narcoleptic patient case study

Case #2: 29-Year-Old Male With Type 2 Narcolepsy

Experts in sleep medicine present a case of a 29-year-old male with EDS, vivid dreams, sleep paralysis, and adult ADD, and share their initial impressions.

EP: 1 . Overview and Triggers of Narcolepsy

EP: 2 . Diagnosis of Narcolepsy and Impact on QoL

EP: 3 . Therapeutic Options for the Management of Narcolepsy

Ep: 4 . newer agents for the management of narcolepsy, ep: 5 . unmet needs in narcolepsy treatment, ep: 6 . case #1: 18-year-old female with type 1 narcolepsy, ep: 7 . case #2: 29-year-old male with type 2 narcolepsy, ep: 8 . practice pearls for narcolepsy management.

Richard K. Bogan, MD, FCCP, FAASM: I’m going to throw another case at you. We’ve got a 29-year-old male project manager who presents with excessive sleepiness. He also has vivid dreams and episodes of awakening in the night feeling as though he is paralyzed and can’t move. He feels short of breath and panics during that. His bed partner says he talks a lot, kicks and yells, and sometimes when he wakes up, he sees these images or hears somebody outside trying to break into the house. He is diagnosed with having adult ADD [attention-deficit disorder] and is placed on extended-release methylphenidate, which helped his sleepiness, interestingly enough, but he is still aggravated by the sleepiness. He can still doze off in the afternoon and has trouble with projects during the day, dozing off when he is not adequately stimulated.

His clinical course has been somewhat problematic because he does have anxiety, some performance anxiety, and the methylphenidate makes his heart rate go up and makes him more nervous. He has not had any episodes of muscle weakness with strong emotions. He’s diagnosed with having an anxiety disorder and placed on escitalopram. His BMI [body mass index] is 32, and his blood pressure is 129 over 89 mm Hg, so his blood pressure is a little high. His heart rate is 78 bpm. He is actually on metoprolol for tachycardia and anxiety. So we have a fellow who is a little overweight, with elevated blood pressure and an anxiety disorder, with those symptoms. I will go ahead and tell you his MSLT [Multiple Sleep Latency Test result] was 6 minutes, and he only had 1 sleep onset REM episode. What do you think?

Asim Roy, MD : There’s another REM dissociation we didn’t get into, which I forgot to mention, but REM behavior disorder might be a feature in narcolepsy as well, where people act out their dreams. Normally, we think about this in individuals in their 50s, 60s, and 70s if they develop REM behavior. It’s a whole different meaning, potential neurodegenerative disease implications with a synucleinopathy world like Parkinson disease or Parkinson-like syndromes. In narcolepsy though, you can have REM behavior disorder at a younger age, and it can be part of that REM phenomena. There was some description of that, it seemed like, potentially; we need to dive deeper. But for me, the PSG [polysomnography], I don’t think there was any mention of the results on the PSG on this case?

Richard K. Bogan, MD, FCCP, FAASM: He did have a bit of mild sleep apnea, with an AHI [apnea-hypopnea index score] of 6, and he had mild intermittent snoring.

Asim Roy, MD : He had mild sleep apnea, I don’t think that by itself explains the degree of sleepiness. Again, you can have REM dissociation, REM-related phenomenon with sleep apnea in normal individuals as well. But again, the profoundness of how often it’s happening and how intense they are, it’s hard for me to blame it on a mild degree of sleep apnea, but it’s possible. And then that 1 SOREMP [sleep onset REM period], to me, again, he’s on an antidepressant, and I’m assuming it was left on board during the test. That may have suppressed a second REM phenomenon, a SOREMP, potentially. But putting it all together, I still have a high suspicion there’s probably type 2 narcolepsy going on with underlying mild sleep apnea. In scenarios like this, he may have some blood pressure issues. He’s on metoprolol, so it might be suppressing his blood pressure already, and that’s slightly elevated.

I would lean toward treating his mild sleep apnea, whether it’s PAP [positive airway pressure] therapy or an oral appliance to manage that component. But my suspicion is his persistent sleepiness, those persistent REM phenomena, may not disappear just by treating the OSA [obstructive sleep apnea]. Then at that point, I would feel more confident saying this is most likely a type 2 narcolepsy and then tackling those REM-related phenomena that are disturbing to him.

Richard K. Bogan, MD, FCCP, FAASM: I think that’s a good point. With the escitalopram, we may have to call the psychiatrist or family practitioner and say, “Hey.” And I’d talk to the patient as well, “Is there any chance we can take this patient off this medicine?” They’ll have to be off of it for a while, probably at least 2 weeks, fluoxetine much longer, but at least 2 weeks before we do the study. Because…we don’t fully know, but there are enough observational data that suggest this is suppressing REM sleep and will affect our nap studies. So that 1 SOREMP may have been distorted by that. Asim, what do you think about solriamfetol in this case?

Asim Roy, MD : I think it definitely has value. He’s on a stimulant, he’s seen some benefit. But could we have a little more enhanced benefit with a nonstimulant option because of his concerns with blood pressure, tachycardia, and anxiety? There are many reasons why we should probably try to get him off the stimulant if we can. With solriamfetol, the data support that there might be very little if any heart rate or blood pressure effect. Then you can get the weight-promoting benefits without having those downstream adverse effects. I think anxiety was only seen in less than 2% or 3% of the cases, using solriamfetol. So again, it’s still possible to have those downstream adverse effects, but the probability is significantly less than the traditional stimulants. I think solriamfetol would be a great option for him…from a cardiovascular standpoint, the anxiety standpoint, and the sustained benefit of something that can last 9 or 10 or so hours. He’s a project manager, and keeping him awake throughout the day can be challenging I would imagine, so replacing the stimulant with solriamfetol, I think would have added value there.

Richard K. Bogan, MD, FCCP, FAASM: I would agree. I think in situations where we have all of this anxiety and tachycardia and issues, blood pressure, we’re going to move more obviously toward the modafinil, armodafinil, and of course the solriamfetol. Then again, thinking about drug-drug interaction and some of those things. Let’s go back to our first case of the young girl with type 1, and we put her on oxybate therapy. I’ve treated her, so she was placed on low oxybate therapy and had significant improvement in the sleep disruption and the vivid dreams paralysis, and the cataplexy. But she was still sleepy, and she was pretty insistent on taking oral contraceptives, steroidal oral contraceptives. What do we do there?

Asim Roy, MD : That’s a great point. As you know, modafinil and armodafinil have a drug-drug interaction. Pitolisant has that drug-drug interaction. So if we decide to go down that road, those are significant counseling discussions with the patient. Again, solriamfetol definitely has a role here in the sense that it does not have that drug-drug interaction, it’s renally metabolized, does not go through any of the cytochrome P systems. It would be the ideal option to allow her to continue the oral contraceptives, supplement the oxybate at night, and get her through the day a bit better; it would be my first choice. The argument there would be around the oral contraceptive contraindications.

Transcript Edited for Clarity

Insomnia and the Antisuicidal Properties of Clozapine

Implementing Effective Insomnia Management: Important Issues in Evaluation and Treatment

The Week in Review: June 17-21

The Week in Review: June 3-7

Everyone Is Wrong About Benzodiazepines

Seltorexant, Major Depressive Disorder, and Insomnia: Thoughts on the New Data

2 Commerce Drive Cranbury, NJ 08512

609-716-7777

• Conversations with Leaders
• Advanced search

Advanced Search

Narcolepsy: Diagnosis and management

• Find this author on Google Scholar
• Find this author on PubMed
• Search for this author on this site
• For correspondence: [email protected]
• Figures & Data
• Info & Metrics

Narcolepsy is a chronic disorder of hypersomnia that can have a significant impact on quality of life and livelihood. However, with appropriate treatment, its symptoms are manageable, and a satisfying personal, social, and professional life can still be enjoyed. Greater awareness of the disorder promotes accurate and efficient diagnosis. With ongoing research into its underlying biology, better treatments for narcolepsy will inevitably become available.

Features of narcolepsy include daytime sleepiness, sleep attacks, cataplexy (in narcolepsy type 1), sleep paralysis, and sleep-related hallucinations.

People with narcolepsy feel sleepy and can fall asleep quickly, but they do not stay asleep for long. They go into rapid eye movement sleep soon after falling asleep. Total sleep time is normal, but sleep is fragmented.

Scheduled naps lasting 15 to 20 minutes can improve alertness. A consistent sleep schedule with good sleep hygiene is also important.

Modafinil, methylphenidate, and amphetamines are used to manage daytime sleepiness, and sodium oxybate and antidepressants are used for cataplexy.

N arcolepsy was originally described in the late 1800s by the French physician Jean-Baptiste-Edouard Gélineau, who reported the case of a wine merchant suffering from somnolence. In this first description, he coined the term narcolepsie by joining the Greek words narke (numbness or stupor) and lepsis (attack). 1

Since then, the disorder has been further characterized, and some insight into its biological underpinnings has been established. Importantly, treatments have improved and expanded, facilitating its management and thereby improving quality of life for those with the disorder.

This review focuses on clinically relevant features of the disorder and proposes management strategies.

• CLINICAL FEATURES

Narcolepsy is characterized by instability of sleep-wake transitions.

Daytime sleepiness

Clinically, narcolepsy manifests with excessive daytime sleepiness that can be personally and socially disabling. Cataplexy, sleep paralysis, and hypnagogic or hypnopompic hallucinations can also be present, 2 , 3 but they are not necessary for diagnosis. In fact, a minority of patients with narcolepsy have all these symptoms. 4 Narcolepsy is divided into type 1 (with cataplexy) and type 2 (without cataplexy). 2

Sleepiness tends to be worse with inactivity, and sleep can often be irresistible. Sleep attacks can come on suddenly and may be brief enough to manifest as a lapse in consciousness.

Short naps tend to be refreshing. Rapid eye movement (REM) latency—the interval between falling asleep and the onset of the REM sleep—is short in narcolepsy, and since the REM stage is when dreaming occurs, naps often include dreaming. Therefore, when taking a history, it is worthwhile to ask patients whether they dream during naps; a yes answer supports the diagnosis of narcolepsy. 5

In children, sleepiness can manifest in reduced concentration and behavioral issues. 6 Napping after age 5 or 6 is considered abnormal and may reflect pathologic sleepiness. 7

Cataplexy—transient muscle weakness triggered by emotion—is a specific feature of narcolepsy type 1. It often begins in the facial muscles and can manifest with slackening of the jaw or brief dropping of the head. However, episodes can be more dramatic and, if the trunk and limb muscles are affected, can result in collapsing to the ground.

Cataplexy usually has its onset at about the same time as the sleepiness associated with narcolepsy, but it can arise even years later. 8 Episodes can last from a few seconds to 2 minutes. Consciousness is always preserved. A range of emotions can trigger cataplexy, but typically the emotion is a positive one such as laughter or excitement. 9 Deep tendon reflexes disappear in cataplexy, so checking reflexes during a witnessed episode can be clinically valuable. 2

Cataplexy can worsen with stress and insufficient sleep, occasionally with “status cataplecticus,” in which repeated, persistent episodes of cataplexy occur over several hours. 8 Status cataplecticus can be spontaneous or an effect of withdrawal from anticataplectic medications. 2

Cataplexy is thought to represent intrusion of REM sleep and its associated muscle atonia during wakefulness.

Sleep paralysis, hallucinations

Sleep paralysis and hallucinations are other features of narcolepsy that reflect this REM dissociation from sleep.

Sleep paralysis occurs most commonly upon awakening, but sometimes just before sleep onset. In most cases, it is manifested by inability to move the limbs or speak, lasting several seconds or, in rare cases, minutes at a time. Sleep paralysis can be associated with a sensation of fear or suffocation, especially when initially experienced. 8

Hypnopompic hallucinations, occurring upon awakening, are more common than hypnagogic hallucinations, which are experienced before falling asleep. The hallucinations are often vivid and usually visual, although other types of hallucinations are possible. Unlike those that occur in psychotic disorders, the hallucinations tend to be associated with preserved insight that they are not real. 10

Notably, both sleep paralysis and hallucinations are nonspecific symptoms that are common in the general population. 8 , 11 , 12

Fragmented sleep

Although they are very sleepy, people with narcolepsy generally cannot stay asleep for very long. Their sleep tends to be extremely fragmented, and they often wake up several times a night. 2

This sleep pattern reflects the inherent instability of sleep-wake transitions in narcolepsy. In fact, over a 24-hour period, adults with narcolepsy have a normal amount of sleep. 13 In children, however, when narcolepsy first arises, the 24-hour sleep time can increase abruptly and can sometimes be associated with persistent cataplexy that can manifest as a clumsy gait. 14

Weight gain, obstructive sleep apnea

Weight gain is common, particularly after symptom onset, and especially in children. As a result, obesity is a frequent comorbidity. 15 Because obstructive sleep apnea can consequently develop, all patients with narcolepsy require screening for sleep-disordered breathing.

Other sleep disorders often accompany narcolepsy and are more common than in the general population. 16 In a study incorporating both clinical and polysomnographic data of 100 patients with narcolepsy, insomnia was the most common comorbid sleep disorder, with a prevalence of 28%; others were REM sleep behavior disorder (24%), restless legs syndrome (24%), obstructive sleep apnea (21%), and non-REM parasomnias. 17

• PSYCHOSOCIAL CONSEQUENCES

Narcolepsy has significant psychosocial consequences. As a result of their symptoms, people with narcolepsy may not be able to meet academic or work-related demands.

Additionally, their risk of a motor vehicle accident is 3 to 4 times higher than in the general population, and more than one-third of patients have been in an accident due to sleepiness. 18 There is some evidence to show that treatment eliminates this risk. 19

Few systematic studies have examined mood disorders in narcolepsy. However, studies tend to show a higher prevalence of psychiatric disorders than in the general population, with depression and anxiety the most common. 20 , 21

• DIAGNOSIS IS OFTEN DELAYED

The prevalence of narcolepsy type 1 is between 25 and 100 per 100,000 people. 22 In a Mayo Clinic study, 23 the incidence of narcolepsy type 1 was estimated to be 0.74 per 100,000 person-years. Epidemiologic data on narcolepsy type 2 are sparse, but patients with narcolepsy without cataplexy are thought to represent only 36% of all narcolepsy patients. 23

Diagnosis is often delayed, with the average time between the onset of symptoms and the diagnosis ranging from 8 to 22 years. With increasing awareness, the efficiency of the diagnostic process is improving, and this delay is expected to lessen accordingly. 24

Symptoms most commonly arise in the second decade; but the age at onset ranges significantly, between the first and fifth decades. Narcolepsy has a bimodal distribution in incidence, with the biggest peak at approximately age 15 and second smaller peak in the mid-30s. Some studies have suggested a slight male predominance. 23 , 25

Narcolepsy should be considered in the differential diagnosis for chronic excessive daytime sleepiness, but this disorder has many mimics ( Table 1 ).

• View inline

Narcolepsy: Differential diagnosis

History is key

The history should include specific questions about the hallmark features of narcolepsy, including cataplexy, sleep paralysis, and sleep-related hallucinations. For individual assessment of subjective sleepiness, the Epworth Sleepiness Scale or Pediatric Daytime Sleepiness Scale can be administered quickly in the office setting. 26 , 27

The Epworth score is calculated from the self-rated likelihood of falling asleep in 8 different situations, with possible scores of 0 (would never doze) to 3 (high chance of dozing) on each question, for a total possible score of 0 to 24. Normal total scores are between 0 and 10, while scores greater than 10 reflect pathologic sleepiness. Scores on the Epworth Sleepiness Scale in those with narcolepsy tend to reflect moderate to severe sleepiness, or at least 13, as opposed to patients with obstructive sleep apnea, whose scores commonly reflect milder sleepiness. 28

Testing with actigraphy and polysomnography

It is imperative to rule out insufficient sleep and other sleep disorders as a cause of daytime sleepiness. This can be done with a careful clinical history, actigraphy with sleep logs, and polysomnography.

