92: Searching for Peace of Mind

So I, of course, would love to just add a plug that I would always love to hear from you, especially if you want to join an episode of Febrile. Febrile really likes to highlight trainees and junior faculty in particular. So if you would like to come on as a representative for your fellowship program, or as an individual, I would love to welcome you to the show for an episode, just let me know. All right. So today we have a great multi level learner team from the University of Minnesota.

Let's meet them. First up, we have Sophie Samson. Sophie is currently a third year medical student at the University of Minnesota Medical School. She plans to train in pediatrics and has a particular interest in pediatric ID and neurology.

In addition to that, she has clinical interest in the care of immunocompromised patients, travel and tropical medicine, and clinical immunology.

Um, I thought it was a lot of fun.

And I play in an accordion group, and we had an opportunity for our group to travel together to eastern Italy to a small town called Castelfidardo, which is home of both the Guinness Book of World Records world largest accordion, which I was able to play, um, and we were able to tour an accordion factory, which is a kind of ground zero for the manufacturer of accordions. And so, uh, that is, that is the, my, my piece of culture for today.

Her eyes were open, but not focused, and she developed left sided, circular arm movements with associated urinary incontinence and tongue biting. She was not interactive, and the episode lasted about one hour, terminating with benzodiazepine given by EMS. In the ED, she had a low grade fever to 104 degrees Fahrenheit, and initial workup showed mild leukocytosis, elevated absolute neutrophil count, normal CMP except for elevated phosphorus, and inflammatory markers within normal limits.

Infectious workup included a group A strep PCR, and a respiratory viral panel, which were both negative. Kristen, if you got a call based on this information, what are you thinking about at this point in terms of differential diagnosis, and what are you thinking about doing for management?

Her low grade fever and leukocytosis in the context of a seizure could be due to the seizure itself. However, I also want to consider infectious etiologies that could have triggered the seizure. At 7 years old, she is older than I would expect for someone having a febrile seizure, so I would like to obtain some additional diagnostic studies to help us investigate the etiology.

I would recommend a lumbar puncture so that we can obtain the cerebrospinal fluid studies in order to evaluate further for an infectious cause. I would send meningitis and encephalitis PCR panel in addition to the standard cell count, glucose, protein, and aerobic culture on the CSF fluid. The meningitis encephalitis panel doesn't test for all pathogens, but it can test for several pathogens that are on my differential. These would include Streptococcus pneumoniae and Herpes Simplex Virus.

Listeria and E. coli are less common at her age of seven, but are still possible. I would also consider Staphylococcus aureus, and if she is unvaccinated, then Haemophilus influenzae would be a higher possibility. Enterovirus is another one that comes to my mind, particularly in the summertime.

And specifically I wanted to bring up a, uh, a, that the topic of CT and, and lumbar puncture was recently discussed in the Choosing Wisely campaign, uh, as something that we do for no reason. And, uh, importantly I think they make this dis-, we make this distinction between patients at high risk and at low risk for abnormal imaging. And both the IDSA and ESCMID guidelines for bacterial meningitis do include new seizures as a high risk feature.

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

If her symptoms have resolved and she is stable, then I think it's reasonable to first obtain the lumbar puncture promptly and then start the empiric antibiotic therapy with, um, I would choose ceftriaxone and vancomycin for her. Given that the meningitis encephalitis panel will result fairly quickly, typically within a few hours, if her clinical status is stable, then I would not start empiric acyclovir at this time for her.

Finally, when considering the differential diagnosis for a seizure, we should also be thinking about alternative causes in case the patient doesn't respond to treatment as we expect. A focal seizure could be caused by a focal brain lesion, such as a brain tumor, which is another reason I favor pursuing head imaging as part of the initial workup.

Other possibilities that are less likely at this time include autoimmune etiologies, such as acute disseminated encephalomyelitis, toxic substance ingestion, or a traumatic injury.

