UA-184069179-1 92: Searching for Peace of Mind - Febrile
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Episode 92

92: Searching for Peace of Mind

Future physician Sophie Samson, Dr. Kristen Bastug, and Dr. Beth Thielen discuss a case of a 7 year old girl who presented with new onset seizure, headache, and fever in Minnesota.

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Febrile is produced with support from the Infectious Diseases Society of America (IDSA)

Transcript
Sara Dong:

Hi everyone, welcome to Febrile, a cultured podcast about

Sara Dong:

all things infectious disease.

Sara Dong:

We use consult questions to dive into ID clinical reasoning, diagnostics,

Sara Dong:

and antimicrobial management.

Sara Dong:

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

Sara Dong:

First, I did just want to announce some wonderful news.

Sara Dong:

Febrile is now partnering with IDSA, who will be helping to produce

Sara Dong:

and expand the podcast platform.

Sara Dong:

So, super excited to continue to share ID knowledge with you and

Sara Dong:

excitement about the field of ID.

Sara Dong:

So I, of course, would love to just add a plug that I would always love

Sara Dong:

to hear from you, especially if you want to join an episode of Febrile.

Sara Dong:

Febrile really likes to highlight trainees and junior faculty in particular.

Sara Dong:

So if you would like to come on as a representative for your fellowship

Sara Dong:

program, or as an individual, I would love to welcome you to the show

Sara Dong:

for an episode, just let me know.

Sara Dong:

All right.

Sara Dong:

So today we have a great multi level learner team from

Sara Dong:

the University of Minnesota.

Sara Dong:

Let's meet them.

Sara Dong:

First up, we have Sophie Samson.

Sara Dong:

Sophie is currently a third year medical student at the University

Sara Dong:

of Minnesota Medical School.

Sara Dong:

She plans to train in pediatrics and has a particular interest

Sara Dong:

in pediatric ID and neurology.

Sophie Samson:

Hi, my name is Sophie, and I'm happy to be here.

Sara Dong:

Next, we have Dr.

Sara Dong:

Kristen Bastug.

Sara Dong:

Kristen is a pediatric ID fellow from the University of Minnesota.

Sara Dong:

She is interested in the intersection of ID, global child health, climate

Sara Dong:

change, and environmental health.

Kristen Bastug:

Hi, this is Kristen.

Kristen Bastug:

Excited to be doing this.

Sara Dong:

And last but not least, we have Dr.

Sara Dong:

Beth Thielen.

Sara Dong:

Beth is an adult and pediatric ID physician scientist at

Sara Dong:

the University of Minnesota.

Sara Dong:

She was previously on episode number 19, Finding a Needle in a Haystack from 2021.

Sara Dong:

She currently leads a lab that is particularly interested in understanding

Sara Dong:

the factors that influence the severity of respiratory viral infections.

Sara Dong:

In addition to that, she has clinical interest in the care of immunocompromised

Sara Dong:

patients, travel and tropical medicine, and clinical immunology.

Beth Thielen:

Hi, this is Beth.

Beth Thielen:

Happy to be back.

Sara Dong:

All right.

Sara Dong:

And as everyone's favorite cultured podcast, we would love

Sara Dong:

to hear a little piece of culture that brings you happiness.

Sophie Samson:

Well, I am a pretty avid reader.

Sophie Samson:

So one of my favorite books in the past year is called Cloud Cuckoo Land.

Sophie Samson:

And it is, um, set in multiple different centuries with a cast of characters and

Sophie Samson:

they're all intertwined in some way.

Sophie Samson:

And it's kind of a, a book that's an ode to book lovers in

Sophie Samson:

a way, so I really enjoyed that.

Sara Dong:

I love that.

Sara Dong:

So someone mentioned that on Febrile before and I bought it and it's

Sara Dong:

actually sitting like right off camera as my like next selection to read.

Sara Dong:

I love it.

Beth Thielen:

I think I heard about it from one of the

Beth Thielen:

Curbsiders podcasts, actually.

Sara Dong:

Yeah, it's good.

Sara Dong:

It means multiple people liked it.

Sara Dong:

Just another endorsement.

Kristen Bastug:

Well, that's great.

Kristen Bastug:

Um, I like to read as well, but I actually saw a really cool Netflix show recently.

Kristen Bastug:

Life on our planet.

Kristen Bastug:

Um, so it's a documentary style film with some CGI graphics.

Kristen Bastug:

Um, actually Morgan Freeman narrates it, but they go through some of the

Kristen Bastug:

really interesting geologic changes of our planet and then the ecosystem

Kristen Bastug:

changes that were part of it.

Kristen Bastug:

But I just really loved seeing the reimagined like graphic

Kristen Bastug:

representation of these weird animals that like hadn't quite evolved yet.

Kristen Bastug:

Um, I thought it was a lot of fun.

Sara Dong:

Very cool.

Beth Thielen:

Well, one of my culture moments is that during the pandemic,

Beth Thielen:

I took up a new hobby, which was learning to play the accordion.

Beth Thielen:

Just a little bit of a realization of a lifelong dream.

