Sara Dong: 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.
We are back with a Febrile StAR episode.
These are featuring topics and authors from the CID journal State of the Art Reviews.
This is our fourth of four launch episodes, so please make sure you listen to the past three episodes as well as number 97 for a quick introduction from the editors of these reviews.
All right, so I'll introduce our guest stars today.
Dr.
Karen Block is a professor of medicine and associate clinical director of the division of infectious diseases at Vanderbilt University Medical Center.
Her clinical and research interests revolve around infections of the central nervous system.
She is a coauthor on the IDSA guidelines for the management of encephalitis and the international encephalitis consortium consensus statement.
Karen Bloch: Hi, I'm Karen Bloch.
Thank you so much for having us on the Febrile podcast.
I'm really excited to be here today, Sara.
Sara Dong: Dr.
Carol Glaser is the Medical Officer for the California Department of Public Health, Center for Laboratory Sciences.
Dr.
Glaser first trained in veterinary medicine and then attended medical school, followed by a pediatric residency and a pediatric ID fellowship.
Her clinical and research interests focus on the diagnosis of encephalitis and other infectious related neurologic conditions, such as acute flaccid myelitis, as well as zoonotic infections.
Carol Glaser: Hi, I'm Carol Glaser.
Very excited also to be here to talk about one of my most favorite subjects, encephalitis.
So thank you for inviting me.
Sara Dong: Dr.
Arun Venkatesan is a professor at the Johns Hopkins University School of Medicine in the Department of Neurology, where he serves as director of the Johns Hopkins Encephalitis Center.
His interests focus on developing biomarkers of infectious and autoimmune encephalitis and studying mechanisms of CNS injury in the setting of infection and neuroinflammation.
Arun Venkatesan: Hi Sara, Arun Venkatesan here.
Really great to be here.
I'm excited.
I'm, I'm a neurologist amongst a bunch of infectious disease folks here.
That's the way I like it.
Sara Dong: Dr.
David Gaston is a clinical microbiologist at Vanderbilt University Medical Center in Nashville, Tennessee.
He is the medical director of molecular microbiology and is also awarded in adult infectious diseases.
His clinical and research interests focus on developing molecular techniques to advance ID diagnostics.
David Gaston: Hey, Sara, David Gaston here.
This is wonderful.
Thanks so much for having us.
It's just got like these bright lights and my neck's kind of hurting a little bit today, so I don't, we'll see how, we'll see how well this goes.
Sara Dong: Excellent lead in.
Well, before we jump into our discussion, I always ask as everyone's favorite cultured podcast, on Febrile, we do like asking our guests to share a little piece of culture, really just something non medical that brings you happiness.
So maybe I'll start with you, Carol.
Carol Glaser: One of the things that brings me total joy every single day is my incredible Australian shepherd.
Who's, if anybody isn't an Australian shepherd owner.
They don't realize that these are the most superior dogs in the whole world.
And I live in Marin County, and we have tons of rain, so going for a walk with her and seeing waterfalls just totally brings me joy.
Sara Dong: Love it.
Karen?
Karen Bloch: So, I have two dogs, but they don't bring me as much joy as Carol's dog does.
I really love a sub genre of literature, um, cozy British mysteries, and I get a lot of pleasure out of reading about people sipping tea in very rural environments with a very bloody body in front of them.
Sara Dong: There's a lot of murder mystery that gets mentioned in the culture.
I don't know if that is just our population or ID docs.
How about you, David?
David Gaston: I am, I'm a big fan of, so we're relatively new to Nashville, lived here for a little under two years.
So love building community, getting to know people.
This is a really incredible city and an incredible place to be.
So just a lot of creative folks around here.
So being, being in community with others and also just in this state of COVID, where we are now, where we are able to get together and build up some community that, you know, has been lost a little bit over the past three or four years, five almost at this point.
So, so if you ever find yourself in Nashville, come, come down, we'll have dinner, we'll go honky tonking on lower Broadway, it's a good time.
Sara Dong: Perfect.
And then last but not least, Arun.
Arun Venkatesan: Building on that, being with this group, of course, brings me a ton of joy.
It's really awesome to be here with all of you.
The other thing that I was going to mention is probably a bit polarizing and that's pickleball.
I've, I've really been enjoying playing a lot of pickleball and that's something else that, that I think brings people together, but occasionally can be divisive.
So take it for what it's worth.
Sara Dong: Excellent.
Well, I am really excited and thankful to have you all here to talk about a pretty huge topic and the focus of your CID state of the art review, which is encephalitis.
I am going to go very basic just to open the conversation because we often have a pretty large range of learners who are listening, and maybe they don't have the best foundation or framework for what is encephalitis?
How is it different from meningitis?
What does it mean when we say meningoencephalitis?