In the 2 to 4 weeks before actigraphy and subsequent testing, all medications with alerting or sedating properties (including antidepressants) should be tapered off to prevent influence on the results of the study.

Actigraphy. Testing should start with a 1- to 2-week monitoring period. The patient wears a bracelet that measures sleep-wake patterns and objectively quantifies sleep duration, bedtimes, and wake-up times ( Figure 1 ). While undergoing this test, the patient should also keep a sleep log, noting perceived sleep quantity and schedule over the time period ( Figure 2 ). This confirms whether sleep quantity is sufficient and helps rule out circadian rhythm disorders such as delayed sleep-phase disorder and insufficient sleep syndrome.

• Download figure
• Open in new tab
• Download powerpoint

Actigraphy report showing sleep schedule with relatively little variation, with bedtimes ranging from 8 to 10 PM and wake-up times from 6 to 9 AM.

Sleep log from the patient in Figure 1 shows relatively good concordance between perceived sleep schedule and actual sleep schedule.

Delayed sleep-phase disorder presents at a similar age as narcolepsy and can be associated with similar degrees of sleepiness. However, individuals with delayed sleep phase disorder have an inappropriately timed sleep-wake cycle so that there is a shift in their desired sleep onset and awakening times. It is common—prevalence estimates vary but average about 1% in the general population. 29

Insufficient sleep syndrome is even more common, especially in teenagers and young adults, with increasing family, social, and academic demands. Sleep needs vary across the life span. A teenager needs 8 to 10 hours of sleep per night, and a young adult needs 7 to 9 hours. A study of 1,285 high school students found that 10.4% were not getting enough sleep. 30

If actigraphy data suggest a circadian rhythm disorder or insufficient sleep that could explain the symptoms of sleepiness, then further testing should be halted and these specific issues should be addressed. In these cases, working with the patient toward maintaining a regular sleep-wake schedule with 7 to 8 hours of nightly sleep will often resolve symptoms.

If actigraphy demonstrates the patient is maintaining a regular sleep schedule and allowing adequate time for nightly sleep, the next step is polysomnography.

Polysomnography is performed to detect other disorders that can disrupt sleep, such as sleep-disordered breathing or periodic limb movement disorder. 2 , 5 In addition, polysomnography can provide assurance that adequate sleep was obtained prior to the next step in testing.

Multiple sleep latency test

If sufficient sleep is obtained on polysomnograpy (at least 6 hours for an adult) and no other sleep disorder is identified, a multiple sleep latency test is performed. A urine toxicology screen is typically performed on the day of the test to ensure that drugs are not affecting the results.

The multiple sleep latency test consists of 4 to 5 nap opportunities at 2-hour intervals in a quiet dark room conducive to sleep, during which both sleep and REM latency are recorded. The sleep latency of those with narcolepsy is significantly shortened, and the diagnosis of narcolepsy requires an average sleep latency of less than 8 minutes.

Given the propensity for REM sleep in narcolepsy, another essential feature for diagnosis is the sleep-onset REM period (SOREMP). A SOREMP is defined as a REM latency of less than 15 minutes. A diagnosis of narcolepsy requires a SOREMP in at least 2 of the naps in a multiple sleep latency test (or 1 nap if the shortened REM latency is seen during polysomnography). 31

The multiple sleep latency test has an imperfect sensitivity, though, and should be repeated when there is a high suspicion of narcolepsy. 32 – 34 It is not completely specific either, and false-positive results occur. In fact, SOREMPs can be seen in the general population, particularly in those with a circadian rhythm disorder, insufficient sleep, or sleep-disordered breathing. Two or more SOREMPs in an multiple sleep latency test can be seen in a small proportion of the general population. 35 The results of a multiple sleep latency test should be interpreted in the clinical context.

Differential diagnosis

Narcolepsy type 1 is distinguished from type 2 by the presence of cataplexy. A cerebrospinal fluid hypocretin 1 level of 110 pg/mL or less, or less than one-third of the mean value obtained in normal individuals, can substitute for the multiple sleep latency test in diagnosing narcolepsy type 1. 31 Currently, hypocretin testing is generally not performed in clinical practice, although it may become a routine part of the narcolepsy evaluation in the future.

Thus, according to the International Classification of Sleep Disorders, 3rd edition , 31 the diagnosis of narcolepsy type 1 requires excessive daytime sleepiness for at least 3 months that cannot be explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder, and at least 1 of the following:

Cataplexy and mean sleep latency of 8 minutes or less with at least 2 SOREMPs on multiple sleep latency testing (1 of which can be on the preceding night’s polysomography)

Cerebrospinal fluid hypocretin 1 levels less than 110 pg/mL or one-third the baseline normal levels and mean sleep latency ≤ 8 minutes with ≥ 2 SOREMPs on multiple sleep latency testing.

Similarly, the diagnosis of narcolepsy type 2 requires excessive daytime sleepiness for at least 3 months that cannot be explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder, plus:

Mean sleep latency of 8 minutes or less with at least 2 SOREMPs on multiple sleep latency testing.

Idiopathic hypersomnia , another disorder of central hypersomnolence, is also characterized by disabling sleepiness. It is diagnostically differentiated from narcolepsy, as there are fewer than 2 SOREMPs. As opposed to narcolepsy, in which naps tend to be refreshing, even prolonged naps in idiopathic hypersomnia are often not helpful in restoring wakefulness. In idiopathic hypersomnia, sleep is usually not fragmented, and there are few nocturnal arousals. Sleep times can often be prolonged as well, whereas in narcolepsy total sleep time through the day may not be increased but is not consolidated.

Kleine-Levin syndrome is a rarer disorder of hypersomnia. It is episodic compared with the relatively persistent sleepiness in narcolepsy and idiopathic hypersomnia. Periods of hypersomnia occur intermittently for days to weeks and are accompanied by cognitive and behavioral changes including hyperphagia and hypersexuality. 4

• LINKED TO HYPOCRETIN DEFICIENCY

Over the past 2 decades, the underlying pathophysiology of narcolepsy type 1 has been better characterized.

Narcolepsy type 1 has been linked to a deficiency in hypocretin in the central nervous system. 36 Hypocretin (also known as orexin) is a hormone produced in the hypothalamus that acts on multiple brain regions and maintains alertness. For unclear reasons, hypothalamic neurons producing hypocretin are selectively reduced in narcolepsy type 1. Hypocretin also stabilizes wakefulness and inhibits REM sleep; therefore, hypocretin deficiency can lead to inappropriate intrusions of REM sleep onto wakefulness, leading to the hallmark features of narcolepsy—cataplexy, sleep-related hallucinations, and sleep paralysis. 37 According to one theory, cataplexy is triggered by emotional stimuli because of a pathway between the medial prefrontal cortex and the amygdala to the pons. 38

Cerebrospinal fluid levels of hypocretin in patients with narcolepsy type 2 tend to be normal, and the biologic underpinnings of narcolepsy type 2 remain mysterious. However, in the subgroup of those with narcolepsy type 2 in which hypocretin is low, many individuals go on to develop cataplexy, thereby evolving to narcolepsy type 1. 36

• POSSIBLE AUTOIMMUNE BASIS

Narcolepsy is typically a sporadic disorder, although familial cases have been described. The risk of a parent with narcolepsy having a child who is affected is approximately 1%. 5

Narcolepsy type 1 is strongly associated with HLA-DQB1*0602 , with up to 95% of those affected having at least one allele. 39 Having 2 copies of the allele further increases the risk of developing narcolepsy. 40 However, this allele is far from specific for narcolepsy with cataplexy, as it occurs in 12% to 38% of the general population. 41 Therefore, HLA typing currently has limited clinical utility. The exact cause is as yet unknown, but substantial literature proposes an autoimmune basis of the disorder, given the strong association with the HLA subtype. 42 – 44

After the 2009 H1N1 influenza pandemic, there was a significant increase in the incidence of narcolepsy with cataplexy, which again sparked interest in an autoimmune etiology underlying the disorder. Pandemrix, an H1N1 vaccine produced as a result of the 2009 pandemic, appeared to also be associated with an increase in the incidence of narcolepsy. An association with other upper respiratory infections has also been noted, further supporting a possible autoimmune basis.

A few studies have looked for serum autoantibodies involved in the pathogenesis of narcolepsy. Thus far, only one has been identified, an antibody to Tribbles homolog 2, found in 20% to 40% of those with new onset of narcolepsy. 42 – 44

• TREATMENTS FOR DAYTIME SLEEPINESS

As with many chronic disorders, the treatment of narcolepsy consists of symptomatic rather than curative management, which can be done through both pharmacologic and nonpharmacologic means.

Nondrug measures

Scheduled naps lasting 15 to 20 minutes can help improve alertness. 45 A consistent sleep schedule with good sleep hygiene, ensuring sufficient nightly sleep, is also important. In one study, the combination of scheduled naps and regular nocturnal sleep times reduced the level of daytime sleepiness and unintentional daytime sleep. Daytime naps were most helpful for those with the highest degree of daytime sleepiness. 45

Strategic use of caffeine can be helpful and can reduce dependence on pharmacologic treatment.

Screening should be performed routinely for other sleep disorders, such as sleep-disordered breathing, which should be treated if identified. 5 , 18 When being treated for other medical conditions, individuals with narcolepsy should avoid medications that can cause sedation, such as opiates or barbiturates; alcohol should be minimized or avoided.

Networking with other individuals with narcolepsy through support groups such as Narcolepsy Network can be valuable for learning coping skills and connecting with community resources. Psychological counseling for the patient, and sometimes the family, can also be useful. School-age children may need special accommodations such as schedule adjustments to allow for scheduled naps or frequent breaks to maintain alertness.

People with narcolepsy tend to function better in careers that do not require long periods of sitting, as sleepiness tends to be worse, but instead offer flexibility and require higher levels of activity that tend to combat sleepiness. They should not work as commercial drivers. 18

Medications

While behavioral interventions in narcolepsy are vital, they are rarely sufficient, and drugs that promote daytime wakefulness are used as an adjunct ( Table 2 ). 46

Drugs to treat excessive daytime sleepiness in narcolepsy

Realistic expectations should be established when starting, as some degree of residual sleepiness usually remains even with optimal medical therapy. Medications should be strategically scheduled to maximize alertness during necessary times such as at work or school or during driving. Patients should specifically be counseled to avoid driving if sleepy. 18 , 47

Modafinil is often used as a first-line therapy, given its favorable side-effect profile and low potential for abuse. Its pharmacologic action has been debated but it probably acts as a selective dopamine reuptake inhibitor. It is typically taken twice daily (upon waking and early afternoon) and is usually well tolerated.

Potential side effects include headache, nausea, dry mouth, anorexia, diarrhea, and, rarely, Stevens-Johnson syndrome. Cardiovascular side effects are minimal, making it a favorable choice in older patients. 18 , 48

A trial in 283 patients showed significantly lower levels of sleepiness in patients taking modafinil 200 mg or 400 mg than in a control group. Other trials have supported these findings and showed improved driving performance on modafinil. 18

Notably, modafinil can increase the metabolism of oral contraceptives, thereby reducing their efficacy. Women of childbearing age should be warned about this interaction and should be transitioned to nonhormonal forms of contraception. 2 , 47

Armodafinil , a purified R-isomer of modafinil, has a longer half-life and requires only once-daily dosing. 5

If modafinil or armodafinil fails to optimally manage daytime sleepiness, a traditional stimulant such as methylphenidate or an amphetamine is often used.

Methylphenidate and amphetamines primarily inhibit the reuptake and increase the release of the monoamines, mainly dopamine, and to a lesser degree serotonin and norepinephrine.

These drugs have more significant adverse effects that can involve the cardiovascular system, causing hypertension and arrhythmias. Anorexia, weight loss, and, particularly with high doses, psychosis can occur. 49

These drugs should be avoided in patients with a history of significant cardiovascular disease. Before starting stimulant therapy, a thorough cardiovascular examination should be done, often including electrocardiography to ensure there is no baseline arrhythmia.

Patients on these medications should be followed closely to ensure that blood pressure, pulse, and weight are not negatively affected. 18 , 50 Addiction and tolerance can develop with these drugs, and follow-up should include assessment for dependence. Some states may require prescription drug monitoring to ensure the drugs are not being abused or diverted.

Short- and long-acting formulations of both methylphenidate and amphetamines are available, and a long-acting form is often used in conjunction with a short-acting form as needed. 18

Addiction and drug-seeking behavior can develop but are unusual in those taking stimulants to treat narcolepsy. 49

Residual daytime sleepiness can be measured subjectively through the Epworth Sleepiness Scale on follow-up. If necessary, a maintenance-of-wakefulness test can provide an objective assessment of treatment efficacy. 18

As narcolepsy is a chronic disorder, treatment should evolve with time. Most medications that treat narcolepsy are categorized by the US Food and Drug Administration as pregnancy category C, as we do not have adequate studies in human pregnancies to evaluate their effects. When a patient with narcolepsy becomes pregnant, she should be counseled about the risks and benefits of remaining on therapy. Treatment should balance the risks of sleepiness with the potential risks of remaining on medications. 50 In the elderly, as cardiovascular comorbidities tend to increase, the risks and benefits of therapy should be routinely reevaluated.

For cataplexy

Medications may not be required to treat mild or infrequent cataplexy. However, treatment may be indicated for more severe cases of cataplexy. Anticataplexy agents are detailed in Table 3 .

Medications to treat cataplexy in narcolepsy

Sodium oxybate , 51 – 53 the most potent anticataplectic drug, is the sodium salt of gamma hydroxybutyrate, a metabolite of gamma-aminobutyric acid. Sodium oxybate can be prescribed in the United States, Canada, and Europe. The American Academy of Sleep Medicine recommends sodium oxybate for cataplexy, daytime sleepiness, and disrupted sleep based on 3 level-1 studies and 2 level-4 studies. 46

Sodium oxybate increases slow-wave sleep, improves sleep continuity, and often helps to mitigate daytime sleepiness. Due to its short half-life, its administration is unusual: the first dose is taken before bedtime and the second dose 2.5 to 4 hours later. Some patients set an alarm clock to take the second dose, while others awaken spontaneously to take the second dose. Most patients find that with adherence to dosing and safety instructions, sodium oxybate can serve as a highly effective form of treatment of both excessive sleepiness and cataplexy and may reduce the need for stimulant-based therapies.

The most common adverse effects are nausea, mood swings, and enuresis. Occasionally, psychosis can result and limit use of the drug. Obstructive sleep apnea can also develop or worsen. 52 Because of its high salt content, sodium oxybate should be used with caution in those with heart failure, hypertension, or renal impairment. Its relative, gamma hydroxybutyrate, causes rapid sedation and has been notorious for illegal use as a date rape drug.

In the United States, sodium oxybate is distributed only through a central pharmacy to mitigate potential abuse. Due to this system, the rates of diversion are extremely low, estimated in a postmarketing analysis to be 1 instance per 5,200 patients treated. In the same study, abuse and dependence were both rare as well, about 1 case for every 2,600 and 6,500 patients treated. 6 , 18 , 52 , 53

Antidepressants promote the action of norepinephrine and, to a lesser degree, serotonin, thereby suppressing REM sleep.