Beth Thielen:

And I play in an accordion group, and we had an opportunity for our group

Beth Thielen:

to travel together to eastern Italy to a small town called Castelfidardo,

Beth Thielen:

which is home of both the Guinness Book of World Records world largest

Beth Thielen:

accordion, which I was able to play, um, and we were able to tour an accordion

Beth Thielen:

factory, which is a kind of ground zero for the manufacturer of accordions.

Beth Thielen:

And so, uh, that is, that is the, my, my piece of culture for today.

Sara Dong:

That is amazing.

Sara Dong:

I love it so much.

Sara Dong:

Awesome.

Sara Dong:

Well, I will hand it over to Sophie to get us started.

Sophie Samson:

Yeah.

Sophie Samson:

So I will start by telling you all a little bit about our patient..

Sophie Samson:

So, our patient is a seven year old girl who presented to the ED a few days before

Sophie Samson:

with an acute onset seizure, headache, fever, and largely intact cognition.

Sophie Samson:

On the morning of admission, she experienced a right

Sophie Samson:

sided temporal headache.

Sophie Samson:

She then developed abdominal pain with one episode of emesis.

Sophie Samson:

She laid down and was found drooling and chewing with the right side of her mouth.

Sophie Samson:

Her eyes were open, but not focused, and she developed left sided, circular

Sophie Samson:

arm movements with associated urinary incontinence and tongue biting.

Sophie Samson:

She was not interactive, and the episode lasted about one hour, terminating

Sophie Samson:

with benzodiazepine given by EMS.

Sophie Samson:

In the ED, she had a low grade fever to 104 degrees Fahrenheit, and initial

Sophie Samson:

workup showed mild leukocytosis, elevated absolute neutrophil count, normal CMP

Sophie Samson:

except for elevated phosphorus, and inflammatory markers within normal limits.

Sophie Samson:

Infectious workup included a group A strep PCR, and a respiratory viral

Sophie Samson:

panel, which were both negative.

Sophie Samson:

Kristen, if you got a call based on this information, what are you

Sophie Samson:

thinking about at this point in terms of differential diagnosis, and what are

Sophie Samson:

you thinking about doing for management?

Kristen Bastug:

Yeah, thanks Sophie.

Kristen Bastug:

Um, so at this point, I think we need to keep our differential

Kristen Bastug:

pretty broad and consider first any etiologies that could be emergent.

Kristen Bastug:

When I hear her presentation, the symptoms of headache, emesis, and

Kristen Bastug:

focal seizure like activity raise my concern that there could be an

Kristen Bastug:

intracranial process occurring.

Kristen Bastug:

An intracranial hemorrhage could present this way, so I think we

Kristen Bastug:

need to consider some head imaging to rule out an acute bleed.

Kristen Bastug:

Her low grade fever and leukocytosis in the context of a seizure could

Kristen Bastug:

be due to the seizure itself.

Kristen Bastug:

However, I also want to consider infectious etiologies that could

Kristen Bastug:

have triggered the seizure.

Kristen Bastug:

At 7 years old, she is older than I would expect for someone having a febrile

Kristen Bastug:

seizure, so I would like to obtain some additional diagnostic studies

Kristen Bastug:

to help us investigate the etiology.

Kristen Bastug:

I would recommend a lumbar puncture so that we can obtain the cerebrospinal

Kristen Bastug:

fluid studies in order to evaluate further for an infectious cause.

Kristen Bastug:

I would send meningitis and encephalitis PCR panel in addition to the standard

Kristen Bastug:

cell count, glucose, protein, and aerobic culture on the CSF fluid.

Kristen Bastug:

The meningitis encephalitis panel doesn't test for all pathogens, but

Kristen Bastug:

it can test for several pathogens that are on my differential.

Kristen Bastug:

These would include Streptococcus pneumoniae and Herpes Simplex Virus.

Kristen Bastug:

Listeria and E.

Kristen Bastug:

coli are less common at her age of seven, but are still possible.

Kristen Bastug:

I would also consider Staphylococcus aureus, and if she is unvaccinated,

Kristen Bastug:

then Haemophilus influenzae would be a higher possibility.

Kristen Bastug:

Enterovirus is another one that comes to my mind, particularly in the summertime.

Beth Thielen:

Thanks, Kristen.

Beth Thielen:

That's a great, uh, kind of, discussion of your thought process.

Beth Thielen:

Um, I did also wanna highlight that since we're discussing the possibility of both

Beth Thielen:

head imaging and an LP in a patient whom we're, uh, ruling out bacterial meningitis

Beth Thielen:

that we should, uh, think, you know, think about some of the literature around this.

Beth Thielen:

And specifically I wanted to bring up a, uh, a, that the topic of CT and, and

Beth Thielen:

lumbar puncture was recently discussed in the Choosing Wisely campaign, uh,

Beth Thielen:

as something that we do for no reason.

Beth Thielen:

And, uh, importantly I think they make this dis-, we make this distinction

Beth Thielen:

between patients at high risk and at low risk for abnormal imaging.

Beth Thielen:

And both the IDSA and ESCMID guidelines for bacterial meningitis do include

Beth Thielen:

new seizures as a high risk feature.

