Exploring Neuroinfectious Emergencies and Differential Diagnosis

Neurologic infections become emergencies when they lead to a rapid decline in a patient’s function; however, neurologic infections are often challenging to recognize.

In this episode, Aaron Berkowitz, MD, PhD, FAAN, speaks with Alexandra S. Reynolds, MD, author of the article “Neuroinfectious Emergencies,” in the Continuum® June 2024 Neurocritical Care issue.

Dr. Berkowitz is a Continuum® Audio interviewer and a professor of clinical neurology at the University of California, San Francisco

Dr. Reynolds is an associate professor in the departments of neurosurgery and neurology at Icahn School of Medicine at Mount Sinai Health System in New York, New York.

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Host: @AaronLBerkowitz

Transcript

Full transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the Journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by visiting the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the show notes. AAN members, stay tuned after the episode to hear how you can get CME for listening.

Dr Berkowitz: This is Dr Aaron Berkowitz, and today, I'm interviewing Dr Alexandra Reynolds about her article on neuroinfectious emergencies, which is part of the June 2024 Continuum issue on neurocritical care. Welcome to the podcast, Dr Reynolds. Um, would you mind, please, introducing yourself to our audience?

Dr Reynolds: Sure. Thank you for the invitation. I’m Alex Reynolds, and I am a neurointensivist at Mount Sinai Hospital in New York City.

Dr Berkowitz: Fantastic. Thanks for joining us. Dr Reynolds has written a really comprehensive article with lots of clinical pearls for the evaluation of patients with neurologic infections. So, to start off, when should we consider a neurologic infection as the cause of a patient's neurologic symptoms?

Dr Reynolds: That is a, really, much more complicated question than I think you recognize. I feel like a lot of it has to do with the risk factors of the patient. So, certainly, you know, a lot of times, we think about a patient who comes in with fever and altered mental status, and that's sort of the patient we're thinking about as having an intracranial infection – but, I do think there are a lot of risk factors that, sort of, may push us in that direction even if the patient doesn't have a fever or even if the patient doesn't seem like meningitis (for example). So, you know, a lot of patients nowadays are immunosuppressed, either because of infections or because of the therapies that we're using as immunosuppressants (so, autoimmune diseases, transplants, bone marrow patients). And then, I think, any patient who has had an intracranial procedure or a spinal procedure, we sort of just have to have in the back of our mind that surgical procedures come, by definition, with risk of infection (and so, that’s always something to think about). And then, certainly, anything in terms of endemic risk factors (so a patient who has come from a country that has an endemic infection), we need to just be a little bit more broad about what we're thinking about in that patient population.

Dr Berkowitz: That's very helpful. You mentioned something I wanted to pick up on. We always think fever, of course we're going to be thinking about a neurologic infection, but some types of neurologic infections and in some patient populations, it's possible to have an infection of the nervous system with no fever, sometimes even no white count. What other clues should be considered, or when would you think about pursuing infection even in patients who don't have a fever or an elevated white count?

Dr Reynolds: So, certainly, in patients who have imaging that’s a little abnormal. I think, oftentimes, the patients that I’ve seen with sort of indolent infections have a subdural collection that just doesn’t look quite right or doesn’t make sense with the clinical history (you know, you can have P. acnes infections that go on for months that people really don’t necessarily notice) - so any imaging, oftentimes on MRI, you’ll see, sort of, diffusion restriction where you don’t really expect to see it. So, those sorts of patients might be ones where if the story is just not really fitting, you might want to think about infection. So, I think it's also important to remember that patients who have procedures elsewhere in the body can sort of seed themselves, and either by direct spread or by hematogenous spread, those infections can kind of seed the CNS - so, patients with valve procedures in the heart, patients who have intraabdominal procedures, there really is no reason that those infections can't travel to the CNS as well. And so, I was sort of always taught, you know, if the story doesn’t make sense, then you have to consider infection, even if the patient doesn’t have a white count or fever. So, I think just having, sort of, that suspicion in the back of your mind that if you can't really make sense of the story, then consider an infection.