So can you guys tell us a little bit just to set the stage before we talk about our case?
Karen Bloch: That's a really important question.
And it's actually not a straightforward answer to it.
Encephalitis is inflammation of the brain tissues, whereas meningitis is inflammation of the meninges, but there's a lot of overlap.
And both of those are pathologic terms rather than clinical terms.
So, back in 2013, Carol, Arun and I, as well as a number of other folks, got together and, as part of the International Encephalitis Consortium, came up with what we thought was a reasonable case definition for encephalitis.
It was, you know, initially formulated as something that could standardize studies, so you could compare apples to apples, but I think it's really gotten a lot of clinical play as well.
And so, I think the most commonly used definition for encephalitis is altered mental status lasting at least 24 hours with at least two other supporting clinical findings, which could include fever, focal neurologic symptoms, new onset seizures, acute abnormalities on neuroimaging, preferably MRI, and then EEG abnormalities.
I think an important caveat, which my co authors may want to talk about a little bit, is that this is really broad.
And so we, we actually intentionally included a disclaimer that if there was a alternative diagnosis that these criteria, then that would exclude a diagnosis of encephalitis.
Arun Venkatesan: Absolutely.
It's, it's really important to exclude other diagnoses because there's so many things that can mimic encephalitis.
Many, both acute neurological disorders and systemic disorders can do so as well.
You know, really thorough workup, often including neuroimaging and looking for, say, toxins or metabolic abnormalities.
Even primary seizure disorders can mimic encephalitis.
There's a whole range of things.
Sara Dong: Great.
And so I have a, I guess I shouldn't say it's a quick case.
I have a case to help us think about these topics.
So we'll, we'll meet our patient.
So we have a 30 year old previously healthy female.
She has come in with about three days of headache and fever.
And actually her family brought her in because, you know, she's just not acting herself.
And then while in the emergency department, she has a witnessed generalized seizure.
Her vitals are stable.
Her temperature is 38.
1 Celsius at that time.
So just to give a little bit of context, it's summertime.
You're located in the northeastern U.
S.
The patient lives in a studio apartment with her beloved pet cat.
She likes to do a lot of outdoor activities, so hiking and biking and camping.
And then she works as a veterinarian.
So can you walk us through your approach to this patient?
Karen Bloch: Well, I had to smile when you said it's not a quick case because encephalitis cases are never quick cases.
And, although you put in a lot of fodder for us to think about.
That's actually very common.
There's always these interesting little epidemiologic links.
And I think those are really important as we think about it.
When we were formulating the state of the art paper, we decided to sort of separate encephalitis into two buckets.
One were relatively common etiologies that we should think about every single time, and so I'll touch on those, and then I'll have my co authors talk about some of these other possibilities that might be linked to some of her exposures.
The pathogens that we felt like were really important to test for, regardless of any of the clinical findings or epidemiology, would be herpes simplex virus 1, varicella zoster virus, West Nile virus, enteroviruses, and those were really the core, and after that, testing can be guided by additional features.
Carol Glaser: I'm going to jump in here and just, can you confirm what kind of veterinarian she is?
Small animal, large animal, mixed?
Exotic, wildlife, zoo.
Sara Dong: Let's pretend it's small animal, but I'd love to hear insight if she was a different type of veterinarian.
Carol Glaser: Okay, so let's go with the small animal that to begin with.
So in our guidelines, we talk about any animal exposure and depending on what kind of animal to consider certain pathogens.
But given that she's, let's say, a small animal veterinarian, Her exposure to animals is going to be much more than somebody that just owns a dog or a cat.
She's literally going to see hundreds of dogs and cats in a given month.
Many of them will be ill, sometimes with unknown illnesses.
Thinking about what things can you get from a dog or a cat, it's actually a fairly small list of things that are going to give you neurologic manifestations.
I would put Bartonella or cat scratch disease high on that list.
That's a relatively common thing you can get from a cat, healthy or unhealthy, from a bite, a scratch, or even a lick to a wound.
And certainly Bartonella can cause seizures.
So that would not be a bad thought at all to put Bartonella on that list.
And then leptospirosis, for instance, even though we rarely see it causing neurologic symptoms, it always kind of enters the picture particularly in somebody who could be exposed.
And that exposure would generally be from animal urine and it would be probably a dog in her practice.
So that leptospirosis would be another thing I would think about.
And then we can never not think about rabies.
I mean, rabies is indeed the quintessential encephalitis.
Having said that though, it is unusual and very unusual in the now to see a dog or cat with rabies, just because our vaccines have worked so well.
But we know that every once in a while, particularly if a feral animal is brought in, there's a possibility of rabies.
So we'll probably get to rabies a little bit later in this discussion and why we should think about it or not think about it, but that's important.
And then I would even go so far as to say, well, does she see what we call pocket pets?