Beth Thielen:

So this is a patient definitely we'd be considering as high risk.

Sophie Samson:

So with what we know at this time, would you recommend

Sophie Samson:

empiric antibiotic treatment?

Kristen Bastug:

I think that in order to help me answer that, it would be

Kristen Bastug:

really helpful to have a, an updated understanding of her neurologic status.

Kristen Bastug:

Because in a patient who's minimally responsive, I would have a lower

Kristen Bastug:

threshold to start antibiotics and even acyclovir as soon as possible.

Kristen Bastug:

If her symptoms have resolved and she is stable, then I think it's reasonable

Kristen Bastug:

to first obtain the lumbar puncture promptly and then start the empiric

Kristen Bastug:

antibiotic therapy with, um, I would choose ceftriaxone and vancomycin for her.

Kristen Bastug:

Given that the meningitis encephalitis panel will result fairly quickly,

Kristen Bastug:

typically within a few hours, if her clinical status is stable,

Kristen Bastug:

then I would not start empiric acyclovir at this time for her.

Kristen Bastug:

Finally, when considering the differential diagnosis for a seizure, we should

Kristen Bastug:

also be thinking about alternative causes in case the patient doesn't

Kristen Bastug:

respond to treatment as we expect.

Kristen Bastug:

A focal seizure could be caused by a focal brain lesion, such as a brain tumor, which

Kristen Bastug:

is another reason I favor pursuing head imaging as part of the initial workup.

Kristen Bastug:

Other possibilities that are less likely at this time include autoimmune

Kristen Bastug:

etiologies, such as acute disseminated encephalomyelitis, toxic substance

Kristen Bastug:

ingestion, or a traumatic injury.

Sophie Samson:

A lumbar puncture was performed due to persistent headache

Sophie Samson:

that migrated to the back of her head and neck and was notable for CSF neutrophil

Sophie Samson:

predominant pleocytosis, 42 nucleated cells with the normal range being

Sophie Samson:

between 0 to 5 cells per microliter, and normal glucose and protein levels,

Sophie Samson:

and a meningitis encephalitis panel, and aerobic CSF cultures that are in process.

Sophie Samson:

MRI was performed later that day and revealed multiple

Sophie Samson:

bilateral T2 hyperintensities.

Sophie Samson:

MRA showed no vascular lesions.

Sophie Samson:

After the initial LP was performed, she was started on ceftriaxone, 100 mg

Sophie Samson:

per kg per day, divided every 12 hours.

Sophie Samson:

She had a clinical seizure captured on EEG lasting 90 seconds, and she was

Sophie Samson:

subsequently started on levetiracetam.

Sophie Samson:

She then spiked two discrete high fevers up to 104.

Sophie Samson:

2 degrees Fahrenheit, prompting a formal pediatric infectious disease consultation.

Sophie Samson:

Cultures are negative to date after 48 hours in the hospital.

Sophie Samson:

Kristen, as the ID fellow on the team with this new information, how

Sophie Samson:

does this change your differential?

Kristen Bastug:

Yeah, I'm glad we got the lumbar puncture because those results will

Kristen Bastug:

really help us adjust our differential.

Kristen Bastug:

So, her normal CSF glucose, normal protein, and mild to moderately elevated

Kristen Bastug:

white blood cell count suggest to me that this is an aseptic meningitis,

Kristen Bastug:

which would include viral processes.

Kristen Bastug:

The MRI findings of multiple T2 hyperintensities also seems

Kristen Bastug:

more consistent with a viral process rather than bacterial.

Kristen Bastug:

The aerobic CSF cultures have been negative for 48 hours at this point

Kristen Bastug:

without any antibiotic pretreatment, which further supports that a bacterial

Kristen Bastug:

cause such as Staph aureus, Strep pneumoniae, or meningococcus are unlikely.

Kristen Bastug:

The negative meningitis encephalitis panel offers some reassurance that this

Kristen Bastug:

patient does not have HSV or enterovirus, though the sensitivity of the ME panel is

Kristen Bastug:

not as high as other testing modalities, such as an HSV 1 or HSV 2 specific PCR.

Kristen Bastug:

I would be interested to hear my attending's perspective on when

Kristen Bastug:

we should consider ordering those additional specific PCR tests

Kristen Bastug:

in addition to the ME panel.

Kristen Bastug:

Finally, I note that her fever curve is uptrending to 104, though given

Kristen Bastug:

that we have good evidence that this is not a bacterial process, I would not

Kristen Bastug:

add any new antibiotics at this time.

Kristen Bastug:

We also have good evidence this is not HSV, and so I

Kristen Bastug:

would not add acyclovir either.

Kristen Bastug:

What I would make sure to do is to follow her neurologic exam closely, and

Kristen Bastug:

if she develops any new symptoms, such as areflexia or paralysis, then I would

Kristen Bastug:

want rapid imaging of her spinal cord and a neurology consult in order to

Kristen Bastug:

evaluate for inflammatory or demyelinating diseases, such as transverse myelitis.

Kristen Bastug:

She should be monitored closely if those processes are suspected

Kristen Bastug:

because respiratory status can rapidly decompensate in that setting.