Venlafaxine, a serotonin-norepinephrine reuptake inhibitor, is often used as a first-line treatment for cataplexy. Selective serotonin reuptake inhibitors such as fluoxetine are also used with success. Tricyclic antidepressants such as protriptyline or clomipramine are extremely effective for cataplexy, but are rarely used due to their adverse effects. 2 , 47

• FUTURE WORK

While our understanding of narcolepsy has advanced, there are still gaps in our knowledge of the disorder—namely, the specific trigger for the loss of hypocretin neurons in type 1 narcolepsy and the underlying pathophysiology of type 2.

A number of emerging therapies target the hypocretin system, including peptide replacement, neuronal transplant, and immunotherapy preventing hypocretin neuronal cell death. 50 , 54 , 55 Additional drugs designed to improve alertness that do not involve the hypocretin system are also being developed, including a histamine inverse agonist. 50 , 56 Sodium oxybate and modafinil, although currently approved for use in adults, are still off-label in pediatric practice. Studies of the safety and efficacy of these medications in children are needed. 7 , 57

• Copyright © 2018 The Cleveland Clinic Foundation. All Rights Reserved.
• Dauvilliers Y ,
• Scammell TE
• Morrish E ,
• Shneerson JM
• Babiker MO ,
• Overeem S ,
• van Nues SJ ,
• van der Zande WL ,
• Donjacour CE ,
• van Mierlo P ,
• Sharpless BA ,
• Broughton R ,
• Duschesne P ,
• Franceschini C ,
• Peltola H ,
• Kotagal S ,
• Tartarotti S ,
• Poryazova R ,
• Baumann CR ,
• Bassetti CL
• Frauscher B ,
• Ehrmann L ,
• Mitterling T ,
• Jaussent I ,
• Fortuyn HD ,
• Lappenschaar MA ,
• Reaven NL ,
• Longstreth WT Jr . ,
• Koepsell TD ,
• Hendrickson AF ,
• van Belle G
• Silber MH ,
• Pankratz VS
• Thorpy MJ ,
• Montplaisir J ,
• Molinari N ,
• Burduvali E ,
• Jefferson C ,
• van der Heide A ,
• van Schie MK ,
• Lammers GJ ,
• Pallesen S ,
• Saxvig IW ,
• Sørensen E ,
• Wilhelmsen-Langeland A ,
• American Academy of Sleep Medicine
• Trotti LM ,
• Andlauer O ,
• Jouhier L ,
• Nishino S ,
• Williams RH ,
• Agostinelli L ,
• Grumet FC ,
• Guilleminault C
• Guilleminault C ,
• Akintomide GS ,
• Mahlios J ,
• De la Herrán-Arita AK ,
• Liblau RS ,
• Vassalli A ,
• Seifinejad A ,
• Rogers AE ,
• Aldrich MS ,
• Morgenthaler TI ,
• Standards of Practice Committee of the American Academy of Sleep Medicine
• Schwartz JR ,
• Hirshkowitz M ,
• Goodman SH ,
• Pankratz VS ,
• Drakatos R ,
• Lykouras D ,
• D’Ancona G ,
• Mansukhani MR ,
• Carter LR ,
• Benowitz NL
• Weinhold SL ,
• Seeck-Hirschner M ,
• Hallschmid M ,
• Arias-Carrion O ,
• Murillo-Rodriguez E
• Leu-Semenescu S ,
• Golmard JL ,
• Lecendreux M ,

In this issue

• Table of Contents
• Table of Contents (PDF)
• Index by author

Thank you for your interest in spreading the word on Cleveland Clinic Journal of Medicine.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Citation Manager Formats

• EndNote (tagged)
• EndNote 8 (xml)
• RefWorks Tagged
• Ref Manager

• Tweet Widget
• Facebook Like
• Linkedin Share Button

Jump to section

Related articles.

• No related articles found.
• Google Scholar

Cited By...

• No citing articles found.

More in this TOC Section

• Helicobacter pylori : A concise review of the latest treatments against an old foe
• Digoxin is still useful, but is still causing toxicity
• Diabetic retinopathy: Screening, prevention, and treatment

Similar Articles

• Drug Therapy
• Sleep Medicine

Advertisement

A practical guide to the pharmacological and behavioral therapy of Narcolepsy 

• Published: 22 April 2021
• Volume 18 , pages 6–19, ( 2021 )

Cite this article

• Christian Franceschini 1 ,
• Fabio Pizza 2 , 4 ,
• Francesca Cavalli 2 &
• Giuseppe Plazzi   ORCID: orcid.org/0000-0002-1051-0472 3 , 4  

6562 Accesses

19 Citations

Explore all metrics

Narcolepsy is a rare, chronic, and disabling central nervous system hypersomnia; two forms can be recognized: narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). Its etiology is still largely unknown, but studies have reported a strong association between NT1 and HLA, as well as a pathogenic association with the deficiency of cerebrospinal hypocretin-1. Thus, the most reliable pathogenic hypothesis is an autoimmune process destroying hypothalamic hypocretin-producing cells. A definitive cure for narcolepsy is not available to date, and although the research in the field is highly promising, up to now, current treatments have aimed to reduce the symptoms by means of different pharmacological approaches. Moreover, overall narcolepsy symptoms management can also benefit from non-pharmacological approaches such as cognitive behavioral therapies (CBTs) and psychosocial interventions to improve the patients’ quality of life in both adult and pediatric-affected individuals as well as the well-being of their families. In this review, we summarize the available therapeutic options for narcolepsy, including the pharmacological, behavioral, and psychosocial interventions.

Similar content being viewed by others

Narcolepsy treatment: pharmacological and behavioral strategies in adults and children

Treatment options for narcolepsy, management of narcolepsy.

Avoid common mistakes on your manuscript.

Introduction

Narcolepsy is a severe, chronic, and rare disorder, classified by the International Classification of Sleep Disorders Third Edition (ICSD-III) [ 1 ] within the central disorders of hypersomnolence (CDH). Narcolepsy is categorized in narcolepsy type 1 (NT1) and in narcolepsy type 2 (NT2). NT1 is biologically marked by low cerebrospinal fluid hypocretin-1 levels (CSF hcrt-1), caused by the selective loss of hypothalamic neurons producing hypocretins, while NT2 is associated with normal levels of CSF hcrt-1 [ 1 ]. Narcolepsy core symptoms are excessive daytime sleepiness (EDS), cataplexy, sleep paralyses, hallucinations, and disrupted nocturnal sleep including frequent parasomnias. Cataplexy, defined as brief episodes of muscle atonia evoked by strong, mainly positive, emotions, is the pathognomonic symptom of NT1, while NT2 does not present with strictly defined cataplexy. Hypocretin-1 contributes to several functions, including circadian rhythm regulation, arousal and appetite control, as well as mood and behavior modulation [ 2 – 4 ]. This neurotransmitter also influences serotonin, histamine, dopamine, acetylcholine, GABA, and glutamate release [ 5 , 6 ]. The hypocretin-producing cell destruction contributes to most of the symptoms of narcolepsy, including EDS with sleep onset REM periods (SOREMPs), and other symptoms reflecting exaggerated REM sleep pressure such as cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations, and REM sleep behavior disorder (RBD), all disclosing an intrinsic overlap between REM sleep and other states.

Narcolepsy onset usually occurs between 10 and 20 years of age, although the diagnosis is mostly established with a substantial delay (mean of 10–15 years). Narcolepsy, as a rare disease, has a prevalence that varies from geographical regions ranging from 0.02 to 0.06% in Europe and the USA [ 8 ], to 0.16–0.18% in Japan [ 7 ]. NT1 is considered more frequent than NT2, both in adults and in children [ 9 ], although real prevalence rates are missing and both disorders may be largely underestimated.

The etiology of narcolepsy is still unknown, but recent studies have suggested an autoimmune hypothesis. Indeed, NT1 is strongly associated with the human leukocyte antigen (HLA) DQB1*0602 allele and other genetic features pointing to a specific configuration of the immune system, and environmental risk factors, such as upper airway infections, may act as triggers leading to the destruction of hypothalamic hypocretin-producing neurons [ 10 ]. On the other hand, the pathophysiology of NT2 is still unclear, and within this diagnosis, some subjects may be in a prodromic phase of NT1 (with subsequent appearance of cataplexy) [ 11 ].

NT1 is also associated with significant medical comorbidities, such as obesity, precocious puberty (in the childhood onset form), and cardiovascular problems [ 12 ], as well as with psychological consequences all to psychiatric diseases [ 13 ]. Narcolepsy has a severe impact on patients’ quality of life, with impairment in performance (e.g., at school, at work, at home) and psychosocial difficulties [ 14 ]. Patients also report additional non-sleep related aspects (i.e., decreased sexual activity or memory complaints) that negatively impact on disease perception and quality of life [ 15 ], and patients’ unmet needs could benefit from new multidisciplinary management strategies [ 16 , 17 ]. Indeed, pharmacological symptom management per se may be insufficient to allow for normal everyday life, so behavioral therapies and interventions remain crucial.

This review seeks to offer clinicians an overview of the available pharmacological treatments for narcolepsy core symptoms (i.e., EDS and cataplexy) in adult and pediatric patients, and to provide a summary of some useful behavioral and psychosocial interventions.

The first author (CF) performed a systematic literature search by using different scientific databases and keywords combinations, and selecting references published or available online in the timespan between 1975 and December 2020. The following scientific databases were used: PubMed, Web of Sciences, and PsycINFO. The following keywords were used alone and in combination to retrieve useful literature on narcolepsy treatment: narcolepsy, narcolepsy type 1, narcolepsy type 2, narcolepsy with cataplaxy, narcolepsy without cataplexy, treatment, pharmacotherapy, cognitive behavioral treatment (CBT), peer support, and counseling. The literature search provided a total amount of 4075 results from PubMed, 1716 from Web of Science, and 2344 from PsycINFO. The results obtained were then merged in order to avoid redundancies, and references were selected by applying the following criteria: (1) publication in English; (2) availability of full text; (3) exclusion of reviews on narcolepsy management, and of single case reports/studies; and (4) author judgement of clinical relevance. The final citation list was then narrowed down to 137 references. We classified drugs as first-line treatments on the basis of the available evidence (i.e. clinical trials) and approval by the authorities.

Pharmacological Treatment

Pharmacological treatment for narcolepsy is necessary to manage symptoms and to improve patients’ quality of life. Available treatments may act on one or multiple symptoms, namely, EDS, cataplexy, and disturbed nocturnal sleep. Given the diverse effect of the different drugs, the choice of a first-line approach should consider the complexity of individual patients, the burden of each symptom, the occurrence of multiple symptoms in combination, and the potential comorbidity/side effects taking into account sleep–wake habits and social patients’ needs. In this review, we will distinguish between first- and second-line approaches on the basis of the available evidence (clinical trials, registration by authorities). Indeed, studies directly comparing the effects of different drugs on EDS and cataplexy are lacking; thus, the choice of the initial treatment should rely on the possibility to access the drug, on clinical judgement (including side effects), and on active discussion with the patients. We suggest starting the treatment with monotherapy, thus preferring the use of drugs acting on multiple symptoms in NT1 (i.e., sodium oxybate or pitolisant), and adding treatment(s) should depend on clinical judgement including careful follow-up with discussions with patients and caregivers. We prefer a patient-centered treatment decision (i.e., the choice to start with night-time versus daytime treatment) that takes into account individual habits and needs, so we do not suggest an a priori pharmacological treatment strategy.

For a number of drugs, and for the treatment of pediatric patients, approval is still pending at the European Medicine Agency (EMA) and/or at the Food and Drug Administration (FDA). Moreover, some treatments (antidepressants), albeit not registered for narcolepsy, have been extensively used for decades and have proven efficacious, so they are still prescribed off-label.

In this review, we will try to summarize the main treatments hitherto available for both adults and children with narcolepsy and the recommendations solely for adult patients with the aim of providing a practical guide for clinicians. We provide, in three tables, an overview of the available pharmacological treatment for EDS in adults (Table 1 ), for cataplexy in adults (Table 2 ), and for EDS and cataplexy in children (Table 3 ).

EDS Pharmacological Treatment in Adults

First-line treatments.

Modafinil is a weak inhibitor of dopamine reuptake that leads to an increase in extracellular dopamine. Although it has found that modafinil selectively stimulates wake-generating sets in the hypothalamus [ 18 ], its mechanism of action is still largely unknown [ 19 ]. At the dosage of 200–400 mg/day, modafinil improves subjective EDS and objective vigilance as measured by sleep latencies on Maintenance of Wakefulness Test (MWT), a finding confirmed by positive changes at the Clinical Global Improvement of Change (CGI-C) [ 20 – 24 ].

Modafinil treatment usually starts with 100 mg (in the morning) and can be titrated gradually to 200 mg in a split dose in the morning (at awakening and at lunch time). After several weeks, the dose can be increased to 200 + 200 mg [ 23 , 24 ].

Approved by the FDA and EMA both for adult narcolepsy patients, modafinil is considered a good therapy because of a low addiction potential and mild side effects—generally headache, nausea, tension/anxiety, and insomnia [ 25 – 29 ]. Modafinil decreases the efficacy of oral contraceptives; thus, higher ethinylestradiol or alternative contraceptive methods are suggested [ 30 ].

Armodafinil

Armodafinil is the active R-enantiomer of modafinil and has a longer half-life. Armodafinil has the effect of reducing EDS in narcolepsy with a significant improvement in both MWT sleep latencies (1.3 to 2.6 min) and in the Epworth Sleepiness Scale (ESS) score (3.8 to 4.1). [ 31 ]. Most common side effects include headache, nausea, dizziness, and decreased appetite. Armodafinil has been approved by the FDA in treating narcolepsy adult patients [ 20 , 21 ]. Its recommended dosage should start with a single dose of 100 mg in the morning up to a maximum of 250 mg/day.

Pitolisant is a selective H3 receptor competitive antagonist/inverse agonist. Pitolisant acts at the presynaptic level by blocking the auto-inhibiting activity of histamine and H3R agonists on endogenous histamine release and leading to increased histamine release. Histaminergic neuron activity in the brain is involved in a large variety of functions, including wakefulness, attention, and memory [ 32 – 35 ]. Pitolisant has proven to have a no lesser efficacy on EDS compared to modafinil [ 32 ] and has also proven efficacious in decreasing cataplexy [ 33 , 34 ]. The efficacy on EDS has been assessed on subjective EDS (ESS improvement of 4–6 points), and on secondary outcomes, namely objective vigilance (MWT) and CGI-C. In adults, pitolisant has been approved by the EMA and FDA for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy [ 36 ].

For pitolisant dosage, the EMA recommends a single-dose intake during breakfast starting from 9 mg and titrating up to 36 mg/day in few weeks. The most effective dosage, prescribed by EMA, is commonly 36 mg/day, and its complete efficacy is reached in a couple of weeks, with little evidence of a clinical long-term efficacy. FDA has approved pitolisant at a lower dosage: starting from 8.9 mg/day reaching 17.8 mg per day after 1 week. The maximum daily dosage for FDA is 35.6 mg, after 2 weeks. Pitolisant was generally well tolerated and showed low abuse potential. Commonly reported side effects were headache, insomnia, abdominal discomfort, nausea, and irritability [ 32 , 33 ].