After the initial LP was performed, she was started on ceftriaxone, 100 mg per kg per day, divided every 12 hours. She had a clinical seizure captured on EEG lasting 90 seconds, and she was subsequently started on levetiracetam. She then spiked two discrete high fevers up to 104. 2 degrees Fahrenheit, prompting a formal pediatric infectious disease consultation. Cultures are negative to date after 48 hours in the hospital.

Kristen, as the ID fellow on the team with this new information, how does this change your differential?

The aerobic CSF cultures have been negative for 48 hours at this point without any antibiotic pretreatment, which further supports that a bacterial cause such as Staph aureus, Strep pneumoniae, or meningococcus are unlikely. The negative meningitis encephalitis panel offers some reassurance that this patient does not have HSV or enterovirus, though the sensitivity of the ME panel is not as high as other testing modalities, such as an HSV 1 or HSV 2 specific PCR.

I would be interested to hear my attending's perspective on when we should consider ordering those additional specific PCR tests in addition to the ME panel. Finally, I note that her fever curve is uptrending to 104, though given that we have good evidence that this is not a bacterial process, I would not add any new antibiotics at this time. We also have good evidence this is not HSV, and so I would not add acyclovir either.

What I would make sure to do is to follow her neurologic exam closely, and if she develops any new symptoms, such as areflexia or paralysis, then I would want rapid imaging of her spinal cord and a neurology consult in order to evaluate for inflammatory or demyelinating diseases, such as transverse myelitis. She should be monitored closely if those processes are suspected because respiratory status can rapidly decompensate in that setting.

Um, but I also want to spend a couple minutes just talking about the performance characteristics of the testing thus far. And so I'm a little bit less reassured that we've adequately ruled out HSV when the clinical picture and in this case, new onset focal seizures would potentially be clinically compatible. And so it's well described that HSV PCR can be falsely negative, particularly early in the disease course.

Um, and I think there's also, there's also been several systematic reviews now with increasing number of patients that have showed lower sensitivity of the multiplex panels for HSV. So I'm really thinking about wanting to repeat the LP, both for more specific testing for things like HSV, but also to see how the CSF parameters have evolved over time.

And I think this would also have the benefit of allowing us to get additional specimen volume to send for that second tier testing, and oftentimes we're limited in terms of CSF volume for the things that we we want to test for. And so we have to be a little bit strategic sometimes about prioritizing our testing and making sure that we have enough sample to get those high priority tests.

Um, in terms of specific microbes, and I'm thinking about, so I think things like arboviruses, LCMV, and Lyme disease or some of the pathogens that aren't included on those multiplex panels. Um, certainly respiratory viruses like flu are associated sometimes with neurological symptoms. Like in her case, we have a negative respiratory panel on admission, so those seem less likely.

Um, I think I also want to ask about TB risk factors, and so that's one of the other, uh, you know, disease processes that wouldn't come up on routine testing and could present with seizures and, and a meningitis type picture.

Um, so some of the infectious processes that I'm thinking about, maybe we may need serology to diagnose them and IVIG would impact, um, our ability to make those diagnoses. Um, furthermore, when an untreated infection is in the differential, I prefer to hold off on steroids. There's definitely some infections where steroids may make things look better for a while before they get worse due to the impairment to the immune control.

And so I think if there's not a compelling reason why urgent treatment is needed, I would, really focus our efforts on making the diagnosis before we embark on a treatment.

And one of the dogs had ticks earlier in the spring, but no ticks were found on family members. She did not have any rodent or bat exposures. Her family camped along a river five days before symptom onset. The patient's mom recalls that there was a transient red bump on her torso present at the time of her initial seizure, but has since resolved. She has not traveled outside of Minnesota, notably. How does this additional information influence the differential diagnosis and management?

There are many diseases in this category, so I'm glad that we have obtained her travel history to help narrow the list down a little bit. It sounds like she and her family have only been in in Minnesota, so I would start building my differential with this location in mind. Given that we already suspect a viral process based on her CSF results, I'm suspicious of an arboviral infection. West Nile virus, Western Equine Encephalitis, and La Crosse encephalitis are considered endemic to Minnesota.

