Transcription:
Medical Mysteries: Diagnosing Infantile Botulism

Bill Klaproth: Solving problems and unraveling mysteries are part of everyday life in the healthcare field. But at a children's hospital where patients often can't tell their doctors what they think is wrong, the situations are intensified. At Le Bonheur Children's Hospital, Dr. Sandra Arnold, Division Chief of Pediatric Infectious Diseases not only helps solve rare and complicated issues seen in children, she also teaches the next generation of providers how to do the same.

This is The Peds Pod by Le Bonheur Children's Hospital. I'm Bill Klaproth. Thanks for being out with us, Dr. Arnold. We really appreciate this. So this is going to be very interesting. I believe you have a case prepared for us that demonstrates how you used clinical resources and parent information to discover a very rare problem in kids.

Dr. Sandra Arnold: Hi, Bill. Yes. Today, I thought we could walk through a case of a disease that's quite rare, but still we see it once or twice a year at Le Bonheur Children's Hospital. The key to making any diagnosis in this one in particular is recognizing what the source of the problem is that the baby's having. So for this particular case, we have permission from the family to tell the story of Luke Moore. His mom, Rachel, is a nurse here and had to turn to Le Bonheur when her healthy baby boy began to deteriorate.

Bill Klaproth: That has got to be intense when that happens. So thank you for sharing with us how these kinds of medical mysteries are unraveled. So let's start at the beginning. What were the first signs that something might be wrong with Luke?

Dr. Sandra Arnold: Luke's parents brought him in for dehydration and he was found to have low blood sugar. What they told us was that he had been eating and drinking less and less over the preceding four days. And his mother said he had only taken in about five ounces in the last two days. She described him though as being hungry and wanting to eat. But then when he tried, he would gurgle and get congested and cry and sometimes spit up. But he'd never had a problem like this before.

She thought maybe that he had an infection because he'd been exposed to someone with hand-foot-and-mouth disease about two weeks before. And then two days before admission, he was seen by his pediatrician and given amoxicillin for an ear infection. When he didn't get better, they took him to the pediatrician again, that was the day before they came to the hospital. At that time, they got him to swallow some liquid from a syringe in the office, so he was sent home. But his mother said after that, he didn't do well at all, even from the syringe. So they continue to worry about him.

Bill Klaproth: So what happened when the family got to Le Bonheur for further examination?

Dr. Sandra Arnold: So the description from the emergency room is that his physical exam appeared pretty normal. He didn't have any fever. And the main concern was that he was having trouble swallowing, possibly due to pain in his throat. His throat appeared normal on exam, but there was concern that maybe the part of the throat that you can't see when you just look inside a child's mouth, that the problem could be there. So he had some x-rays done of his neck where they thought they might see some swelling or a foreign body, something that he might have put in his mouth that could be stuck there and preventing him from swallowing or an infection, like I said, that could be causing swelling in the throat or neck.

They did some blood tests and these were all normal, except that he had some indications on these tests that he was dehydrated and had a low blood sugar, which goes along with that. He was seen by an ENT specialist in the emergency department and they couldn't find anything wrong, although they didn't look all the way down at that point. They did that a bit later. And so they admitted him for management of his dehydration and low blood sugar, but it really wasn't clear what was wrong with him when he first was admitted to the hospital.

Bill Klaproth: So then what were the other signs showing that this wasn't something as simple as a case of dehydration?

Dr. Sandra Arnold: So dehydration is usually caused by having an illness where you vomit and have diarrhea. In this case, it was really because he wouldn't eat and drink. He wasn't having a gastrointestinal illness. He continued to have trouble swallowing. But again, like I said, there wasn't anything obvious when you looked in his throat that would explain why he wasn't swallowing.

The ENT doctor actually came by the next day when he was in the hospital and looked down with a small flexible fiberoptic laryngoscope, and they couldn't see anything wrong with the throat area below where you could see just with a regular light. And so they said they didn't know what was wrong with him. So it wasn't the obvious things that there was hand-foot-and-mouth disease with some sores in the back of his throat or strep throat or something like that.

That same day, the hospitalist who was caring for him, Dr. Cross, noticed that his muscle tone wasn't quite right. So muscle tone is the amount of tension in your muscles at rest. And you would test this by bending and straightening the limbs to see how much resistance to movement there is. And you can tell whether it's increased or decreased and that's something you just learn over time by checking that on lots of people at different ages.