Sodium Oxybate or Gamma Hydroxybutyrrate

Sodium oxybate is the sodium salt of γ-hydroxybutyrate, an endogenous metabolite of the inhibitory neurotransmitter GABA. Sodium oxybate is a gamma-hydroxybutyric acid B-subtype (GABAb) receptor agonist. GABAb receptors within the central nervous system are diffused in the hypothalamus and basal ganglia. Although the mechanism of action of sodium oxybate is unclear, the drug showed a strong effect in promoting nocturnal slow-wave sleep, suppressing REM sleep and leading to an overall improvement of sleep efficiency [ 37 , 38 ]. Sodium oxybate has shown efficacy in reducing subjective EDS and increasing objective alertness with a median increase of > 10 min at MWT [ 39 , 40 ]. Although the mechanism of action of sodium oxybate on EDS has not been elucidated, it may be related to the effect on nocturnal sleep as well as its biphasic dopaminergic activity with immediate suppression promoting sleep, and subsequent release promoting wakefulness. Sodium oxybate also showed efficacy on cataplexy [ 41 , 42 ] and disturbed nocturnal sleep [ 37 , 38 ]. For the more appropriate dosage and best effect on EDS, it is often necessary to wait several weeks in order to allow an individualized titration.

Sodium oxybate is available only in liquid form. The drug has a short half-life (40–60 min), and therefore should be taken in two doses per night. The dosage usually starts with 4.5 g/night (split into two doses of 2.25 g the first at bedtime, the second 2.5–4 h after the first intake, so the patient must be woken up to take the second dose) for 4 weeks and then progressively increasing 1.5 g/night per week to reach the target dosage of 6–9 g/night. According to this titration scheme, EDS improvements should appear in 4–8 weeks from the treatment start.

Side effects for this drug are nausea, dizziness/confusion, weight loss, enuresis, anxiety, and depressive symptoms. Some concerns are related to the potential interactions with other sedating drugs, to the possible depression of the respiratory drive in patients with sleep-related breathing disturbances or lung comorbidities, to the possible misuse as a “date rape” drug, as well as to the important salt load that may have cardiovascular effects.

The FDA has approved sodium oxybate for adults and children narcolepsy patients over 7 years old in narcolepsy for the treatment of EDS or cataplexy, while the EMA has approved the drug for the treatment narcolepsy with cataplexy in adult patients, adolescents, and children from the age of 7 years [ 43 , 44 ].

Solriamfetol

Solriamfetol (75 up to 150 mg/day) is a selective inhibitor of the reuptake of dopamine and norepinephrine. This new treatment is different from other wake-promoting agents for its dual action. Moreover, it does not promote the release of monoamines as amphetamines, thus leading to lower risk of abuse and withdrawal effects. Solriamfetol efficaciously reduced subjective EDS (ESS), and improved vigilance (MWT) with a dose–response effect [ 45 , 46 ]. The effect was confirmed also in long-term clinical trials [ 47 ].

Solriamfetol has been approved for the adult treatment of EDS by FDA and EMA in adult patients with narcolepsy [ 48 ]. Commonly reported side effects include headache, nausea, diminished appetite, nasopharyngitis, dry mouth, and anxiety.

Second-Line Treatments

Methylphenidate.

When other wake-promoting agents show no effectiveness, methylphenidate represents a second-line option. Methylphenidate increases dopamine and norepinephrine transmission. Although widely used, only a few studies [ 49 , 50 ] have reported significant differences in the methylphenidate effect on the ability to stay awake and active in narcolepsy patients. In clinical practice EDS improved within few days of lowest dose administration (10 mg), while a dose of 60 mg and higher can be used to achieve a clinically meaningful response [ 20 , 21 ].

Methylphenidate has been approved for treatment in adult NT1 and NT2 patients by the EMA (but it is not registered in all EU countries) and the FDA.

Side effects of methylphenidate include tachycardia, hypertension, sweating, palpitations, irritability, hyperactivity, mood swings, weight loss, anorexia, and insomnia. Albeit mild, there are risks of abuse and dependence for methilphenidate.

The dosage starts with a dose of 10–20 mg in the morning at breakfast and additional 10–20 mg at lunch, to reach the maximum dosage of 60 mg, usually taken in 2–4 portions during the daytime [ 50 ].

Amphetamines and Other Therapeutic Options

Amphetamines are another treatment option for EDS [ 20 , 21 ]. They increase the concentration of dopamine and norepinephrine, and are approved in some European countries [ 20 ]. Treatment with dextroamphetamine usually starts with 10 mg, and therapeutic dosages may reach a maximum of 60 mg per day [ 49 ]. Other options include selegeline and reboxetine [ 51 , 52 ]. Amphetamines may induce not only common side effects (irritability, aggressiveness, insomnia, and hypertension) but also severe consequences (abnormal movements, cardiac arrhythmias, and psychotic symptoms) that make their use dangerous especially in patients with cardiovascular comorbidity. Moreover, although rare in narcolepsy, amphetamines suffer from a risk of abuse [ 49 , 51 , 52 ].

FDA recently approved two different combinations: one associates amphetamine and dextroamphetamine (Adderall™), and another has amphetamine sulfate as the main active ingredient (Evekeo™).

Cataplexy Pharmacological Treatment in Adults

Sodium oxybate.

Sodium oxybate is recognized as an efficacious drug against cataplexy [ 41 , 42 ]. Several clinical trials, including data on a prolonged follow-up of 18 months, showed a significant decrease in cataplectic attacks after a few weeks of therapy with a dose-dependent effect [ 53 – 56 ]. Importantly, abrupt sodium oxybate withdrawal does not induce a rebound effect. The FDA has approved sodium oxybate for adults and children narcolepsy patients over 7 years of age for the treatment of EDS or cataplexy, while the EMA approved the drug for the treatment of narcolepsy with cataplexy in adult patients, adolescents and children from the age of 7 years [ 43 , 44 ].

Pitolisant has proven efficacy in reducing daily cataplexy attacks [ 57 ]. A randomized double-blind and placebo-controlled trial conducted on 105 NT1 patients taking pitolisant disclosed an important decrease in cataplectic attacks [ 33 ], an effect confirmed in long-term studies [ 58 ].

In adults, pitolisant has been approved by EMA and FDA for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy [ 36 ].

Venlafaxine

Although it is not approved, venlafaxine is a selective serotonine-norepinephrine reuptake inhibitor widely prescribed in NT1 patients, and only on the basis of clinical recommendations it can be considered a first-line pharmacological approach [ 20 , 21 ]. Venlafaxine has an effect as an anticataplectic that reaches its peak in few days. It is well tolerated and has some typical side effects: increased blood pressure, headache, dry mouth, nausea, and dizziness.

Its dosage starts with 37.5 mg reaching the maximum dose of 225 mg in the morning [ 60 ]. Patients should be advised that abrupt withdrawal can produce a severe rebound effect up to the occurrence of subcontinuous invalidating cataplexy episodes, a condition defined as “cataplectic status” [ 61 ].

Other Antidepressants: Fluoxetine, Citalopram, and Clomipramine

As second-line treatments for cataplexy in NT1, there are selective serotonin reuptake inhibitors (SSRIs), especially fluoxetine (10–20 up to 60 mg/day) and citalopram (10–20 up to 40 mg/day) [ 20 , 21 ]. Common side effects are excitation, gastrointestinal problems, insomnia, and sexual difficulties, and they should not be underestimated, because they can limit applicability in clinical practice [ 49 , 59 , 62 , 63 ]. As for venlafaxine, abrupt withdrawal can lead to a severe rebound effect [ 64 ]. Their use should considered with extreme caution by physicians especially when used with young patients.

Also, clomipramine, a tricyclic antidepressant, is used with a daily dosage that ranges from 10–25 up to 75 mg/day. Since the 1960s, several observations have confirmed clomipramine effect on reducing cataplectic attacks, but the drug has not been officially approved by the EMA and the FDA [ 20 , 21 , 65 – 67 ]. Antidepressants (fluoxetine, citalopram, and clomipramine) have only been approved in Germany.

Clomipramine suffers from common side effects, such as dry mouth, sweating, constipation, diarrhea, tachycardia, weight gain, hypotension, difficulty in urinating, and impotence.

EDS Pharmacological Treatment in Childhood

Nowadays, within all the EDS treatments, only sodium oxybate has been approved by FDA and EMA for treatment in children and adolescents. The other treatments for pediatric patients are considered only at empirical level as off-label [ 68 , 69 ].

Modafinil and Armodafinil

Both the treatments are used off-label by physicians for patients under the age of 16, because they have not yet been approved by the FDA for young people below the age of 16 [ 20 , 21 ]. For children, the daily dosage of modafinil and armodafinil is 50–400 mg/day in two doses at the morning to support children in school performance and after lunch, for after-school activities and homework. In case of sudden withdrawal, modafinil does not cause EDS rebound. Commonly reported side effects in young patients are headache, nausea, and vomiting. Moreover, a single case of Stevens–Johnson syndrome has been reported in a patient taking modafinil [ 70 ]. Steven–Johnson syndrome is a delayed hypersensitivity reaction that develops from a few days to weeks after beginning the therapy, and it appears as red or purple skin rash that gradually spreads. The only piece of evidence is a level 4 study by Ivanenko and colleagues [ 71 ]. Modafinil therapy in children and adolescents contributes to a subjective improvement in EDS. Furthermore, the study showed objective improvement in the average sleep latency on the MSLT from a baseline of 6.6 ± 3.7 to 10.2 ± 4.8 min.

Up to now, a few uncontrolled data have reported the efficacy and safety of pitolisant in reducing EDS in children and adolescents. The dosage for children is 4.5 mg up to 36 mg per day.

Minor side effects have been reported (insomnia, headache, hot flushes, leg pain, and hallucinations), and all but insomnia were transient [ 72 ].

Sodium oxybate is used for NT1 treatment in children, for its effects on reducing EDS and cataplexy. The drug is used in monotherapy or in association with other stimulants [ 73 ]. Its efficacy on EDS and cataplexy has been demonstrated in 88% of NT1 children [ 44 , 74 ], but sodium oxybate side effects maintain a high-risk ratio: sleep walking, sleep enuresis, exacerbation of sleep apnea, tremor, constipation, exacerbation of pre-existing depressive tendencies, weight loss, nausea, irritability, and episodes of sleep drunkenness. Abrupt drug withdrawal does not cause rebound effects [ 73 ]. Recent data have also shown a positive effect on sleep disruption and on REM sleep behavior disorder [ 74 – 76 ].

Administration of this treatment requires particular care. In fact, dispensation is made from central pharmacies, and before making out, the prescription clinicians and physicians have to register and train patients or their caregiver for proper use. This high level of care required for the drug assumption is due to the risk of misuse/abuse reported in several clinical cases. Therefore, the patient and his/her family need proper training before starting the treatment. It is recommended that a family member should be in attendance during the drug administration and should be responsible for storing the medication in proper locked place. Given the liquid form of the drug and its salty taste, it can be administrated with addition of flavor. The right dosage varies from 2 to 8 g per night, and the drug should be given in two administrations: one before falling asleep and the other one 3–4 h after the first dose.

Amphetamines and Methylphenidate

Amphetamine (dextro-amphetamine) and andmethylphenidate enhance dopaminergic and norepinephrinergic activity [ 20 , 21 ]. Both drugs are also used to treat attention-deficit/hyperactivity disorder in children and adults. Recommended dosages are 2.5 to 20 mg twice a day for dextro-amphetamine and 10 to 40 mg for methylphenidate. Their use in adults is supported by three phase 2 and four level 5 studies that support the effectiveness of those stimulants in treating EDS [ 21 ]. Side effects include tics, anorexia, headache, nervousness, insomnia, and weight loss [ 77 ]. Their use in children below the age of six is not approved by FDA and is discouraged in children with a diagnosed heart disease [ 78 , 79 ]. Moreover, while rare in narcolepsy, amphetamines and methylphenidate suffer from a risk of abuse.

Cataplexy Pharmacological Treatment in Childhood

To date, only sodium oxybate has been approved by FDA and EMA as a treatment for cataplexy in children and adolescents. Thus, the selection of medications in the pediatric population is based only on an empirical, off-label, basis [ 69 ].

Sodium Oxybate or Gamma Hydroxybutyrate

The information about sodium oxybate’s effect on cataplexy in childhood is included in the previous paragraph “EDS pharmacological treatment in childhood.”

Ongoing trials are evaluating the efficacy and safety profile of pitolisant in children, and to date, a slight improvement of cataplexy frequency and severity has been reported in children in an uncontrolled case series [ 72 ].

Selective Norepinephrine Reuptake Inhibitors

Venlafaxine is commonly used against cataplexy with a dosage of 37.5–75 mg per day [ 20 , 21 ]. Due to the high risk of suicide reported in adolescents, the administration of venlafaxine for adolescents and children must be strictly controlled [ 80 ]. In addition, side effects due to the interactions with monoamine oxidase inhibitors include dizziness, headache, and insomnia. Further studies are warranted, given that only a few observational data are available with 2-year follow-up [ 81 , 82 ].

Tricyclic Agents

In addition, imprimine, clomipramine, and protryptiline are commonly used for control cataplexy. Their dosages are, respectively, 10–100 mg, 10–150 mg, and 2.5–5 mg per day. The most commonly reported side effects are dry mouth, blurring, drowsiness, orthostatic hypotension, and weight gain [ 20 , 21 ].

Selective Serotonin Reuptake Inhibitors

Within SSRI, the most typically used agent is fluoxetine with a daily administration dosage of 10–30 mg [ 20 , 21 ]. Commonly reported side effects are nervousness, insomnia, and tremor. As for other antidepressants, sudden drug withdrawal or irregular intake may induce a rebound of cataplexy up to “status cataplecticus” [ 83 ].

Immunotherapy

Findings reported associations that support an autoimmune mechanism underlying the onset of NT1 that suggest the use of immunomodulation therapy with intravenous immunoglobulin G (IVIG) close to disease onset. Only a few studies [ 84 – 87 ] have analyzed IVIG therapeutic efficacy in early onset NT1cases. To date, the results have been controversial due to the small sample size, open label design, and self-reported observations. However, an improvement in cataplexy frequency and severity, as well as in EDS, was reported, but further data are required to exclude the possibility of a spontaneous improvement in NT1 symptoms during the disease course [ 88 ]. Overall, despite some promising results, further studies should address the role of immunotherapy in NT1 [ 89 ].

Non-pharmacological Treatment

Psychological difficulties are one of the main issues affecting narcolepsy patients, who often report a significantly lower quality of life [ 14 , 90 – 92 ]. In fact, narcolepsy is associated with some difficulties including work performance, sexual activity [ 93 ], higher risk of car accidents [ 94 ], neuropsychiatric alterations [ 95 – 100 ], and psychological disorders [ 97 – 101 ]

Non-pharmacological treatments are regularly used to manage EDS, either as an adjunct to drug therapy or as an alternative treatment. Several authors have reported that medications alone may not completely resolve EDS, in particular about 15% of patients with narcolepsy depend on medications alone [ 98 ] and up to 54% of these patients require behavioral strategies [ 102 , 103 , 104 ].

Although only a little evidence on the effect of daytime napping on EDS in NT1 is available [ 105 ], the importance of cognitive and behavioral therapies for narcolepsy treatment is fully recognized from a clinical point of view. The American Academy of Sleep Medicine is the only institution presenting treatments other than the pharmacological ones [ 20 ], while scheduled naps, sleep hygiene, balanced diet, and physical activities are within the clinical guidelines of associations of sleep medicine or neurology from several countries. Among these, both the UK and European Association of Neurology for Europe, the American Academy of Sleep Medicine for North America, and the Brazilian Sleep Society [ 20 , 21 , 106 , 107 ] agree on the importance of cognitive and behavioral actions to contain narcolepsy symptoms, reduce the negative effects, and gain a better compliance with drug therapy. In particular, the guidelines proposed by the UK Consensuses [ 106 ] suggest a symptomatologic approach, focused on increasing the patient’s knowledge of his/her disease, integrated with psychological support, in planning scheduled naps, promoting regular nocturnal sleep duration, and helping with the management of work, the home and recreational activities.