And that's gerbils and mice and hamsters, because if she does, then we have to think of, of yet another group of organisms.
particularly something like lymphocytic choriomeningitis virus.
Now importantly, that virus, when it does give you neurologic manifestations, it's often in an immunocompromised host, so I guess I'm going to stop here too and just confirm, is she known to be immunocompetent?
Sara Dong: As far as we know, she is immunocompetent.
Carol Glaser: So LCMV or lymphocytic choriomeningitis can occasionally cause a meningitis in a normal host.
It is unusual, but again, she's going to have above normal exposures.
And as Karen started off by saying, the line between meningitis and encephalitis is often very blurred.
So I would also be considering that at some point in the differential.
Karen Bloch: Arun, Baltimore may be closest to the northeast of any of our geographic locations.
Does her residence in the northeast make you think of any pathogens, particularly with her outdoor activities?
Arun Venkatesan: Yeah, yeah, certainly.
And geography really is super important to consider here.
From the standpoint of the Northeast, there are a couple of interesting pathogens to think about.
One is Powassan virus, of which there are, you know, nowadays, you know, 30 to 40 cases per year.
This is a tick borne encephalitis virus.
It's, uh, it's a flavivirus.
The interesting thing about this virus is that the tick attachment time can be as short as 15 to 30 minutes.
So it's very different than something like Lyme disease, where the tick needs to attach to the host for many hours.
Here, it can be very quick.
Lyme disease, of course, we need to think about as well, although Lyme will typically cause a meningitis as compared to an encephalitis.
You know, anywhere in the U.
S.
one needs to consider West Nile virus as well, and you mentioned that as well as kind of core testing that we would consider.
Karen Bloch: So in the part of the world that we are from, David, I guess we have slightly different vector borne diseases here.
Things that I might think about in a patient if she lived in the Southeast or South Central United States would be things like Lacrosse virus, more common in kids but can be seen in adults.
I think about the tick borne pathogens.
I have tick borne on the brain sometimes during the summer months because it's so common here.
We see both Ehrlichia chaffeensis and Rickettsia rickettsii, both of which can cause CNS disease.
And I think that's sometimes underappreciated, particularly if you consider the fact that they are both treatable pathogens.
Arun Venkatesan: It's something that we might both see, Karen, is Eastern equine encephalitis, which really can present all along the eastern seaboard.
Very few cases yearly, typically, you know, 5 to 10 cases, although some years there can be 3 to 4 times that many.
But that is another pathogen to consider.
Karen Bloch: Carol, what does the West Coast have that we haven't mentioned so far?
Carol Glaser: So West Coast, we mostly have West Nile as far as an arbovirus.
We do, for reasons we don't quite understand, we've had St.
Louis encephalitis.
It kind of went away for a few years.
It's now resurfacing and we're seeing those cases again.
Those are our primary arboviruses.
And like you, we have tick borne diseases, although we don't have nearly as much Ehrlichia as you do, we have Anaplasma, and as you mentioned, all of those can cause neurologic features.
I would also add the fact that she's a veterinarian, she is going to be exposed to ticks that much more.
I mean, we mentioned that she, you know, is hiking and camping, and that will expose her.
But don't forget the dogs and the cats are also bringing in fleas, and ticks into her practice on a daily basis, probably this time of year.
David Gaston: Just to round out that differential, looking at table three from the manuscript here, since she's a veterinarian, if she's dealt with macaques at all, having an animal bite, then herpes B virus is always on there.
But it's wonderful to be able to build such a gorgeous differential like this.
Testing for all of those is a lot harder.
And being able to, to really differentiate which of these is, is she at the most risk for, which of these not, and where do you start testing is a continual struggle with any sort of clinical provider, be it an admitting hospitalist team, be it an infectious disease
consult team, but to really say, where, where do you start and Karen, you start off with saying some of the most common pathogens.
That's a great place to start just to have some of the targeted testing that focuses on the most common pathogens, but also using diagnostic testing that can capture much more and always want to emphasize the basics.
Standard bacterial culture, if the patient is at risk, fungal culture, mycobacteriology culture, those basics are always going to be with us in laboratory medicine and you can learn so much from those.
And we're in the molecular era and it is absolutely phenomenal.
That's my bias towards molecular microbiology.
So focusing on your dedicated PCRs, which are so well tuned and do work very well.
HSV, enterovirus, and then thinking, is this the right kind of patient where you would want to use broader testing, like at a multiplex panel that is able to go through and detect multiple highly likely pathogens?
There are not a lot of pathogens that are on those panels that are too obscure, depends on which panel you're talking about.
But for something like meningitis encephalitis, there's a set of organisms that we're looking for.
Those panels are generally designed to be able to target those, depending upon which population we're looking at, too, because there are different pathogens that are more common in children versus those that are more common in adult.