Dr Berkowitz: Yeah. So, obviously, fever, white count, those would clue us in that a patient with new neurologic symptoms (signs) may have an infection as a cause. But, as you said, they may not be present in patients who have had any type of neurosurgical procedure (or you've just taught us even non-neurosurgical procedures elsewhere in the body) that could have led to bacteremia. And then, you mentioned earlier, also patients who are immunocompromised may develop a neurologic infection without fever or white count, and our threshold is certainly lower to pursue that possibility in that population as well. Other points on that before we move on?

Dr Reynolds: I had an attending that told me if you're thinking about a lumbar puncture, you better just do it – so, I think those are wise words to sort of live by. If you're thinking about an infection, you better just work it up.

Dr Berkowitz: Yeah. I think that's right. I heard something similar that if you're standing around on rounds debating whether the patient should get a lumbar puncture, probably, if you've talked about it that much, you should probably do it. I think we've heard the same things in different places. Along those lines of who needs a lumbar puncture, many patients with systemic infections can develop a headache, even if it's just from systemic infection (you don't necessarily have meningitis and cephalitis), and many patients, particularly older patients, develop confusion in the course of systemic infections, like pneumonia and urinary tract infections. And as neurologists, we are often consulted on these patients because they are confused, they are febrile, they may have an elevated white count, and people start to wonder, Could this patient have meningitis? Could this patient have encephalitis? In many cases, at least in my experience (I'm curious to hear your experience), it turns out that these patients have a systemic infection and the confusion and/or headache are related to that systemic infection, not a primary neurologic infection - but based on that topic we just discussed about, if you've talked about lumbar puncture enough, probably best to do it. How do you think about these patients who are, for example, admitted to a medical service for fever and confusion, may or may not have had a systemic source identified, but the suspicion is there? How do you think about which of those patients need a lumbar puncture, or what clues you into thinking to have a higher concern for meningitis, encephalitis, abscess, other neurologic infections in this context?

Dr Reynolds: It's such a good question, because I think, especially as we get older, you know, even things like nuchal rigidity might be hard to assess in a patient who’s sort of started to fuse their spine - so, I think it can be really challenging. I think, you know, always go back to basics. Is there any new laterality that doesn't really make sense? Is there a sort of disconnect between imaging and how the patient looks? And it can be so confounded, because these are patients who are also on antibiotics (which themselves can be neurotoxic), and so, it can be really hard to sort of parse that out. But, I do think that there are some less invasive things you can try to do first to sort of help risk stratify your patient. So, you know, certainly, getting a CAT scan and just making sure that everything looks as you would expect it to look - there's no, sort of, hydro out of proportion to what you might expect. I’ve definitely seen patients who have meningitis that we caught because they have just a little bit of pus in the ventricles that was interpreted as intraventricular hemorrhage. And you sort of just have to sit there and think, like, Does that make sense, or is it an infection? EEG can be helpful, too, if it’s lateralizing. You know, I think we don’t think as much about HSV in the hospital. But, certainly, if you have something lateralizing on your EEG that just doesn't make sense, I think that could sort of push you in that direction as well. But, again, I think in most cases, unless the patient's very thrombocytopenic or coagulopathic, the risk of an LP sort of doesn't really outweigh the benefit of feeling confident that you haven't missed something, because I think, you know, one of the big points of this article is that if you catch these CNS infections early, people can actually do really well, and, really, most of the morbidity and mortality is from missing the infection - so we've been trying to move away from LP-ing everybody on admission, but I do think that you should be tapping some people that are not infected, because then you're probably catching everyone who is.

