Rachel: welcome to The New England Journal of Medicine ’s “Intention to Treat.” I'm Rachel .
Today, let’s talk about narcolepsy. It’s not just a sleep disorder.
Ebony : You know that situation where you wake up in the morning and you feel groggy and you can go back to sleep? There is always a mist surrounding me, this heaviness, like a feeling that forces me to lie down and sleep.
Jessica : I took her to the emergency room and she kept sleeping. By the time they put her in a hospital gown, she was already asleep. She was still sleeping when they performed the CT scan. All test results were completely normal. But the ER doctors and nurses did take a look at me and they said, "I don't know what's wrong with her, but I know this isn't normal."
Rachel: This is "Intention to treat" in the New England Journal of Medicine . We interview a scientist who has spent his life trying to find answers to the mysteries of sleep. But first. . .
Ebony : My name is Ebony . I am 41 years old and was diagnosed with narcolepsy with cataplexy at the age of 32. This has been a very difficult, long road for me. I can't remember a time when I wasn't sleepy. It was almost like a personality quirk of mine when I was a little kid. Whenever I get high, I lose all muscle control. I would fall over, or every muscle in my face would fall out, and my dad would call it "making faces." I would have these super vivid dreams that felt like I was awake and I would just hear or see these distressing things, but I couldn't move. I'm speechless. I couldn't scream. I'm just stuck there and there's nothing I can do.
My mom said that when I was six years old, she would catch me laughing and falling. She would take me to the pediatrician because she was worried that I would keep wanting to sleep and I would have all these clumsy accidents. So she would take me to the pediatrician every now and then, and they would check me out, and they'd be like, "Oh, no. She's healthy. These are probably growing pains." And then, when I was a teenager, " Maybe she might be suffering from depression. So let's give her antidepressants and see if that helps." or "She's sleeping more now," followed by "Well, she's a teenager, so... ”.
Well, this is definitely a struggle that I have with my family. Because if they catch me trying to lie down somewhere, they'll say, "If you sleep too much, it's just going to make you feel more tired. You should get up and walk around." And then every now and then, I hit a wall. , even if I tried to force myself not to nod off, I couldn't think straight and putting the two strings together felt impossible. So I would break down and start crying. They would back off, leave me alone, and I would fall asleep.
I have an identical twin sister who is not as sleepy as I am. My family, they were worried, especially my mom. She would take me to the pediatrician. These doctors would give me a full body exam and they wouldn't find anything wrong with me. She'd say, well, what do they recommend? Basically, they told her not to worry. I'm a growing kid and it will probably work itself out. As I got older, my symptoms became more frequent to the point where I started going to the doctor on my own and saying, "Hey, in class today, when I walked down the hall, I couldn't move my legs." I just fell down. ” So the doctor tested my reaction and he said, “Well, it’s not a problem with your nervous system. ” Then I would say how tired I was. Again, “It could be depression.” ” Or just say, “You have a lot to do. You’re such a busy girl.”
I never really talked about the vivid dreams and sleep paralysis troubles I was having at night because I didn't know these were things I could tell a doctor about. But just being tired, there is always a layer of fog surrounding me. Over time, this feeling can become a bit heavy, like there's a feeling that forces you to lie down and sleep. I feel like either I'm crazy or they think I'm looking for an excuse not to do something, so I shouldn't talk about it anymore. So I feel like a failure overall.
Since I had good grades and I was a quiet kid, a lot of teachers left me alone. I was able to cover up a lot. It's like my resting position makes me look like I'm studying seriously instead of dozing off. I remember one time, I fell asleep at my desk, and when I woke up, all the kids around me were complaining, "Hey, why wasn't she detained? She was asleep." He said, "She got a 100 on her last test. points. She brought her homework. Did you bring your homework?" You know, like, "She's a good student. If she wants to sleep, I'll let her sleep." At the end of my freshman year in college, I barely passed course. I didn't have the energy to walk across campus, so I just stayed in bed.