So having algorithms that you work with in your medical system to be able to say, when's the right time to be able to order those tests?
And then if that testing is not revealing, saying, well, when's the right time to really get into testing that we don't fully understand how they perform yet?
Things like metagenomics, where we're coming into a spot that there is certainly a place for those, those testing, but we don't, we don't really know where that is yet.
Is it best to test at the beginning of a syndrome or is it best to test later when everything else has come back negative?
What is the performance characteristic compared to a well tuned PCR?
This is one of those places in, in molecular microbiology where the testing is broader, but you may not have as low of a limit of detection.
There might need to be more organism burden present to be able to detect with something like metagenomics.
And if you're later in a presentation or even in a clinical syndrome, where if it's a virus, if there's a viral load is present, even before symptoms come on, you might miss it.
So there, there are a lot of considerations going into that, but that's why we all work together as a clinical team.
Carol Glaser: David, you point out, you know, how great molecular is, and certainly it's really revolutionized our ability to diagnose it, but there's a lot of limitations and very important limitations I think that sometimes physicians overlook.
One, some false, you know, negative PCRs.
I think, you know, it's not that uncommon for people to be falsely reassured when they have that first negative HSV.
West Nile, I think, is another example where the PCR for West Nile is rarely positive in the spinal fluid because the, the lumbar puncture is done just a little bit too late to pick up viral load.
So, I, can you just talk about that a little bit more?
David Gaston: Sure, Carol.
Those are great points.
You're getting at the normal pathogenesis of a process, so like with West Nile where the viremic phase, the viremic phase is in the CSF, is before someone presents symptoms and then as the inflammatory action is coming in, you're getting more symptoms.
There may not be as much virus present there.
So, even the the most well tuned test, there's always a limit of detection.
There's always an amount of pathogen below which we just simply can't detect it.
And so that can be part of the problem.
But then there are also various tests that are designed differently.
Every test that's performed in a different laboratory, if it's designed by that laboratory is going to perform a little bit different than another test that's performed elsewhere.
So without getting into the weeds of regulatory environments and utilizing tests that are the same test used by everyone, which is not the state that we're in in the United States, nor is it necessarily a state I think we need to be in, you just need to work with your laboratory and the laboratory that is serving you and is serving your patients.
It's our job to know the limitations of those tests.
So to have that kind of ongoing discussion to say, Hey, I'm a well trained clinician.
I have this clinical suspicion that this could be something like HSV encephalitis, yet this test is negative.
Can we talk through some of the limitations of that test?
What's the right way to go forward?
Should we get another lumbar puncture?
In a few days, should we retest using a different test?
Should we broaden our differential to be thinking about something else?
That's something that the lab is there to help you with.
We are effectively a consultant service for the consultants.
So reach out.
We're, we're happy to talk.
Karen Bloch: You mentioned the meningitis encephalitis or ME panel.
And I think that's really revolutionized our ability to rapidly diagnose and expanded the spectrum of pathogens that we're seeing with encephalitis and CNS infections.
One thing I just wanted to raise, and I think the group will have comments on this, is how to interpret a positive HHV 6 PCR test.
David Gaston: HHV 6 is detected quite frequently.
Looking back through our data, it's actually the most commonly detected target on that panel, I'm going to say target not pathogen because it may not be a pathogen in immunocompromised patients.
Carol, you were asking earlier, is this an immunocompromised patient?
Sure, it can be.
Yet in someone who is not immunocompromised, if it's chromosomally integrated, it can be present in the CSF and may not be causing the clinical syndrome that this patient is currently coming in and presenting with.
Carol Glaser: David, I do want to add to that, that that may not be causing the problem.
The issue that we've run into quite a bit here in California with HHV 6 is that sometimes it's the only pathogen that's found.
And so clinicians feel like, well, you know, I have to do something, the patient is sick.
And unlike acyclovir, which is what we use for herpes, drugs like foscarnet and ganciclovir are much more toxic.
Even though we'll talk to clinicians and we'll explain that, you know, there's a very high likely that this is chromosomal integration, that they really feel compelled to do something and in doing something, sometimes we, it does create harm.
So I do worry a little bit that we haven't educated our physicians enough about HHV 6 and the limitations of the testing.
David Gaston: There's power in a name, and this is something that we get to a lot in clinical microbiology of determining how do we present results that are clinically actionable without just presenting more data that can potentially lead folks down a path that is not going to be the most beneficial to the patient.
And there, there's a real balance there.
Uh, with tests like an ME panel, it's an FDA IVD certified test.
So what we detect is what we report.
If it's there, then we are obligated to, to report it.