Dr Berkowitz: It's great to hear your approach, and I think that aligns with my thinking as well. I do want to ask as a follow-up to that question (I've asked this of internists I work with and other neurologists) - I totally agree with everything you said in the sense that, you know, we are consulted by our internists, we presume that they haven't found a reason that the patient is febrile and confused from a systemic standpoint, and that's why we're being consulted. There are, obviously, many patients who are febrile and confused in the hospital where neurology has not been called because there's other obvious reasons, as you have mentioned. However, as you said, if the patient has some immunocompromise, maybe there’s some features that are suggestive in the history or nuchal rigidity - as you said, harder in older patients - but there’s something there that you sort of think, maybe we should just do a lumbar puncture just to make sure we sort of settle this because we keep thinking about it. The question is, in your experience, when you've gotten a lumbar puncture more as a rule-out, or you think, I think this is the patient's pneumonia and they're confused because they're delirious in the hospital (sort of toxic metabolic encephalopathy), have you ever been surprised? Talking to an internist colleague, I've said, I feel like I haven't actually seen that much bacterial meningitis in the U.S., fortunately, thanks to vaccination. And, usually, the patient is coming in with a pretty profound syndrome of meningitis or encephalitis. But, as far as patients in the hospital with a fever, where you’re thinking, "This is kind of a rule-out, so just make sure, even though I don’t think I’m going to find meningitis in a patient who is immunocompetent”, have you ever been surprised and found meningitis encephalitis when you didn't expect to find it? Or, what's been your experience when you, as you said, tap these patients because you'd rather get a few normal ones in there to make sure you never missed the abnormal?

Dr Reynolds: I would say the few times that I've been surprised were not with fully immunocompetent patients. You know, someone with a splenectomy who otherwise looks immunocompetent, someone with pretty advanced cancer - those are examples where you wouldn't necessarily have thought about it as being immunocompromised, but they are. Certainly, I think patients with advanced cancer can, really - they're much higher risk than I used to think about. The more I've taken care of them, the more I've realized how sensitive they are to infections and how quickly that can spread, even if they're not actively getting chemotherapy. But, I would say in general, for the truly immunocompetent patient, I would say I haven't really diagnosed anything super exciting.

Dr Berkowitz: Yeah, that's good to hear. I love to, on these Continuum Audio interviews, poll experts in other institutions who trained other places and, you know, learn from different patient populations if your experience resonates with mine and others I've spoken to. Yeah, that sounds similar to my experience as well, yeah, if the patient is immunocompromised - and as you said, we maybe need to broaden that from being truly profoundly immunocompromised by congenital immunodeficiency or HIV or immunomodulatory therapy to have a slightly broader perspective on what could constitute immunocompromise - and, of course, we'd have an extremely low threshold to perform a lumbar puncture in such patients, as you said. You reminded me of a case I was trying to remember the details (which I don't) – it was a patient, actually, with a temporal lobe glioblastoma that had been resected and had some recurrence and was worsening, and it looked like it was tumor recurrence/progression. And I don't - wasn't my patient, I just sort of heard about it - but I don't know which attending or resident or fellow decided that the patient should get a lumbar puncture, and the patient actually developed HSV encephalitis of the temporal lobe, where the glioblastoma was.

Dr Reynolds: Wow.

Dr Berkowitz: Patients with cancer, especially with all the new immunotherapies - and even without them, as you said - this is a state in which people may be vulnerable to infections and ones you might not immediately think of. So, those are some great pearls. Speaking of pearls, you have a really fantastic section in your article on neurologic complications of CNS infections. In other words, you've already diagnosed the meningitis, encephalitis, abscess, or otherwise, and all the other neurologic complications that can occur in the course of this illness. So, it'd be great to talk with you a little bit about that here. So, if a patient is diagnosed with infectious meningitis or encephalitis (we've made that diagnosis by the clinical picture, the lumbar puncture findings, and/or the neuroimaging), we're following them along, we think we have them on appropriate therapy, (antimicrobial therapy), and their neurologic status worsens - what's the differential diagnosis for this worsening? What are some things we can think about? How do we look for them on exam? How do we work them up?