More recently, Jamestown Canyon virus is also emerging as a cause of disease in our state. Of these possibilities, La Crosse encephalitis more often affects children compared to adults. In fact, the most common arboviral cause of central nervous system infection in children in the United States is La Crosse virus. There are about 80 to 100 cases reported annually in the U. S., and 90 percent of those occur in children.

This is in contrast to West Nile virus, which shows a peak incidence in adults over 60 years old. Jamestown Canyon epidemiology also indicates a lower percent of children with these cases, at about 7%. These viruses are all spread from animal reservoirs to humans through mosquitoes. However, we do have other important vector borne diseases in Minnesota. With the outdoor exposure, I think it's worth considering if there are other etiologies we could be missing.

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

Knowing a patient is in a general location where they may have been exposed to a specific tick or mosquito is more helpful to keep in mind.

The Minnesota Department of Health requested blood, serum, and CSF samples for IgM antibody and RNA detection. They had listed some specific tests, such as an IgM for West Nile virus, Powassan virus, Jamestown Canyon, Western and Eastern Equine Encephalitis, California Group Encephalitis, and St. Louis encephalitis, which was ordered. Urine, blood, and urine RT PCR for West Nile virus was also ordered.

Given this large panel of viruses, I'm bracing myself for the potential of some cross reactivity and I'll need to discuss these results carefully with my attending in order to interpret them. In the event that we had used our in house laboratory for testing, I think it's important for everyone to note that arbovirus disease is reportable, at least in Minnesota, to our state health department. And it has to be reported within one working day.

Focusing in on those serologies, a single positive IgG is difficult to interpret given the relatively high risk of past undiagnosed exposure in our region, but a fourfold rise between an acute and a convalescent collected sample would be supportive. For this case where we're looking at acute testing, we're really looking for positive IgMs to indicate that acute infection, but they may be falsely positive in other inflammatory disorders or cross reactive against related viruses.

And so, uh, typically a positive result in an IgM is followed up with a plaque reduction neutralization assay in which serial dilutions of patient serum or CSF are incubated with virus in vitro to determine the concentration of the virus at which antibodies are able to inactivate viruses such that they can no longer infect cells and replicate in culture.

So in this case, higher titers would be indicate a more specific reaction against a particular virus and would support it being a true pathogen and not cross reactive. So such confirmatory plaque neutralization assays are really commonly used in arbovirology to distinguish between cross reactive viruses.

So, examples would be the California serogroup bunyaviruses, which would include Jamestown Canyon virus and La Crosse virus, and then also the flaviviruses like West Nile, yellow fever, and dengue.

Urine PCR for West Nile virus was also negative. Confirmatory testing was sent to Arboviral Diseases Branch Diagnostic and Reference Laboratory in Fort Collins, Colorado. Serum testing revealed positive IgM for Jamestown Canyon Virus and La Crosse by IgM capture ELISA and negative for IgM for Powassan. La Crosse plaque reduction neutralization occurred at a greater than 1:4096 titer, but unfortunately there was not sufficient sample for Jamestown Canyon virus testing.

Plaque duction, neutralization testing was also performed on CSF and was positive at a 1:128 titer against La Crosse, 1:4 for Jamestown Canyon and was negative for Powassan. Beth, can you discuss the interpretation of these results? Sure

And this is an example where the confirmatory plaque reduction neutralization assays were really critical. So the results came back with very high titers against La Crosse virus encephalitis pathogen with much lower titers against the Jamestown Canyon virus and a negative capture IgM against Powassan. So overall, these results were interpreted as being confirmatory of La Crosse virus infection being the primary pathogen in this case.

