: Narcolepsy is a chronic neurological disorder that affects the brain’s ability to control sleep-wake cycles, which can greatly affect daily activities. Excessive daytime sleepiness is a major symptom of narcolepsy, and it’s characterized by the persistence of sleepiness regardless of how much sleep somebody gets at night. If left untreated, narcolepsy can interfere with psychological, social, and cognitive functions. 

In this NeurologyLive® Peer Exchange discussion entitled, “Management of Narcolepsy and Excessive Daytime Sleepiness,” I am joined by a panel of my colleagues—all experts in the field of sleep disorders. Together we are going to discuss the use of new therapeutic options, review the latest clinical trials, and provide practical perspective on how the recent data might apply to your clinical practice. 

I am Dr Michael Thorpy, the director of the Sleep-Wake Disorders Center at the Montefiore Medical Center in Bronx, New York, and professor of neurology at the Albert Einstein College of Medicine. 

Participating today on our distinguished panel are Dr Alon Avidan, professor in the Department of Neurology at the David Geffen School of Medicine at UCLA and director of the UCLA Sleep Disorders Center in Los Angeles, California; Dr Eveline Honig, executive director of Narcolepsy Network in New York; Dr Kiran Maski, assistant professor of Neurology at Harvard Medical School, and director of the Sleep Clinic in the Department of Neurology at Boston Children’s Hospital in Boston, Massachusetts; and Dr Russell Rosenberg, chief science officer and CEO of Neurotrials Research in Atlanta, Georgia. 

Thank you so much for joining us… Let’s begin.  

First of all, I want to ask Dr Rosenberg about excessive daytime sleepiness. Can you tell us a little bit about how you distinguish this? Everybody is a bit tired at some time in their life. How do we know when somebody really has a problem with excessive daytime sleepiness? How does that sleepiness affect them? 

: Thank you, Dr Thorpy. This is an interesting question because I think everyone here on the panel today could say they experience tiredness or excessive sleepiness from time to time. It’s highly prevalent in our society that people are sleepy, so it is a difficult task or an important task to determine the normal amount of sleepiness that many of us really experience versus when it becomes a clinical matter that requires seeing a physician. We shouldn’t forget here on the panel that the most common reason for excessive sleepiness is just chronic sleep deprivation. This is self-imposed. We’re looking at the TV or [on] the internet and are cutting our sleep short. But when it gets to a point where it is interfering with work, with relationships, with other social activities—and then in situations where an individual has to stay alert while driving or doing some other activities where the individual must stay away to be safe&mdash;then it really becomes a serious problem. 

: Now, Kiran, is it easy to recognize this in children, or is it more difficult to pick up excessive sleepiness in children? 

: That’s a good question. I think it’s more difficult because kids, oftentimes, look hyperactive, or impulsive, or inattentive when they’re sleepy. Sometimes I hear that they were misdiagnosed as having attention-deficit/hyperactivity disorder and were not recognized for the sleepiness. Sometimes they have behavioral components—they’re more irritable or they have more aggressive behaviors when they’re sleepy&mdash;and that catches people’s attention. And parents usually pick up on this and notice that if the child takes a nap, they actually get a lot better. 

: So that’s quite different from the adult who tends to be more and more tired and lethargic as they get sleepy. But sometimes children can become hyperactive, and that may be a sign. What tests can we use to help assess if somebody has excessive sleepiness? 

: I think many people wait way too long to address their sleepiness or excessive sleepiness before they go to a physician. The tests that we can use in the clinic include things like the Epworth Sleepiness Scale. This is an 8-item questionnaire that a patient can fill out. They’re asked how likely it is they’re going to doze off in a variety of situations. This is a fairly well-validated and reliable measure for adults. There is a child version, of course. This is a self-report measure.  

There are a few tests that we can do in the sleep laboratory that help measure the amount of sleep pressure or sleep propensity. One of them that’s commonly used is called the multiple sleep latency test [MSLT], in which an individual has already undergone an overnight sleep test. They stay the next day and do a series of naps at 2-hour intervals, and we measure how fast they fall asleep in those 2-hour intervals. Of course, we’re encouraging them to stay awake in between those naps. And then we’re also looking at what type of sleep they might have had during those naps to make some decisions about a diagnosis. So it’s a very useful tool. 

: You need to have a sleep center to do that, so you need a sleep specialist to be involved in doing the MSLT? 

: Sure, sure. And these tests cannot be done at home. I know there’s a big increase in using home sleep tests, but you can’t really measure the excessive sleepiness in a home sleep test. They must come into the sleep laboratory. 

: Now, what about the Epworth Sleepiness Scale? Is this something that neurologists or primary care physicians can give to their patients? 

: Absolutely. People complete that before seeing the physician. They can complete it online. So, yeah, I think it’s very useful. It’s very easy to interpret. It doesn’t take a lot of fancy arithmetic. You add up the score. If the score is 10 or more, that’s considered abnormally sleepy. And we see patients who are terribly sleepy, excessively sleepy, scoring 15 or more. You can’t really diagnose someone with a specific disorder from the Epworth Sleepiness Scale, but it does give the clinician a sense of just how sleepy this person is across a variety of situations. It is easily done in a neurologist’s office or by a primary care professional. 

Overview of Excessive Daytime Sleepiness 

: Now you mentioned that a common cause of excessive sleepiness is not getting enough sleep at night. But there are other relatively common causes of sleepiness, right?  

: Such as obstructive sleep apnea syndrome, narcolepsy. We’re going to focus on narcolepsy today. Kiran, what is narcolepsy? 

: Narcolepsy is a chronic neurologic condition that causes excessive daytime sleepiness. But it’s more than that. It’s really a problem of sleep-wake stability. Patients, oftentimes, have difficulty staying awake during daytime hours, but at night they also have problems kind of consolidating or maintaining sleep. And most specifically, it’s a disorder of REM [rapid eye movement] sleep. So some of the symptoms, which we’ll go over in a second, relate to that inappropriate REM sleep that comes on during daytime periods or during sleep-wake transitions. 

: There are 2 subtypes of narcolepsy. There’s type 1, which is narcolepsy with cataplexy, and type 2, which is narcolepsy without cataplexy. Type 1, the subtype with cataplexy, is related to low hypocretin levels. Hypocretin is a neuropeptide in the brain that helps stabilize these sleep and wake states. When it’s gone, there’s sort of this imbalance between sleep and wake, and a fluidity between those states. We think that loss of hypocretin may be related to an autoimmune process because nearly 90% of patients with type 1, if not more, are positive for a specific HLA [human leukocyte antigen] allele, DQB1*0602. We really don’t know what causes type 2. 

: And what may cause this loss of hypocretin and this autoimmune response? Are there any theories? 

: We don’t have the direct mechanism mapped out, but there is definitely tantalizing evidence. A recent study shows that patients with type 1 tend to have these autoreactive T-cells. So we think this may be a more T-cell—mediated process that recognizes hypocretin peptides. So yes, we’re getting closer to understanding that it may be a disorder of T-cell immunopathology rather than, say, autoantibodies. 

: And it’s been suggested that in many patients, an infective stimulus may set off this process. 

: Yes, and that’s been observed based on epidemiologic data showing spikes in incidence with cases of streptococcus, the H1N1 flu, and then with the specific H1N1 vaccination called Pandemrix, which was used in European countries. 

