When doctors don't know what's wrong

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1:04Need a hiring hero? This is a job for Indeed sponsored jobs. As a journalist covering health and science, Alexandra Sifferlin got used to a very specific kind of email from readers. One of the top things that readers would email me about was their personal experiences with trying to find an accurate and timely diagnosis. They'd tell her how hard it was to get answers about what was going on with their health. And it happened with such frequency that I became very interested in understanding what was going on here. So she looked around for some numbers, like how many people have had problems getting a diagnosis or how many people have gotten an incorrect or a delayed diagnosis.

1:48It's hard to answer those questions exactly, but there have been some attempts to gather data on this. One of the best versions was this big report released in 2015 by the National Academies of Sciences, Engineering and Medicine. And they end up concluding that nearly every person will experience at least one diagnostic error in their lifetime, sometimes with devastating consequences. Now, that does not mean that every person will have a doctor miss a cancerous tumor or something. There is a spectrum here, and some of those errors are less devastating than others. But still, that is a lot of diagnostic error.

2:29In her research, Alexandra was also exploring questions about why this was happening, why it was sometimes so hard to get a diagnosis, what even goes into a diagnosis in the first place. And I realized, you know, there are so many different elements to this, and it just became a bigger and bigger project. Such a big project, in fact, that it turned into a book called The Elusive Body, Patients, Doctors, and the Diagnosis Crisis. And as Alexandra got deeper into her research for that book, she started digging into one story in particular. The story of a woman with an incredibly rare disease. That story reflected a lot of the problems that Alexandra was encountering with diagnosis more generally.

3:18And so this is Unexplainable. I'm Bird Pinkerton. And today on the show, we are doing a book club. Alexandra Siverlin, author of The Elusive Body, will tell us about this one woman's journey to a diagnosis and how it illuminates both the problems with how we diagnose disease and how we might do a better job of answering people's unanswered health questions.

3:56Let's start with an introduction to a woman named Louise Proctor. Louise Proctor is the eldest of five Proctor siblings who all grew up in very rural Kentucky. You know, she describes her childhood as pretty ordinary. She was pretty active. She would play outside with her friends. She was in band. But in 1980, when Louise was 25 years old, her life started to change. She remembers very specifically this one day where she's walking during her lunch break and she's going up a hill. And all of a sudden, she experiences this excruciating pain and a very bizarre sensation, whereby it feels as if her legs are turning to stone, as she describes it.

4:45it's like she's freezing in place and she can't move one step further. And that sort of sensation started happening with increasing frequency over the course of her life. The amount of time that she could walk without experiencing pain got shorter, and the pain got worse. So, of course, she talked to her doctor about it. the initial diagnoses, if you will, were things like, you probably should just be exercising more. Like, this wouldn't be happening if you were a little bit more fit. Or she would hear things like, maybe you have early stage arthritis, but she would be prescribed medications and they would have no effect.

5:29And she just felt really frustrated in the unknown and as if her pain just really wasn't being taken very seriously at all. This lack of a diagnosis went on for decades. She would talk about how it felt like nobody believed her. And because she otherwise appeared quite healthy, like this was sort of a sensation that would come and go, she just felt like when she did need accommodations, like she was going to the airport and needed a wheelchair. That, you know, people around her would kind of look at her like, what are you doing? Like, I just, you're over-exaggerating. And the pain was getting worse.

6:12Like, the condition is getting worse over time. In addition, because she has no diagnosis, she has no prognosis. So she has no idea where this is going. In the midst of all this, Louise also had two children to take care of. And in 1984, her infant daughter, Suzanne, was diagnosed with cystic fibrosis. Today, there are promising treatments and therapies, though it is still a very challenging diagnosis. But at the time, there really weren't any options. It's a fatal disease. And so, you know, tragically, her daughter does end up dying of cystic fibrosis when she's a young teenager. This was devastating for Louise.