Same with, you know, any test that would be similar but would be a laboratory developed test where you're able to, to really say, hey, we are reporting this because we've done this testing in our laboratory, we know how it performs with our design and, you know, would validate different reporting strategies if that's, if that's part of it, but education is the real point there
to be able to say, And hopefully your consultants would be relying upon your expertise where you say, well, if this is present, that may be true, true, unrelated, um, that it's not, it's not driving this syndrome, but I do worry about anchoring that happens again, being a clinician myself and remembering times where I found one thing and then said, okay, well, this must be it.
And then, you know, a well, very wise person would come around and say, well, David, hold on, maybe, maybe there might be something else going on.
And there's a lot of wisdom in saying, okay, we've got this.
Let's not anchor.
Let's keep driving.
Let's, let's really find the right answer.
Cause if there is that little red flag in the back of your mind that says that might not be it, that's, that's an important red flag to listen to.
Sara Dong: So I'll take us back to the case.
We get a little bit more information.
We have an initial MRI of the head that was completed with gadolinium enhancement, which shows abnormal signal hyperintensity on T2 weighted imaging and FLAIR with diffusion restriction on diffusion weighted images, both involving the left temporal lobe.
Her LP demonstrates a lymphocytic pleocytosis, so she had about 100 white blood cells, 85 percent lymphocytes.
There was a slightly elevated protein, uh, increased red blood cells.
Her CSF sample is sent for bacterial culture, which is pending, but you have back that the Gram stain is negative.
And her initial CSF HSV1 and HSV2, VZV and enterovirus PCRs were ordered.
And I'll just go ahead and let you know that they're negative.
And this is all on her initial presentation.
So we also have HIV antigen antibody screening that was negative and an RPR, which is negative.
She was empirically placed on acyclovir, vancomycin, and ceftraxone while awaiting results.
So now that we have some of this information back, the patient is relatively in the same place that she was before.
You know, what are, what are you considering?
What might be your next steps?
Arun Venkatesan: Well, what's interesting here, Sara, is that there's evidence of temporal lobe involvement, and it's probably of no surprise to much of the audience that herpes simplex virus still needs to be a prime consideration here.
Now, there are other causes of temporal lobe encephalitis, and Carol and I have looked at this previously through the California Encephalitis Project, as has Dr.
Richard Whitley, but certainly HSV 1 still has to be a very prime consideration here.
So, I think it's It's quite reasonable to continue the acyclovir because as was just mentioned, false negatives can occur.
The HSV PCR is a very good test.
The sensitivity is over 90%, but we know that if that lumbar puncture is performed early, that one can have false negatives.
Karen Bloch: Something that I've grown to appreciate over time is the fact that although having temporal lobe focality certainly increases my concern for herpes encephalitis.
What's become apparent with the increasing utilization availability of PCR is that there's a huge diversity of presentations.
And so that the typical herpes simplex virus 1 causing temporal lobe involvement is true.
But we can certainly see atypical presentations as well.
And I think that's particularly true in, in peds.
Isn't that the case, Carol?
Carol Glaser: Yeah.
Thanks, Karen.
That is a great point.
So in pediatrics, even though we sometimes see more of the classic presentation of herpes simplex, similar to what you see in adults, there are a number of atypical presentations and for mainly two things, both in clinical presentations, So they don't always have seizures
and the hemiparesis and the dysphagia, but sometimes they'll have some things like ataxia, which is not normally what you'd think about.
But importantly too, we probably have a higher number of false negatives with our herpes.
We don't quite understand it.
And these are based on relatively small case series, but both in the California encephalitis project, as well as a pretty big study out of Toronto.
We found 20 to 25 percent false negatives on that first LP.
Probably a little bit of an overinflation, partly because we're a biased sample in, with the encephalitis project, but really important to consider in pediatrics that if you have a, negative herpes, and if there's anything that is looking at all like herpes, you really have to reconsider an LP and repeat that herpes simplex.
David Gaston: No test is perfect, even excellent HSV PCR tests.
And that's fun to, it's fun to think through, in just the history of molecular microbiology.
HSV is really what started the current era of molecular microbiology and HSV in CNS infections.
And Arun, you brought up the work that Rich Whitley did down at UAB.
I trained in Rich's lab.
He was my PhD mentor.
He's a great guy.
So the work that he did and Fred Lakeman and others really just set this route that we're on.
And it's remarkable to see where we are, but yeah, that no, no test is perfect.
And there are multiple different HSV PCRs that are used at different institutions.
Some institutions use their own laboratory developed tests.
Some institutions use FDA IVD certified tests.
They're all very similar, but they're not exactly the same.
And so the performance characteristics are going to be different, which again, just getting back to the idea of talk to your lab so that you understand how that works.
And then your point about repeat testing is critical.
The tests do perform, and this is a very broad statement, so take that with a block of salt.
The tests do perform very similarly.