Cognitive Behavioral Therapy

Several countries recommend use of cognitive and behavioral strategies as adjunctive treatment to reduce the patient’s dysfunctions, to obtain a better response, to and decrease the amount of drugs that need to be administered. Within behavioral sleep medicine (BSM), cognitive behavioral therapy for insomnia (CBT-I) has gained prominence as an empirically supported treatment for chronic insomnia. Up to now, less attention has been paid to develop and validate methods for disorders related to the hypersomnia family.

The main goals of CBT are to apply strategies focused on the resolution of symptoms, identify, and modify dysfunctional thought patterns with negative influence on behaviors and emotions. In particular, it is possible to help narcoleptic patients to identify and improve dysfunctional cognitions, enhance treatment adherence, take medications at the appropriate times, maintain good sleep hygiene, and take scheduled naps to address the psychosocial needs of such patients. This sort of therapy should be performed only by psychologists, interested in BSM, who graduated from a school with an AASM-accredited sleep program or with a teacher with experience in sleep, and who completed a sleep-related internship at a local sleep clinic.

Currently, there is an insufficient number of clinical studies on patients with narcolepsy that present a standardized and unambiguous protocol on how to manage symptomatology and its psychosocial functioning. Patients under CBT also receive help to manage the impact that narcolepsy has on their quality of life, ranging from emotional to social levels [ 108 ] and health-related stigma [ 109 ].

A randomized study reported that patients undergoing cognitive therapy showed significant improvements in the subjective perception of their quality of life (i.e., physical function, social function, vitality, and emotional role) and EDS, through self-reported measures (i.e., the ESS, Ullanlinna Scale, SF-36) [ 110 , 111 , 112 ]. The aim of this study was to evaluate whether a multicomponent (sleep satiation, nap training, cognitive restructuring, and problem-solving techniques) treatment could provide better results than the standard treatments alone (control group, 6 months, and 1 year on treatment).

Other studies tried to assess how effective the cognitive measures could be in coping with narcolepsy [ 113 ]. To estimate the extent to which CBT—based on cognitive restructuring intervention—was effective, these authors measured quality of life, beliefs, and attitude of narcolepsy patients, finding that patients under CBT had significantly superior ( p  < 0.005) post-treatment assessment scores than the control and drug treatment groups.

Finally, Ong et al. have developed a novel CBT for hypersomnia (CBT-H) in people with CDH and co-occurring depressive symptoms, using an online access model for delivery and assessment [ 114 ]. At baseline and post-treatment, 35 adults with a diagnosis of CDH were evaluated with Patient-Reported Outcomes Measurement Information System measures, ESS, and other patient-reported outcomes. Moreover, they received a six-section CBT-H, delivered individually or in a small group, using a telehealth online platform by an expert psychologist therapist. Cognitive interventions were aimed at processing changes in personal identity or functional limitations that emerged due to symptoms of CDH. Topics included treating the stigma of CDH diagnosis, implications of CDH symptoms on self-perception, professional goals and interpersonal relationships, and specific coping skills to manage mood and anxiety, associated with the unpredictability of CDH symptoms.

Further research and clinical trial are needed to support the sporadic clinical evidence of CBT programs in narcolepsy.

Behavioral Treatment for EDS

Such techniques represent a useful tool for improving or controlling sleep disorder behaviors. Several studies have shown [ 20 , 21 ] that planning two or three short (15–20 min) naps at specific times of the day ( scheduled daytime naps ) is the most common behavioral recommendation [ 102 , 115 – 119 ]. Naps should be short to avoid sleep inertia at reawaking [ 102 , 105 , 106 ,  115 , 119 – 121 ].

Nevertheless, this is just an indication, since not every narcoleptic patient benefits from short naps [ 115 ] Indeed, some patients could benefit from longer naps [ 115 ]. Moreover, other studies have suggested an overall benefit in daytime alertness, when scheduled naps are associated with regular nocturnal bedtime [ 102 ].

Another strategy for improving EDS is reaching sleep satiation through sleep extension . Based on the sleep homeostasis theory, sleep satiation technique requires scheduled extension of nocturnal sleep: for 2 weeks from 10.00 p.m. to 6.00 a.m. [ 122 ]. This technique requires the detection of the behavior frequency: identifying the degree of sleepiness and filling in a sleep diary that determines the number of sessions. After that, continuous 1-day episodes are scheduled without light–dark cues. Improvements that follow naps and scheduled nocturnal sleep extension can be clarified by this behavioral disposition.

Physical activity may also has a positive effect on EDS. Experimental studies (in mice) showed that wheel running increased wakefulness in not only hypocretin knockout, but also cataplexy [ 123 ]. A relationship between physical activity and quality of sleep was recorded in healthy adolescents. This led to the hypothesis that physical activity may stabilize the circadian rhythm, following the improvement in sleep quality, but the mechanism that explain this relationship remains under investigation.

In any case, an actigraphic study with NT1 children and adolescents detected that regular physical activity was associated with significant differences in children’s sleepiness (lower subjective ESS-CHAD scores) and sleep/wake profile (fewer daily naps and less time asleep during daytime), but without triggering cataplexy [ 124 ].

In addition, narcoleptic patients also reported the utility of controlling their environment (e.g., avoiding hot rooms, keeping the room cool, seeking fresh air), engaging themselves in certain activities (e.g., being active in conversations, avoiding boring events, restricting evening events), and different physical activities (e.g., pinching oneself and clenching one’s teeth) on EDS management [ 103 , 111 ].

Broughton and Murray reported the success of these self-behavioral stimulations in six out of 13 patients [ 125 ]. Furthermore, a survey evaluating the most common behavioral strategies found that daytime napping (86%), scheduled nocturnal sleep (i.e., bedtime and wake-up time, 76%), caffeine use (76%), physical exercise (57%), diet (50%), temperature manipulations (42%), chewing gum (30%), nicotine (23%), mindfulness (21%), and yoga (18%) were efficacious in managing EDS [ 99 ].

However, no clinical trials have addressed the efficacy of behavioral approaches on EDS in narcolepsy, and therefore, further research is needed on patients.

Cognitive and Behavioral Treatment for Cataplexy

CBT is also used for cataplexy treatment, particularly through systematic desensitization, that helps patients to find coping strategies to manage their emotions. This symptomatic strategy—an evidence-based therapy approach that combines relaxation techniques with gradual exposure to help overcome a particularly stressful condition—gradually reduces the impact of the emotional triggering stimulus by guiding the patient through situations where the frequency and intensity of this stimulus increase. To arrange the systematic desensitization technique, it is necessary for stressful and hyperactivating stimuli (e.g., like a funny video), to be previously assessed by patients, confirming that they are triggers for cataplexy. Then, clinicians ask the patients, in a state of deeply relaxation, to figure in their mind the hyperactivating stimulus, through the illustration of the situations in all their details [ 126 ].

Within the CBT approach, other procedures for cataplexy reduction are the emotional techniques (e.g., avoiding emotional experience, excitement) for the management of symptoms and the stimulus satiation, in which the clinician maintains what reinforces the cataplectic behavior in the patient until it loses its effect [ 126 ]. In a qualitative study on the cataplexy experience, some patients reported a sort of ability to control the attacks by focusing on the inhibition/avoidance of the emotional triggers (such as laughter), or seeking support or trying to sit down, to avoid falling to the ground [ 127 ].

This approach should be performed only by a psychologist experienced in behavioral sleep medicine.

Psychological counseling offers a space to improve symptom management and treatment for both patients and relatives, through proper education and information about the disease, particularly when the diagnosis has just been made. With psychological counseling patients can better understand how narcolepsy can change their life and accordingly develop strategies to deal with it. Through psychological counseling patients can be informed about all the available pharmacological and behavioral therapies (e.g., good sleep hygiene) and their outcomes, and finally other lifestyle factors that could affect the symptoms (e.g., the influence of alcohol on EDS) [ 128 ].

Furthermore, researchers are becoming increasingly aware of the importance of peer support, as a form of psychosocial support offered by someone with experiential knowledge of the disease [ 128 ]. With peer support, patients can also face the sense of isolation, improve their knowledge and confidence in dealing with the symptoms [ 129 ], and positively influence each other’s hopes about the future, despite the limitations of the disease. Indeed, the support coming from sharing experiences with others has been shown to be constructive also for patient’s family members [ 130 , 131 , 132 ]. However, finding peer support could be complicated when experiencing a rare disease [ 130 , 131 , 132 ], but there still are chances to recover, also thanks to all the associations that operate to bring the patients closer and fill this gap. Furthermore, the development of new technologies may be of help to connect patients and peers.

In Italy, narcoleptic patients are grouped in the Associazione Italiana Narcolettici ed Ipersonni (AIN onlus, http://www.narcolessia.org/ ). The association now gives support to many narcoleptic patients, representing not only the opportunity to be in contact with other people who share the same condition but also a place where sleep experts can cooperate and share information about different and specific case/symptoms, and thus improve their knowledge of the disease. This network was founded by the father of a young patient, after considerable efforts made to find a diagnosis and a cure. Today, the AIN is very active also at international level. Indeed, the AIN is working to spread the connections with other European narcoleptic patient associations, through eNAP, the new European Narcolepsy Alliance for Patient ( https://narcolepsy.eu/ ). Furthermore, we report the website address of other important patient support associations:

Austria: www.narkolepsie.at

Belgium: www.narcolepsie-cataplexie.be

Denmark: www.dansknarkolepsiforening.dk

France: www.anc-narcolepsie.com

Germany: http://www.dng-ev.de/

Ireland: http://soundireland.ie/

Netherlands: www.narcolepsie.nl

Norway: http://www.sovnforeningen.no/

Poland: http://www.narkolepsja.pl/

Spain: http://www.narcolepsia.org/

Sweden: http://www.narkolepsiforeningen.se/

Switzerland: https://www.snane.ch/

UK: www.narcolepsy.org.uk

USA: NORD (National Organization for Rare Disorders): https://rarediseases.org/rare-diseases/narcolepsy/

USA: Wake up Narcolepsy: https://www.wakeupnarcolepsy.org/

USA: Narcolepsy Network: www.narcolepsynetwork.org

USA: Project Sleep: https://project-sleep.com/

In summary, the following intervention is proposed for patients with narcolepsy, to be adopted especially in a multidisciplinary sleep medicine center. The first choice is pharmacological treatment with the integration of behavioral strategies for EDS and night sleep management. For those patients with impaired quality of life, anxiety-depressive comorbidity, and serious consequences on emotional and working life, pharmacological treatment should be integrated with a CBT treatment, focused on the cognitive and psychopathological consequences of narcolepsy. In addition, a counseling service and focus group therapy centered on peer support should be offered to increase the awareness of the disease condition, the patient’s personal esteem, and a proper management of drug therapy, in terms of safety and compliance to the medication therapy.

Child and Relatives

Narcolepsy has a major negative impact on the child’s social realm. Parents and caregivers facing child problems could undergo truly overwhelming stress levels, for the problems expressed that they cannot fully understand or detect.

Moreover, professional figures do not always offer enough support to the child, probably due to the rarity of the disorder and the consequent focus that physicians have to invest in the diagnostic and medical challenges. Encouragements mainly come from close family members who may be unprepared to meet the child’s worries.

Kippola-Pääkkönen and colleagues studied the expectations and perceive support of children with narcolepsy after the pandemic influenza in Finland [ 133 ]. In their research, they proposed educational, psychological, and social interventions: lectures, individual psychosocial counseling, group discussions, and skill training. Also, parents completed a baseline (58) and a final (40) questionnaire. Findings reported that parents’ worries were focused on the impact of narcolepsy on coping skills and the limitation of their time as a couple. In addition, parents received most of the support from their partners (77%), then from sleep physicians (27%) or teachers and school educators (23%). Then, researchers recommended offering psychological support to patients also during the hospitalizations in order to help families obtain informal and professional support.

The 20–40% incidence of depressive symptoms in narcoleptic pediatric patients [ 134 ] should encourage the scientific community to build a task force of experts that tries to understand the most disabling aspects of childhood or adolescent narcolepsy, such as access to drugs, symptom management with peer and family, school management of scheduled naps or management of drug therapy during school trips, psychopathological symptoms and their support, and support for families with access to peer help groups.

Conclusions

NT1 is a rare chronic disorder characterized by EDS, cataplexy, hypnagogic hallucinations, sleep paralysis, and disrupted night-time sleep [ 1 ]. For its diagnosis, multiple sleep latency test (MSLT) and polysomnography (PSG) are used [ 1 , 36 ,  134 ]. The occurrence of hallucinations and sleep paralysis shifts in terms of frequency and impact in narcoleptic patients. In some cases, sodium oxybate turned out to be effective in reducing the number of hallucinations during the day [ 135 ], but other therapies, such as venlafaxine, also have a good therapeutic effect [ 28 ].

A recent review of the literature on disrupted nighttime sleep in patients with narcolepsy has shown that nocturnal sleep is characterized—both in PSG and subjective reports—by frequent brief awakenings, awakenings, and a high level of light sleep, which is also associated with poor quality of sleep at night [ 135 ]. Sodium oxybate seems to be a gold standard treatment in consolidating nocturnal sleep [ 38 , 74 , 75 ].

Today, narcolepsy is still a complex disease, and despite new scientific discoveries about its pathophysiology, currently available treatments remain scarce and only symptomatic. Moreover, many drugs used in the clinical practice to cure children are still prescribed as “off-label” treatments.

Furthermore, new immune-modulating and hypocretin replacement treatments should be verified more systematically [ 89 ], especially in patients and children with recent-onset narcolepsy in order to figure out their potential in treating the disease. Non-pharmacological interventions as well have been shown to contribute in helping patients and family members and to have a role in improving patients’ quality of life, so for the future, it is advisable that outcome measures and multicompetent interventions should be guaranteed to patients and their families [ 17 , 105 ].

Recently, research to find proper treatments for rare disorders has received a new attention from the European Union that has addressed programs and policies also to this area of health programs and policies, in order to balance attention between rare and common disorders (European Commission, 2014) [ 136 ].

AASM: American Academy of Sleep Medicine. ICSD-3: international classification of sleep disorders, 3rd edn. Amer Acad Sleep Med, Daniel (IL) 2014.

Hagan JJ, Leslie RA, Patel S, et al. Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc Natl Acad Sci U S A 1999;96:10911–10916.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Sutcliffe JG, de Lecea L. The hypocretins: excitatory neuromodulatory peptides for multiple homeostatic systems, including sleep and feeding. J Neurosci Res 2000;62:161–168.

Article   CAS   PubMed   Google Scholar  

Brown RE, Sergeeva O, Eriksson KS, Haas HL. Orexin A excites serotonergic neurons in the dorsal raphe nucleus of the rat. Neuropharmacology 2001;40:457–459.

Dye TJ, Gurbani N, Simakajornboon N. Epidemiology and Pathophysiology of Childhood Narcolepsy. Paediatr Respir Rev 2018;25:14–18.

PubMed   Google Scholar  

Shibata M, Mondal MS, Date Y, Nakazato M, Suzuki H, Ueta Y. Distribution of orexins-containing fibers and contents of orexins in the rat olfactory bulb. Neurosci Res 2008;61:99–105.

Tashiro T, Kanbayashi T, Iijima S, Hishikawa Y. An epidemiological study of narcolepsy in Japanese. J Sleep Res 1992;1:228.