There was also a concern that he was acting lethargic. And what lethargic means is that he was sleepier than normal. He didn't seem to wake up and open his eyes and be active and alert. So she started to have concerned about a possible neurologic problem. But then later that day, he seemed to be better. He was sitting up and playing when she went in and he was holding his head up and everything looked great.

But according to his mom, this was actually short-lived. And by the next day, he really wasn't any better and was probably worse. He wasn't able to sit up for very long, really only for a minute at a time or so. And he was still not eating. And she noticed that he wasn't sucking on his pacifier or on a bottle at all. She noticed he wasn't smiling. And also that it looked like his eyelids were starting to droop.

The other thing that was noted was that he hadn't had a bowel movement in two days, which is unusual. Babies tend to have bowel movements multiple times a day, rather than just once a day like an adult. And for him, not going for two days was quite unusual. So it was at that point that the doctors decided to ask neurology and infectious diseases to get involved in the case.

Bill Klaproth: So after learning all of this and going through your examination, where was your mind at at this point? What was your thought process behind figuring this out?

Dr. Sandra Arnold: So you have to go back to the very beginning and take the whole story. You need to think about what is the source of the problem? So he was admitted because he couldn't drink enough to keep himself from getting dehydrated and needed IV fluids, that's what landed him in the hospital. But the dehydration was just another symptom of the problem.

Like I said before, dehydration occurs usually because you have a gastrointestinal illness where you can't keep anything down. You also lose extra fluid by vomiting or you have diarrhea and you can get dehydrated pretty quickly that way. In this case, he didn't have any of the symptoms. So it was felt that his trouble swallowing was probably due to pain. Because when you think about what is common, viral infections, throat infections are actually very common like gastrointestinal illnesses.

But usually, there's some indicator that something like that is going on. You look at the throat and the throat is red. Or there are sores, like if he had hand-foot-and-mouth disease, because he was exposed to somebody with that illness. It's just a virus that causes painful ulcers in the throat, which if it's really bad, can lead to dehydration because the child does not want to swallow anything. It's like having a really, really bad strep throat if you remember from when you were a child. It's really unpleasant to swallow and it can certainly lead to dehydration.

The other concern was that he had just started crawling, which meant he could get around. And even though parents try to make sure there aren't things that their child can put in their mouth and swallow or choke on on the floor, of course, we're all imperfect and it's certainly possible he could have been crawling around and put something in his mouth and got it lodged in his throat and so he wasn't swallowing because that was a problem. But once the ENT doctor looked down there and said everything looked fine, we knew for sure it wasn't any of these problems.

By the second day in the hospital, it was becoming more clear that the problem wasn't just with swallowing. So swallowing is a motor activity. It requires strong muscles to do this. And there were other indications now that there was something wrong with how his muscles were working. So he was felt to be hypotonic, like I said, having low muscle tone or low resting muscle tension.

And it looked like he was getting weak because he couldn't sit up for very long. He wasn't sucking on his pacifier. Sucking and swallowing are motor activities. He wasn't even swallowing his own saliva very well. He was drooling much more than usual, and then his eyelids began to droop. This progression that was observed while he was in the hospital led the doctors to think that he had a neurologic problem.

So then you have to think about, well, what will cause weakness and low muscle tone in an infant? And the first thing that will come to anybody's mind who's trained in pediatrics is that maybe this child has an infection. And I'm not talking about an infection of the nervous system necessarily. Any serious infection can make an infant this age become sort of droopy and listless and have low muscle tone. It's something that we see all the time, such as with a urinary tract infection. That has nothing to do with the brain or the spinal cord, but those babies can often present very listless and their muscle tone can be low. And then you treat them and everything gets better. You could also have an infection in the nervous system such as meningitis or encephalitis that could cause this.

But like I said, it really could be any serious infections. So not just a cold, but something a little more invasive. And so when a baby presents like this, because infections are so common, we will usually do all the tests looking for major infections in the body. So you would take blood and urine and often spinal fluid, send that to the lab for them to look at it, and to do cultures to try to grow bacteria and then start antibiotics.