7:04But as Alexandra noted, Suzanne's experience also showed the power of a diagnosis. Even though it was terrible, the people in Louise's family and in her community knew what was happening to Louise's daughter. Everybody from teachers to neighbors were there to accommodate them. And when Suzanne did end up passing away, this whole community fills the hospital. They're there for her. And it was sort of like this diagnosis gave people a context to understand what was happening to this girl and to support her and her family. And so it was interesting for Louise, I think. I mean, it was awful. But, you know, she was able to sort of see the contrast in what a diagnosis can provide, even if it's not good news.

7:56After Suzanne's death, Louise redoubled her efforts to get answers about her own situation. She's really just angry. And she's like, I've had it. Like, I cannot handle this cosmic grief in addition to physical disability that nobody seems to believe me over. And so she talks about having this appointment where she goes to her doctor and she has a total breakdown in the doctor's office. And she's very upset. And she's basically saying, you know, I can't even do my laundry because my laundry is in the basement and I can't walk downstairs. And so she finally gets some imaging done of her legs. And I mean, this is decades since she has been complaining about this, that she finally gets some real ultrasound-related images.

8:47And it's revealed that she does have very abnormal buildup of calcium in her legs. Alexandra was actually able to speak to the lab technician who did the scans because this was a small town. and the technician was a family friend of Louise's. And, you know, she mentioned to me, like, I had never seen this level of calcification in the legs of someone who's alive, much less someone who is young and otherwise seems very healthy. Basically, if you think of your big blood vessels as highways for your blood, it was like some of Louise's highways were full of big calcium rocks. And so in some cases, the blood is still able to kind of go around the rocks, if you will.

9:34But in other cases, her vessels are so clogged with calcium that what ends up happening, and the reason that she is still alive, is that the vessels start sprouting other smaller vessels, basically. Like little emergency side roads for the blood to move through. Those roads are not as big as the main highway. And because they're not the size of the highway, it's painful. Like it just simply, there's backup, the blood isn't getting where it needs to go. And so that's where the pain is coming from. There were other unusual things about this calcium buildup. But the main thing was that it was there, right on the scans.

10:18Proof that Louise was not making things up. So now suddenly Louise is being sent to many more specialists. And people are really trying. And her primary care doctor is really trying. And everyone's really trying to figure this out. But nobody had seen this before, even the specialists. So it quickly then becomes clear that Louise is experiencing something very unusual.

10:47It was also starting to become clear that it wasn't just Louise. Her siblings were beginning to experience strange symptoms, too. Her youngest sibling was experiencing the leg freezing issue. Her brothers also had problems. And Louise's doctor was working with her sister Paula as well, who, much like Louise, had pain when she walked on treadmills for extended periods of time. So what did this mean? What did it mean for the siblings? If it was genetic, what did it mean for their kids? with her kids at risk? What was the problem here? It wasn't clear how Louise or her family members were going to get answers to these questions until Louise's case wound up in front of a special group at the National Institutes of Health.

11:34More on that after the break.

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13:47But it still doesn't account for other symptoms. No, but it does tell us something. Though I have no idea what. In 2009, Louise's case was reviewed by a group known as the Undiagnosed Diseases Program. Which at the time was a very new program that the NIH was running. It was a successful program. And in the years since, the NIH has actually built on it and turned it into something called the Undiagnosed Diseases Network, a rare disease investigation unit, essentially. They were taking some of the most complicated medical mysteries that doctors were referring to them across the country. And geneticists, neurologists, all sorts of physicians would come together and try to crack the case as a team.

14:37Right from the beginning, the program got a lot of applicants and could not accept them all. But Louise's case did get accepted, in part because it seemed quite unique, in part because it seemed like genetics were involved, and in part because the program was interested in cases that seemed broadly relevant. Cases where even if this turns out to be a very rare condition, we think that there's something to be learned from that condition that could apply across the board. Louise clearly had an issue related to her blood vessels, and issues related to blood vessels are extremely common. So they had a feeling, you know, if we could crack this case, maybe the rare condition that these siblings are experiencing will have something to say about the wider issue of arterial diseases.

15:31And once the case was accepted, the program really kicked into gear. They're coming at it from this very unique method where they take experts from different fields. And even before a patient arrives at the clinic, they look through their medical history. They look through the letters that typically a doctor sends. Sometimes the patient sends a letter themselves or a family member. They read through all of that and they come up with a plan. The plan, in Louise and her sister Paula's case, involved them going into the NIH, getting a variety of tests. So there were a bunch of different types of scans, but also genetic tests.