: Yeah. That didn’t happen in the United States, I understand. There wasn’t any vaccine-induced narcolepsy in the United States. What about the prevalence? When does narcolepsy generally start, and what is the prevalence of narcolepsy? 

: Narcolepsy typically starts between the first and second decade of life, in most patients. Even when it’s diagnosed as adult onset, in retrospect, almost 50% of patients report having some symptoms during childhood. So typically 10 to 20 years of age is the peak incidence, and then there’s maybe another peak...20 to 30 years of age. The incidence is not clearly known, but it’s somewhere between 0.3 and 0.5 per 100,000 people. So this is a rare disorder. And in children, it’s not exactly well known, but it may be 0.8 per 100,000. But, of course, there’s the delayed diagnosis problem, where there may have been pediatric onset but it’s not diagnosed until adulthood. 

: Alon, for someone with narcolepsy, how do we begin to tell? What are the main symptoms that patients present with if they have narcolepsy? 

: So before answering this question, I’d like to just contribute 1 other point to what Dr Rosenberg eloquently described, which is the use of the sleep diary or sleep log. I would urge all clinicians in all practices that—when they see a patient with excessive daytime sleepiness&mdash;they provide some measurement of how much sleep and how regular the patient’s sleep-wake patterns are. The sleep log or sleep diary really is the 1 beautiful test that can tell us if the patient is sleep deprived. Do they have irregularities in their sleep-wake patterns? You don’t need a sophisticated watch-like device like the accelerometer, although having it is an advantage. So this is really a bridge between the patient’s symptoms to deciding when the patient should undergo a more sophisticated sleep test. 

: Even if a physician doesn’t have a sleep log available, it’s most important for every physician to understand what that patient’s sleep-wake pattern is. And it’s not just a matter of asking someone what they usually do because most patients are going to tell you, “Well, I go to bed at 11 and I get up at 7 in the morning.” They neglect to tell you that on the weekends, they go to bed at 3 AM and sometimes can be in bed until midday or after, or they may get very short amounts of sleep on the weekends because they’re up so late. So understanding that sleep pattern is important. 

Overview of Narcolepsy

: After we’ve assessed the patient’s sleep-wake pattern, what are the symptoms we want to look for in narcolepsy? 

: This is the 1 condition where, besides excessive daytime sleepiness, hypersomnolence as the sine qua non of the disease, you cannot really make a diagnosis without daytime sleepiness as a fundamental symptom. Besides daytime sleepiness, there are at least 4 or 5 other symptoms that I think are useful for clinicians to appraise. The first and foremost is cataplexy. Cataplexy is really a unique condition that patients often describe as a gradual loss of muscle tone that is triggered when they hear a funny joke or they get surprised. Usually, positive emotions tend to bring on this episode. Patients may have a sagging of their jaw, or may slur their speech, or may even find that it’s hard to maintain their posture or muscle tone. And it goes on fairly gradually for maybe a few seconds up to a minute. It typically does not last for more than a minute. Cataplexy is really what helps differentiate between the 2 types of narcolepsy, which is something we’ll go into in a little bit. 

: How easy is it for physicians to recognize that somebody has cataplexy? Or can it be quite difficult? 

: It is extremely difficult, and I’ll tell you why. I’m just curious, among everyone here, how many of you have witnessed cataplexy in your patients? 

: I think all of us have, because we’re dealing with this commonly. But I would say that most physicians have never seen it. 

: Most physicians have not, and I actually surveyed on this topic not too long ago. In a group of 50, 1 person had actually witnessed it. So it’s hard to validate. It’s hard to corroborate. Patients don’t present with cataplexy when they come in to see you. If you see it, it’s really helpful, but it requires validation. And things that can look like cataplexy are often not cataplexy. I think this is really the critical point of validating what the patient perceives as being abnormal. 

: How about in children, Kiran? Is cataplexy different in children as compared to adults? 

: Yes. So a subset of children with narcolepsy can have what’s called static cataplexy, which is not triggered by emotion. They just look like they’re hypotonic. Their face looks droopy. Their eyes may be partially closed. Their mouth may be hanging open. They may even have what looks somewhat like an ataxic gait, but their neurologic exam is normal. It’s a unique presentation in children. And to add to your point, I’ve found that having parents bring in videos of events that they believe to be cataplexy can be very helpful. 

: What about the other symptoms, Alon, besides cataplexy? 

: Besides cataplexy, the next symptom to look for is sleep paralysis. Sleep paralysis is described as the inability to move—almost complete paralysis with the exception of breathing and eye movements&mdash;that typically occurs at the offset of sleep when the patient wakes up. It’s rather disruptive and disturbing to the patient. Often, they are quite anxious because of it. The good thing is that it goes away within a few minutes. Now, sleep paralysis is not unique to narcolepsy. Certainly, we have isolated sleep paralysis as a parasomnia, as an abnormal behavior, or as a sensory phenomenon during sleep or sleep-wake transition. But it is common in sleep deprivation, and it’s common, very common, in narcolepsy. 

There are also some hypnagogic and hypnopompic hallucinations in narcolepsy. The hypnopompic occur as visually disruptive hallucinations when the patient wakes up. The hypnagogic hallucinations occur when the patient transitions into sleep. They are not typical dream-like experiences that you and I probably experience, but they’re rather abrupt onset into REM [rapid eye movement] sleep. And the experiences are rather visually disturbing to the patient.  

Besides the hallucinatory experiences, sleep paralysis, and cataplexy, 1 of the fundamental issues that occurs in narcolepsy, which is related indirectly to the orexin hypocretin deficiency, is that besides the inability to maintain wakefulness in the day, there is inability to maintain sleep during the night. So insomnia, severe disrupted sleep onset, and sleep maintenance insomnia are very common in narcolepsy. You would think otherwise. You would think that those individuals would fall asleep and sleep soundly during the night, but it’s quite the opposite. 

: So this is really a 24-hours-a-day disorder, right? Patients have the sleepiness and the cataplexy during the daytime, but then they have these abnormal REM sleep phenomena and disrupted sleep at night. You rightly mentioned that sleep paralysis is more common upon awaking in the morning. But if you get it at the beginning of the night, is that more specific for narcolepsy? 

: I believe there are some studies that demonstrate that sleep paralysis at the onset of sleep is more specific to the narcolepsy phenotype as opposed to sleep paralysis in the setting of sleep deprivation that usually occurs in the morning. 

: Right. Typically, we don’t have REM sleep at the beginning of the night in normal individuals, do we? But we do have it at the end of the night. So if sleep is disrupted, we may be more likely to get that sleep paralysis when we wake up in the morning. But if you get abnormal REM at night, and you get sleep paralysis or hallucinations as you’re falling asleep at night, that really is a little bit more indicative of narcolepsy.  

Signs and Symptoms of Narcolepsy

: We talked a little about the different types of narcolepsy—type 1 and type 2. Type 1 is associated with cataplexy, which needs to be present for type 1 narcolepsy. You need to have those sleep studies, as Russ mentioned&mdash;the multiple sleep latency test&mdash;to document sleep onset REM [rapid eye movement] periods during the day, and also looking for sleep onset REM periods at night. That’s a new feature in the diagnostic criteria&mdash;having a sleep onset period at night counts toward having type 2. If a patient has 2 sleep onset REM periods&mdash;1 during the day and 1 at night&mdash;that’s consistent with the diagnosis of narcolepsy. But also measurement of CSF [cerebrospinal fluid] hypocretin.  

