Prepare for the Worst, Hope for the Best

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This story is from the Anamnesis episode called Mysteries at 3:44 in the podcast. It’s from pediatric neurologist Jeffrey Russ, MD, PhD, of Duke Children’s Health Center Neurology Clinic in Durham, North Carolina.

The family originally had noticed that their otherwise totally healthy, full-term baby had started to not act like herself. Some of the things that they noticed early on were that she just was much more irritable than normal, and that’s always hard because babies are irritable sometimes and it’s hard to know what’s different from normal.

But their instinct was that something was different from her normal self. She was vomiting more, which was unusual for her, and that she started to have some unusual eye movements. I think that was really the thing that first stood out. They described episodes where her eyes would get stuck sort of downward, and we call that sundowning in some circumstances. But it sounded like she was having these episodes of just her eyes being stuck in a downward position.

I think there were enough immediate red flags that most neurologists would probably hear that story, share the parents’ concern, and have them go to the hospital for more of an inpatient workup. Inpatient we can be more dedicated, expedited, and just sort of get a bigger workup done faster.

Something’s Not Quite Right

She had an EEG [electroencephalogram] that was pretty normal, which was a little bit surprising, and told us maybe this isn’t seizures that we’re dealing with. She had gotten a very brief MRI that basically just wasn’t quite as in-depth as some of the MRIs we normally get, more like a screening MRI, and that looked normal. At that point, I think everybody was sort of thinking something is going on with Stevie, something is not quite right.

There were three of us who were involved in the case: Dr. Carolyn Pizoli, who was their outpatient neurologist, but she also is our director of Neurocritical Care and does a lot of our inpatient neurology as well; myself; and then Dr. Kayli Maney, who is one of our senior residents at this point who also happened to be inpatient at the time this patient came in.

It’s always a little disconcerting to a family when the medical team says, “Okay, we’re done in the hospital. It’s time for you to go home,” and they feel like, “Well, this hasn’t been solved yet. We don’t know what’s happening with my kid.” From a medical perspective, we often think about it as we don’t want you in the hospital if you don’t need to be in the hospital.

When Stevie went home, she continued to progress pretty quickly. The family got in touch with Dr. Pizoli, who again was seeing them as an outpatient, and said, “We’re still noticing things and, if anything, it seems like it’s getting worse.”

At that point, they were noticing not just the eye movements, but now it was eye movements accompanied by arm movements. She would sort of flex one arm or straighten one arm, things that again raise a red flag for seizures. She was starting to lose some head control, which made us a little bit worried, and that’s where I met her.

Things Were Getting Worse

When I first met them, it was clear that something was wrong. I had seen videos — the parents were really great about capturing some of these episodes on videos, which helps us so much in neurology to see the actual episode. We witnessed a couple when we were there in the hospital. It was clear that these were not normal movements.

To me, when I get a baby with spells of abnormal movement, there is a couple of categories that we think of. The first one that should probably pop into most people’s mind is seizures — in particular, for this age we’re thinking about a couple of different types of seizures. There can be seizures that happen from a brain injury; a baby has a stroke or something like that, or a bleed. The brain is irritable because it’s inflamed; it’s been insulted.

Another category of seizures that we often think about is something called infantile spasms. Those tend to be very short movements that are less than a second, that can have some abnormal eye movements, eye widening, and some little arm movements, all of which were being described in Stevie by her parents and all of which we saw on a video. Those can also sometimes come with developmental regression. If you let them go on long enough without treating them, infantile spasms can eventually lead to developmental regression and loss of milestones.

I think the first thing that probably all of us were thinking about, as we’re kind of hearing this constellation that Stevie has, is infantile spasms, which is always a good reason to send a kid to a hospital to get an EEG. The surprising thing about Stevie was just hearing the symptoms, I think would make most people think first about infantile spasms, yet we got an EEG and everything was pretty normal. But it definitely left us wondering what category we were in if we weren’t talking about seizures and epilepsy.

You start to think about other types of things that can lead to abnormal movements. Movement disorders, for example. In babies, there are different things — there is a type of tumor that presents sometimes in young babies called neuroblastoma. The hallmark of that is really chaotic, abnormal eye movements. It wasn’t exactly what Stevie was having, but another thing that you just wouldn’t want to miss. There are some urine tests for that. We did those; they were negative.