Beth Thielen:

Thanks, Kristen.

Beth Thielen:

Yeah, I agree that at this point, 48 hours into illness, I think my suspicion

Beth Thielen:

for atypical bacterial meningitis is much, much lower and particularly

Beth Thielen:

given we have negative cultures and negative meningitis encephalitis panel

Beth Thielen:

and fevers that have persisted despite appropriately doses of ceftriaxone.

Beth Thielen:

I think at this point where I'm thinking about going is moving on to our next

Beth Thielen:

tier testing for more unusual pathogens.

Beth Thielen:

Um, but I also want to spend a couple minutes just talking about the performance

Beth Thielen:

characteristics of the testing thus far.

Beth Thielen:

And so I'm a little bit less reassured that we've adequately ruled out HSV

Beth Thielen:

when the clinical picture and in this case, new onset focal seizures would

Beth Thielen:

potentially be clinically compatible.

Beth Thielen:

And so it's well described that HSV PCR can be falsely negative,

Beth Thielen:

particularly early in the disease course.

Beth Thielen:

Um, and I think there's also, there's also been several systematic reviews

Beth Thielen:

now with increasing number of patients that have showed lower sensitivity

Beth Thielen:

of the multiplex panels for HSV.

Beth Thielen:

So I'm really thinking about wanting to repeat the LP, both for more

Beth Thielen:

specific testing for things like HSV, but also to see how the CSF

Beth Thielen:

parameters have evolved over time.

Beth Thielen:

And I think this would also have the benefit of allowing us to get additional

Beth Thielen:

specimen volume to send for that second tier testing, and oftentimes we're

Beth Thielen:

limited in terms of CSF volume for the things that we we want to test for.

Beth Thielen:

And so we have to be a little bit strategic sometimes about

Beth Thielen:

prioritizing our testing and making sure that we have enough sample

Beth Thielen:

to get those high priority tests.

Beth Thielen:

Um, in terms of specific microbes, and I'm thinking about, so I think things

Beth Thielen:

like arboviruses, LCMV, and Lyme disease or some of the pathogens that aren't

Beth Thielen:

included on those multiplex panels.

Beth Thielen:

Um, certainly respiratory viruses like flu are associated sometimes

Beth Thielen:

with neurological symptoms.

Beth Thielen:

Like in her case, we have a negative respiratory panel on admission,

Beth Thielen:

so those seem less likely.

Beth Thielen:

Um, I think I also want to ask about TB risk factors, and so that's one of the

Beth Thielen:

other, uh, you know, disease processes that wouldn't come up on routine

Beth Thielen:

testing and could present with seizures and, and a meningitis type picture.

Sophie Samson:

And a big question brought up by the neurology team was

Sophie Samson:

whether to treat with steroids or IVIG for a possible autoimmune encephalitis.

Sophie Samson:

Beth, what were the considerations there?

Beth Thielen:

Yeah, so I think I'd want to know a bit more about how

Beth Thielen:

consistent the neurology team thinks the features are with an autoimmune process.

Beth Thielen:

Um, and in this case, talking with them, I feel like they, um, were not, really

Beth Thielen:

super convinced that this is what they thought was going on and at this point, I

Beth Thielen:

don't feel like we have a clear diagnosis and so in cases like that when we have

Beth Thielen:

the two immunomodulatory therapies mentioned, I think IVIG would be the

Beth Thielen:

safer option, but it still has downsides.

Beth Thielen:

Um, so some of the infectious processes that I'm thinking about,

Beth Thielen:

maybe we may need serology to diagnose them and IVIG would impact, um, our

Beth Thielen:

ability to make those diagnoses.

Beth Thielen:

Um, furthermore, when an untreated infection is in the differential,

Beth Thielen:

I prefer to hold off on steroids.

Beth Thielen:

There's definitely some infections where steroids may make things look better

Beth Thielen:

for a while before they get worse due to the impairment to the immune control.

Beth Thielen:

And so I think if there's not a compelling reason why urgent treatment

Beth Thielen:

is needed, I would, really focus our efforts on making the diagnosis

Beth Thielen:

before we embark on a treatment.

Kristen Bastug:

Yeah, it sounds like we are in agreement that a viral process is

Kristen Bastug:

at least very likely, um, and we want to recommend additional studies at this time.

Kristen Bastug:

It would be helpful to also obtain additional exposure history for

Kristen Bastug:

this patient, particularly outdoor exposure, travel history, animal

Kristen Bastug:

exposures, and social history.

Kristen Bastug:

Sophie, do you have any more of that for us?

Sophie Samson:

Yeah, um, and the neurology team doesn't feel strongly

Sophie Samson:

that this looks like an autoimmune process, but don't have any other ideas.

Sophie Samson:

They've sent autoantibodies, but these will take days to come back.

Sophie Samson:

Um, so to fill you in on some of the social history, it's currently mid July.

Sophie Samson:

The patient lives in a suburb of the Twin Cities and has been

Sophie Samson:

regularly active outside around the family's home this summer.

Sophie Samson:

The family has dogs, cats, and chickens.