How easy is it to get CSF hypocretin measured? 

: Well, not many patients want to undergo a lumbar puncture to get that cerebrospinal fluid, and there are limited places in the United States that do this. My experience is that very few sleep specialists will actually do that. Maybe Dr Maski can talk about this, too, because in those cases where we’re just not sure—and it’s really important to nail down that diagnosis&mdash;I’ve known patients to agree to undergo that test. 

: And is it more important to be able to do it in children than in adults? Or not necessarily? 

: I think that in cases where you’re not able to access a sleep study or a pediatric sleep center to do the testing appropriately, it is another way of making the diagnosis. Depression is a common comorbidity of narcolepsy, and oftentimes patients are on medications like SSRIs [selective serotonin reuptake inhibitors] or SNRIs [serotonin-norepinephrine reuptake inhibitors] that actually suppress REM sleep. So when somebody goes to do the polysomnogram and the multiple sleep latency test, it’s a false-negative test because it suppresses REM. So in those cases where narcolepsy is highly suspected—and I would say also, I test for this HLA [human leukocyte antigen] allele&mdash;it increases the likelihood that the hypocretin would be low if the HLA is, in fact, positive. So in those situations, I’ll favor doing a lumbar puncture for low hypocretin values. 

: A value, of course, in type 1 narcolepsy because type 2 narcolepsy patients have normal hypocretin. They have the same sleep study findings as the type 1 patients—with the sleep onset REM periods and the sleepiness&mdash;but, of course, they don’t have cataplexy. If you were to do CSF hypocretin, you’d find that it was normal in those patients.  

: Dr Thorpy, I just wanted to follow up on 1 thing from Dr Avidan, and this isn’t part of the diagnostic criteria. Often, patients with narcolepsy have epic dreaming. I think this is somewhat overlooked, even by some sleep specialists. They don’t ask about the quality and the content of dreams. These patients have some of the most action-packed dreams I’ve ever heard. I think that speaks to this whole idea that Dr Maski was talking about. This is a REM-based disorder, so there’s REM breakthrough during the daytime but at nighttime, they are really going to town with regard to their dreams.  

: Yes. This can be particularly helpful information if you have somebody who doesn’t quite meet the diagnostic criteria for narcolepsy and may not have those 2 sleep onset REM periods but are very sleepy. Finding out about this abnormal dream phenomena at night—the paralysis, the bizarre dreams, the nightmares, the hallucinations&mdash;all that can add up to illustrating a picture that would make you think about narcolepsy. 

Narcolepsy Type 1 and Type 2

: It can be quite difficult to make the diagnosis of narcolepsy, can’t it, Eveline? What causes an underdiagnosis of narcolepsy and a delay in patients getting diagnosed with the condition? 

: I think there are many reasons for this. One of them is the misunderstanding in the general community—but even in the community of physicians, pediatricians. People don’t really know what it is. I’ve spoken to groups of school nurses, guidance counselors, school principals. They know what narcolepsy is, but they say, “Oh, isn’t that when somebody is very sleepy?” So there’s still a lot of misunderstanding. I think even in medical schools, none of us really learned what narcolepsy was, aside from maybe reading a little paragraph about it in a neurology book.  

But seeing a patient with narcolepsy and having this whole group of symptoms is just something that we don’t really connect. It’s a group of symptoms that’s not always so easy to diagnose. It’s not like, “My leg hurts,” or “I fell and my wrist hurts.” It’s something where people are sleepy. Very often, they’re diagnosed in their community as lazy. Or people say, “Oh, sleepy. Yeah, I have that, too. We all have sleepiness.” That’s something that all of them hear. So they already feel there’s a little barrier to going to the doctor and saying, “I’m tired” or “I’m sleepy.”  

They, oftentimes, don’t connect that maybe they’re experiencing cataplexy. And it doesn’t have to be falling down all the way, but just the head, maybe, a little bit. But it’s not something they connect with a syndrome or disorder. And the hallucinations, again, are something that gets associated with people with psychosis. So, people don’t really want to talk about it.  

So it’s very difficult for someone—if they already go to their doctor&mdash;to talk about all the things they have going on. And then if doctors don’t know what narcolepsy is, they don’t ask, “Do you fall down when you feel emotional? Do you feel weakness in your knees, maybe? Do you have crazy dreams? Do you have scary dreams?” That’s not something that people ask, generally, let alone in a school community. School nurses don’t think about narcolepsy. It’s a word they know, but they may not understand what it really is. 

: And even if they do recognize the tiredness and sleepiness, sometimes patients still get misdiagnosed. How about in children, Kiran? What are some of the misdiagnoses for narcolepsy in children? 

: That’s a good question. ADHD [attention-deficit/hyperactivity disorder] would be a common one. The ADHD population, in particular, is oftentimes treated with stimulants, so there is some partial improvement in the symptoms—so the diagnosis is even further confounded. In the teenaged population, I oftentimes see them coming in with primary depression as the cause of their fatigue, or sleepiness, or vivid dreams. And then, epilepsy. Oftentimes, the cataplexy could be misdiagnosed as seizures or atonic seizures. Patients are put on medications inappropriately. 

: And in the adults, Alon, what’s being misdiagnosed? 

: Just to add to what Kiran mentioned, in children you can sometimes see REM [rapid eye movement] without atonia or REM sleep behavior disorder [RBD] on the polysomnogram even before the onset of daytime sleepiness. You have to watch for the development of daytime sleepiness later on. But there are few reports of RBD in the pediatric population as a manifestation of early narcolepsy.  

: It is interesting. Again, talking about the dysregulation of rapid eye movement sleep, which both RBD and narcolepsy share, I do want to mention 1 interesting anecdote. I saw, a few years ago, a young girl from Southern California who actually presented with episodes where she fell to the ground, and she had these spells every time she hit the soccer ball and got really excited. She went to see 2 physicians—her family physician and then a psychiatrist&mdash;both of whom, unfortunately, did not make the diagnosis of narcolepsy but felt that this was a psychosomatic sort of reaction to some underlying family dynamics.  

And interestingly, she was placed on an antidepressant, which actually worked for the cataplexy—but for the wrong reason. So again, it speaks to how the under-recognition of the key symptoms often is a barrier for making the appropriate diagnosis. And there is almost a 10-year delay from the onset of the disease to when someone eventually makes the correct diagnosis. And it is, in fact, a pediatric condition, isn’t it? And oftentimes, we have an opportunity to make a diagnosis. 

Some other symptoms that are often misdiagnosed in adults, I would second what was already said about attention-deficit/hyperactivity disorder. Occasionally, though, we see individuals who are labeled as having depression or some sort of an irregular or underlying sleep deprivation without really recognizing that there is a little bit more to that. And I think the labeling issue is a huge problem, in that we often inherit patients who were given a diagnosis—sometimes correctly, sometimes incorrectly. And it speaks to the fact that we often have to validate every time we see this patient who is labeled as having a certain hyperactivity disorder or depression&mdash;to just go back and re-review the symptoms to make sure we’re not missing the diagnosis of narcolepsy. 