He also had blood tests that looked for indirect indicators of infection, like a high white blood cell count or a high level of something called C-reactive protein, so these are markers of inflammation in the blood. These were all normal. He also hadn't had fever. When they sent his urine to the lab, it didn't have any white blood cells in it, which would be an indicator of infection. And they also did a spinal fluid test and that did not have any white blood cells in it either.

And so it really didn't seem like he had infection cause he was completely lacking in any of the signs or symptoms of inflammation in his blood, urine, spinal fluid. So then we started thinking, "Well, maybe it's a nervous system disease." And the nervous system has two parts, the central nervous system, which is the brain and spinal cord, and then the peripheral nervous system, which is nerves and muscles.

And it can be really difficult in a baby this age to distinguish lethargy, meaning sleepiness, altered level of consciousness, from weakness of the muscles because of that eyelid drooping. So if your muscles are weak and you can't hold your eyelids open, it looks like you're sleeping. And so was he lethargic, basically sleeping all the time? Or was it that he was awake, but he just couldn't keep his eyes open because his eyelid muscles were weak?

Babies can't talk and tell us what's going on. So you have to look at them. You have to really go back and take a detailed history and figure out "Am I dealing with muscle weakness or am I dealing with a problem with the brain and level of consciousness like you might see with meningitis or with some sort of brain disorder, like a stroke or something like that, which babies can have, but are very rare?"

But because of the way the story went, that it started with him being okay, but really having muscle weakness as the first thing that happened and then mother stating that his eyelids looked like they were drooping really led everybody to think that this was most likely a disorder of nerves and muscles rather than a disorder of the brain where he was sleepy or unconscious leading to his eyelids being closed. And so when you start thinking about that and then the acute illness that would cause this progression of weakness over a few days, everybody suddenly knew what was going on and that that was the most likely to be infant botulism.

Bill Klaproth: So following a very thorough examination and process of elimination, it comes down to infantile botulism. Wow. All right. So can you explain to us what is that?

Dr. Sandra Arnold: So botulism is a disease that's caused by a neurotoxin called botulinum toxin. And this toxin is produced by a bacteria that's found in our environment all over the world. It's called Clostridium botulinum. It lives in the soil and dust. We're all exposed to it, but it generally doesn't make us sick.

The ways that it makes people sick is that it can cause something called botulism without the word infant in front of it, just ordinary botulism. It's usually a foodborne disease. It's pretty rare. But what happens is that the spores that are in the environment can get into food and then, under the right conditions, start multiplying and producing this toxin. And then when you eat the food, you ingest the toxin. So the bacteria doesn't make you sick, it's the toxin.

And like I said, it's really considered the most powerful neurotoxin in the world. And so it causes progressive paralysis and death if you don't get appropriate medical care. It usually affects foods that have all the air taken out of them because the bacteria likes to live in a place where there isn't a lot of oxygen. And so the classic cases, things that have been canned or jarred at home, home canning of foods where all the air is sucked out of the jar in order to preserve it for long periods of time. But it can also occur from other kinds of foods. There are outbreaks occasionally in this country, but it's pretty rare.

Wounds can be contaminated with soil and dust, and you can get botulism if this bacteria infects an open wound and then divides and multiplies and starts producing the toxin, which can then diffuse out from the wound and cause the person to become paralyzed. Again, a pretty rare thing.

But infant botulism is actually a little more common than either of these other kinds of botulism, but it's quite different. In this case, the spores are ingested and they get into the infant's colon and then they multiply and divide there and produce toxin that then eventually leads to the weakness and paralysis in the infant.

And this is unique to very young children. There seems to be something about the infant bowel that allows this bacteria to colonize there, to sort of set up shop and live there for a little while. This does not happen in older children or adults at all. So even though we probably all are exposed to this bacteria in the dirt and the dust, it doesn't get into the colon of an adult or even an older child and do this. This is distinctly an infantile disease.

It has not really been found to be associated with any particular kinds of food, except for honey. So there are cases where honey was the source of the botulism. And so that's why infants are recommended not to ingest honey at all. Otherwise, there have been some cases associated with powdered infant formula. But in fact, when people have done studies looking for associations, what might be the cause of infant botulism, breastfeeding was actually a higher risk factor than powdered infant formula. Nobody really knows why that is. It's not probably because they're more likely to ingest it, but there might be something about the way the breast milk interacts with the bacteria that normally live in the bowel that make the bowel of a breastfed infant more able to be colonized by this bacteria, but nobody really knows for sure.