Sophie Samson:

And one of the dogs had ticks earlier in the spring, but no

Sophie Samson:

ticks were found on family members.

Sophie Samson:

She did not have any rodent or bat exposures.

Sophie Samson:

Her family camped along a river five days before symptom onset.

Sophie Samson:

The patient's mom recalls that there was a transient red bump on her torso

Sophie Samson:

present at the time of her initial seizure, but has since resolved.

Sophie Samson:

She has not traveled outside of Minnesota, notably.

Sophie Samson:

How does this additional information influence the differential

Sophie Samson:

diagnosis and management?

Kristen Bastug:

Thanks, Sophie.

Kristen Bastug:

That history is really helpful.

Kristen Bastug:

It stands out to me that her symptoms started five days after

Kristen Bastug:

the family went camping in July.

Kristen Bastug:

I wonder if the skin bump that was described could be a mosquito bite.

Kristen Bastug:

The outdoor exposure brings into question if her illness is potentially caused by

Kristen Bastug:

a vector borne disease, which we do see more of in the summer months in Minnesota.

Kristen Bastug:

There are many diseases in this category, so I'm glad that we have

Kristen Bastug:

obtained her travel history to help narrow the list down a little bit.

Kristen Bastug:

It sounds like she and her family have only been in in Minnesota, so I

Kristen Bastug:

would start building my differential with this location in mind.

Kristen Bastug:

Given that we already suspect a viral process based on her CSF results, I'm

Kristen Bastug:

suspicious of an arboviral infection.

Kristen Bastug:

West Nile virus, Western Equine Encephalitis, and La Crosse encephalitis

Kristen Bastug:

are considered endemic to Minnesota.

Kristen Bastug:

More recently, Jamestown Canyon virus is also emerging as a

Kristen Bastug:

cause of disease in our state.

Kristen Bastug:

Of these possibilities, La Crosse encephalitis more often affects

Kristen Bastug:

children compared to adults.

Kristen Bastug:

In fact, the most common arboviral cause of central nervous system

Kristen Bastug:

infection in children in the United States is La Crosse virus.

Kristen Bastug:

There are about 80 to 100 cases reported annually in the U.

Kristen Bastug:

S., and 90 percent of those occur in children.

Kristen Bastug:

This is in contrast to West Nile virus, which shows a peak incidence

Kristen Bastug:

in adults over 60 years old.

Kristen Bastug:

Jamestown Canyon epidemiology also indicates a lower percent of children

Kristen Bastug:

with these cases, at about 7%.

Kristen Bastug:

These viruses are all spread from animal reservoirs to humans through mosquitoes.

Kristen Bastug:

However, we do have other important vector borne diseases in Minnesota.

Kristen Bastug:

With the outdoor exposure, I think it's worth considering if there are

Kristen Bastug:

other etiologies we could be missing.

Kristen Bastug:

Sophie, what are some additional vector borne diseases that we could consider?

Sophie Samson:

Well, Kristen, thanks for covering viruses spread by mosquitoes

Sophie Samson:

that we think about in Minnesota.

Sophie Samson:

We also want to think about vector borne diseases spread by ticks in this area.

Sophie Samson:

This includes Lyme and other Borrelia species, Anaplasma and

Sophie Samson:

Babesia, as well as tularemia, ehrlichiosis, and Powassan virus.

Sophie Samson:

It's important to note that lacking known exposure has a low negative

Sophie Samson:

predictive value for these vector borne diseases since bites often go unnoticed.

Sophie Samson:

Knowing a patient is in a general location where they may have been

Sophie Samson:

exposed to a specific tick or mosquito is more helpful to keep in mind.

Kristen Bastug:

Thanks, Sophie.

Kristen Bastug:

At this point for our patient, I think we need to obtain additional testing

Kristen Bastug:

to evaluate for arboviral disease.

Kristen Bastug:

I want to contact the Minnesota Department of Health at this time

Kristen Bastug:

because their laboratory will be the one to process the studies.

Kristen Bastug:

I often find it helpful to know ahead of time what types of specimens

Kristen Bastug:

they'll require for the testing.

Kristen Bastug:

Particularly for samples such as cerebrospinal fluid, I want

Kristen Bastug:

to make sure that it's processed appropriately and not wasted.

Kristen Bastug:

The Minnesota Department of Health requested blood, serum, and CSF samples

Kristen Bastug:

for IgM antibody and RNA detection.

Kristen Bastug:

They had listed some specific tests, such as an IgM for West Nile virus,

Kristen Bastug:

Powassan virus, Jamestown Canyon, Western and Eastern Equine Encephalitis,

Kristen Bastug:

California Group Encephalitis, and St.

Kristen Bastug:

Louis encephalitis, which was ordered.

Kristen Bastug:

Urine, blood, and urine RT PCR for West Nile virus was also ordered.

Kristen Bastug:

Given this large panel of viruses, I'm bracing myself for the potential of

Kristen Bastug:

some cross reactivity and I'll need to discuss these results carefully with my

Kristen Bastug:

attending in order to interpret them.