: How about obstructive sleep apnea? It’s such a common disorder. Can that be a problem with regard to a diagnosis of narcolepsy? 

: Definitely. In fact, obstructive sleep apnea can present with symptoms similar to narcolepsy. And, in fact, when you do the test for narcolepsy, many individuals with untreated or suboptimally treated sleep apnea may have the same markers of disease severity that you see in narcolepsy. And certainly, the complication is that 10% to 60% of patients who have treated sleep apnea are still very, very sleepy, to the point of sometimes having an underlying comorbid narcolepsy—type 1 or type 2&mdash;which often complicates the picture. 

 Diagnosis of Narcolepsy

: So once we’ve actually been able to make a diagnosis of narcolepsy, then we need to treat it. Russ, what are the goals of treatment in narcolepsy? 

: Well, we’ve talked about a number of the symptoms, so what we want to do is improve that patient’s functioning. I think we want everyone watching this to absolutely understand that this disorder of narcolepsy can have a profound impact on a person’s functioning. We want to encourage everyone to ask about these symptoms because the earlier we can detect narcolepsy, the better we can change that whole trajectory of that person’s life going forward.  

Certainly, we want to improve on their excessive daytime sleepiness, and this can be tricky. I know we’ll talk about different ways to do this, but in regard to excessive sleepiness, making sure they’re safe in their environment and safe in what they do every day. We want to optimize their ability to learn, if they’re children. We want to make sure that they’re keeping up with other kids and that they’re able to participate in not only academic activities but sports activities and other activities they would enjoy doing—dancing or whatnot. And then we want to make sure that adults are able to maintain alertness at work so they can function properly and do their job. I think in most work situations, if you’re found asleep on the job, that results in an immediate firing. And so it has an economic impact as well. 

Beyond that, we want to make sure that they can function in social relationships, and marriages, and whatever relationships they have, and that they don’t experience some of these other symptoms that Dr Avidan talked about like sleep paralysis, which can be frightening but can be treated as part of an overall package of pharmacotherapy. The frightening dreams or the hypnagogic or hypnopompic hallucinations—we spoke about this epic dreaming and so forth. So all of these REM phenomena can be treated and managed. 

Something I think I’ll reference you for, Dr Thorpy, is that these patients never normalize. Despite everyone’s best efforts to adjust medications and to do what you can for patients—we’ll talk about non-pharmacologic treatments in a moment&mdash;the patient continues to struggle to manage or balance times they want to be awake, activities that they do. It’s very difficult, even with the advances in today’s therapies, to make them feel as if they’re not experiencing narcolepsy anymore. They’re always carrying this around with them. 

: How about safety of these patients? Is there a risk associated with narcolepsy? 

: Oh, there’s absolutely a risk. We could talk about the excessive sleepiness and motor vehicle accidents. I think that can be affected, also, by cataplexy. I’ve had some adult patients who were so upset at people cutting them off while driving that they couldn’t pick up their leg to press the brake—and rear-ended somebody else. So I think both the sleepiness and the cataplexy can be a cause of accidents, either on the job or just in daytime functioning.  

The other issue is cataplexy. Dr Avidan talked about the full-blown cataplexy attacks, where people go to the floor. There are certain situations where you just can’t do that, or you end up in a lot of trouble. So cataplexy and the sleepiness, together, really increase a number of risk factors. 

: Yeah. And there are a lot of jobs where people are at risk if they have cataplectic episodes or fall asleep on the job. Really, one of the goals is not only protecting them, but also protecting others around them. 

Goals of Therapy in Narcolepsy

: These days, people are very interested in holistic treatments, nonpharmacologic treatments, and behavioral treatments. What are some of these nonpharmacologic treatments that can be helpful, Eveline? 

: I have heard from a lot of people that a gluten-free diet works for them. Also, just generally making sure that if they have to be alert after lunch, they don’t eat a lot of carbohydrates but, instead, have a protein-rich lunch or not much lunch at all. 

: Generally, proteins keep us more alert than carbohydrates? Is that what people find? 

: Definitely. I think for the general population, we all get a little more sleepy from carbohydrates. Turkey is one of the things we should stay away from, especially people with narcolepsy. Usually it takes a little bit of experimenting to see what works. And I think it’s important to encourage a healthy diet.  

Naps, of course, are very important. Most people with narcolepsy can function with 1 or 2 naps. It’s important that people in the environment of a child or adult in a work situation know about the narcolepsy so they cooperate. For children, it’s so important—they can take a nap in school. Right after lunch is usually a good time. People with narcolepsy function better when they have naps. 

: And it’s important to keep their naps relatively short, right? They shouldn’t have long naps. 

: That takes away from their nighttime sleep. What would you recommend? How long should naps be? 

: It’s a little bit different for everybody. Some people do well with a 10-minute nap. Others, half an hour. I hear very often, “I don’t want to go to my bed, so I just nap on the couch.” Or, “I have a couch at school.” That’s really very helpful.  

It should be the same time every day. People should really try to stick with a regular schedule for medications, and naps, and eating. 

: How about vitamins? Are vitamins going to be helpful at all with this disorder? 

: I think just like for the general population, it’s important to keep yourself healthy. Very often, I find that people with narcolepsy are affected more by things like the flu. So if vitamins work, that’s great. Exercise, I think, is important for people with narcolepsy. Staying fit. They tend to be a little bit overweight. For children, that’s sometimes one of the first symptoms—they gained a lot of weight. As long as they can do it, sticking with an exercise routine is very important.  

Dr Rosenberg mentioned social life. I think that is extremely important for children and adults. Children should be encouraged to go to a sleepover and to have friends. Individuals with narcolepsy tend to become isolated and have problems with friendships. They are sleepy. They want to stay home. And, this can cause a lot of friction in marital situations. 

Nonpharmacologic Therapies for Narcolepsy

: So managing these lifestyle and psychosocial aspects are very important for patients with narcolepsy, but eventually every patient with narcolepsy is going to require medication as well, aren’t they? Alon, what are the current medications? We’ll get into the newer ones that will become available, but what has been the traditional treatment for narcolepsy up until the past 12 months or so? 

: Sure. Let me just reflect on a few items that Eveline noted and mention that I also check vitamin D levels on these patients. We find that folks who have vitamin D deficiency have a harder time maintaining wakefulness. Vitamin D, apparently, does have a cofactor and a physiologic mechanism of action, not only on circadian-rhythm vitality but also on sleep and wakefulness. Those who are vitamin D deficient should be supplemented. The other thing is just running a basic laboratory evaluation, paying particular attention to thyroid function and making sure they’re not hypothyroid.  

The other thing I wanted to mention is making sure the patient has resources. There are organizations and foundations that support patients with narcolepsy. Also, it’s important to keep in mind that we’re not only treating the patient, but also the family, the significant other, the spouse, the school. Oftentimes, when I write letters asking for special accommodations for the patient, I give them some information on narcolepsy. It’s surprising that a lot of organizations and schools are very attuned to the need to support the patient by providing them with a place to take those power naps. I think it is our role, as clinicians, to really help facilitate that and make it easier for the patient to function. 

