The inflammatory and infectious optic neuropathies are a broad, heterogeneous, and common group of diseases producing visual loss. Although many now-distinct syndromes have been previously combined as “typical or atypical optic neuritis,” recent developments highlight the importance of precision terminology as well as an individualized evaluation and treatment approach.

In this episode, Gordon Smith, MD, FAAN speaks with Eric Eggenberger, DO, MS, FAAN, author of the article “Optic Neuritis” in the Continuum® April 2025 Neuro-ophthalmology issue.

Dr. Smith is a Continuum® Audio interviewer and a professor and chair of neurology at Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research at Virginia Commonwealth University in Richmond, Virginia.

Dr. Eggenberger is a professor of ophthalmology, neurology, and neurosurgery at the Mayo Clinic in Jacksonville, Florida.

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Read the article: Optic Neuritis

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Host: @gordonsmithMD

Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast.

Dr Smith: This is Dr Gordon Smith. Today I'm interviewing someone who really needs no introduction, Dr Eric Eggenberger, about his article on optic neuritis, which appears in the April 2025 Continuum issue on neuro-ophthalmology. Eric, welcome to the podcast, and maybe you can introduce yourself to our audience.

Dr Eggenberger: Thank you. Thanks for having me. So, my name is Eric Eggenberger. I work at Mayo Clinic Florida, and I am involved exclusively in neuro-ophthalmology.

Dr Smith: I just had the pleasure, Eric, of talking yesterday with Lindsey De Lott about non-optic neuritis causes of optic neuropathy. And so, I'm going to kind of reference a little bit what I learned yesterday. She was great. I wonder if you might begin by talking a little bit about nomenclature. You talk about the need for use of precise terminology in your article. And yesterday she taught me a lot about the risk of misdiagnosis and other causes of optic neuropathy, and the two seem related. So, I wonder if you can maybe lay the foundation for our conversation by talking about terminology?

Dr Eggenberger: I think that's a great point. So, we are in an era now where, instead of lumping all these different diagnoses together, we have learned to split apart some of these clinical entities. And so, I think it's really important that we focus on precise terminology and recognize that all optic neuritis is not the same. And we have very different, distinct clinical pathways for these imaging pathways, treatment pathways, for these different types of optic neuritis, whether that's MS related, whether it's MOG related or aquaporin-4 related.

Dr Smith: So, I wonder maybe we can begin by just, you know, giving our listeners wisdom, pearls, and pitfalls about, how do you recognize when someone with a suspected optic neuropathy has optic neuritis versus a noninflammatory optic neuropathy?

Dr Eggenberger: So, that's a really important issue because there's a lot of clinical overlap in terms of exam findings. So, for instance, in any optic neuropathy, let's say it's unilateral, you typically are going to see decreases in acuity and field and color, and you're going to see a relative afferent pupillary defect. And then it's really the context that that occurs in that helps us distinguish different disease entities. So, with optic neuritis, typically you're going to have pain. And that's oftentimes going to be in the younger populations compared to some of the other common optic neuropathies we see, like ischemic optic neuropathy, for instance.

Dr Smith: Right. So maybe we can talk a little bit about, kind of, your overall diagnostic approach, right? A lot of this is, of course, based on age and context, but young people get ischemic lesions and older people can have inflammatory lesions. So, what's your overall approach to the patient you just described? Let's say it's a forty-eight-year-old woman who comes to the emergency department with subacute unilateral vision loss and there's dyschromatopsia, APD, reduced acuity. And, you know, let's just say a fairly, you know, benign-looking fundoscopic exam. What do you do to evaluate that patient?