Kristen Bastug:

In the event that we had used our in house laboratory for testing, I

Kristen Bastug:

think it's important for everyone to note that arbovirus disease is

Kristen Bastug:

reportable, at least in Minnesota, to our state health department.

Kristen Bastug:

And it has to be reported within one working day.

Sophie Samson:

A lumbar puncture was repeated for this patient due to her

Sophie Samson:

high grade fevers despite starting ceftriaxone, as well as the seizures.

Sophie Samson:

Opening pressure of the repeat lumbar puncture was 21.

Sophie Samson:

5 centimeters of water.

Sophie Samson:

CSF studies show evolution over time with an increase to 578 nucleated cells per

Sophie Samson:

microliter with 78 percent lymphocytes, stable glucose, and now protein elevation.

Sophie Samson:

Kristen, how does this new information impact your diagnostic thinking?

Kristen Bastug:

This lumbar puncture shows an increased white blood cell

Kristen Bastug:

count that is predominantly lymphocytic.

Kristen Bastug:

As long as her clinical status is stable, this is consistent with the evolution

Kristen Bastug:

of a viral central nervous infection.

Kristen Bastug:

I'm glad that we can send a CSF to the health department and

Kristen Bastug:

hopefully identify the etiology.

Sophie Samson:

You mentioned that both serology and nucleic acid based testing

Sophie Samson:

was sent to the health department.

Sophie Samson:

What is the role of serology versus molecular or nucleic acid

Sophie Samson:

based tests in arboviral disease?

Beth Thielen:

Yeah, so for many arboviral infections, the period during

Beth Thielen:

which virus can be detected in any body fluid is typically quite short.

Beth Thielen:

And for this reason, PCRs can be helpful if they're positive, but

Beth Thielen:

are not necessarily sensitive enough to rule out disease.

Beth Thielen:

So our health department offers a PCR for West Nile virus, but not the

Beth Thielen:

other viruses in our differential.

Beth Thielen:

And so therefore, serological testing is the mainstay for diagnosis.

Beth Thielen:

Focusing in on those serologies, a single positive IgG is difficult to

Beth Thielen:

interpret given the relatively high risk of past undiagnosed exposure

Beth Thielen:

in our region, but a fourfold rise between an acute and a convalescent

Beth Thielen:

collected sample would be supportive.

Beth Thielen:

For this case where we're looking at acute testing, we're really looking for

Beth Thielen:

positive IgMs to indicate that acute infection, but they may be falsely

Beth Thielen:

positive in other inflammatory disorders or cross reactive against related viruses.

Beth Thielen:

And so, uh, typically a positive result in an IgM is followed up with a plaque

Beth Thielen:

reduction neutralization assay in which serial dilutions of patient serum or

Beth Thielen:

CSF are incubated with virus in vitro to determine the concentration of the virus

Beth Thielen:

at which antibodies are able to inactivate viruses such that they can no longer

Beth Thielen:

infect cells and replicate in culture.

Beth Thielen:

So in this case, higher titers would be indicate a more specific

Beth Thielen:

reaction against a particular virus and would support it being a true

Beth Thielen:

pathogen and not cross reactive.

Beth Thielen:

So such confirmatory plaque neutralization assays are really commonly used

Beth Thielen:

in arbovirology to distinguish between cross reactive viruses.

Beth Thielen:

So, examples would be the California serogroup bunyaviruses, which

Beth Thielen:

would include Jamestown Canyon virus and La Crosse virus, and then

Beth Thielen:

also the flaviviruses like West Nile, yellow fever, and dengue.

Sophie Samson:

So, for our patient, an initial screening arbovirus IgM

Sophie Samson:

IFA that tests for California group encephalitis viruses, EEEV, WEV, and SLEV

Sophie Samson:

was positive for the California group.

Sophie Samson:

Initial IgM EIA testing done at MDH on serum was positive for Jamestown

Sophie Samson:

Canyon virus, equivocal for Powassan and negative for West Nile virus.

Sophie Samson:

Serum PCR was negative for West Nile virus.

Sophie Samson:

CSF IgM EIA testing was positive for Jamestown Canyon virus and

Sophie Samson:

Powassan and negative for West Nile virus by both IgM and PCR.

Sophie Samson:

Urine PCR for West Nile virus was also negative.

Sophie Samson:

Confirmatory testing was sent to Arboviral Diseases Branch Diagnostic and Reference

Sophie Samson:

Laboratory in Fort Collins, Colorado.

Sophie Samson:

Serum testing revealed positive IgM for Jamestown Canyon Virus

Sophie Samson:

and La Crosse by IgM capture ELISA and negative for IgM for Powassan.

Sophie Samson:

La Crosse plaque reduction neutralization occurred at a greater than 1:4096 titer,

Sophie Samson:

but unfortunately there was not sufficient sample for Jamestown Canyon virus testing.

Sophie Samson:

Plaque duction, neutralization testing was also performed on CSF

Sophie Samson:

and was positive at a 1:128 titer against La Crosse, 1:4 for Jamestown

Sophie Samson:

Canyon and was negative for Powassan.

Sophie Samson:

Beth, can you discuss the interpretation of these results?