Google Scholar  

Mignot E. Genetic and familial aspects of narcolepsy. Neurology 1998;50:S16-S22.

Baumann CR, Mignot E, Lammers GJ, et al. Challenges in diagnosing narcolepsy without cataplexy: a consensus statement. Sleep 2014;37:1035–1042.

Article   PubMed   PubMed Central   Google Scholar  

Miyagawa T, Tokunaga K. Genetics of narcolepsy. Hum Genome Var 2019;6:4.

Article   PubMed   Google Scholar  

Fronczek R, Arnulf I, Baumann CR, Maski K, Pizza F, Trotti LM. To split or to lump? Classifying the central disorders of hypersomnolence. Sleep 2020;43.

Dauvilliers Y, Jaussent I, Krams B, et al. Non-dipping blood pressure profile in narcolepsy with cataplexy. PLoS One 2012;7:e38977.

Rocca FL, Pizza F, Ricci E, Plazzi G. Narcolepsy during Childhood: An Update. Neuropediatrics 2015;46:181–198.

Ingravallo F, Gnucci V, Pizza F, et al. The burden of narcolepsy with cataplexy: how disease history and clinical features influence socio-economic outcomes. Sleep Med 2012;13:1293–1300.

Ton TGN, Watson NF, Koepsell TD, Longstreth WT. Narcolepsy and the Sickness Impact Profile: A general health status measure. Sleep Sci 2014;7:5–12.

Maski K, Steinhart E, Williams D, et al. Listening to the Patient Voice in Narcolepsy: Diagnostic Delay, Disease Burden, and Treatment Efficacy. J Clin Sleep Med 2017;13:419–425

Pascoe M, Bena J, Foldvary-Schaefer N. Effects of Pharmacotherapy Treatment on Patient-Reported Outcomes in a Narcolepsy and Idiopathic Hypersomnia Cohort. J Clin Sleep Med 2019;15:1799–806

Scammell TE, Estabrooke IV, McCarthy MT, et al. Hypothalamic arousal regions are activated during modafinil-induced wakefulness. J Neurosci 2000;20:8620–8628.

Wisor J. Modafinil as a catecholaminergic agent: empirical evidence and unanswered questions. Front Neurol 2013;4:139.

Billiard M, Bassetti C, Dauvilliers Y, et al. EFNS guidelines on management of narcolepsy. Eur J Neurol 2006;13:1035–1048.

Morgenthaler TI, Kapur VK, Brown T, et al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep 2007;30:1705–1711.

Schwartz JRL, Feldman NT, Bogan RK. Dose effects of modafinil in sustaining wakefulness in narcolepsy patients with residual evening sleepiness. J Neuropsychiatry Clin Neurosci 2005;17:405–412.

Schwartz JRL, Feldman NT, Bogan RK, Nelson MT, Hughes RJ. Dosing regimen effects of modafinil for improving daytime wakefulness in patients with narcolepsy. Clin Neuropharmacol 2003;26:252–257.

Schwartz JRL, Nelson MT, Schwartz ER, Hughes RJ. Effects of modafinil on wakefulness and executive function in patients with narcolepsy experiencing late-day sleepiness. Clin Neuropharmacol 2004;27:74–79.

Billiard M, Besset A, Montplaisir J, et al. Modafinil: a double-blind multicentric study. Sleep 1994;17:S107-S112.

Broughton RJ, Fleming JA, George CF, et al. Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy. Neurology 1997;49:444–451.

Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy: US Modafinil in Narcolepsy Multicenter Study Group. Neurology 2000;54:1166–1175.

Beusterien KM, Rogers AE, Walsleben JA, et al. Health-related quality of life effects of modafinil for treatment of narcolepsy. Sleep 1999;22:757–765.

Thakrar C, Patel K, D’ancona G, et al. Effectiveness and side-effect profile of stimulant therapy as monotherapy and in combination in the central hypersomnias in clinical practice. J Sleep Res 2018;27:e12627.

Palovaara S, Kivistö KT, Tapanainen P, Manninen P, Neuvonen PJ, Laine K. Effect of an oral contraceptive preparation containing ethinylestradiol and gestodene on CYP3A4 activity as measured by midazolam 1’-hydroxylation. Br J Clin Pharmacol 2000;50:333–337.

Harsh JR, Hayduk R, Rosenberg R, et al. The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness associated with narcolepsy. Curr Med Res Opin 2006;22:761–774.

Dauvilliers Y, Bassetti C, Lammers GJ, et al. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol 2013;12:1068–1075.

Szakacs Z, Dauvilliers Y, Mikhaylov V, et al. Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2017;16:200–207.

Lehert P, Szoeke C. Comparison of modafinil and pitolisant in narcolepsy: a non-inferiority meta-analytical approach. Drugs Context 2020;9.

Lin JS, Dauvilliers Y, Arnulf I, et al. An inverse agonist of the histamine H(3) receptor improves wakefulness in narcolepsy: studies in orexin-/- mice and patients. Neurobiol Dis 2008;30:74–83.

Syed YY. Pitolisant: First Global Approval. Drugs 2016;76:1313–1318.

Mamelak M, Escriu JM, Stokan O. The effects of gamma-hydroxybutyrate on sleep. Biol Psychiatry 1977;12:273–288.

CAS   PubMed   Google Scholar  

Roth T, Dauvilliers Y, Guinta D, Alvarez-Horine S, Dynin E, Black J. Effect of sodium oxybate on disrupted nighttime sleep in patients with narcolepsy. J Sleep Res 2017;26:407–414.

Mansukhani MP, Kotagal S. Sodium oxybate in the treatment of childhood narcolepsy-cataplexy: a retrospective study. Sleep Med 2012;13:606–610.

US Xyrem Multicenter Study Group. A 12-month, open- label multicenter extension trial of orally administered sodium oxybate for the reatment of narcolepsy. Sleep 2003;26:31–35.

Xyrem International Study Group. Further evidence supporting the use of sodium oxybate for the treatment of cataplexy: a double-blind, placebo-controlled study in 228 patients. Sleep Med 2005;6:415–421.

Article   Google Scholar  

U.S. Xyrem Multicenter Study Group. Sodium oxybate demonstrates long-term efficacy for the treatment of cataplexy in patients with narcolepsy. Sleep Med 2004;5:119–123

PDR.net. Available at: https://www.fda.gov/Drugs/DrugSafety/ucm332029.htm 2016.

Plazzi G, Ruoff C, Lecendreux M, et al. Treatment of paediatric narcolepsy with sodium oxybate: a double-blind, placebo-controlled, randomised-withdrawal multicentre study and open-label investigation. Lancet Child Adolesc Health 2018;2:483–494.

Thorpy MJ, Shapiro C, Mayer G, et al. A randomized study of solriamfetol for excessive sleepiness in narcolepsy. Ann Neurol 2019;85:359–370.

Dauvilliers Y, Shapiro C, Mayer G, et al. Solriamfetol for the Treatment of Excessive Daytime Sleepiness in Participants with Narcolepsy with and without Cataplexy: Subgroup Analysis of Efficacy and Safety Data by Cataplexy Status in a Randomized Controlled Trial. CNS Drugs 2020;34:773–784.

Malhotra A, Shapiro C, Pepin JL, et al. Long-term study of the safety and maintenance of efficacy of solriamfetol (JZP-110) in the treatment of excessive sleepiness in participants with narcolepsy or obstructive sleep apnea. Sleep 2020;43.

Sleepfoundation.org. Sleep Apnea | National Sleep Foundation [online]. Available at:  https://www.sleepfoundation.org/sleep-disorders-problems/sleep-apnea 2019.

Mitler MM, Shafor R, Hajdukovich R, Timms RM, Browman CP. Treatment of narcolepsy: objective studies on methylphenidate, pemoline, and protriptyline. Sleep 1986;9:260–264.

Leonard BE, McCartan D, White J, King DJ. Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects. Hum Psychopharmacol 2004;19:151–180.

Mayer G, Ewert Meier K, Hephata K. Selegeline hydrochloride treatment in narcolepsy. A double-blind, placebo-controlled study. Clin Neuropharmacol 1995;18:306–319.

Larrosa O, de la Llave Y, Bario S, Granizo JJ, Garcia-Borreguero D. Stimulant and anticataplectic effects of reboxetine in patients with narcolepsy: a pilot study. Sleep 2001;24:282–285,

Boscolo-Berto R, Viel G, Montagnese S, Raduazzo DI, Ferrara SD, Dauvilliers Y. Narcolepsy and effectiveness of gamma-hydroxybutyrate (GHB): a systematic review and meta-analysis of randomized controlled trials. Sleep Med Rev 2012;16:431–443.

Alshaikh MK, Tricco AC, Tashkandi M, Mamdani M, Straus SE, BaHammam AS. Sodium oxybate for narcolepsy with cataplexy: systematic review and meta-analysis. J Clin Sleep Med 2012;8:451–458.

US Xyrem Multicenter Study Group. A randomized, double-blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep 2002;25:42–49.

Mayer G, Plazzi G, Iranzo Á, et al. Long-term compliance, safety, and tolerability of sodium oxybate treatment in patients with narcolepsy type 1: a postauthorization, noninterventional surveillance study. Sleep 2018;41.

Kollb-Sielecka M, Demolis P, Emmerich J, Markey G, Salmonson T, Haas M. The European Medicines Agency review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for Medicinal Products for Human Use. Sleep Med 2017;33:125–129.

Dauvilliers Y, Arnulf I, Szakacs Z, et al. Long-term use of pitolisant to treat patients with narcolepsy: Harmony III Study. Sleep 201921;42.

Langdon N, Shindler J, Parkes JD, Bandak S. Fluoxetine in the treatment of cataplexy. Sleep 1986;9:371–373.

Pillen S, Pizza F, Dhondt K, Scammell TE, Overeem S. Cataplexy and Its Mimics: Clinical Recognition and Management. Curr Treat Options Neurol 2017;19:23.

Wang J, Greenberg H. Status cataplecticus precipitated by abrupt withdrawal of venlafaxine. J Clin Sleep Med 2013;9:715–716.

Frey J, Darbonne C. Fluoxetine suppresses human cataplexy: a pilot study. Neurology 1994;44:707–709.

Thirumalai null, Shubin null. The use of citalopram in resistant cataplexy. Sleep Med 1 2000;1:313–316.

Poryazova R, Siccoli M, Werth E, Bassetti CL. Unusually prolonged rebound cataplexy after withdrawal of fluoxetine. Neurology 2005;65:967–968.

Schachter M, Parkes JD. Fluvoxamine and clomipramine in the treatment of cataplexy. J Neurol Neurosurg Psychiatry 1980;43:171–174.

Shapiro WR. Treatment of Cataplexy with Clomipramine. Arch Neurol 1975;32:653–656.

Guilleminault C, Raynal D, Takahashi S, Carskadon M, Dement W. Evaluation of short-term and long-term treatment of the narcolepsy syndrome with clomipramine hydrochloride. Acta Neurol Scand 1976;54:71–87.

Lecendreux M, Bruni O, Franco P, et al. Clinical experience suggests that modafinil is an effective and safe treatment for paediatric narcolepsy. J Sleep Res 2012;21:481–483.

Aran A, Einen M, Lin L, Plazzi G, Nishino S, Mignot E. Clinical and therapeutic aspects of childhood narcolepsy-cataplexy: a retrospective study of 51 children. Sleep 2010;33:1457–1464.

Rugino T. A review of modafinil film-coated tablets for attention-deficit/hyperactivity disorder in children and adolescents. Neuropsychiatr Dis Treat 2007;3:293–301.

CAS   PubMed   PubMed Central   Google Scholar  

Ivanenko A, Tauman R, Gozal D. Modafinil in the treatment of excessive daytime sleepiness in children. Sleep Med 2003;4:579–582.

Inocente C, Arnulf I, Bastuji H, et al. Pitolisant, an inverse agonist of the histamine H3 receptor: an alternative stimulant for narcolepsy-cataplexy in teenagers with refractory sleepiness. Clin Neuropharmacol 2012;35:55–60.

Moresco M, Pizza F, Antelmi E, Plazzi G. Sodium Oxybate Treatment in Pediatric Type 1 Narcolepsy. Curr Drug Metab 2018;19(13):1073–1079.

Murali H, Kotagal S. Off-label treatment of severe childhood narcolepsy-cataplexy with sodium oxybate. Sleep 2006;29:1025–1029.

Antelmi E, Plazzi G, Pizza F, Vandi S, Aricò D, Ferri R. Impact of acute administration of sodium oxybate on heart rate variability in children with type 1 narcolepsy. Sleep Med 2018;47:1–6.

Filardi M, Pizza F, Antelmi E, Ferri R, Natale V, Plazzi G. In-field assessment of sodium oxybate effect in pediatric type 1 narcolepsy: an actigraphic study. Sleep 2018;41.

Dopheide JA, Pliszka SR. Attention-deficit-hyperactivity disorder: an update. Pharmacotherapy 2009;29:656–679.

Product information. Dextroamphetamine sulfate oral tablets, dextroamphetamine sulfate oral tablets. St. Louis, MO: Mallinckrodt 2007.

Product information. RITALIN: oral tablets, methylphenidate hydrochloride oral tablets. East Hanover, NJ: Novartis 2007.

Boaden K, Tomlinson A, Cortese S, Cipriani A. Antidepressants in Children and Adolescents: Meta-Review of Efficacy, Tolerability and Suicidality in Acute Treatment. Front Psychiatry 2020;11:717.

Ratkiewicz M, Splaingard M. Treatment of cataplexy in a three-year-old using venlafaxine. J Clin Sleep Med 2013;9:1341–1342.

Møller LR, Østergaard JR. Treatment with venlafaxine in six cases of children with narcolepsy and with cataplexy and hypnagogic hallucinations. J Child Adolesc Psychopharmacol 2009;19:197–201.

Ristanovic RK, Liang H, Hornfeldt CS, Lai C. Exacerbation of cataplexy following gradual withdrawal of antidepressants: manifestation of probable protracted rebound cataplexy. Sleep Med 2009;10:416–421.

Dauvilliers Y, Carlander B, Rivier F, Touchon J, Tafti M. Successful management of cataplexy with intravenous immunoglobulins at narcolepsy onset. Ann Neurol 2004;56:905–908.

Plazzi G, Poli F, Franceschini C, et al. Intravenous high-dose immunoglobulin treatment in recent onset childhood narcolepsy with cataplexy. J Neurol 2008;255:1549–1554.

Knudsen S, Biering-Sørensen B, Kornum BR, et al. Early IVIg treatment has no effect on post-H1N1 narcolepsy phenotype or hypocretin deficiency. Neurology 2012;79:102–103.

Lecendreux M, Berthier J, Corny J, Bourdon O, Dossier C, Delclaux C. Intravenous Immunoglobulin Therapy in Pediatric Narcolepsy: A Nonrandomized, Open-Label, Controlled, Longitudinal Observational Study. J Clin Sleep Med 2017;13:441–453.

Ruppert E, Zagala H, Chambe J, et al. Intravenous Immunoglobulin Therapy Administered Early after Narcolepsy Type 1 Onset in Three Patients Evaluated by Clinical and Polysomnographic Follow-Up. Behav Neurol 2018;2018:1671072.

Giannoccaro MP, Sallemi G, Liguori R, Plazzi G, Pizza F. Immunotherapy in Narcolepsy. Curr Treat Options Neurol. 2020 Jan 30;22(1):2.

Chapter   Google Scholar  

Vignatelli L, Plazzi G, Peschechera F, Delaj L, D’Alessandro R. A 5-year prospective cohort study on health-related quality of life in patients with narcolepsy. Sleep Med 2011;12:19–23.