: I’m sorry to interrupt you, but Eveline was talking about some of the psychosocial aspects and the fact that kids, especially, tend to avoid those situations that evoke a cataplectic episode. So sometimes they’re seen as depressed or they become socially isolated. They’ve isolated themselves because they’re embarrassed—by the tongue thrusting, or the jaw dropping, or whatever experience they’re having. And so, not only is it important to identify these patients early, but also to understand that they may sort of shut down their emotions and stay isolated, which could be a source of significant depression. 

: And I would also add a driving assessment on a regular basis, just to make sure the patient is safe. We’re not doing the driving assessments ourselves, but rather, raising awareness by engaging the patient to make sure they are OK to drive. 

Laboratory Testing in Patients with Narcolepsy

: You really need to have comprehensive management of a patient diagnosed with narcolepsy, and it’s important to deal with the lifestyle, psychosocial aspects as well. With regard to the medications, Alon, what medications do we currently use for narcolepsy? 

: The traditional medications for narcolepsy have been psychostimulants, which have probably been around the longest. They do work. They work very effectively, but they often have some adverse effects often related to their mechanism of action of being somewhat sympathomimetics.  

: Specifically, you’re talking about the amphetamine agents and methylphenidate, is that right? 

: Exactly. In the 1990s, we saw the development of 2 medications that share 2 different mechanisms of action. One was a wake-promoting agent. We’re specifically talking about modafinil. And later on, armodafinil, the (R)-isomer of modafinil. The wake-promoting agents have the advantage of being taken once a day without inducing the sympathetic hyperactivity, which is often unique to the amphetamine-type medications.  

Sodium oxybate also came around at the same time. Sodium oxybate is very different than the traditional stimulants because it’s not a stimulant and it’s not taken during the day. We give it at night, and it works by fundamentally improving nocturnal sleep. When nocturnal sleep is improved, daytime functioning improves as well. So it is, in fact, a hypnotic, and it does work in consolidating nocturnal sleep. So those were the 4 primary treatments up until recently. With newer ones now available, we have new mechanisms of action and new opportunities for management. 

: Do the traditional stimulants and the modafinils have any effect on cataplexy, or are they just for the sleepiness? 

: The traditional stimulants do have some effect on cataplexy. The traditional wake-promoting agents do not. That is 1 differentiation, although the wake-promoting agents are not marketed or prescribed specifically to address cataplexy. But if we have someone with narcolepsy type 1 who has more difficulties with cataplexy, certainly a stimulant may have better activity. However, the 1 drug—currently the only drug&mdash;in the United States that actually has an impact on cataplexy is, in fact, sodium oxybate.  

: That’s the only one that’s FDA approved. When those stimulants do have a slight effect on cataplexy, do you think it’s mainly because they are affecting the alertness and sleepiness and, therefore, there’s not that pressure for developing cataplexy? Or do you think it’s a more specific effect on cataplexy? 

: I think it’s more of the former. They do tend to affect alertness and indirectly reduce the propensity for going into REM [rapid eye movement] sleep or inducing a REM intrusion, rather than specifically working on the underlying mechanism of action of cataplexy. 

: Now Kiran, are these same medications used for children? 

: Yes. For children, I think psychostimulants are probably the most commonly used. The only FDA-approved medications are psychostimulants. And, as of 2 years ago, sodium oxybate. There was a clinical trial showing efficacy, so that’s been added to our regimen. 

: So the modafinils are not approved for children? 

: Well, modafinil is not approved for children younger than 17 years, but certainly is used clinically and has been shown to be fairly safe. The reason it wasn’t approved for daytime sleepiness is because there were a handful of cases of Stevens-Johnson syndrome. And patients should know that if taken, it can interfere with birth control, so there’s maybe an increased risk of pregnancy. So those are some considerations. Otherwise, for children we use SSRI [selective serotonin reuptake inhibitor] and SNRI [serotonin-norepinephrine reuptake inhibitor] medications to treat cataplexy. 

: You mentioned that sodium oxybate was only just recently approved for children? 

: Yeah. It was recently approved for the treatment of daytime sleepiness and cataplexy in children aged 7 and older. In those trials, it was shown to be very effective for the treatment of cataplexy and sleepiness. Adverse effects ranged from a whole host of minor things—including nocturnal enuresis, dizziness, feeling unsteady on the feet, and weight loss&mdash;to a few cases of more severe adverse effects, such as affected mood and the development of central sleep apnea. There was even a case of suicidality in that cohort. 

: But in general, is it fairly well tolerated in children? 

: People have been concerned about sodium oxybate because it’s a derivative of gamma-hydroxybutyrate, and there have been a lot of questions about using that in adults. And yet, this drug is FDA approved for children. So in general, do they tolerate it pretty well? 

: Yes. So the patients benefit because it treats multiple symptoms of narcolepsy. It treats the daytime sleepiness. It treats the nighttime sleep disruptions. It treats cataplexy. So, in many ways, using fewer medications for the pediatric population is an advantage. And they do tolerate it well. The dosing is different than it is for the adult population. Oftentimes, I’ll slow the titration in the pediatric population. That helps avoid some of the adverse effects that I talked about. But you do have to counsel them and follow them closely for any mood-issue concerns that may develop along the way. 

Traditional Treatments for Narcolepsy

: In the last year or so, we’ve had 2 new medications approved for the treatment of narcolepsy. Russ, would you like to discuss this? There’s one called pitolisant. Tell us about that. 

: That’s probably the most recent FDA [Food and Drug Administration]-approved drug for improving alertness or wakefulness during the daytime. It’s only indicated for narcolepsy. The modafinils, as you know, are approved for other disorders of sleepiness. But Wakix, or pitolisant, is the one that, most recently, was shown to be effective for excessive daytime sleepiness associated with narcolepsy. A couple different clinical trials are worth discussing, just briefly. They used the Epworth Sleepiness Scale and found that during the course of the initial trials—an 8-week period&mdash;the scores improved. In Europe, the drug is approved for both improving wakefulness and treating cataplexy. In this country, the FDA has not yet approved it for the treatment of cataplexy. It does seem to have some positive impact on reducing cataplexy, and I do know of some sleep specialists who are using it off label for that particular purpose. 

It’s nice because this is the only wakefulness drug that is nonscheduled, so it’s easier for physicians to prescribe and may be easier to get multiple prescriptions or enough that the patient doesn’t have to come back every month to get a new prescription. But it’s not without its potential adverse effects and issues that physicians need to be cautious about. Similar to the modafinils, it can reduce the efficacy of oral contraceptives. But it’s certainly a nice new tool for physicians to have in their toolbox for treating narcolepsy. 

: There were 2 major studies done with pitolisant: 1 for cataplexy and 1 for excessive sleepiness. These studies were done in Europe, and they were shown to be effective in treating both cataplexy and sleepiness. But in the United States, it was only approved by the FDA for sleepiness. Do you think that when using it to treat those type 1 narcolepsy patients who have both cataplexy and sleepiness that it will have some beneficial effect on the cataplexy? 

: I do think it will have some beneficial effect in those patients who have cataplexy. I should also mention that this is a once-a-day dosing. There’s no need to give a second dose. We participated in an early access program for this drug and found that it seemed to carry most patients through the late afternoon, in terms of keeping them alert and awake. It didn’t run out of steam by lunchtime. It just kept going. One of the adverse effects of any potential wake-promoting drug is causing insomnia in patients. We did see a little bit of that, but I don’t think that’s unique to pitolisant. I think you have to be careful and make sure patients are taking the dose right when they wake up in the morning, especially if they’re having any difficulty falling asleep at night. 