You think a little bit about there is some more benign things. There is something called hyperekplexia, which is just a really exaggerated startle in a baby that can be genetic. You think about reflux is another common reason. Just basically babies will feed and they will have a little bit of heartburn or reflux and that can be uncomfortable for them. They can move their arms or arch their back. If a baby can’t really communicate to you “I’m having reflux,” they’ll just look kind of distressed and irritable, and maybe have some abnormal movements.

Once we were fairly certain that wasn’t seizures, we started to cast a much wider net to try to understand what we were dealing with.

The two other things that we had thought about, even though they seemed a little less likely, was increased pressure in your brain can lead babies to be irritable. It can make them vomit, which she had had a little bit of, and can make them have their eyes stuck in a downward position. The nice thing about babies is that they have a fontanelle, which is like an open soft spot on their brain. That’s actually a really nice window into what’s happening into their brain. If it’s really full and tense like a water balloon, you start to worry about pressure. But hers was nice and soft.

Then we had also thought about that there were some really rare case reports of babies with just benign abnormal eye movements that they eventually grew out of. Because her first MRI was a screening MRI, we wanted to get a much more thorough high-resolution MRI with more of what we call sequences — more different types of pictures that can show us what’s going on. When we did that MRI, that was when we started to have a much clearer sense of what was happening.

There were some particular sequences that are really sensitive to injury in neurons. When neurons are injured, that area shows up really bright. On her, there were two very symmetric areas that were bright white in a region that’s called the basal ganglia. The basal ganglia in the brain is … but in general, it tends to help with planning and execution of movement. If the basal ganglia is injured, you can have abnormal movements, and that can be abnormal eye movements. That can be abnormal arm movements or other body movements.

The problem is that as soon as I saw that pattern on the MRI, my heart sank because not many things show up on MRI with this exact pattern of really bright basal ganglia that are symmetric in a baby. There is just not that many things on the list of diseases that can cause that kind of pattern on imaging.

Bracing for a Hard Conversation

Injury from low oxygen can do it, but Stevie didn’t have a history of that. There are some very rare metabolic disorders that can look like that. Then there is a syndrome called Leigh syndrome, which is a diagnosis that no child neurologist ever wants to make. That’s what you typically think of when you see that pattern on imaging. The second that her MRI came back and I pulled it up to look at it and saw that, my heart sank.

I called Dr. Maney, our resident, and said, “We need to go talk to the family right away.”

My immediate thought was just bracing for our really hard conversation with this family. Leigh syndrome is not one disease. It’s kind of a description of a category of diseases that are usually caused by mitochondrial disorders. The basal ganglia are really high-energy areas of the brain, and that’s why they are particularly susceptible to energy failure and mitochondrial breakdown in these types of diseases. Almost uniformly, they have really bad prognoses. Essentially, they’ll present really early in neonates or early infant-hood with seizures, movement disorders, developmental delay, developmental regression, loss of milestones, and usually those kids end up just doing worse and worse and worse.

You can try to treat it. You can try some of what we call metabolic cocktails, which is sort of supplementing with different vitamins or different nutritional supplements. You can try to treat seizures. You can try to do physical therapy, but most of those kids with Leigh syndrome end up losing milestones and deteriorating, and often dying at a very young age. That’s pretty uniform for Leigh syndrome. It’s usually by about 2 years old — pretty young, pretty young. It’s a pretty horrible thing to have to diagnose.

When you’re giving such a bad prognosis … I mean, there were times where we have conversations about prognostic uncertainty. Things might be bad, they might not be. But this was, we’re really worried that your daughter will die in infancy essentially. It’s a horrible conversation, and the least that we can do is just sit with them.

Sometimes I feel like … I mean, obviously, our impulse as doctors is to want to do something and fix something, and treat something. Sometimes when I’m in a situation where that’s probably not going to be the case, and I can’t do that and I feel a little helpless, the one thing I sort of feel like I can do for them is to be a witness and just sort of witness their pain, and witness their child, who at that moment in time was still a sweet, adorable, generally healthy, functioning child. That’s kind of all you can do for them.