Ingravallo F, Plazzi G. Medico-legal aspects of disability in narcolepsy. In: Goswami M, Pandi- Perumal SR, Thorpy MJ, Narcolepsy: a clinical guide, New York, Springer Humana Press 2010;231–238.

Shneerson J. Narcolepsy and mental health. In: Goswami M, Pandi- Perumal SR, Thorpy MJ, Narcolepsy: a clinical guide. Springer Humana Press, New York 2010;239–250.

Lindsley G. Narcolepsy, intima1cy and sexuality. In: Goswami M, Pandi-Perumal SR, Thorpy MJ, Narcolepsy: a clinical guide, New York: Springer Humana Press 2010;205–216.

Donjacour C, Mets MAJ, Verster JC. Narcolepsy, driving and traffic safety. In: Goswami M, Pandi-Perumal SR, Thorpy MJ, Narcolepsy: a clinical guide, New York: Springer Humana Press 2010. p. 217–22.

Naumann A, Bellebaum C, Daum I. Cognitive deficits in narcolepsy. J Sleep Res 2006;15:329–338.

Bellebaum C, Daum I. Memory and cognition in narcolepsy. In: Goswami M, Pandi-Perumal SR, Thorpy MJ, Narcolepsy: a clinical guide. New York, Springer Humana Press 2010;223–230.

Dauvilliers Y, Paquereau J, Bastuji H, Drouot X, Weil JS, Viot-Blanc V. Psychological health in central hypersomnias: the French Harmony study. J Neurol Neurosurg Psychiatry 2009;80:636–641.

Ohayon MM. Narcolepsy is complicated by high medical and psychiatric comorbidities: a comparison with the general population. Sleep Med 2013;14:488–492.

Neikrug AB, Crawford MR, Ong JC. Behavioral Sleep Medicine Services for Hypersomnia Disorders: A Survey Study. Behav Sleep Med 2017;15:158–171

Alaia SL. Life Effects of Narcolepsy. null 1992;5:1–22.

Plazzi G, Fabbri C, Pizza F, Serretti A. Schizophrenia-like symptoms in narcolepsy type 1: shared and distinctive clinical characteristics. Neuropsychobiology 2015;71:218–224.

Bruck D, Broughton R. Achieving control over sleepiness in narcolepsy. Australian journal of primary health 2001;7:16–24.

Cohen FL, Nehring WM, Cloninger L. Symptom description and management in narcolepsy. Holist Nurs Pract 1996;10:44–53.

Daniels E, King MA, Smith IE, Shneerson JM. Health-related quality of life in narcolepsy. J Sleep Res 2001;10:75–81.

Postiglione E, Pizza F, Ingravallo F, et al. Impact of COVID-19 pandemic lockdown on narcolepsy type 1 management. Brain Behav 2021;11:e01955.

Britton T, Hansen A, Hicks J, Howard R, Meredith A. Guidelines on the diagnosis and management of narcolepsy in adults and children. Evidence-Based Guidelines for the UK with Graded Recommendations. Ashtead, UK: Taylor Patten Communications Ltd 2002.

Alóe F, Alves RC, Araújo JF, et al. [Brazilian guidelines for the treatment of narcolepsy]. Braz J Psychiatry 2010;32:305–314.

Rogers AE. Problems and coping strategies identified by narcoleptic patients. J Neurosurg Nurs 1984 Dec;16(6):326–34.

Kapella MC, Berger BE, Vern BA, Vispute S, Prasad B, Carley DW. Health-related stigma as a determinant of functioning in young adults with narcolepsy. PLoS One. 2015;10:e0122478.

Marin-Agudelo H. Multicomponent Cognitive Behavioral treatment efficacy for narcolepsy (MCBT-N). Sleep Med 2011;12:S55.

Conroy DA, Novick DM, Swanson LM. Behavioral management of hypersomnia. Sleep Med Clin 2012;7:325–331.

Marı´n-Agudelo H, Jime´nez Correa U. Scheduled naps and systematic desensitization in the emotional processing in patients with narcolepsy: a comparative study of autonomic and cognitive evoked potentials. Sleep 2012;35: A275

Marín-Agudelo H, Jiménez Correa U. Beliefs and dysfunctional attitudes in patients with narcolepsy; double-blind study of treatment efficacy. Sleep 2013;36.

Ong JC, Dawson SC, Mundt JM, Moore C. Developing a cognitive behavioral therapy for hypersomnia using telehealth: a feasibility study. J Clin Sleep Med 2020;16:2047–2062.

Mullington J, Broughton R. Scheduled naps in the management of daytime sleepiness in narcolepsy-cataplexy. Sleep 1993 Aug;16(5):444–56.

Billiard M, Salva MQ, De Koninck J, Besset A, Touchon J, Cadilhac J. Daytime sleep characteristics and their relationships with night sleep in the narcoleptic patient. Sleep 1986;9(1 Pt 2):167–74. 

Krahn LE, Hershner S, Loeding LD, et al. Quality measures for the care of patients with narcolepsy. J Clin Sleep Med 2015;11:335.

Helmus T, Rosenthal L, Bishop C, Roehrs T, Syron ML, Roth T. The alerting effects of short and long naps in narcoleptic, sleep deprived, and alert individuals. Sleep 1997;20:251–257.

Ebben MR. Nonpharmacologic Management of Excessive Daytime Sleepiness. Sleep Med Clin 2020;15:195–203.

Rogers AE, Aldrich MS, Lin X. A comparison of three different sleep schedules for reducing daytime sleepiness in narcolepsy. Sleep. 2001 Jun 15;24(4):385–91.

Chaiard J, Weaver TE. Update on Research and Practices in Major Sleep Disorders: Part II-Insomnia, Willis-Ekbom Disease (Restless Leg Syndrome), and Narcolepsy. J Nurs Scholarsh. 2019 Nov;51(6):624–33.

Uchiyama M, Mayer G, Meier-Ewert K. Differential effects of extended sleep in narcoleptic patients. Electroencephalogr Clin Neurophysiol 1994 Sep;91(3):212–218.

España RA, McCormack SL, Mochizuki T, Scammell TE. Running promotes wakefulness and increases cataplexy in orexin knockout mice. Sleep 2007 Nov;30(11):1417–25.

Filardi M, Pizza F, Antelmi E, Pillastrini P, Natale V, Plazzi G. Physical Activity and Sleep/Wake Behavior, Anthropometric, and Metabolic Profile in Pediatric Narcolepsy Type 1. Front Neurol 2018;9:707.

Broughton R J, Murray B J. The behavioral management of narcolepsy. In: Bassetti C L, Billard M, Mignot E, editors. Narcolepsy and hypersomnia. Informa Healthcare; 2007. pp. 497–512.

Marín Agudelo HA, Jiménez Correa U, Carlos Sierra J, Pandi-Perumal SR, Schenck CH. Cognitive behavioral treatment for narcolepsy: can it complement pharmacotherapy? Sleep Sci 2014 Mar;7(1):30–42.

Franceschini C, Fante C, Folli MC, Filosa M, Pizza F, Antelmi E, et al. Giving a voice to cataplectic experience: recollections from patients with narcolepsy type 1. J Clin Sleep Med. 2020 Apr 15;16(4):597–603.

Dennis CL. Peer support within a health care context: a concept analysis. Int J Nurs Stud 2003 Mar;40(3):321–32.

Franceschini C, Fante C, Filardi M, Folli MC, Brazzi F, Pizza F, et al. Can a Peer Support the Process of Self-Management in Narcolepsy? A Qualitative Narrative Analysis of a Narcoleptic Patient. Front Psychol. 2020;11:1353.

Embuldeniya G, Veinot P, Bell E, Bell M, Nyhof-Young J, Sale JEM, et al. The experience and impact of chronic disease peer support interventions: a qualitative synthesis. Patient Educ Couns 2013 Jul;92(1):3–12.

Shilling V, Morris C, Thompson-Coon J, Ukoumunne O, Rogers M, Logan S. Peer support for parents of children with chronic disabling conditions: a systematic review of quantitative and qualitative studies. Dev Med Child Neurol 2013 Jul;55(7):602–9.

Anderson M, Elliott EJ, Zurynski YA. Australian families living with rare disease: experiences of diagnosis, health services use and needs for psychosocial support. Orphanet J Rare Dis 2013 Feb 11;8:22.

Kippola-Pääkkönen A, Härkäpää K, Valkonen J, Tuulio-Henriksson A, Autti-Rämö I. Psychosocial intervention for children with narcolepsy: Parents’ expectations and perceived support. J Child Health Care 2016 Dec;20(4):521–9.

Szakács A, Hallböök T, Tideman P, Darin N, Wentz E. Psychiatric comorbidity and cognitive profile in children with narcolepsy with or without association to the H1N1 influenza vaccination. Sleep. 2015 Apr 1;38(4):615–21.

Roth T, Dauvilliers Y, Mignot E, Montplaisir J, Paul J, Swick T, et al. Disrupted nighttime sleep in narcolepsy. J Clin Sleep Med 2013 Sept 15;9(9):955–65.

European Commission. Implementation report on the Commission communication on rare diseases: Europe’s challenges and Council Recommendation of 8 June 2009 on an action in the field of rare diseases. Available at: http://ec.europa.eu/health/rare_diseases/docs/2014_rarediseases_implementationreport_en.pd

Download references

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Author information

Authors and affiliations.

Department of Medicine and Surgery, University of Parma, Parma, Italy

Christian Franceschini

Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy

Fabio Pizza & Francesca Cavalli

Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy

Giuseppe Plazzi

IRCCS Istituto Delle Scienze Neurologiche Di Bologna, Bologna, Italy

Fabio Pizza & Giuseppe Plazzi

You can also search for this author in PubMed   Google Scholar

Corresponding author

Correspondence to Giuseppe Plazzi .

Ethics declarations

Conflict of interest.

CF, FP, and FC declare that they have no conflict of interest. GP participated in advisory board for UCB Pharma, Jazz Pharmaceuticals, Bioprojet, and Takeda, outside the submitted work.

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 3409 KB)

Supplementary file2 (pdf 2376 kb), supplementary file3 (pdf 3431 kb), supplementary file4 (pdf 2695 kb), rights and permissions.

Reprints and permissions

About this article

Franceschini, C., Pizza, F., Cavalli, F. et al. A practical guide to the pharmacological and behavioral therapy of Narcolepsy . Neurotherapeutics 18 , 6–19 (2021). https://doi.org/10.1007/s13311-021-01051-4

Download citation

Accepted : 23 March 2021

Published : 22 April 2021

Issue Date : January 2021

DOI : https://doi.org/10.1007/s13311-021-01051-4

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Pharmacological treatment
• Cognitive behavioral treatment
• Behavioral treatment
• Find a journal
• Publish with us
• Track your research

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Review Article
• Published: 19 July 2019

Narcolepsy — clinical spectrum, aetiopathophysiology, diagnosis and treatment

• Claudio L. A. Bassetti   ORCID: orcid.org/0000-0002-4535-0245 1 ,
• Antoine Adamantidis 1 ,
• Denis Burdakov   ORCID: orcid.org/0000-0002-9134-9165 2 , 3 , 4 ,
• Fang Han 5 ,
• Steffen Gay 6 ,
• Ulf Kallweit 1 , 7 ,
• Ramin Khatami 1 , 8 ,
• Frits Koning   ORCID: orcid.org/0000-0002-4007-5715 9 ,
• Brigitte R. Kornum 10 ,
• Gert Jan Lammers 11 , 12 ,
• Roland S. Liblau 13 ,
• Pierre H. Luppi 14 , 15 ,
• Geert Mayer 16 ,
• Thomas Pollmächer 17 ,
• Takeshi Sakurai 18 ,
• Federica Sallusto 19 , 20 ,
• Thomas E. Scammell 21 ,
• Mehdi Tafti   ORCID: orcid.org/0000-0002-6997-3914 22 , 23 &
• Yves Dauvilliers 24 , 25 , 26  

Nature Reviews Neurology volume  15 ,  pages 519–539 ( 2019 ) Cite this article

15k Accesses

379 Citations

171 Altmetric

Metrics details

• Immunological disorders
• MHC class II
• Neurological manifestations
• Sleep disorders

Narcolepsy is a rare brain disorder that reflects a selective loss or dysfunction of orexin (also known as hypocretin) neurons of the lateral hypothalamus. Narcolepsy type 1 (NT1) is characterized by excessive daytime sleepiness and cataplexy, accompanied by sleep–wake symptoms, such as hallucinations, sleep paralysis and disturbed sleep. Diagnosis is based on these clinical features and supported by biomarkers: evidence of rapid eye movement sleep periods soon after sleep onset; cerebrospinal fluid orexin deficiency; and positivity for HLA-DQB1*06:02. Symptomatic treatment with stimulant and anticataplectic drugs is usually efficacious. This Review focuses on our current understanding of how genetic, environmental and immune-related factors contribute to a prominent (but not isolated) orexin signalling deficiency in patients with NT1. Data supporting the view of NT1 as a hypothalamic disorder affecting not only sleep–wake but also motor, psychiatric, emotional, cognitive, metabolic and autonomic functions are presented, along with uncertainties concerning the ‘narcoleptic borderland’, including narcolepsy type 2 (NT2). The limitations of current diagnostic criteria for narcolepsy are discussed, and a possible new classification system incorporating the borderland conditions is presented. Finally, advances and obstacles in the symptomatic and causal treatment of narcolepsy are reviewed.

Narcolepsy is a rare and often disabling hypothalamic disorder that presents with sleep–wake dysregulation (excessive daytime sleepiness (EDS), cataplexy, hallucinations, sleep paralysis and disturbed sleep) and motor, cognitive, psychiatric, metabolic and autonomic disturbances.

Narcolepsy arises from the interaction of genetic and environmental factors, which lead to an immune-mediated selective loss or dysfunction of orexin neurons in the lateral hypothalamus.

Patients with narcolepsy type 1 have cataplexy and little or no orexin in cerebrospinal fluid; narcolepsy type 2 is a diagnosis of exclusion requiring ancillary tests ruling out other causes of EDS.

Several drugs (including modafinil, sodium oxybate, pitolisant, solriamfetol and methylphenidate) improve narcoleptic symptoms in most patients.

More research is needed to understand the clinical spectrum of narcolepsy, the exact mechanisms leading to orexin neuronal loss and the value of new treatments, including orexin agonists and immunomodulation.

Awareness of narcolepsy, assessments of treatment efficacy, treatment of children or during pregnancy and management of comorbidities are still suboptimal in narcolepsy and require improvement.

This is a preview of subscription content, access via your institution

Access options

Access Nature and 54 other Nature Portfolio journals

Get Nature+, our best-value online-access subscription

24,99 € / 30 days

cancel any time

Subscribe to this journal

Receive 12 print issues and online access

195,33 € per year

only 16,28 € per issue

Buy this article

• Purchase on SpringerLink
• Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

The immunopathogenesis of narcolepsy type 1

Increased very low frequency pulsations and decreased cardiorespiratory pulsations suggest altered brain clearance in narcolepsy

A rare genetic variant in the cleavage site of prepro-orexin is associated with idiopathic hypersomnia

Bassetti, C. & Aldrich, M. Narcolepsy. Neurol. Clin. 14 , 545–571 (1996).

Article   CAS   PubMed   Google Scholar  

Westphal, C. Eigentümliche mit Einschlafen verbundene Anfälle. Arch. Psychiatr. Nervenkr. 7 , 631–635 (1877).

Google Scholar  

Gélineau, J. B. E. De la narcolepsie [French]. Gaz. Hop. 53–54 , 626–637 (1880).