Dr Eggenberger: In that particular context, I think we're looking at other contextual clues. Is there other vascular risk factors or other things to point you in one direction or the other? One of the important parts you mentioned was the fundus exam. So, we know with ischemic optic neuropathy, 100% of the time with AIOM, you're going to see disc edema. And so, in the context of that story, we want to confirm on our exam an optic neuropathy, and then we can kind of focus on the retrobulbar courses or different types of optic neuropathies. From an exam perspective, in that particular patient we’d be looking to measure the acuity, quantify that. And in the ER, you're not going to be able to do a perfect field, but you'll get some sense of the field and how much field loss there is. And then as you mentioned, the afferent pupillary defect is critical. And we're going to get a little bit of the historical features in terms of pain. With typical retrobulbar optic neuritis, most of those patients are going to experience some pain, and usually it's pain on eye movements. And those would be the clinical things to focus on. Other exposures the patient may or may not have had, any other concomitant conditions, would all help point you in different directions, perhaps, and then we're probably on towards imaging.

Dr Smith: Yeah, maybe you can talk a little bit about that? What's the appropriate use of imaging? I mean, presumably the patients, like the one I just threw out there, are pretty much all going to get neuroimaging. What's your approach to that? How do you protocol the study? What should we be looking for?

Dr Eggenberger: In our clinic, we would typically be ordering an MRI orbit and brain, and each of those has a specific purpose. The orbit is going to show us the extent of the optic neuropathy. So, we're particularly looking for a longitudinally extensive optic nerve lesion or more than half of the optic nerve involved. And most patients acutely, if it isn't an “itis" situation, we'll see enhancement. And then the MR brain is going to be useful for looking for other evidence of demyelination within the central nervous system. We may at some point get down to doing an MR cord, but I think acutely it's going to be brain and orbit that most of our patients are getting.

Dr Smith: Let's say that we did the scan and, sure enough, there's sort of a shorter segment, so less than half the length of the nerve region of enhancement. What's the rest of your diagnostic evaluation look like for that patient?

Dr Eggenberger: So, in that particular case, we would look at the remainder of the brain. So, we're looking for other evidence of demyelination and any other contextual clues, systemically that would point you one direction or another. But with a shorter segment involved, one of the more common things we might encounter would be multiple sclerosis-related optic neuritis.

Dr Smith: Would you look for aquaporin-4 and MOG in a patient with what appears to be an isolated, uncomplicated short segment optic neuritis?

Dr Eggenberger: So, I think it really depends a bit on the context. I would never fault anybody for looking at MOG or an aquaporin-4 in that context because those are really treatment-altering diagnoses, but the yield in this particular case with a short segment involved and depending on the acuity and other features is probably going to be pretty low.

Dr Smith: I really liked as an aside- I wasn't going to go there next, but you kind of got me thinking about it, you have a really nice section in your article. Which, all of it's great, but talking about how to manage low titer MOG antibodies. I wonder if you could talk about that because I think that's a lesson, maybe, that is transferable to a lot of other testing that we do. in terms of pre-prior probability and titer and so forth.

Dr Eggenberger: Yeah, that's really an important point. So, we've seen this come up a number of times where the MOG antibody is a very good test, but in low titer it has a relatively low positive predictive value, perhaps 50%. In those cases, particularly without a classic clinical context, you have to be extremely alert for some other diagnosis that could mimic what you think is inflammatory demyelinating optic neuritis, but in fact is infectious or some other cause.

Dr Smith: Yeah, super, super important and helpful. In terms of aquaporin-4, how does that compare in terms of predictive values, lower titer positive results?

Dr Eggenberger: So aquaporin-4, the test has a very high specificity. So, it's quite useful if positive. You have to keep in mind there can be some false negatives, but the test otherwise is quite specific. And that is a diagnosis, you know, we never want to miss. It's a vicious disease. It tends to be a blinding disease, particularly without treatment. Bad things happen when we miss that, and we want to get on that diagnosis early and do pretty aggressive early and prophylactic treatment.

Dr Smith: Your article covers not only the common causes of optic neuritis and, you know, MS, isolated optic neuritis, MOGAD NMO, you talk about a bunch of other things. I wonder, in this patient that we've been discussing, in the absence of any other historical information that seems relevant---or maybe you can define what would seem relevant---would you do other evaluation in that individual, other serologic evaluation and so forth, just in terms of diagnosis?