Such that if you retest the same CSF specimen with a different test, that's not necessarily going to be helpful because the limited detection for these assays is so low and the targets are somewhat similar, that may not help, but testing a few days later with a different CSF specimen that can be very beneficial and if you work in pre
test probability into all of this and if you have a patient that still is clinically highly suspicious for HSV encephalitis, but you have a second negative test, then that really makes you start saying, okay, we've got to go back to our differential and go down to say, This gets knocked down lower on the differentials, what comes up higher?
Karen Bloch: One thing I wanted to mention, I think there'd been an emphasis that this was an outdoors person that she enjoyed activities outside.
And because tick borne pathogens are on our list, and again, many of those are treatable if they're in the Rickettsia family.
I would probably advocate for broadening her empiric antibiotics to include doxycycline, uh, either until you found an alternative pathogen or if there's no clinical response after three days, you can be pretty certain that it's not a tick borne infection.
So just something to keep in mind as we consider empiric treatment in this population.
Carol Glaser: Karen, I'll just add, just, you know, being the pediatrician in the group, that In pediatrics, many of us were trained that we shouldn't be using tetracycline or doxycycline because of the teeth staining, but in a scenario, if you were to have a child,
particularly in the ICU, and there was any concerns about tick borne illness, it's absolutely fine to go ahead and start doxycycline.
You're not going to get into the issues of teeth staining with one course of doxycycline, and it can be absolutely life saving.
So, pediatricians in the past have been very reticent to start doxycycline, but in a scenario with a child with encephalitis, with any concerns about tick borne encephalitis, you should consider starting doxy and not waiting for those tests to come back.
Sara Dong: Great.
In our case, the patient ultimately has a repeat LP about six days later, and we have an HSV PCR that returns positive.
So it's diagnosed with HSV encephalitis.
So the antibiotics, the vancomycin, ceftriaxone, and doxycycline are stopped.
She completes about a three week course of the IV acyclovir and has some overall clinical improvement, is able to go home, but actually comes back to care.
And this time her family says, you know, she just.
It's really strange.
She seems really paranoid.
She's not really sleeping well.
We've also noticed that there's these more unusual movements in her hands, and they actually are worried that she might be seeing things that aren't truly there and hallucinating.
A repeat MRI is done that shows some slight improvement in those temporal lobe changes I mentioned before.
And so they're wondering, you know, is this related to her HSV?
Is this something we should expect?
But as a medical team, now they're coming to our encephalitis consult team here to ask, what else should we be considering and thinking about in this scenario?
Arun Venkatesan: It's a really interesting situation, Sara, and certainly something that's been increasingly recognized in recent years, that patients with very adequately treated herpes simplex encephalitis can develop new or recurrent neurologic symptoms in the weeks to several months following the initial infectious encephalitis.
And so then the question is, what's driving that process?
And for a long time, we thought, Oh, well, maybe they're having seizures.
Maybe there's a viral recurrence.
It turns out that in most of these cases, there's an autoimmune process that follows the initial herpes simplex encephalitis.
And that autoimmune encephalitis is often though not always associated with antibodies against the NMDA receptor.
There can be antibodies against other neuronal proteins as well that can develop, and this happens in probably, well, up to about a fifth of patients with herpes simplex encephalitis.
So it's not uncommon, and I think it's something that's really important to recognize.
Karen Bloch: As an ID doctor, one of the questions we frequently get asked on the consult team is often by the neurology team, saying, we have a suspicion.
It's going to take days to weeks before we get the testing results back.
Since we haven't completely confirmed the diagnosis of an autoimmune phenomenon and we can't completely exclude the possibility of infectious, is it safe to start immunosuppression?
That's one reason of many that the infectious disease community really needs to know about the autoimmune encephalitis and think about risk benefit in terms of early initiation of any inflammatory treatments.
David Gaston: One point I'd like to throw in just for clarity on the listener's side.
We're, we're saying herpes encephalitis.
I think we're meaning HSV 1.
Herpes simplex virus in HSV 1 causes an encephalitis that if untreated is fatal, whereas HSV 2 can cause a recurrent meningitis that arguably may not even need to be treated.
Mollaret meningitis.
And once a patient knows that that's what's going on, you could either have a pill in pocket if that is a symptomatic improvement, but not necessarily saying, you've got to be on weeks of IV acyclovir.
Whereas with HSV 1 encephalitis, which is what we're talking about here, yes, that's got to be there.
Back to Karen's point about what follows when is immune suppression needed after that with steroids to be able to help with some of the secondary factors, then, um, I'll, I'll not comment on that.
Arun Venkatesan: Yeah, I can take that one, David.
The presentation of autoimmune encephalitis can differ from that of infectious encephalitis.
And in particular, it can be a little bit more subacute in its onset.
Some of the cognitive changes can be more subtle.
Certainly, behavioral changes can be very pronounced.