I don’t think I ever came to terms with the fact that it was my narcolepsy that caused me to drop out of school. I always put this responsibility on myself. I just entered the labor market and skipped a lot of temporary jobs. Because I would be a great worker, efficient, detailed, and deliver great work, but I would always have trouble getting up in the morning and getting out the door. I'll keep doing that job until they lose patience with me. I continued doing this until my mid-twenties, where I found a dream job where I trained as a receptionist. That guy, he saw potential in me. So he gave me an apprenticeship in telecommunications engineering and I became a detail engineer myself. It gives me the flexibility to work through sleepiness so I can get the work done that needs to be done.
In my 30s it was hopeless for me because I never talked about it, being sleep paralyzed at night and having horrible dreams - I would wake up and not be able to move. I would see my front door open and then this dark intruder burst into my apartment and charge towards me. Or sometimes I might hear my sister screaming my name or calling for help. People are panicking and fearful that something terrible is happening.
Even though I felt like I needed to sleep, I was afraid of sleeping. I don't want to sleep. I just desperately need some kind of solution. So I went to my doctor and begged her to find something that would allow me to sleep through the night undisturbed. There was an intern next to her that day, and it was actually the intern who suggested that I do a sleep study. Even before the sleep study, the person who just did the sleep questionnaire, she just looked at all my answers and asked me if I thought I might have narcolepsy.
I laughed when she asked me this question because I have some stereotypes about narcolepsy. I didn't think it was possible because if I needed to stay awake, I could force myself to stay awake. She then explained my symptoms and for the first time someone understood what I was going through. I was diagnosed with narcolepsy with cataplexy. We developed a treatment plan that incorporated medication and scheduled naps. There is currently no cure, but with treatment, it has been able to help reduce my symptoms. It felt like I no longer had to fight to stay awake.
Jessica : My name is Jessica and my daughter, Chloe, was diagnosed with narcolepsy type 1 when she was 4 years old. Chloe is now 7 years old. My daughter is perfectly normal and healthy. About a month after her fourth birthday, she took her first nap, which was unusual. Then one nap turned into several naps a day and she would tell me she was going to play and then she would actually go and tuck herself into bed. She was taking about eight or nine naps a day and then all of a sudden she was running around and playing and started tripping over herself and her tongue started sticking out.
We have been going to the pediatrician to try to figure out why she is so sleepy. She was tested for mononucleosis, thyroid disease, iron deficiency, and basic cancer screenings, all of which came back negative. A few weeks later, I thought, "Well, maybe she has a UTI." That's when I brought her in again, another pediatrician, and she looked at me and said, "I suspect this is a UTI." . We can check it out. But do you think she might have been sexually assaulted or taking naps for attention?" So I was a little offended because I don't think a four year old is sleeping all day because they want attention Or they were sexually assaulted.
There is no answer. Everything is going on with blood work, any little scans are good. Totally normal. I know she's not normal. I started losing a child. Her paralysis was so severe that she couldn't even walk. Her tongue kept hanging out. She looks severely disabled, which is the only way I can explain it. We were in a restaurant. She couldn't even eat. She just kept falling asleep and falling asleep. She couldn't speak and could only babble. I remember leaving the restaurant and we got in the car and I started screaming to my husband, "She's dying and no one is listening to me! No one cares that there's anything serious wrong."
So we walked into the elementary children's emergency room and a nurse came around the corner and she didn't even really ask me what was wrong. Because her eyes were droopy and she couldn't stand, she was simply labeled as having a possible stroke. So we went back to the trauma room and they started running every possible test. I started researching why some people get drowsy and I came across some YouTube videos of people suffering from narcolepsy. The next morning, I met with 29 doctors at Primary Children's Hospital, one of whom was a neurologist. So I asked, "Do you think this could be narcolepsy?" He was really nice, but he looked at me and said, "I don't think so. I've been here 20 years and I've never seen anything like this." This is quite rare in young children."