Dr Eggenberger: In that particular case, without other red flags, I don't think I would initially. And follow-up is going to give you a lot of this context. So, you'd be on the lookout for other systemic conditions. So, if the patient had some arthropathy, if the patient had any pulmonary disease hints, if there was anything else that could lead you on a broader expedition. But I think in the context of this case, acutely in the ER, I probably wouldn't do a big lab plug for this. I probably would kind of go down the most likely road and start our treatments, and then follow that patient up.

Dr Smith: Yeah, I know your article does a really great job, I think, of outlining when do you need to think about some of these less common causes. Well, can we talk about treatment, Eric? Because I want to move on to some other things. But- so, we've got a patient with isolated optic neuritis, nothing else, you know, in terms of the other antibodies we've talked about. What state-of-the-care- or, state-of-the-art treatment for that patient?

Dr Eggenberger: So, the acute treatment for these inflammatory, optic neuritis-type cases is very similar Initially. High dose steroids remains kind of the standard. And then, in MS-related optic neuritis, we may or may not see a taper. So many times it's just an acute treatment of three to five days high dose. Whether that's oral or PO, we could institute either depending on the particular case. And then the taper would depend on the potential cause. So, for instance, with these antibody-driven diseases---so with MOG- or particularly with aquaporin-4---if it's a longitudinally extensive region of optic nerve involved, we tend to use a longitudinally extensive taper. And so, we use prednisone in those cases for several months while we're getting everything else set and deciding what the overall course is going to bring.

Dr Smith: What about IV versus oral? There must be something about my practice. I was telling this to Lindsey. Every time on our hospital service, we seem to have at least two patients with optic neuropathies, which I always enjoy, but I find it's a little weird to admit someone who's doing just fine otherwise to the hospital with three days of IV SOLU-MEDROL. So, I'm always trying to figure out, like, how can I get this patient home? And your article had the best term I've heard in a long time, which is “SOLU smoothies.” I mean, are there other strategies that you sometimes use, other than just high-dose IV methylprednisolone?

Dr Eggenberger: So, I agree with you. It's sometimes hard to admit somebody for just an IV therapy. And we'll do this as an outpatient, high-dose IV, but we'll also use high-dose orals. And in times in the past when there's been methylprednisolone shortage, we've used high-dose oral or IV dexamethasone as well. I think the IV form, although it's the gold standard, the high-dose oral forms have pretty equivalent bioavailability and are pretty tolerable in my experience. And certainly more convenient.

Dr Smith: I wonder if we should switch and maybe talk a little bit about aquaporin-4, I mean, you emphasized that this is a vicious disease---I love the way you describe that---and often blinding. What updates do you have in terms of our therapeutic approach to NMO? That's been rapidly evolving of late.

Dr Eggenberger: Right, so these are cases we're always going to share with neuroimmunology. And it requires kind of a multidisciplinary approach, in my opinion, for ideal or for best outcomes. And so, all of these patients are going to get put on prophylactic medications. So, this is a disease you just can't leave untreated. Bad stuff will happen for sure. And we now, fortunately, have some approved, FDA-approved medications that can positively impact the course of this disease. So, that's been a welcome addition.

Dr Smith: What are the FDA-approved medications at this point for NMO?

Dr Eggenberger: So, there are several at this point, and this is an area that's in growth, fortunately. And again, these are cases we're going to be sharing with our neuroimmunology colleagues. So, these are IV medications typically aimed at complement or CD19. And they all are relatively effective at quieting the course of the disease.

Dr Smith: Maybe we can talk a little bit about MOG? I think that most of our listeners are probably pretty familiar with aquaporin-4 and NMO, what- maybe you could describe MOG a little bit and the therapeutic approach for patients with MOG-associated disease?

Dr Eggenberger: So, MOG has been a real interesting kind of condition to learn more about. We certainly see a lot of MOG, and I'm sure we saw MOG before it was formally described, but I think we just thought it was kind of a benign, maybe monophasic MS type of presentation. But MOG tends to come in with a loss of acuity that kind of rivals aquaporin-4. So, the acuity tends to be pretty, pretty depressed, but it's very steroid-responsive. So, a lot of times these are the patients, you'll see that their vision will start to improve even when they're on the initial few days of the high-dose steroids. And many times we can get their vision back to 20/20 or very close to that.