Dr Reynolds: Yeah. It's funny, because, you know, the topic of this is neuroinfectious emergencies, and when I first heard about it, I was like, “Every neuroinfection is an emergency”, and I think part of the reason I felt that way is because as a neuro ICU physician, I see the complications a lot more. You know, I think, from a meningitis and encephalitis standpoint, certainly cerebral edema (whether it be focal or global) is sort of your biggest concern. If you've used your adjunctive steroid therapy at the beginning before you've started antibiotics, you know the idea is that might help – and, certainly, it should help with potential hearing loss as a result of meningitis - but I would say cerebral edema or development of abscesses because of delayed antibiotic initiation is certainly a concern. If a patient’s getting lethargic, hydrocephalus can often be a concern - and that may be obstructive hydrocephalus or communicating hydrocephalus – either way, that is a situation where, really, the patient may need, depending on the etiology of the hydrocephalus, either another lumbar puncture (for example, in the case of cryptococcal meningitis) or an external ventricular drain placement (which would bring them to the ICU in cases where there is an obstructive component). So, I do think hydrocephalus is hard to diagnose. My go-to is to sort of check tone in the legs every day, because a lot of times, patients with developing hydro will start to have really high tone in their legs - so, that's sort of my go-to physical exam finding, although, obviously, hydrocephalus can present as just sort of generalized lethargy or even, you know, worsening nausea and vomiting, for example. And then, I think, you know, if someone starts to be localizing on exam, I think that can be concerning not only for abscess, but potentially for ischemic stroke related to a vasculopathy, for example, or hemorrhage in the context of mycotic aneurysm formation, for example - and, so, I do think there is a role, if a patient starts to become lateralizing, for emergent imaging. And generally, we should be able to see most of the stuff on just a plain CAT scan to start. You know, certainly, localizing stuff can also be as a result of seizures, but I think that that's sort of a diagnosis of exclusion, and rapidly imaging a patient with new focal signs is probably the way to go before putting them on EEG.

Dr Berkowitz: Very helpful pearls. So, um, shifting gears a little bit, right before we began our conversation, you were telling me you had done some work in Malawi, and you were reflecting on some of the differences in epidemiology of neuroinfectious disease and resources available to diagnose neuroinfectious disease. So, I'm sure it would be very interesting for our listeners to hear a little bit about the perspective you bring to the diagnosis and treatment of patients with neurologic infections from your experience in Malawi.

Dr Reynolds: Yeah. So, I was lucky enough as a trainee to be able to go to Malawi for a few weeks with my neuroinfectious disease attending, and I think that it’s pretty striking (the difference that we see in lower income countries, compared to the U.S.). I think a lot of the disease processes that we sort of take for granted as being easily treatable are not necessarily easily treatable, not only because of lack of access to medications and antibiotics, but also because of sort of a stigma that might be associated with the workup. So, for example, a lot of people were very hesitant to consent to lumbar puncture, because they had seen that their friends and family members who had gotten lumbar punctures ultimately died, and it didn't seem necessarily clear that the reason that they had died was from the primary infection itself. So, I think that really being attuned to disparities not only abroad, but even - you know, working in New York City, I can say that there are definitely disparities in terms of access to care and health equity, and, certainly, the timing of your presentation almost necessarily will change the outcome, and people who are presenting to the hospital later because of infections that were sort of ignored or because of lack of access to healthcare, those patients, really, by definition, end up doing worse - and so, I think that that is really a big thing to think about in our resource-rich areas, think about these infections.

Dr Berkowitz: Well, thank you for sharing those valuable and important perspectives both from Malawi and from your work in New York City.

Dr Reynolds: Thank you.

Dr Berkowitz: Well, thank you so much, Dr Reynolds, for joining me today on Continuum Audio. I've enjoyed our discussion and learned a lot from it. Again, today, we've been interviewing Dr Alexandra Reynolds, whose article on neuroinfectious emergencies appears in the most recent issue of Continuum on neurocritical care. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to all of our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, please consider subscribing to the journal. There's a link in the episode notes. We'd also appreciate you following the podcast and rating or reviewing it. AAN members, go to the link in the episode notes and complete the evaluation to get CME for this episode. Thank you for listening to Continuum Audio.