Over four days, she was tested for epilepsy, nocturnal epilepsy, spinal cancer, myasthenia, botulism - I mean, everything you can think of, she was tested for it, and so was I asked. All of these tests came back negative. The neurologist did come to see me the next morning, he came on his own, and he said to me, "I think you're probably right. I think narcolepsy type 1 is going to be her next possible diagnosis." ” He did send her spinal fluid to the Mayo Clinic, and then they were willing to enroll her in a sleep study because the spinal fluid came back and showed 100% that she had type 1 narcolepsy.
She lives a more normal life. She does sleep two to three times a day and still has cataplexy every day, but she is back to being a more normal, functioning child. She does have to take naps at school to function, even though she doesn't like it. The school has always been very inclusive. They had a special room for her to sleep in. They gave her extra time for the exam. Cataplexy - She learns how to fake a smile because if she does, she collapses and becomes paralyzed. So she learned how to fake a smile and try to be a normal kid. If she was doing something and someone was chasing her to play hide and seek, she would actually yell at them instead of laughing because it would keep her upright. So she's like, "Don't chase me." So that's why she's smirking.
As a parent, you have to mourn the loss of a child because they are no longer that child. They will never be that kid again. Then you get to know a new child all over again and learn how to raise and care for a brand new child.
Rachel: This is "Intention to treat" in the New England Journal of Medicine . I'm Rachel . Dr. Emmanuel also joined. He is director of sleep science and medicine at Stanford University. Dr. Emmanuel, please tell us about narcolepsy. How is the patient doing?
Emmanuel : Basically, in narcolepsy, the brain doesn't work properly, so sleep suddenly turns into wakefulness, and wakefulness is mixed with dreaming. So people with narcolepsy feel tired all the time. They were asleep everywhere. And, best of all, when they fall asleep, they go straight into dream sleep, which is REM sleep. Many times, they experience these symptoms while half awake and half asleep. Because while you're dreaming, you're paralyzed - we're all paralyzed in our dreams; otherwise, we're living our dreams - and these patients are sometimes paralyzed, for example during REM sleep, but at the same time they're awake. So this can be very scary. It can happen in the middle of the night. They wake up and oh, they can't move. This is called sleep paralysis.
And then they also have a lot of half-asleep and half-awake symptoms. So a lot of times they might start seeing things that aren't there, or some monsters will come at them while they're asleep. Often, when they wake up, they are absolutely sure what happened. For example, I have many patients who dreamed that someone came into the house, and when they woke up, they believed that this had happened. But in fact, it was in their dreams. When they're emotional - which is the most specific symptom of narcolepsy, called cataplexy - when they're happy about something, it usually has to be a funny joke and very specific. The joke must be funny to the patient. If they find it funny, then boom. Suddenly, they were paralyzed. This is called cataplexy.
Rachel : So what’s going on biologically?
Emmanuel : Narcolepsy is simple. Narcolepsy is caused simply by a lack of a chemical in the brain called orexin. If you don't have it, you get narcolepsy. Narcolepsy is very similar to type 1 diabetes, when you don't have insulin and need insulin injections. Here, you don't have orexin. You can't stay awake, you can't control your dreams, you have narcolepsy. This is an autoimmune disease. As a result, the immune system attacks the cells in the brain that produce orexin. Once they're no longer there, you develop narcolepsy. In fact, the trigger is the flu. Surprisingly, we found that if you get the wrong flu at the wrong time, then the immune system starts attacking the flu and mistakes it in a way where it starts linking the flu to the orexin-producing cells in the brain. Confused. It thinks they're infected, and they're not, and then it kills them. And then you get narcolepsy.
Rachel : What did we learn, what did you discover, and how did you discover it, that led to this research and these new drugs that have the potential to reverse the symptoms of this disease?
Emmanuel : Basically, when I came to the United States from France, I was very interested in narcolepsy. I think this might be the key to understanding sleep in general, because it's a very strange disorder where people's brains are messed up and sleep doesn't work. They have dogs with narcolepsy. Not only people can get narcolepsy, but dogs can too. In fact, I have a dog myself, Watson, who suffers from narcolepsy. I have to show it to you.