: It has quite a novel mechanism of action, doesn’t it? Do you want to discuss that? 

: We know the usual suspects—dopamine, norepinephrine, acetylcholine, and serotonin. But 1 neurotransmitter that has not been previously implicated in excessive sleepiness has been histamine, although I think we all know that the antihistamines do cause sleepiness. So anything that improves or increases the amount of available histamine can have a positive impact. That’s this drug. This is the only drug that does actually have an impact on increasing histamine in the brain&mdash;therefore causing wakefulness. There may be others coming down the line after pitolisant, but this is currently the only drug to address that mechanism of action. 

: Can you use this drug in children, Kiran? 

: There’s a clinical trial in Europe, so hopefully we too will have another tool in our toolbox. I see patients aged 25 and younger. I also was part of the early access program. I think this medication has a slightly lower adverse effect profile in terms of anxiety or mood disorders, so it’s been beneficial for patients who have those comorbidities where stimulants can really make those situations worse. This is a medication that seems to be a little bit more neutral in regard to mood comorbidities. 

Pitolisant: Recently FDA Approved for Narcolepsy

: There’s another medication that’s been FDA approved in the past 12 months: solriamfetol, which is a dual-acting dopamine and norepinephrine reuptake inhibitor. Alon, do you have experience with this new medication?  

: I don’t particularly have experience with it. I haven’t prescribed it before, but it does have an interesting mechanism of action. It is noradrenergic and dopaminergic without really creating an amphetamine-type effect. It targets the structures in the brain that are promoting wakefulness. So in my mind, it has the unique ability to promote a level of alertness that you would see with the psychostimulants but without the sympathomimetic adverse effects. 

: I think the studies were quite impressive, Russ, in terms of the effectiveness of this agent. 

: Yes. With the self-report measures like the Epworth Sleepiness Scale that we talked about earlier, as well as another test called the Maintenance of Wakefulness Test, which is sort of the flipside of the Multiple Sleep Latency Test, where we put patients in a dimly lit room, boring situation, and ask them to try to stay awake. Patients who are pathologically sleepy have great difficulty staying alert. And so this drug did show pretty impressive results on those tests.  

It’s a Schedule IV drug, so it’s not like pitolisant in the sense of scheduling. We’ve been using this term toolbox, and I think it’s another good tool to consider. And as we spoke about earlier, we need to manage polypharmacy in patients, so this would be an option to think about. 

: It is not, but I’ve had some experience with it. I think an advantage is that it’s long acting, just like pitolisant. That is always helpful. I think in the clinical trial there was a slight increase in heart rate and blood pressure, so it does have to be followed. 

: Right, yeah. Hopefully this will be another drug that will be studied in children and shown to be helpful. 

Solriamfetol: Recently FDA Approved for Narcolepsy

 There are a number of different medications now available to us for the treatment of narcolepsy. How do we decide how we’re going to treat a patient with narcolepsy? Do you have a particular sort of algorithm you use, Alon, for treating narcolepsy? What would be your first sort of go-to drug for narcolepsy now?

That’s a really important question. I do not have an algorithm that I put the patient through and then that’s the only algorithm I follow, because all of these medications have their pluses and minuses. Patients may present with narcolepsy as a different phenotype, in that some patients may have underlying depression or anxiety. Some may have certain underlying comorbidities for which some of these agents may not be the most appropriate first-line therapy.

As a general rule, for folks who have narcolepsy type 1 and type 2, the most commonly prescribed group of drugs is the wake-promoting agents. And the advantage here: It’s a once-a-day, perhaps twice-a-day formulation. Patients take it in the morning. They may follow with a second dose later in the morning or early afternoon. We may be able to, at that point, assess the patient and evaluate whether to prescribe additional therapy. And for those individuals, if they do feel sleepy at 1 o’clock, 2 o’clock, or if they feel so sleepy that it’s affecting their driving, then a short-acting methylphenidate medication would actually be effective.

Now, the other patient who presents with excessive daytime sleepiness and cataplexy, where the cataplexy is quite frequent, would probably be most appropriately treated with sodium oxybate—and have 1 drug that addresses multiple facets of the disease by being taken at night, with a second dose 2 to 4 hours later. The advantages here are both improvement of daytime sleepiness and very effective improvement of cataplexy. Bear in mind that a lot of patients who have cataplexy may have a few episodes per week or may not require traditional therapy or a specific therapy for cataplexy itself and are able to manage it by avoiding situations&mdash;nothing that I would advocate the patients do, but they may not require a specific therapy directed at the cataplexy.

I think that with the new agents—pitolisant, solriamfetol&mdash;having the ability now to provide treatments for those who still have daytime sleepiness with the traditional stimulants and the wake-promoting agents&mdash;and knowing that 10% to 60% of those patients still experience significant daytime sleepiness that is paralyzing them&mdash;providing add-on therapy is probably going to be advocated for. Then we would have to experiment with multiple add-on therapies based on the patient phenotype.

Deciding Which Drug to Use in Narcolepsy

: All of this assumes that patients are able to get these medications. But what are you hearing, Eveline, from patients? Are they having trouble getting some of these medications because of insurance issues? Is that much of a problem here? 

: Yes, we do hear that, unfortunately. Not everybody has insurance, and even if they do, insurance doesn’t always cover medications. There are some organizations that can help with payments. However, we do hear, “I had to quit because I just can’t afford the medication.”  

: Yeah. And the newer drugs tend to be more expensive, so some insurance companies don’t want to cover them. What are you finding in regard to children, Kiran?  

: We have similar issues. Oftentimes, insurance will require that children try 2 different types of psychostimulants, and then it’s possible to cover some of these other medications, including sodium oxybate. 

Part of the fun of being a doctor is getting to know the patient—what’s important to them, what they need to be awake for. Sleepiness, as Alon was saying, is usually the fundamental issue. So finding out when they’re most sleepy is important. Would they benefit from a long-acting drug? Which is probably ideal for a school situation. And then, if they have after-school activities, we usually give low doses of methylphenidate or amphetamines to get them through that afternoon period and homework. There’s more to their day, sometimes, than just the school day. 

: With pitolisant, utilize a central pharmacy and have a robust program around patients. They’re really patient centered, and they do pretty much everything they can to help the patient navigate insurance hoops. 

: But I found in our area, either for pitolisant or solriamfetol, patients have to fail 1 of the psychostimulants, 1 of the modafinils. If they’ve been on modafinil or armodafinil and it’s worked suboptimally, then insurance companies will allow pitolisant or solriamfetol. So the patient doesn’t really have to wait. For newly identified patients, we’ve found that it’s difficult to get prescribed 1 of those drugs before trying modafinil. 

: Yeah. I should mention that sodium oxybate is the only drug that’s FDA approved for cataplexy. But if you have a child who, for 1 reason or another, can’t take sodium oxybate, what can you use for cataplexy? 

: We use SSRI [selective serotonin reuptake inhibitor] or SNRI [serotonin—norepinephrine reuptake inhibitors] medications, which I’m sure is similar to the adult practices. Specifically, we use Prozac [fluoxetine] or Effexor [venlafaxine].  

: So the antidepressants can be helpful. 