Sophie Samson:

Sure

Beth Thielen:

In this case, our initial testing was a little bit

Beth Thielen:

confusing because the results supported, uh, potential, potentially

Beth Thielen:

either or both, uh, California group encephalitis virus, of which Jamestown

Beth Thielen:

Canyon was one, uh, and Powassan.

Beth Thielen:

Uh, and there's, uh, since there was not a specific screening IgM for La

Beth Thielen:

Crosse, uh, we, we were not able to test for that and then specifically

Beth Thielen:

in the initial round of testing.

Beth Thielen:

And this is an example where the confirmatory plaque

Beth Thielen:

reduction neutralization assays were really critical.

Beth Thielen:

So the results came back with very high titers against La Crosse virus

Beth Thielen:

encephalitis pathogen with much lower titers against the Jamestown

Beth Thielen:

Canyon virus and a negative capture IgM against Powassan.

Beth Thielen:

So overall, these results were interpreted as being confirmatory

Beth Thielen:

of La Crosse virus infection being the primary pathogen in this case.

Sophie Samson:

And Beth, what do we know about the epidemiology

Sophie Samson:

of La Crosse encephalitis?

Beth Thielen:

Yeah, so this, uh, this pathogen was first described

Beth Thielen:

in the literature in 1965, uh, in a 4-year-old child from south southeastern

Beth Thielen:

Minnesota who sought care in La Crosse, Wisconsin, and ultimately died

Beth Thielen:

from an acute neurological illness.

Beth Thielen:

So that's the, hence the origin of the name.

Beth Thielen:

Um, so as, as Kristen mentioned, there's really a range of any, anywhere

Beth Thielen:

as low as 30 up to 90 or, or more, uh, cases per year of neuro invasive

Beth Thielen:

disease reported in the United States.

Beth Thielen:

Uh, and the vast, vast majority of those are among children.

Beth Thielen:

Um.

Beth Thielen:

The neurological disease is probably just the tip of the iceberg as there's

Beth Thielen:

substantial under-diagnosis and under-reporting of less severe cases.

Beth Thielen:

And so, so how do we know this?

Beth Thielen:

So there was a serological survey that was done, um, in, in a town in

Beth Thielen:

southeastern Minnesota called Winona, and they had sero positivity rates of

Beth Thielen:

up to 28% in some of the rural areas.

Beth Thielen:

So I think in places where there's the right geographic exposure in

Beth Thielen:

sort of a high risk population, like residents in a rural region, there's

Beth Thielen:

probably quite a lot of exposure on an infection that we're not - it's not,

Beth Thielen:

it's not coming to medical attention.

Beth Thielen:

Um, and so there's really a couple of pockets of this, of where this

Beth Thielen:

disease is predominantly diagnosed.

Beth Thielen:

So it's the upper Midwest, so Minnesota and Wisconsin are really high, high areas,

Beth Thielen:

and then also through, through Appalachia.

Beth Thielen:

So Ohio, Kentucky, West Virginia, North Carolina are big pockets of this disease.

Beth Thielen:

Um, it's really not clear why only a small fraction of the people who are

Beth Thielen:

exposed develop neuroinvasive disease.

Beth Thielen:

Um, And something that my lab is particularly interested in

Beth Thielen:

is, is host susceptibility.

Beth Thielen:

Um, and there's really been some interesting data that have come out

Beth Thielen:

in the last year, looking at, uh, the prevalence of auto antibodies against

Beth Thielen:

type one interferons in patients who develop neuroinvasive West Nile.

Beth Thielen:

And so I think there's more, more to come and more to learn about what,

Beth Thielen:

why it is that some people are more susceptible to these severe manifestations

Beth Thielen:

of viral pathogens than others.

Beth Thielen:

So Sophie, you had some time to interact with our health department.

Beth Thielen:

Uh, what can you tell us about what can be done to prevent lacrosse encephalitis?

Sophie Samson:

Yeah, so as the medical student on the team, I was able to

Sophie Samson:

speak with an epidemiologist on the Vector Borne Disease Unit at the

Sophie Samson:

Minnesota Department of Health and learn more about the follow up and

Sophie Samson:

prevention measures taken at this case.

Sophie Samson:

So early on, MDH involved the Metropolitan Mosquito Control District and the family

Sophie Samson:

allowed them to inspect their property.

Sophie Samson:

The initial evaluation involved removal of old tires and

Sophie Samson:

containers from the family's yard.

Sophie Samson:

The mosquito control district removed 8 tires, 4 of which had larvae, and

Sophie Samson:

32 containers, 20 of which had larvae.

Sophie Samson:

Aedes triseriatus was found in seven of the larval habitats.

Sophie Samson:

The family was educated on the importance of dumping standing water in toys and

Sophie Samson:

containers since they can serve as a breeding site for this mosquito.

Sophie Samson:

They filled one tree hole near the residence with soil, although mosquito

Sophie Samson:

larvae was absent upon further inspection.

Sophie Samson:

The Mosquito Control District also sampled adult mosquitoes and sprayed

Sophie Samson:

adulticides the following day.