16:09And then their other siblings were tested, too, as well as their parents. So when they have all these results back, all of these NIH scientists or clinicians, what have you, they're experts in their particular field, come together. And through that process, they try to come to a diagnosis or a conclusion. There were a few possible outcomes for this process. Either the researchers would be able to come up with some kind of an answer. Maybe this is such and such particular disease or, you know, this is a new disease that we have not seen before. Or, as does happen, the researchers, despite their best efforts, still wouldn't be able to get to a firm diagnosis.

16:57But once you're in this program, you're invited back every single year. So that's another element that I think is really important is there's this sort of commitment that this team is going to be with you on this journey, even if it is going to continue to take a long time because we can't quite figure it out yet, either because we don't have the technology available yet. You might be a case that's sort of on the edge of current medical knowledge. But the hope is that over time, we will be able to figure it out. We'll do further investigation. And perhaps we will ultimately reach a diagnosis together.

17:32In Louise's case, though, a team came together. And then there was a bit of serendipity. There happened to be a postdoc on the team who had done her PhD thesis on mice. She was studying what happened when those mice were missing a particular gene. And it gets a little complicated, but basically, when that gene was missing, it resulted in a strange pattern in the mouse's blood vessels that kind of matched the strange calcification pattern in Louise's family. So they thought that was very intriguing, but were also like, what are the odds that this random thing that the postdoc had been studying would be relevant to this case?

18:15It turns out it was very relevant. Once they went through all the tests and the data, they discovered that the Proctor's condition was very much related to the postdoc's research, which helped them figure out that the problem here was a deficiency of an enzyme called CD73. And that was like, you know, in some ways just an incredible coincidence, but in other ways I think just underscored how much can be gained by having this bigger team approach where you're including people who have different insights, different areas of research. They've come across different things. And through that, you end up raising potential possibilities that you wouldn't have otherwise.

19:00And so after 30 years, Louise Proctor finally got a diagnosis and her siblings finally got a diagnosis. They all had this newly named disease called arterial calcification due to deficiency of CD73, also known as ACDC for short. You know, it's so fun to hear them talk about it because in so many ways, they were just amazed that anyone had taken it this seriously. Like, to have gone to the NIH, to have undergone all of these tests, to know that this entire team of just really smart, dedicated scientists were focusing so much attention on this thing that they had gone decades experiencing with really, you know, not feeling like they were getting any support.

19:56There's a lot to take away here. In 2011, the researchers published their findings about this disease. They'd found a few other people that had it. Alexandra says the estimate is now 20 people worldwide. But the postdoc who spotted the connection to her thesis is actually still studying it. She's gone on to open her own lab where she studies CD73 and peripheral arterial disease full-time. And her whole research has been informed by this and with the goal to develop more treatments, hopefully for ACDC, but also for diseases of the arteries in general. But in Alexandra's reporting, some of the biggest takeaways might be less about this one specific disease and more about what we might learn from the Undiagnosed Diseases Network.

20:49She says there are lessons to be learned here, even if we're trying to diagnose more regular things. The issues related to getting a diagnosis for a rare disease are actually in many ways the same issues that people run into if they're trying to get diagnosed with something that is not rare. People are dealing with and complaining about the same issues with the health care system.

21:17Like, I think it's possible to see Louise's story, for example, and think that as soon as she got the right scans and tests, doctors were able to find solutions for her. But not every disease shows up on a scan. And Alexandra says that in one of the reports she read, she warned against the idea that scans or tech would solve everything. Instead, she says diagnostic error is this thorny, complex problem connected to a lot of different systemic issues. So, for example, one thing she encountered over and over when she talked to patients who'd had a diagnostic issue was the problem of time. They would say, it took me forever to get a doctor's appointment.