Uh, and the vast, vast majority of those are among children. Um. The neurological disease is probably just the tip of the iceberg as there's substantial under-diagnosis and under-reporting of less severe cases. And so, so how do we know this? So there was a serological survey that was done, um, in, in a town in southeastern Minnesota called Winona, and they had sero positivity rates of up to 28% in some of the rural areas.

So I think in places where there's the right geographic exposure in sort of a high risk population, like residents in a rural region, there's probably quite a lot of exposure on an infection that we're not - it's not, it's not coming to medical attention. Um, and so there's really a couple of pockets of this, of where this disease is predominantly diagnosed. So it's the upper Midwest, so Minnesota and Wisconsin are really high, high areas, and then also through, through Appalachia.

So Ohio, Kentucky, West Virginia, North Carolina are big pockets of this disease. Um, it's really not clear why only a small fraction of the people who are exposed develop neuroinvasive disease. Um, And something that my lab is particularly interested in is, is host susceptibility. Um, and there's really been some interesting data that have come out in the last year, looking at, uh, the prevalence of auto antibodies against type one interferons in patients who develop neuroinvasive West Nile.

And so I think there's more, more to come and more to learn about what, why it is that some people are more susceptible to these severe manifestations of viral pathogens than others. So Sophie, you had some time to interact with our health department. Uh, what can you tell us about what can be done to prevent lacrosse encephalitis?

The mosquito control district removed 8 tires, 4 of which had larvae, and 32 containers, 20 of which had larvae. Aedes triseriatus was found in seven of the larval habitats. The family was educated on the importance of dumping standing water in toys and containers since they can serve as a breeding site for this mosquito. They filled one tree hole near the residence with soil, although mosquito larvae was absent upon further inspection.

The Mosquito Control District also sampled adult mosquitoes and sprayed adulticides the following day. They attempted similar surveillance and control measures in the surrounding area and notified neighboring houses about lacrosse risk in the area. The neighborhood will have continued surveillance for several years to eliminate larvae that may carry lacrosse virus.

MDH provided their unique perspective on the epidemiology of previous La Crosse cases they've been involved in and educated the family on mosquito bite prevention. Kristen, can you tell us more about standard mosquito precautions?

The American Academy of Pediatrics recommends selecting a concentration of DEET that matches your expected outdoor exposure time. For example, 10 percent DEET provides protection for about 2 hours and 30 percent DEET provides protection for about 5 hours. The maximum concentration you should buy is 50 percent because anything beyond that does not actually provide longer protection, despite a potentially higher price for something that says 100 percent DEET.

Picaridin is another active ingredient that can repel mosquitos and ticks. Similar to DEET, the concentration correlates with duration of protection. 5 percent picaridin provides about 3 4 hours of protection, while 20 percent can provide protection for 8-12 hours. Oil of lemon eucalyptus is the other option I mentioned, but it's important to know that this is not the same as lemon oil.

You should make sure that your OLE product is registered by the EPA and it should not be used in children under 3 years old. OLE of a concentration of 8-10 percent can protect for up to 2 hours and 30 percent concentration, up to 40 percent concentration can protect for about 6 hours.

For all of these products, it's important to read the label and avoid applying them directly to a child's hands because we all know that the hands are going to end up in the mouth and the eyes and increase risk for ingestion or eye irritation. When using insect repellent with sunscreen, the sunscreen should be applied first. Other than topical bug spray, you can also choose to wear long sleeve clothing and pre treat the clothing with permethrin.

You could also choose to avoid areas with dense vegetation. Finally, mosquito nets are a great option and you can pre treat those with an insecticide as well. So for our patient, it sounds like Sophie, you had some excellent communication with the Department of Health and they worked with the family to talk about prevention. What did you learn from talking to the family or from MDH about how the child's doing now and what the future might look like?

She's tapering off levetiracetam and will continue to follow up with neurology. The parents shared that while seeing their daughter so sick and having seizures was incredibly scary, they felt supported by all the teams involved in her care, and they're happy to see her back on track and doing the things she enjoys.