He's my lab assistant, you know? You see, he is happy. Yes. He is very cute. He is a Chihuahua. Every time he gets high, boom, he crashes. So, like narcoleptics, when they hear a good joke, they have a meltdown. For him it was more about food or having fun and seeing me. Then he gets so excited that he becomes paralyzed. Of course, he was sleeping the whole time, too. But of course, for a dog with narcolepsy, it's not as serious as a patient.
So we have these dogs with narcolepsy. But unlike humans, it's purely genetic. So if you have two dogs with narcolepsy, they both have narcolepsy. So I spent a decade following these families of dogs with narcolepsy, trying to identify the genes that cause narcolepsy. When we discovered it, it was a mutation in the receptors for a chemical called orexin, which was thought to be involved in appetite at the time. But it's actually a chemical associated with sleep. So the next thing we have to do is look at human patients. We know this is different because in human patients it is not a genetic disease. As I mentioned, this is an autoimmune disease. So we examined whether orexin itself was missing, and found that orexin itself was not present in the brains of people with narcolepsy. So the reason is simple. There is just a lack of this orexin chemical. It's all down to the dogs.
Rachel : It appears that narcolepsy is underdiagnosed. why is that?
Emmanuel : When I first started researching narcolepsy, I read the newspapers and they said it was about a guy who was 2000 years old. So it's not super rare, but it's not super common either. This is one of the intermediate frequency diseases. But a lot of neurologists say, "Oh, I've never seen anyone with narcolepsy. It's very rare." But I think unfortunately, it's not diagnosed. I think the reason it goes undiagnosed is because patients don't often come to their doctor to explain their symptoms. You see, sleepiness isn't always considered a disease. People might say, "Oh, I'm like that sometimes." And then the doctor doesn't recognize it and then passes it on to the neurologist. And then I think when it goes through neurologists, they see very little and often they don't even diagnose it.
So unfortunately, they were all missed. I started seeing kids with narcolepsy. I used to see only adults, but the disease started 20 years ago. They suffer from narcolepsy their entire lives. Often, they don't even remember when it started. They say, "Oh, I'm tired all the time." And then I start seeing the kids, and in the kids, it's a very different picture. They often become very obese very quickly and suddenly begin to suffer from narcolepsy. They gain a lot of weight and then suffer a lot. They had been sleeping, almost paralyzed. Even their mouths will open and their tongues will stick out because their jaw muscles are weak. It's really dramatic and they often have to stop going to school. We now know that 50% of people with narcolepsy begin in childhood before the age of 18. So they were all missed.
This is the first thing. The second thing is that we used to treat narcolepsy with stimulants like amphetamines and antidepressants. Why? Because antidepressants can eliminate dreams. They somehow improve abnormal dreams. And then there are stimulants, I mean, we know they keep you awake. But when you take amphetamines, you often get a little overstimulated. It keeps you awake, but in a robotic way. You are not completely normal. In fact, if the dose is too high, people can become paranoid. They become hypersensitive to everything that happens. So this is definitely not an ideal treatment.
Then a new drug came along called sodium oxybate. Somehow, this drug puts people to sleep, but also in a very intense state of sleep. Rather than being an anesthetic that flattens your EEG, it actually creates these large waves, like if you were deeply asleep. Additionally, it is also a very controversial drug as it is occasionally used as a date rape drug. We found that this drug really works and it really changes the lives of many people with narcolepsy. This is not ideal. It does not cure the cause of the disease, but it is arguably an improvement. And then, of course, the ideal, everyone's waiting for, the Holy Grail is replacing what's really missing. Because that's the root of the problem, orexin.
Rachel : Please tell us about your research and what you found.