Sophie Samson:

They attempted similar surveillance and control measures in the surrounding

Sophie Samson:

area and notified neighboring houses about lacrosse risk in the area.

Sophie Samson:

The neighborhood will have continued surveillance for

Sophie Samson:

several years to eliminate larvae that may carry lacrosse virus.

Sophie Samson:

MDH provided their unique perspective on the epidemiology of

Sophie Samson:

previous La Crosse cases they've been involved in and educated the

Sophie Samson:

family on mosquito bite prevention.

Sophie Samson:

Kristen, can you tell us more about standard mosquito precautions?

Kristen Bastug:

Absolutely, Sophie.

Kristen Bastug:

There are several approaches to reduce the risk of mosquito bites.

Kristen Bastug:

First, bug spray can be used on the skin whenever there's a risk for

Kristen Bastug:

exposure to mosquitoes or ticks, particularly during the months of

Kristen Bastug:

April through November in Minnesota.

Kristen Bastug:

There are many products available, but you want to make sure it's a

Kristen Bastug:

product registered by the Environmental Protection Agency, or the EPA.

Kristen Bastug:

The most common active ingredients include DEET, picaridin,

Kristen Bastug:

and oil of lemon eucalyptus.

Kristen Bastug:

The American Academy of Pediatrics recommends selecting a concentration

Kristen Bastug:

of DEET that matches your expected outdoor exposure time.

Kristen Bastug:

For example, 10 percent DEET provides protection for about 2

Kristen Bastug:

hours and 30 percent DEET provides protection for about 5 hours.

Kristen Bastug:

The maximum concentration you should buy is 50 percent because anything

Kristen Bastug:

beyond that does not actually provide longer protection, despite

Kristen Bastug:

a potentially higher price for something that says 100 percent DEET.

Kristen Bastug:

Picaridin is another active ingredient that can repel mosquitos and ticks.

Kristen Bastug:

Similar to DEET, the concentration correlates with duration of protection.

Kristen Bastug:

5 percent picaridin provides about 3 4 hours of protection, while 20 percent

Kristen Bastug:

can provide protection for 8-12 hours.

Kristen Bastug:

Oil of lemon eucalyptus is the other option I mentioned, but

Kristen Bastug:

it's important to know that this is not the same as lemon oil.

Kristen Bastug:

You should make sure that your OLE product is registered by the EPA and it should

Kristen Bastug:

not be used in children under 3 years old.

Kristen Bastug:

OLE of a concentration of 8-10 percent can protect for up to 2

Kristen Bastug:

hours and 30 percent concentration, up to 40 percent concentration

Kristen Bastug:

can protect for about 6 hours.

Kristen Bastug:

For all of these products, it's important to read the label and avoid applying them

Kristen Bastug:

directly to a child's hands because we all know that the hands are going to end

Kristen Bastug:

up in the mouth and the eyes and increase risk for ingestion or eye irritation.

Kristen Bastug:

When using insect repellent with sunscreen, the sunscreen

Kristen Bastug:

should be applied first.

Kristen Bastug:

Other than topical bug spray, you can also choose to wear long sleeve clothing and

Kristen Bastug:

pre treat the clothing with permethrin.

Kristen Bastug:

You could also choose to avoid areas with dense vegetation.

Kristen Bastug:

Finally, mosquito nets are a great option and you can pre treat

Kristen Bastug:

those with an insecticide as well.

Kristen Bastug:

So for our patient, it sounds like Sophie, you had some excellent communication with

Kristen Bastug:

the Department of Health and they worked with the family to talk about prevention.

Kristen Bastug:

What did you learn from talking to the family or from MDH about

Kristen Bastug:

how the child's doing now and what the future might look like?

Sophie Samson:

Well, when I was able to speak with the family, they updated

Sophie Samson:

me on her six week follow up after discharge and shared that at that time

Sophie Samson:

she was having headaches about every two weeks, but she has had no new seizures.

Sophie Samson:

She's doing well in school and remains social and active with

Sophie Samson:

some activity modification to follow seizure precautions,

Sophie Samson:

but overall is doing excellent.

Sophie Samson:

Repeat brain imaging, um, both MRI and EEG done at the follow up

Sophie Samson:

showed resolution of prior lesions.

Sophie Samson:

She's tapering off levetiracetam and will continue to follow up with neurology.

Sophie Samson:

The parents shared that while seeing their daughter so sick and having seizures was

Sophie Samson:

incredibly scary, they felt supported by all the teams involved in her care,

Sophie Samson:

and they're happy to see her back on track and doing the things she enjoys.

Sara Dong:

Thanks again to Sophie, Kristen, and Beth

Sara Dong:

for joining Febrile today.

Sara Dong:

Febrile is produced with support from the Infectious Diseases

Sara Dong:

Society of America, or IDSA.

Sara Dong:

Don't forget to check out the website, febrilepodcast.

Sara Dong:

com, where you can find the Consult Notes, which are written complements

Sara Dong:

of the show with links to references, our library of ID infographics,

Sara Dong:

and a link to our merch store.

Sara Dong:

Thanks for listening.

Sara Dong:

Stay safe and we'll see you next time.

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