They had lots of great questions about how likely did we think it was that it was Leigh syndrome. How likely did we think it was that it was this treatable biotin-thiamine-responsive basal ganglia disease. Of course, we told them Leigh syndrome is already really rare and it’s way more rare that it would be this treatable one, but let’s at least hope that it’s that and treat it.

‘Sliver of a Chance’

There is a framework that I like in neonatal neurology that’s prepare for the worst, but hope for the best. We talked about that and I think we were all preparing for the worst. Honestly, I thought we were going to be dealing with the worst, even though I think we all sort of hoped for the sliver of the chance that it could be this treatable disease. That’s where we left things.

The next morning, we came in to visit them again. They had done more reading online. I think they had a good sense of how things were going. I felt awful for them because they were preparing to potentially move closer to family, having to figure out what to do about their jobs, having to figure out how they were going to get help and support at home, support services like physical therapy.

That next morning I think was really hard for everybody. Again, more tears were shed and at that point we had done all of the things that we needed them in the hospital for. The plan was, “Okay. We are treating this sliver of a chance. We’re going to send you home. We’ll have you follow up closely with your neurologist, Dr. Pizoli, as an outpatient. When the genetic testing comes back, we’ll call you as soon as it comes back.”

I remember walking out into the hall and it was me and Dr. Maney the resident, and our pediatrics team. Stevie’s dad came out and gave us a huge hug and thanked us, and he was tearful. We both immediately choked up and had tears. I mean, we really connected with them in this week that we spent with them and really, really, really wanted the best outcome, even though I have to say I was not thinking that that was going to be the case. That moment is the one that I think stuck with me the most, and I’m sure Dr. Maney and hopefully the family.

For Stevie’s dad, in what was probably one of the worst moments of his life, to think about us was really moving. I’m honestly getting choked up even just like remembering that moment. But that I think was really kind of the peak moment of this for me. Other than several weeks later, getting the genetic testing back, and it came back positive for this even more rare disorder called biotin-thiamine-responsive basal ganglia disorder. Which actually is one of the treatable metabolic disorders that has a very similar pattern that we were already empirically treating with thiamine and biotin — these two vitamins.

The same thing as with the MRI, calling Dr. Maney immediately and saying, “Did you see the genetic testing for Stevie? She has biotin-thiamine-responsive basal ganglia disease. I can’t believe that’s what we’re dealing with. I’m so glad we’re already treating it.” We were incredibly relieved. I know her parents were incredibly relieved that she had a treatable disorder and was already on treatment for it. We were all just so thankful that that’s the case.

There are probably less than 100 total case reports of all ages and all spectrums of disease for this particular disorder. For those that present in neonates as young as Stevie, there is maybe a dozen. From initial symptoms to genetic diagnosis was one of the fastest processes that I have seen. Stevie had a problem basically absorbing and using thiamine, vitamin B1.

It turns out that the way that this disease works is if you just treat with really high doses of vitamin B1, then her sort of natural channels don’t have to work quite as hard to extract this B1 and bring it into her bloodstream and brain. You just flood it. Then that way a lot more of that vitamin B1 gets across those cell membranes for her to use a lot more easily. That’s how you can treat it.

Leigh syndrome is already incredibly rare, but some of these other metabolic disorders are even more rare. But you should still try to treat with vitamins regardless, just in case you have this disorder. We started her on vitamin supplementation anyway just in case.

From what I have read in their notes, because they keep an eye on them, and from what I have heard through Dr. Pizoli, they feel like her head control has come back, that she is not irritable anymore, she is back to being her happy self. I have heard them say that they got their baby back and I just really hope it all stays that way.

This is where that preparing for the worst and hoping for the best comes in, because sometimes you do get a really good outcome when you’re not expecting it, which is fantastic.

For the time being she is now, I think about 7 or 8 months old at this point, Dr. Pizoli still sees her regularly and speaks with the family more regularly. Because this is so rare we don’t know with certainty what the outcomes are going to be. Obviously, I really hope that she does well and there are some cases of kids doing really well on supplementation with biotin and thiamine.

She seems to be doing really well so far, and I just really hope it stays that way.

Check out the other stories from the Mysteries episode, including “Not Diagnosed Sooner Because He Wasn’t White.” and “You Have to Treat the Entire Patient.”