For example, psychosis can occur in autoimmune encephalitis.
And what we typically use to treat autoimmune processes, of course, as first line are corticosteroids.
But that may actually be contraindicated in some of these patients because of the extreme degrees of psychosis.
And so other first line agents that we might think about would include intravenous immunoglobulin or even plasmapheresis, plasma exchange in an effort to control the autoimmune process in these patients.
Carol Glaser: So Arun, to follow up about some of the clinical presentations of autoimmune, particularly anti NMDAR.
In the early days of anti NMDAR encephalitis and the recognition of that before there wasn't even commercial tests available.
For that, we were getting a fair number of cases referred into the state health department, people thinking they were rabies, and they weren't rabies, and because actually the tempo wasn't quite right, but there's an incredible overlap with the clinical presentation of some of those anti NMDR receptor encephalitis cases and rabies.
You know that incredible psychosis, the agitation, the autonomic instability.
So keep in mind there can be incredible overlap.
In the textbooks it all looks like they they separate out very nicely, but they really don't.
So both needs to stay on your differential with the idea that the autoimmune are going to be in this country going to be much more common than something like rabies.
But again, in this case, she's a veterinarian.
She's got more than your normal exposure to animals.
So that should be in the back of folks mind.
Karen Bloch: Again, anti NMDAR has sort of stolen the limelight here, but there are a number of other autoimmune antibodies and even some that I think don't have names, but appear to be important causes.
And so I know there are panels out there and Arun, my question for you is when you see a patient where this is a concern, do you send a panel and do you differentiate CSF versus serum?
Arun Venkatesan: Yeah.
So certainly when we're suspicious of an autoimmune encephalitis, It's wise to send a broad panel because like you mentioned, there are many potential antibodies.
There's a lot of clinical overlap between these autoimmune encephalitides.
We like to try to send the CSF because it's a little bit more sensitive in many cases than the serum.
And there can be both false negatives and false positives from the serum.
CSF tends to be better in terms of its testing characteristics.
And then of course, there's often a delay between when we send the testing and when we receive the results.
So, if we think we've reliably excluded infections at this stage, then certainly it makes sense to initiate empiric immunosuppressive therapy.
And like I mentioned, typical first line treatments would be corticosteroids, IVIG, or plasma exchange.
And then there are second line treatments as well.
For example, rituximab or cyclophosphamide or, or others.
There's a growing list of immune modulatory agents that have shown promise in autoimmune encephalitis.
David Gaston: Let's draw the listener's attention to table 10, which back when I was an ID fellow would have loved to have had in my back pocket to look into, which is in categories of autoimmune encephalitis, which has a great list on there.
Thanks, Arun, for that.
It's great.
Sara Dong: Yeah.
And I was going to sort of oversimplify this case and say, this patient is diagnosed ultimately with anti NMDA receptor encephalitis based on CSF studies with oligoclonal bands and IgG anti NMDA receptor antibodies.
But really the reason I'm oversimplifying is to just open it up to talk about any other challenges you see with teasing these apart both for diagnosis and management, because I think, as you all are alluding to, these cases are typically not so linear.
Arun Venkatesan: Yeah, this is a really nice case of an infectious encephalitis followed by an autoimmune encephalitis.
And I think you're right.
It does highlight some of the challenges of trying to distinguish between the two and also remaining really vigilant for the possibility of evolution of symptomatology.
Infections can trigger autoimmunity and this has been something that's been recognized for many decades but has really come to the light now in the kind of neuro ID field with cases of herpes simplex encephalitis followed by autoimmune encephalitis.
Herpes simplex encephalitis is not the only encephalitis that can do this.
Many other pathogens can, even after adequate treatment, then result in an autoimmune encephalitis that follows.
And the thought is that many of these pathogens are destructive.
You're getting release of neuronal antigens that typically don't get seen by the immune system, but once they're released in this way, the immune system sees them, recognizes them as foreign and that triggers an autoimmune attack.
Karen Bloch: Before we knew about anti NMDAR, I think the classic example was ADEM.
Arun Venkatesan: That's right, Karen, acute disseminated encephalomyelitis, which is, you know, classically preceded by an infection.
In fact, any number of infections can do this and is accompanied often by antibodies against components to myelin and results in an acute inflammatory demyelinating process that can respond to immuno modulation, and it's a situation where the infection is typically not seen in the central nervous system.
This is a peripheral process that then results in central nervous system demyelination.
Sara Dong: So I want to thank you all so much for this awesome overview.
We obviously cannot fit everything about encephalitis and even from your review into this podcast.
So I was going to open it up at the end to ask if you could share either a take home point or an interesting pearl related to encephalitis, just because there's so much out there we could talk about.
For me, I am going to put on my pediatric hat and just say, you know, we didn't talk as much about too many pediatric specific things.
