they, if they give treatment for some other etiology and either it works, uh, incompletely or it, it recurs, that can suggest maybe this truly is due to untreated TB.

One important lesson, and that comes up in this case, is that a response to steroids does not rule out TB.

So the nature of a sort of TB uveitis, uh, is that it will respond to steroids in some way, but probably incompletely and, and without like a long duration.

And, and so you might get that recurrence, but, um, sometimes people will think like, okay, well, if this truly was an infection, that wouldn't have helped, but that that's not true here.

And so it can't necessarily be used.

So, uh, while evidence of concurrent active or systemic TB can be supportive, um, many, or most patients probably won't have other evidence of active TB.

And so in practical application, you know, we look for it and usually don't find it and then still have to decide what to do.

So sometimes, and this is kind of what we did a lot of the time, is you decide if there's enough there for you to try therapy and basically see how they respond.

And so that would be sort of observing a clinical response over weeks to months.

And empiric treatment is similar to other forms of TB and may include RIPE, but sometimes we'll avoid ethambutol and replace it with moxifloxacin instead, because we're trying to avoid further eye toxicity.

And then you can actually get paradoxical worsening after starting TB therapy, and that can be treated with steroids.

And sometimes it actually makes you feel a little bit better about your decision to treat, because if, uh, you know, maybe the TB therapy is actually working and causing die off of organisms and, and, um, confirming the diagnosis, but it is really tricky.

And, you know, sometimes you go months into a treatment course, and then, uh, ultimately, you say, I guess, you know.

If it didn't work, you're either stuck deciding whether this is a resistant TB or whether it just wasn't TB at all.

And so, um, it is a, it's a challenging area of communication with patients, primarily just because there's so much uncertainty and, um, and you just need to get very comfortable with that uncertainty together and, and decide on a management plan.

I'll let Miriam add anything.

Yeah, that was a great summary of what our lives are like in trying to, um, yeah, deciding what the right thing is to do for patients.

I think it helps if the patient has a good understanding about the idea that the treatment is diagnosis, essentially trying to diagnose based on the response to treatment.

Um, usually even if it's clear that there's no clinical response to the treatment, we try to finish out the duration of latent TB treatment with the TB meds so they've kind of cleared the air and that they can again, get whatever immunosuppressive treatments are felt to be more appropriate for what's more likely an autoimmune condition cause of their uveitis.

Well, thank you guys so much for taking us through this long clinic day.

This was quite the tour de force of ocular infections.

So I really hope that people take a listen, read the paper, and start to feel more comfortable in approaching these cases.

And I really love your emphasis on really partnering and communicating with your ophthalmology colleagues and your patients.

So before we wrap up, I will open the floor just to see if you have any other final closing thoughts or comments.

So I wanted to take the opportunity to thank our dream team of authors.

I feel like that was actually one of the most satisfying parts of the whole project, was to be able to get with, to get to work with and write with such amazing people.

Dr.

Dolman, who's a, um, corneal specialist.

Dr.

Papaliotis, who's trained in both ophthalmology and medicine, um, and Akash andAmir, um, and Dr.

Marlene Durand, who was my mentor and has been at Mass Eye and Ear for over 20 years, and probably taught most of us, that we know about eye infections.

Um, yeah, I totally agree with that.

It was really fun and, you know, we all took point on different sections and it was actually really fun to read other people's sections, um, because I invariably just reading them, I, I learned things I didn't know.

Um, and so it was just fun to have that group.

Thank you to Miriam and Akash for joining us today.

If you want to check out their article, make sure to look at Clinical Infectious Disease or CID State of the Art Review Ocular Infection.

So this will be linked in the consult notes as well as in the episode info description.

Don't forget to check out our website, febrawlpodcast.

com, where you will find the consult notes, which are written supplements of the episodes with links to references.

Our library of ID infographics and a link to our merch store.

Febraw is produced with the support of the Infectious Diseases Society of America or IDSA.

Please reach out if you have any suggestions for future shows or want to be more involved with Febraw.

Thanks for listening.

Stay safe.

And I'll see you next time.