21:58Then I finally got the appointment and I was in there for maybe 10 minutes most with the doctor. And during that appointment, the doctor was looking at their computer the entire time, typing into it, and I don't feel like they were listening to me, and that's why I think I didn't get the correct diagnosis to start. And then I would go and talk to physicians, and I would say, from your perspective, what do you think are some of the factors that play into situations where you might have gotten the diagnosis wrong or you just couldn't quite figure it out? And I would basically hear the same complaints.

22:31They would say, I have to see 20 patients in a given day. I'm only allotted a tiny amount of time. And during that time, I'm supposed to be typing information into the electronic health record. and I feel like I'm not able to give the patient my full attention, or I wish I had more time in that appointment with the patient, or I wish I had more time to review that patient's medical record, or I wish I had more time to think, to like really sit with the information provided and try to piece it together. In the NIH program, these doctors were able to give Louise time, not just in the sort of thorough initial meetings, but also in the follow-ups that occurred across the years.

23:14And that care was also coordinated, which was another factor that Alexandra heard and read about as she was trying to suss out the reasons for diagnostic error. Often patients feel that they themselves are the ones that have to be in charge of bringing their entire medical history from doctor to doctor. Like, there's not a lot of coordination. It ends up, you know, one physician may say, I don't have an answer for you, but I'm going to send you to this specialist. and they're an expert in XYZ and they can be able to help. But the problem is that the patient then feels like they're starting from scratch.

23:49So they get to that next person and they might come with literal binders of information because they just feel like, you know, this doctor isn't talking to this doctor and things are being missed in that handoff. That really stands in stark contrast with this undiagnosed diseases model where doctors get into a room and talk to each other about the patient before the tests are run and then talk about the test together again afterwards. Now, Alexandra did tell me that there are a lot of issues that contribute to diagnostic error. Like, how tired a doctor is when they see you can be a factor. Or, in like a bigger picture sense, it can be hard for some doctors to get feedback on whether their diagnosis was correct or not and to therefore learn from their mistakes.

24:37So the undiagnosed diseases model is not going to solve, like, every problem here. But she still thinks it would be useful to borrow from it. I mean, I would love to see most hospital systems have a version, even if it's much more modest, of the undiagnosed diseases network. work. Physicians need somewhere or someone to send cases that they simply don't necessarily have the time to figure out or they don't have the technologies available to them to figure out. But you can't just dump people from one doctor to the next. And of course, it's never going to be a guarantee that you will get an immediate diagnosis, especially for something very complicated.

25:23But at least you can go somewhere where you know that they're going to throw everything at the wall and try. Alexandra has seen medical clinics and systems that are recognizing the value of getting more people that are involved in a patient's care just kind of talking with each other. And she's even seen people with models that look something like the Undiagnosed Diseases Network. Dr. Lisa Saunders at Yale, who writes a diagnosis column for the New York Times, for instance, largely her clinic is focused on long COVID. Her approach, the way that she sets up her appointments and the way that she interacts with other experts, it is in many ways very similar to the undiagnosed diseases network.

26:08You know, even just having a little bit more time with patients who have these more complicated conditions, I think, can go a long way. Even if every system does learn from the undiagnosed diseases model, though, and doctors have the time and the resources and the coordination to come to a diagnosis, that is just the beginning of the story. To go back to the Proctor siblings, it's a little bit bittersweet as well. Because though they got this diagnosis and they contributed to medical science because it was the discovery of a completely new disease, there isn't a cure or really a very effective treatment yet for ACDC.

26:51And I was really interested in that aspect of their story, too, because it made me wonder, a diagnosis without a cure, what does that really get you? Because ultimately, you're still experiencing the same symptoms and you're not getting relief. And, you know, they're honest that that's really frustrating. However, we talk about how with this diagnosis, they found out that this particular genetic disorder cannot be passed down to their children. So that was huge. And then two, all of the siblings are really interested in this idea that scientists are going to be able to learn something potentially from their case that could inform future care.

27:35And lastly, again, this part of the Undiagnosed Diseases Network ethos of staying with people over time, the hope is that they will continue to research them. The siblings go back every single year to the NIH to go through, again, a lot of physical exams, tests. And the hope is that over time, they will find a treatment and they will get relief. And so they feel like this has been worthwhile because they're at least on a path somewhere.