Emmanuel : So the study was very simple. You have to stop all medications and then take a placebo, or different active doses of this particular drug, TAK-994 (an orexin agonist). I have about eight patients in clinical trials, and eight of my hundreds of patients happen to be taking active drugs. I noticed right away that no one was taking a placebo because that was pretty obvious. Unlike amphetamines, they are not overstimulating or robotic. They feel awake but calm. I could see a transformation in all of them. I mean, that's a big difference. Even patients who are treated well with conventional medicine, because sometimes we get them back to 80 percent normal, they are not normal. They were still a little sleepy. When they have a lot of emotions, they get into trouble. It will never be perfect.
But with this drug, we can see patients and even their personality change a little bit. I mean, I never realized the eyes, but the eyes were more open. So it's fundamentally different from anything we've tried. We have a test to test the severity of narcolepsy. Basically, we put people with narcolepsy in a room and tell them to sit down and do nothing. It was unbearable. People with narcolepsy cannot stay for more than three minutes, five minutes - I mean, do nothing. They can't watch TV, they can't read, they can't read - they can only try to stay awake. impossible. They just, snap, fell asleep immediately. With all the treatments and everything else that we do, we can stretch that time out to about 10 minutes. With this type of drug, because they tried another drug, they could stay awake like normal people for 40 minutes, which is the length of the test.
Virtually all patients who tried the drug wanted to continue taking it. They don't want to switch back to their old medication. But here, very unfortunately, there are liver side effects. I mean, three patients had liver inflammation. Therefore, the medication must be discontinued. Of course, this is extremely devastating because many patients are doing fine. Just getting them to stop treatment would be a real disaster. That's why it ended up being more of a proof of concept, a very effective mode of action, but not really an ideal drug. Now new drugs are being tried that I don't think will have this side effect.
Rachel : Do all people with narcolepsy lack orexin? Aren’t there some patients who believe this is not the case, and that it may not help them?
Emmanuel : That’s a great question. Of course, there are two types of narcolepsy. There is a type of narcolepsy we call type 1. Kind of like type 1 diabetes, they don't have insulin. But some people feel tired and experience some symptoms of narcolepsy. Symptoms such as cataplexy, agitation, and paralysis generally do not occur. Orexin is normal in these patients. So their problem is not caused by a lack of orexin.
So you may be wondering, does this drug help? In fact, this is also true. We are convinced that the drug works better in patients without orexin. Of course - it's replacing something they lack. In comparison, people who have orexin and feel tired for other reasons usually need a higher dose, about three times as much, to get the same effect but still be effective. We know that the cause of ADHD or fatigue is not a lack of dopamine. However, the drugs we give to increase dopamine do help. Therefore, we treat hundreds of cases symptomatically with medications. So basically, orexin agonists treat narcolepsy type 2 and people who are tired for other reasons by increasing orexin.
Rachel : So in your opinion, what needs to happen in the future?
Emmanuel : So we know that about a quarter of people have sleep problems, and obviously these medications that can help you stay awake may have more applications than narcolepsy type 1. For example, in the world of depression, there's apparently a subtype where patients are very, very tired and sleepy, but we don't really understand why. I think some of these patients could benefit greatly from a little bit of orexin. We have to discover where it works best. So there is no free lunch in pharmacology. This is the essence of taking any aggressive treatment. So of course we have to understand the risks of orexin as well. So I think the logical thing to do is to start with these type 1 narcolepsy patients and type 2 narcolepsy patients. Try to really understand how it happened. It may then extend to other people where it may be more difficult, such as depression and so on.
Rachel : If you find that half of people with narcolepsy were misdiagnosed in childhood, what do clinicians need to know?
Emmanuel : So I feel strongly that we should educate pediatricians more. Because it does look different for kids, and I think they often go undiagnosed as kids. We really need to educate patients about the fact that sleep is a problem. Drowsiness can be a medical condition. This is not normal. The second thing I think is important is for doctors, especially pediatricians, to recognize this and take it seriously.
Rachel : Thank you so much for joining us.
Emmanuel : It’s really nice.
Rachel : Dr. Emmanuel is the director of the Center for Sleep Science and Medicine at Stanford University.