In most infants, they haven't ingested honey, we really have no exact source for the baby acquiring this bacteria and we figured that it's probably most of them just swallowing dust and dirt that's in the air that might have these spores for this bacteria attached to it. But there's never any way to really prove that. Apparently, there was some construction going on near Luke's home. And when we see that or hear that, we go, "Aha. It must be the construction because that makes lots of dust." But there's really no way for us to ever prove that he hadn't eaten any honey. So it's really an unknown. It probably was just something he got from the environment.

Bill Klaproth: So you mentioned that this is rare. I'm curious, how rare is it? And I imagine something like this is difficult to diagnose, because many of the symptoms are common to other conditions and illnesses. Is that right?

Dr. Sandra Arnold: Absolutely. It's rarely the first thing that somebody thinks of when they see a child presenting with this kind of weakness. It's pretty rare, like I said. We see one or two cases a year here Le Bonheur Children's Hospital. Even though it's the most common form of botulism in the US, there are really only about 70 cases a year reported. So when you think about that, that's a pretty rare disease.

The most common diagnosis that infants who are ultimately diagnosed with botulism are given when they're admitted to the hospital is a serious infection, like I said, because common things are common. And little babies get infections pretty frequently. It's the most common reason that they're ever admitted to the hospital. And so we worry about things like bloodstream infection, meningitis, urinary tract infection. So usually what happens is they come in, they get all the tests done that Luke had, and are given antibiotics. But of course. It doesn't make them better.

There may be other neurologic diseases that could be mistaken for infant botulism. And these are things that people may or may not have heard of, spinal muscular atrophy, mitochondrial diseases, myasthenia gravis, myotonic dystrophy, and a host of other even more rare neuromuscular diseases. But botulism is something that presents very quickly, and these are things that would be more chronic and present more slowly with the weakness not being as obvious early on. And so the fact that this weakness presented and got so much worse over the course of a few days is really what triggered us to think that it was most likely botulism.

Untreated infant botulism will continue to progress and eventually lead to paralysis. And so most infants who have this disease will be admitted to an ICU and have to be placed on a ventilator to help them breathe until they recover. They do recover. They eventually regain their strength, but they're usually in the ICU for several weeks. It's a very protracted illness as the bacteria start to die off. They don't stay there forever and ever, and then there's no more toxin around, but the toxin binds to these receptors at the end of the nerves where nerves bind to muscle. And the toxin can stay there for a long time. It doesn't just bind for a short time and be released. And so it can take quite a while for them to get better, although they eventually do with modern medical care. We are lucky that we have ICUs that can keep babies alive while they go through this paralysis.

However, we do have a treatment. And all of this can be prevented or at least the most severe parts of it can be prevented or the amount of time spent in the ICU can be shortened when we do give treatment for this disease.

Bill Klaproth: All right. So you said 70 cases a year, that is rare. And you just mentioned treatment for this disease. So how do you treat infantile botulism?

Dr. Sandra Arnold: So the treatment has a great name. It's called BabyBIG, which stands for baby botulism immune globulin. And what that is is a product that was developed by the California Department of Health. It's a product of antibodies against the botulinum toxin. They will bind to the toxin and keep it from binding to that receptor at the junction of the nerve and the muscle, what we call the neuromuscular junction.

So how they do this is that they take healthy adult volunteers and they immunize them with inactivated botulinum toxin. So we do that with all kinds of other immunizations, like for diphtheria and tetanus. So in this case, they get volunteers to take this vaccine and then that stimulates their immune systems to produce large amounts of antibodies against the toxin. And then they donate their plasma and they have ways of selecting out the antibodies that are specifically for botulinum toxin. And then they basically pool those all together and they make a product which is very, very enriched for antibodies against the botulinum toxin.

So if we suspect that a baby has infant botulism, we have to call the California Department of Health and they basically overnight ship the dose to us. We usually get it within several hours. And it works really well if it's given within a short period of time. The longer you wait to give it, the less effective it's going to be, because the more toxin there will be already bound to the muscle, preventing the transmission of the nerve signals to the muscle.