We did recently have a Febrile episode number 92 on an interesting case of arboviral encephalitis.
So if people want to hear more, I encourage them to listen there.
And then I was going to take the opportunity to reinforce a concept that I definitely was tested on for my peds [pediatric] ID certification, even though I have not seen this in real life.
But the association of EBV encephalitis and the Alice in Wonderland presentation with metamorphopsia, you guys can correct me if I'm wrong, I see nods, but basically these distortions of something like visual perception, like size and body image, and even the experience of time.
And that is not specific to EBV, it can be caused by epilepsy and brain tumors and perhaps drug use, but I thought that was a useful pearl, and it is mentioned in the paper.
So I'll open it up to you guys.
What are some other things you want to share before we wrap up?
Karen Bloch: I think there's a misperception sometimes that outside of herpes simplex virus encephalitis that they're not treatable causes, and we've already mentioned tick borne, but I wanted to throw in one that I don't think got a lot of play here, but is an increasing concern in adult population throughout the United States and internationally as well, and that's syphilis.
Never forget, syphilis is a treatable cause.
It can mimic herpes encephalitis with temporal lobe focality.
It can be chronic.
It can be acute.
So as was the case in this vignette, checking an RPR, antitreponemal antibodies, is really a key part of the workup of any patient with encephalitis.
Carol Glaser: As long as Karen is mentioning treatable things, I want to talk about an organism that up until now we've thought not to be treatable.
We thought that the mortality was close to a hundred percent, but there's a type of free living amoeba called Balamuthia mandrillis, which is traditionally thought to be a very esoteric cause of encephalitis.
In California, where we were diligently looking at it for this organism for years, we were finding it much more than expected.
It's not common.
I don't want to pretend it's common, but it certainly should be considered in individuals with encephalitis when there's a parenchymal lesions and when the spinal fluid is appropriate and you've sort of wiped out the first tier and maybe even the second tier.
But I bring it up as something maybe treatable because there's been a recent case report and I'm aware of another case out there where the investigators used nitroxoline as a drug, which is crazy because it's really a UTI drug that is used in Europe, but we have to always push the envelope with encephalitis.
We can't just sit back and say, yeah, it's, it's.
People are, this is usually fatal.
We're not going to do anything about it.
That's really important to try to push for an early diagnosis because it may make a huge difference.
And certainly we've seen a few success stories with Balamuthia.
David Gaston: I want to play off that idea of pushing the envelope with encephalitis, particularly from a diagnostic standpoint.
It's still a challenging diagnosis to make from laboratory medicine.
And a lot of that is the nature of the pathogens that we're dealing with.
To some degree, that's the nature of the tests that we're using, but want to emphasize the importance of collaboratively working together with the primary teams, with the consultants, with the clinical microbiology lab to really get at what's happening, secure all the points you made of, you know, we're definitely not going to be sitting back to say, well, this is almost universally fatal.
So let's, let's all head home early, but it's hard work to be able to go through and do that.
And it's thrilling to see where the field of diagnosis is going with, again, my bias being molecular microbiology, but moving more towards broad diagnostics like clinical metagenomics and Arun, you're, you're up there at Hopkins and the Hopkins lab has developed an in house metagenomics assay that you can utilize.
There's only one sent out in the US out at UCSF, but I hope that that's a place where we as, as a community can continue moving.
It's going to take a long time.
It's a lot of work.
These are highly complicated tests.
There are a lot of limitations to them, but they potentially can really fill in some gaps and not replace the other tests that we're using either.
There, there will always be a place for culture, there will always be a place for targeted assays.
I think we're learning what is the place for these advanced diagnostics like clinical metagenomics.
Arun Venkatesan: The other thing that we're really learning about is that Yes, these patients come in with an acute syndrome, an acute encephalitis, but the picture can evolve, and it can evolve over weeks to subsequent months.
I think that really highlights the importance of careful follow up of these patients.
It's not enough just to do our best for these patients in the hospital and then send them home or to wherever it is that they go after that.
I think it's really important to keep a close eye on them and make sure that we understand what the biology of the disease is and how it's unfolding in these patients.
Sara Dong: Thanks again to our guest stars, Karen, Carol, David, and Arun for joining today.
You can find their article, State of the Art Review, Acute Encephalitis, from CID, linked in the episode information and on the Consult Notes.
Please be on the lookout for future STAR episodes, which will be noted in the title.
We're still catching up on the previously published articles and then moving forward as we have new releases, we'll bring you new episodes.
Don't forget to check out the website, febrilepodcast.
com, where you will find the Consult Notes, which are written complements to the episodes, our library of ID infographics, and a link to our merch store.
Febrile is produced with support from the Infectious Diseases Society of America, IDSA, Audio editing and mixing is provided by Bentley Brown.
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