Insurance Coverage For Drugs to Treat Narcolepsy

: Treating narcolepsy, as we’ve mentioned, is really done through a holistic approach, as Alon mentioned. You have to treat patients psychosocially as well as pharmacologically. But many of these patients need a lot of support, don’t they, Eveline? What can the Narcolepsy Network to do help them? 

: Support is so important. In the doctor’s office, where they go once every 3 months or so, they get 15 to 30 minutes to discuss their condition, but they really need help in so many other areas of life. So at the Narcolepsy Network, we provide all kinds of services. We have an annual conference. This is a weekend-long conference where we have all kinds of speakers. Discussions range from the latest research, to medications, to even lawyers to help with driver’s licenses and legal issues that people run into all the time, to school issues, to special education plans, to nutrition, to lifestyle. This is a whole weekend filled with main sessions and breakout sessions. There are a lot of support sessions. We do 1-day meetings. I know all of you have been to them.  

We also have support groups. People really like to meet face to face. Then they discover they’re dealing with similar challenges. For example, one thing that wasn’t mentioned yet: A lot of people with narcolepsy struggle with being disorganized. They lose everything. They can’t find their keys. They say, “Oh, you have that too? I didn’t know that was part of it. I thought it was just part of my personality.” They find out they all have that. So they like to compare, and they also talk about medications, of course.  

We also have a relatively new program called the Youth Ambassador Program. This is for young people [aged 15 to 22]. We train them. They have a short presentation—a bit like what we do here, but a very short version&mdash;and they go out to their communities. They go to schools. They go to service clubs like rotaries, churches, synagogues, or sometimes just a family group. They connect with the newspapers [media]. They talk about narcolepsy. They don’t necessarily talk about their personal experiences. We prefer that it’s someone with narcolepsy. So this is a growing program, and it works really well. These are young people talking about narcolepsy and what it’s like to have the condition. 

: Yeah. I find that when I see a patient with narcolepsy, in most cases they don’t know anyone else who has narcolepsy. And of course, narcolepsy usually occurs as an isolated condition in a family. There are not other family members with it, in most cases. So the opportunity to meet with other people at your conferences is an enormous help to these patients. Just to see somebody else who’s going through the same thing is a great benefit to them. And for children, too. 

: I’d echo all of that. In our clinic, we’re very lucky to have a cognitive behavior therapist, too. This is very helpful for management of medications. Kids don’t like to break up their day and go to a school nurse to nap, but the therapist kind of emphasizes the importance of that. And, sleep hygiene. I think this type of guidance gives kids a sense of control over their symptoms. They can control the condition, to some degree, and that’s very important. It’s also very important to be able to confidently talk about narcolepsy and their needs. And so, in addition to medication, I find this is an important tool. 

: Oftentimes, we realize we just don’t have enough time to spend with these patients. During the last few years, I really needed to set up more time. Oftentimes, I set my initial consultation with anyone suspected of having narcolepsy as my last appointment of the day. I realize this is the time when you have to review symptoms. You have to corroborate and rereview diagnostic tests. You have to look at the patient’s expectations. You have to then look at what medication would be best for them and educate them about the medication. That cannot happen in a 1-hour appointment, and certainly not in half an hour.  

So the message is to really spend as much time as a patient needs. Follow-up visits, especially with family members and spouses, are really critical. We’ve also started to use video visits to just touch base with patients after giving them a certain medication. We do this to make sure the patient is responding to the drug. We prefer not to wait for the patient to contact us with certain complaints that we did not expect. So I think that’s a huge opportunity for everyone—to be ready and be attuned to those needs from this really unique patient population. 

: Regarding the Narcolepsy Network, I’ll just mention that I was at the last meeting. For younger people, it gives them a sense of hope. There was a physician with narcolepsy who spoke. There are lawyers. There are people who are very high functioning. Patients don’t feel so helpless. If they do want to achieve something, they still have that ability to do it. They have a sort of proverbial hand-behind-the-back situation, but they can really achieve a lot. But the disease burden is just so high for many of them. They attend those meetings and get a sense of hope, which they did not have before. 

: Definitely. I think that’s very important, and it’s important to keep the right balance. We don’t want people to think, “Oh, you have narcolepsy. If you get medications, you can become a sleep doctor like one of our board members or a high-functioning lawyer.” There is a balance. There’s still a lot of people struggling despite the medications, and not everybody can become a sleep doctor or a lawyer. But still, it’s very important to give people hope.

Patient Resources Including the Narcolepsy Network 

: Well, we’ve certainly discussed a lot about narcolepsy today. We talked about its causes and symptoms. We discussed behavioral and nonpharmacological treatments. We’ve discussed all the current therapies available for narcolepsy. But now the question is, where do we go next? What’s happening? Are there new drugs on the horizon? What have you found, Russ? 

: I’m very optimistic about what we’ve seen in the last 2 years. We went a long time without anything new—between the time that the modafinils were FDA approved to the more recent approvals for pitolisant and solriamfetol, and the use of sodium oxybate in younger patients. I think that physicians need to understand that it’s not stopping here. We still need more tools. There are other good things coming, such as a longer-acting sodium oxybate that is administered as once-a-night dosing. The currently available dosing is twice a night, typically. 

: So people have to wake up in the middle of the night to take a second dose? 

: Correct. I think it does give the physician a chance to sort of regulate the total dose a little easier. When it’s a once-a-night dose, there’s no more. You just take whatever you’re prescribed and go forward from there. 

: There are some people who have difficulty waking up for that middle-of-the-night dose. Maybe this once-a-night formulation, when it becomes available, could be helpful? 

: Yeah. It will first become available for adults and maybe later for children. I’m sure you’ve heard parents say, “You mean I have to disturb my sleep?” Parents are very willing to do most anything for their children, but this is one of the things they wish would go away. There’s also a lower-sodium oxybate formulation in development. The salt load is found to be too high for patients who have certain cardiovascular diseases. I think this will be a benefit to many patients. I think especially for patients with narcolepsy, we’re all trying to reduce salt intake. This will be a big help. And then sort of going more upstream pharmacologically, there are orexin agonists in development. These are in development not just for narcolepsy but for other disorders of excessive sleepiness. But that’s more years away compared to the low-salt and the longer-acting sodium oxybate. Those could be available to patients in the next 2 years. 

: This orexin agonist is replacing this neuropeptide that Kiran was talking about earlier. It’s also known as hypocretin. 

: But the drugs are actually under the name orexin agonists. They sound very exciting. Since we discovered in 1999 that low orexin was responsible for many cases of narcolepsy, we’ve waited for some way to be able to replace it. So the thought that there may be drugs coming out to help replace that lost orexin. 

: It’s very promising. I think with the initial attempts at orexin agonists, the trouble was that it crossed the blood-brain barrier. And now, with better technology, there are ways to overcome that. I think these advancements will help many, many patients. 

: Yes. But it’s still going to be a few years before those are available, right?  

: Yes. The orexin agonists could be 5 or more years away. The others might be more like 2 years away. 

: If low-sodium oxybate is available in the future, Alon, do you think that’s going to be useful for patients? How do you see that sort of interacting with the standard sodium oxybate that we have now? Do you think it will replace it, or will it be used sort of equally? 