We can confirm the diagnosis of infant botulism by identifying the toxin in the stool of an affected infant. But we can't do that at a hospital like Le Bonheur. These tests have to be sent out. The state health department does them. So you have to send the baby's stool to the state health department. They have to receive it, run the tests, get back to us. And that can take up to a week or so. We do not want to wait for confirmation of the diagnosis because after a week that baby will be on a ventilator in the ICU and our opportunity to shorten the duration of illness has not necessarily passed, but we're not going to have as good effect from the treatment.

So we have to basically confirm the diagnosis clinically. The California Department of Health, they have doctors there. Because they do so much of this, they'll run through the case with you and say, "Yes, we think that that's what it is and we're going to send you the product." So you get sort of outside confirmation that somebody agrees with you that this is in fact infant botulism.

And then they send the drug and we give it and hopefully we've given it soon enough that the baby doesn't end up in the ICU or, even if they're in the ICU, they're just there for a relatively short period of time. And that's what happened with Luke. He got the treatment right away and he did really, really well. And he's perfectly fine now.

Bill Klaproth: So I'm very glad that Luke is going to be okay. When you first started this story, I was getting a little bit concerned. But it's good that there is a happy ending. So through all of this, what is the lesson to be learned from a case like this?

Dr. Sandra Arnold: Most important lesson is to continue to think about your patients, especially if the situation is evolving. In Luke's case, he continued to have the same problem and it continued to worsen and the new problems were added onto it.

The other issue is that you also want to continue to think about things and come up with other diagnoses that a patient could have when all the findings don't fit with the initial diagnosis. So in this case, the thought was initially that he was having problems swallowing because of a localized problem in his throat. But as time went on, it became quite clear that was not the issue. And you have to sort of pull yourself out of that.

Sometimes it's really easy to get locked into a diagnosis. And amazingly the brain can make you sort of ignore other things that don't fit with that diagnosis. And you have to be really aware that that's going on when you're going through a problem like this, so that you don't get locked in there. These are certain biases that our brain has. "If you can't swallow your, throat less hurt" and then everything that doesn't fit with "your throat hurts" kind of gets ignored. But in this case, if you can force yourself to see the new issues that are coming up and say, "Okay, I've ruled out the problem of the throat," then you can see the other issues and make the diagnosis. Sometimes you can't make the diagnosis right away, but you have to keep your mind open so that you're seeing the symptoms as they evolve. And then you can see what's actually going on.

I think what happened with Luke was that even though at the beginning, everybody was pointed in this one direction towards his throat, a primary problem with his throat being the issue, the doctors were able to see past that the next day and see that there had been a progression of symptoms. It also helped that his mother was a nurse, I think, and was able to express what she was seeing very well with what was going on with Luke. But I think also the doctors kept their minds really open and realized that this was a more generalized problem and not just a problem of swallowing. And so we were able to get treatment for Luke very quickly and help him recover from this much more quickly than we would have had it taken longer to come to the diagnosis.

The other issue is trying to figure out what part of the nervous system is involved. And as I said earlier, in these cases, it can be very difficult to distinguish a problem in the brain leading to altered level of consciousness from a problem in the muscles. But again, a careful history and physical exam and ongoing observation can usually help to sort that out.

Bill Klaproth: Well, it seems to make sense that having an open mind would help you ultimately find the correct diagnosis and also having the experience to know what to look for. So thank you so much for walking us through this, Dr. Arnold. I think this really illustrates the importance of places like Le Bonheur, which may have some of the only physicians to have seen these kinds of cases, like the story you just told us about Luke when many others couldn't. So that's that experience that I'm talking about, the experience of the Le Bonheur physicians. What a great story. Thank you so much for sharing it with us. This has really been informative, Dr. Arnold. Thank you so much.  

Dr. Sandra Arnold: Thanks so much.

Bill Klaproth: That's Dr. Sandra Arnold. And to learn more, please visit LeBonheur.org/podcast. And be sure to subscribe to The Peds Pod on Apple podcasts, Google podcasts, or wherever you listen to your podcasts. You can also check out LeBonheur.org/podcast to view our full podcast library. And if you found this podcast helpful, please share it on your social channels. This is The Peds Pod by Le Bonheur Children's Hospital. Thanks for listening.