Dr Smith: And do these patients need chronic management?

Dr Eggenberger: So, that's an area of controversy to some degree. About 50% of the optic neuritis MOG-related cases are going to have a relapsing course. And because the disease is steroid-responsive, many times we'll follow these patients after a first attack to see if this is the condition that’s going to declare itself to be relapsing or if this is just going to be a monophasic kind of presentation of optic neuritis. We don't have great biomarkers to separate patients who are going to be in that 50% monophasic course versus the other half. It'll be relapsing. And so, it depends on the patient. If there's somebody that's, as many of these patients are, been very steroid responsive, they get back to 20/20, we can teach them about the disease so that if they do have a relapse, we can get them high-dose steroids in a relatively rapid fashion and they're otherwise healthy, we're probably going to watch that patient. And if it's somebody that doesn't recover 100%, there's other issues with treating them with high-dose steroids potentially in the future, then we may learn more towards an earlier prophylactic approach in that patient.

Dr Smith: And what would that approach look like? Is it different from NMO or using more IVIG or B cell depletion as opposed to complement inhibition, for instance?

Dr Eggenberger: In MOG, we know that the B cell depletion strategies don't work as well. And so most times we're turning to IVIG, and we found that pretty effective. That's kind of our go-to at this point.

Dr Smith: Eric, it's a joy talking to you and I'd love to keep going about content, but I'll refer our listeners to your outstanding article. I mean, you're such a highly regarded neuro-ophthalmologist and educator. I wonder if you could talk to us about why you've done neuro-ophthalmology, and maybe this is an opportunity for you to convince all of our great residents that are listening or students what's great about being a neuro-ophthalmologist.

Dr Eggenberger: I think neuro-ophthalmology is by far the most interesting part of neurology. So, it's an area that I think a lot of general neurologists, in my view, don't get enough of in their residency. But it's kind of the essence of neurology, where in neurology you're localizing down to the millimeter and in neuro-ophthalmology,  we're localizing down to the micron level. We have several new emerging diseases like these varieties of optic neuritis we're focused on. We're learning lots about those. You get to be involved in lots of different areas of neurology. So, we'll see not just demyelinating conditions, we'll see trauma as it relates to the visual system. And we'll see tumor, and we see all different flavors, stroke, and in any piece of neurology, commonly we'll have some vision aspect that we that we get involved in. So, we see a wide variety of conditions. So, I think it's been a really exciting place to be within neurology. And it's rapidly changing at this point. We're getting new therapeutics. So, it's, I think it's a great time to be a neuro-ophthalmologist.

Dr Smith: Yeah, listening to you talk and just reflecting on it, it's really true. Neuro-ophthalmology does cover the entire span of neurology, right? I'm a neuromuscular guy and we see a lot of ocular myasthenia, which is another super exciting area. But we've been talking about optic neuritis, and your article talks about infectious causes and the paraneoplastic and a whole host of things. So, you're a great advocate and salesperson for your field. You convinced me.

Dr Eggenberger: Efferent neuro-ophthalmology we love, we could talk about ocular myasthenia and other aspects for another hour. And we get involved in all kinds of cases: third nerve palsies, ocular myasthenia, trauma that involves the efferent system, all different aspects. It's really a great subspecialty, and you get to see a bit of all of neurology.

Dr Smith: I'm trying to remember who it was, Eric. It was an attending of mine at medical school. I went to medical school at the Mayo Clinic in Rochester, and I want to say it was Manny Gomez, who was a very famous tuberous sclerosis person, who told me that neuro-ophthalmology was the most elegant specialty within neurology. That stuck with me. Thank you so much for joining me today. I really appreciate it.

Dr Eggenberger: Thank you. I appreciate it as well.

Dr Smith: So again, today I've been interviewing Dr Eric Eggenberger about his really wonderful article on optic neuritis, which appears in the most recent issue of Continuum on neuro-ophthalmology. Be sure to check out Continuum audio episodes from the neuro-ophthalmology and other issues. And listeners, thank you very much for joining us today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.