: I have not prescribed sodium oxybate because I was concerned that someone’s salt load was too high to make the justification that the risk of the sodium load was overwhelming the need to control daytime sleepiness. The 1 scenario where it did happen was a gentleman who had secondary narcolepsy with destruction of the hypothalamus and SIADH [syndrome of inappropriate antidiuretic hormone secretion], who had difficulty with his salt balance. But by and large, I think it’s healthy. It’s nice not to give patients a high sodium load, but it’s not one of those reasons that we, as clinicians, do not prescribe sodium oxybate. 

: But in the elderly patients who have potential for hypertension, renal disease, cardiovascular problems… 

: It should be an advantage when it becomes available. There are other medications also being investigated. There’s a drug called reboxetine that’s just gone through some initial studies. This is a norepinephrine reuptake inhibitor, and it’s like other antidepressants. But the interesting thing about the studies done with this drug is—whereas traditional antidepressants and norepinephrine reuptake inhibitors solely affect cataplexy&mdash;this drug was shown in these latest studies to improve sleepiness as well as cataplexy. And it didn’t disturb nighttime sleep. So that’s something that we need to look for. 

Again, it’s going to be a number of years before that drug, if it ever gets approved, becomes available. But it’s exciting to think that we’ve got more options on the horizon. As you were saying earlier, Alon, we’re entering the phase of polypharmacy for patients with narcolepsy. It’s very hard to really cure these patients. You can’t cure them. However, to optimize their functions, we really need to have quite a number of options available. 

: Absolutely. I just read a recent study highlighting that folks with narcolepsy type 1 run a higher diastolic blood pressure than folks who are not on stimulants. Being on this older-generation medication, someone with an underlying condition can end up with conditions that we don’t want them to have—hypertension and cardiovascular disease. So, certainly, we’re aiming for and we’re reaching the precision medicine realm fairly quickly with more disease-modifying agents and agents that are more specific to the disease pathology, which is, in my opinion, very exciting. 

Drugs in Development for Treatment of Narcolepsy

: What are you hearing, Eveline, from patients about unmet needs in narcolepsy? What are patients really looking forward to regarding the future management of narcolepsy? 

: There’s always been the complaint that there are not enough medications available. It takes forever to get a medication approved. That’s also why we’ve been going to the FDA requesting more medications. That’s really very important so people have a choice. And, as this panel said before, not everything works for everybody. People need to experiment. It takes a while. It’s good when there is more of a choice. I think that’s really important. 

: What do you find to be the most difficult symptom in the treatment of narcolepsy? Kiran or Russ, is it the cataplexy, the sleepiness? 

: For me, it’s the nonspecific symptoms of narcolepsy. It’s the fatigue—what’s described as brain fog. This difficulty thinking, conveying thoughts, or speaking. The symptoms that are not studied or not responsive to medications are really functionally limiting to patients. 

: My experience in our research as well as in the clinic is that patients will say, “Some of these medications keep my eyes open, but I just can’t think straight.” So the cognitive complaint that you mentioned, like the brain fog, is pervasive. Just staying awake is not enough for these patients. We really need to find a way to help them overcome the cognitive problems too. 

: Right. I think some of the newer drugs are a bit better than the older ones in that regard. Very rarely will you hear a patient who is on sodium oxybate say, “This has dramatically changed my life. I really feel more normal.” Unfortunately, it doesn’t happen enough. But it does happen occasionally. In regard to the older drugs—particularly the amphetamines and methylphenidate&mdash;although they help patients stay awake, patients can still fall asleep. You have a patient with narcolepsy, you give them amphetamines, even high doses, or high doses of methylphenidate, and then you put them in a darkened room and turn off the lights&mdash;and they’re asleep right away.  

I think part of this may explain some of that sort of background cognitive impairment because the patients are able to do things better with these medications, but there’s still that background pressure for sleep—even though they are seemingly more awake. Hopefully, in the future, the drugs will be more effective at actually eliminating that pressure for sleep that’s in the background. 

Unmet Needs in the Treatment of Narcolepsy

: Most of these patients, as we mentioned earlier, are not easy to diagnose. Sleepiness is so common, and physicians need to think about it. What should community physicians know about narcolepsy and about recognizing narcolepsy? Alon, what do you think they need to do to heighten their awareness of this condition? 

: That’s a really critical question. I think they need to recognize that narcolepsy actually presents in late childhood, early teenage years. The symptoms may not be very apparent. It’s often difficult to differentiate a child who is excessively sleepy from a variety of other reasons. And knowing that the disease actually manifests itself early, in the early teenage years—only to be diagnosed 10 years later&mdash;that gap really needs to be narrowed. Folks are not asking the right questions, and we don’t have easy tests to make the diagnosis. The tests for narcolepsy are extremely difficult.  

: The median age of onset is age 16, and we know that the majority of patients don’t get a diagnosis within their first 16 years of life. So this is a big problem in pediatrics—recognizing the symptoms. 

: Yes. I think we need to recognize that children may present differently than adults in terms of their sleepiness and that there can be some behavioral manifestations. People are busy in clinic, so using a validated tool like the Epworth Sleepiness Scale or the Pediatric Daytime Sleepiness Scale can really tell you if you’re dealing with someone who has severe sleepiness that you need to take more seriously than someone who occasionally has sleepiness. And then I think it’s a great tip to use sleep logs. These are easily available tools. You can quickly make sure you’re not missing a routine sleep disorder like insufficient sleep or delayed sleep phase. And if you’re not, I think it’s appropriate to refer to someone who knows narcolepsy or is familiar with the workup of it, or to become more knowledgeable about the testing protocols. 

: Russ, what’s important for neurologists and primary care physicians to know if they have patients with narcolepsy, either in terms of treatment or diagnosis? 

: First of all, everybody in primary care has a patient with narcolepsy in their practice, whether they know it or not. This is based on the numbers alone. They need to be more proactive and spend more time with that patient who complains of sleepiness. Because as Dr Avidan said, it’s not necessarily an easy diagnosis to make. I think most neurologists have a board-certified sleep specialist they can refer to. Maybe this is less so in primary care. Do not just refer to the sleep laboratory, per se, but really find somebody you know and trust who will spend the time and has that expertise. It’s important to have a good relationship with a sleep specialist. 

: Yes. What I’d like to tell clinicians is that for any instance where a patient presents with excessive daytime sleepiness, they need to include narcolepsy in the differential diagnosis. Even if the patient has sleep apnea or some other disorder that may be contributing to the sleepiness, clinicians need to include narcolepsy in the differential diagnosis. Otherwise, they’re going to miss it. We know this disorder commonly gets missed because physicians are sort of swayed by the other conditions—and they may miss the fact that the patient also has narcolepsy. 

Advice for Community Physicians Treating Narcolepsy

: Once a patient receives a diagnosis, goes to a sleep center, and gets put on medication, what is the role of the neurologist and primary care physician? How should they be interacting with the sleep specialist, Eveline?  

: I think it’s important they keep in close contact with the sleep physician, with the sleep center. Very often, there’s embarrassment, “I don’t know too much about narcolepsy.” That should be taken away so the patient can be treated in the most successful way possible. I think it’s important to stay connected. Maybe sleep physicians should even offer to stay in touch and make themselves available to answer questions. I think it’s important to get some guidance. 

Management of Narcolepsy and Excessive Daytime Sleepiness