Fischer, F. Epileptoide Schlafzustände [German]. Arch. Psychiatr. Nervenkr. 8 , 200–203 (1878).

Article   Google Scholar  

Henneberg, R. Über genuine Narkolepsie [German]. Neurol. Zbl. 30 , 282–290 (1916).

Löwenfeld, L. Über Narkolepsie [German]. Münch. Med. Wochenschr. 49 , 1041–1045 (1902).

Redlich, E. Zur Narkolepsiefrage [German]. Monatsschr. Psychiatr. Neurol. 37 , 85 (1915).

Redlich, E. Über Narkolepsie [German]. Z. Gesamte Neurol. Psychiatr. 95 , 256–270 (1924).

Daniels, L. E. Narcolepsy. Medicine 13 , 1–122 (1934).

Yoss, R. E. & Daly, D. D. Criteria for the diagnosis of the narcoleptic syndrome. Mayo Clin. Proc. 32 , 320–328 (1957).

CAS   Google Scholar  

Wilder, J. in Handbuch der Neurologie Vol. 17 (eds Braun, E., Bumke, O. & Förster, O.) 87–141 (Springer, 1935).

Adie, W. J. Idiopathic narcolepsy: a disease sui generis ; with remarks on the mechanism of sleep. Brain 49 , 257–306 (1926).

Wilson, S. A. The narcolepsies. Brain 51 , 63–109 (1928).

Vogel, G. Studies in psychophysiology of dreams III. The dreams of narcolepsy. Arch. Gen. Psychiatry 3 , 421–428 (1960).

Honda, Y., Asaka, A., Tanaka, Y. & Juji, T. Discrimination of narcolepsy by using genetic markers and HLA. Sleep Res. 12 , 254 (1983).

Juji, T., Satake, M., Honda, Y. & Doi, Y. HLA antigens in Japanese patients with narcolepsy. All the patients were DR2 positive. Tissue Antigens 24 , 316–319 (1984).

Nishino, N., Ripley, B., Overeem, S., Lammers, G. J. & Mignot, E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355 , 39–40 (2000).

American Academy of Sleep Medicine. International Classification of Sleep Disorders (ICSD-3) 3rd edn (AASM, 2014).

Juji, T., Matsuki, L., Tokunaga, K., Naohara, K. & Honda, Y. Narcolepsy and HLA in the Japanese. Ann. NY Acad. Sci. 540 , 106–114 (1988).

Hublin, S. et al. The prevalence of narcolepsy: an epidemiological study of the Finnish twin cohort. Ann. Neurol. 35 , 709–716 (1994).

Silber, M. H., Krahn, L. E., Olson, E. J. & Pankratz, V. S. The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. Sleep 25, (197–202 (2002).

Ohayon, M., Priest, R. G., Zulley, J., Smirne, S. & Paiva, T. Prevalence of narcolepsy symptomatology and diagnosis in the European general population. Neurology 58 , 1826–1833 (2002).

Wilner, A. et al. Narcolepsy-cataplexy in Israeli Jews is associated exclusively with the HLA DR2 haplotype. Hum. Immunol. 21 , 15–22 (1988).

al Rajeh, S. et al. A community survey of neurological disorders in Saudi Arabia: the Thugbah study. Neuroepidemiology 12 , 164–178 (1993).

Jennum, J., Ibsen, R., Petersen, E. R., Knudsen, S. & Kjellberg, J. Health, social and economic consequences of narcolepsy: a controlled national study evaluating the societal effect on patients and their partners. Sleep Med. 13 , 1086–1093 (2012).

Article   PubMed   Google Scholar  

Jennum, P., Thorstensen, E. W., Pickering, L., Ibsen, R. & Kjellberg, J. Morbidity and mortality of middle-aged and elderly narcoleptics. Sleep Med. 36 , 23–28 (2017).

Dauvilliers, Y. et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology 57 , 2029–2033 (2001).

Rocca, F. L., Pizza, F., Ricci, E. & Plazzi, G. Narcolepsy during childhood: an update. Neuropediatrics 46 , 181–198 (2015).

Yoss, R. & Daly, D. Narcolepsy in children. Pediatrics 25 , 1025–1033 (1960).

CAS   PubMed   Google Scholar  

Challamel, M. J. et al. Narcolepsy in children. Sleep 17 , 17–20 (1994).

Guilleminault, C. & Pelayo, R. Narcolepsy in prepubertal children. Ann. Neurol. 43 , 135–142 (1998).

Pizza, F. et al. Primary progressive narcolepsy type 1: the other side of the coin. Neurology 83 , 2189–2190 (2014).

Article   PubMed   PubMed Central   Google Scholar  

Luca, G. et al. Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study. J. Sleep Res. 22 , 482–495 (2013).

Sturzenegger, C. & Bassetti, C. L. The clinical spectrum of narcolepsy with cataplexy: a reappraisal. J. Sleep Res. 13 , 395–406 (2004).

van Dijk, J. G., Lammers, G. J. & Blansjaar, B. A. Isolated cataplexy of more than 40 years’ duration. Br. J. Psychiatry 159 , 719–721 (1991).

Andlauer, O. et al. Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy. Sleep 35 , 1247–1255 (2012).

Trotti, L. M., Staab, B. A. & Rye, D. B. Test-retest reliability of the multiple sleep latency test in narcolepsy without cataplexy and idiopathic hypersomnia. J. Clin. Sleep Med. 9 , 789–785 (2013).

PubMed   PubMed Central   Google Scholar  

Lopez, R. et al. Test-retest reliability of the multiple sleep latency test in central disorders of hypersomnolence. Sleep 40 , 164–168 (2017).

Dauvilliers, Y., Abril, B., Mas, E., Michel, F. & Tafti, M. Normalization of hypocretin-1 in narcolepsy after intravenous immunoglobulin treatment. Neurology 73 , 1333–1334 (2009).

Symonds, C. P. Narcolepsy as a symptom of encephalitis lethargica. Lancet 173 , 1214–1125 (1922).

Mankowski, B. Zur Pathogenese kataplegisches Anfälle bei Narkolepsie (auf Grund eines Falls von Encephalitis epidemica) [German]. Monatschr. Psychiatr. Neurol. 61 , 340–349 (1926).

Langdon, N., Welsh, K. I., van Dam, M., Vaughan, R. W. & Parkes, D. Genetic markers in narcolepsy. Lancet 2 , 1178–1180 (1984).

Peyron, C. et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat. Med. 6 , 991–997 (2000).

Thannickal, T. C. et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 27 , 469–474 (2000).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Crocker, A. et al. Concomitant loss of dynorphin, NARP, and orexin in narcolepsy. Neurology 65 , 1184–1188 (2005).

de Lecea, L. et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl Acad. Sci. USA 95 , 322–327 (1998).

Sakurai, T. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92 , 573–585 (1998).

Krahn, L. E. Reevaluating spells initially identified as cataplexy. Sleep Med. 6 , 537–542 (2005).

Desseilles, M. et al. Neuroimaging insights into the pathophysiology of sleep disorders. Sleep 31 , 777–794 (2008).

Burgess, C. R. & Scammell, T. E. Narcolepsy: neural mechanisms of sleepiness and cataplexy. J. Neurosci. 32 , 12305–12311 (2012).

Broughton, R. et al. Excessive daytime sleepiness and the pathophysiology of narcolepsy-cataplexy: a laboratory perspective. Sleep 9 , 205–215 (1986).

Nishino, S. & Kanbayashi, T. Symptomatic narcolepsy, cataplexy, and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Sleep Med. Rev. 9 , 269–310 (2005).

Baumann, C. R. et al. Hypocretin-1 (orexin A) deficiency in acute traumatic brain injury. Neurology 65 , 147–149 (2005).

Baumann, C. R. et al. Loss of hypocretin (orexin) neurons with trumatic brain injury. Ann. Neurol. 66 , 555–559 (2009).

Baumann, C. R., Bassetti, C. L., Hersberger, M. & Jung, H. H. Excessive daytime sleepiness in Behçet’s disease with diencephalic lesions and hypocretin dysfunction. Eur. Neurol. 63 , 190 (2010).

Mignot, E. et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch. Neurol. 59 , 1553–1562 (2002).

Bassetti, C. L. Selective hypocretin (orexin) neuronal loss and multiple signaling deficiencies. Neurology 65 , 1152–1153 (2005).

Latorre, D. et al. T cells in patients with narcolepsy target self-antigens of hypocretin neurons. Nature 562 , 63–68 (2018).

Lippert, J. et al. Specific T cell activation in peripheral blood and cerebrospinal fluid in central disorders of hypersomnolence. Sleep 42 , zsy223 (2019).

Luo, F. et al. Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy. Proc. Natl Acad. Sci. USA 115 , E12323–E12332 (2018).

Pedersen, N. W. et al. CD8 + T cells from patients with narcolepsy and healthy controls recognize hypocretin neuron-specific antigens. Nat. Commun. 10 , 837 (2019).

Article   PubMed   PubMed Central   CAS   Google Scholar  

Thannickal, T. C., Nienhuis, R. & Siegel, J. M. Localized loss of hypocretin (orexin) cells in narcolepsy without cataplexy. Sleep 32 , 993–998 (2009).

Valko, P. O. et al. Increase of histaminergic tuberomammillary neurons in narcolepsy. Ann. Neurol. 74 , 794–804 (2013).

Honda, M. et al. Absence of ubiquitinated inclusions in hypocretin neurons of patients with narcolepsy. Neurology 18 , 511–517 (2009).

Article   CAS   Google Scholar  

Gerashchenko, D. et al. Relationship between CSF hypocretin levels and hypocretin neuronal loss. Exp. Neurol. 184 , 1010–1016 (2003).

John, J. et al. Greatly increased numbers of histamine cells in human narcolepsy with cataplexy. Ann. Neurol. 74 , 786–793 (2013).

Khatami, R. et al. Monozygotic twins concordant for narcolepsy-cataplexy without any detectable abnormality in the hypocretin (orexin) pathway. Lancet 363 , 1199–1200 (2004).

Dauvilliers, Y. et al. A monozygotic twin pair discordant for narcolepsy and CSF hypocretin-1. Neurology 62 , 2137–2138 (2004).

Hor, H. et al. A missense mutation in myelin oligdendrocyte glycoprotein as a cause of familial narcolepsy with cataplexy. Am. J. Hum. Genet. 89 , 474–479 (2011).

Degn, M. et al. Rare missense mutations in P2RY11 in narcolepsy with cataplexy. Brain 140 , 1657–1668 (2017).

Mignot, E. Genetic and familial aspects of narcolepsy. Neurology 50 , S16–S22 (1998).

Dauvilliers, Y. et al. A narcolepsy susceptibility locus maps to a 5 Mb region of chromosome 21q. Ann. Neurol. 56 , 382–388 (2004).

Mignot, E. et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am. J. Hum. Genet. 68 , 686–699 (2001).

Tafti, M. et al. DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. Sleep 37 , 19–25 (2014).

Mignot, E., Young, T., Lin, L., Finn, L. & Palta, M. Reduction of REM sleep latency associated with HLA-DQB1*0602 in normal adults. Lancet 351 , 727 (1998).

Ollila, H. M. et al. HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy. Am. J. Hum. Genet. 96 , 136–146 (2015).

Han, F. et al. Genome wide analysis of narcolepsy in China implicates novel immune loci and reveals changes in association prior to versus after the 2009 H1N1 influenza pandemic. PLOS Genet. 9 , e1003880 (2013).

Tafti, M. et al. Narcolepsy-associated HLA class I alleles implicate cell-mediated cytotoxicity. Sleep 39 , 581–587 (2016).

Hor, H. et al. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. Nat. Genet. 42 , 786–789 (2010).

Hallmayer, J. et al. Narcolepsy is strongly associated with the T cell receptor alpha locus. Nat. Genet. 41 , 708–711 (2009).

Faraco, J. et al. Immunochip study implicates antigen presentation to T cells in narcolepsy. PLOS Genet. 9 , e1003270 (2013).

Kornum, B. R. et al. Common variants in P2RY11 are associated with narcolepsy. Nat. Genet. 43 , 66–71 (2011).

Singh, A. K., Mahlios, J. & Mignot, E. Genetic association, seasonal infections and autoimmune basis of narcolepsy. J. Autoimmun. 43 , 26–31 (2013).

Shimada, M., Miyagawa, T., Toyoda, H., Tokunaga, K. & Honda, M. Epigenome-wide association study of DNA methylation in narcolepsy: an integrated genetic and epigenetic approach. Sleep 41 , zsy019 (2018).

Imlah, N. W. Narcolepsy in identical twins. J. Neurol. Neurosurg. Psychiatry 24 , 158–160 (1961).

Pollmächer, T. et al. DR2-positive monozygotic twins discordant for narcolepsy. Sleep 13 , 336–343 (1990).

Partinen, M., Hublin, C., Kaprio, J., Koskenvuo, M. & Guilleminault, C. Twin studies in narcolepsy. Sleep 17 , S13–S16 (1994).

Dahmen, N. & Tonn, P. Season of birth effect in narcolepsy. Neurology 61 , 1016–1017 (2003).

Dauvilliers, Y. et al. Month of birth as a risk factor for narcolepsy. Sleep 26 , 663–665 (2003).

Picchioni, D., Mignot, E. & Harsh, J. R. The month-of-birth pattern in narcolepsy is moderated by cataplexy severity and may be independent of HLA-DQB1*0602. Sleep 27 , 1471–1475 (2004).

Donjacour, C. E., Fronczek, R., Le Cessie, Lammers, S., G. J. & Van Dijk, J. G. Month of birth is not a risk factor for narcolepsy with cataplexy in the Netherlands. J. Sleep Res. 20 , 522–525 (2011).

von Economo, C. Sleep as a problem of localization. J. Nerv. Ment. Dis. 71 , 249–259 (1930).

Aran, A. et al. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep 32 , 979–993 (2009).

Partinen, M. et al. Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. Lancet Neurol. 13 , 600–613 (2014).

Dauvilliers, Y. et al. Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France. Brain 136 , 2486–2496 (2013).

Ahmed, S. S. et al. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci. Transl Med. 7 , 294ra105 (2015).

Article   PubMed   CAS   Google Scholar  

Saariaho, A. H. et al. Autoantibodies against ganglioside GM3 are associated with narcolepsy-cataplexy developing after Pandemrix vaccination against 2009 pandemic H1N1 type influenza virus. J. Autoimmun. 63 , 68–75 (2015).

Han, F., Lin, L., Li, J., Dong, X. S. & Mignot, E. Decreased incidence of childhood narcolepsy 2 years after the 2009 H1N1 winter flu pandemic. Ann. Neurol. 73 , 560 (2013).

Sarkanen, T., Alakuijala, A., Julkunen, I. & Partinen, M. Narcolepsy associated with Pandemrix vaccine. Curr. Neurol. Neurosci. Rep. 18 , 43 (2018).

Heyck, H. & Hess, R. Some results of clinical studies on narcolepsy. Schweiz. Arch. Neurol. Psychiatr. 75 , 401–402 (1955).

Hidalgo, H., Kallweit, U., Mathis, J. & Bassetti, C. L. Post Tick-borne encephalitis virus vaccination narcolepsy with cataplexy. Sleep 39 , 1811–1814 (2016).

Lankford, D. A., Wellmann, J. J. & O’Hara, C. Posttraumatic narcolepsy in mild to moderate closed head injury. Sleep 17 , S25–S28 (1994).

Silber, M. H. Narcolepsy, head injury, and the problem of causality. J. Clin. Sleep Med. 1 , 157–158 (2005).

PubMed   Google Scholar  

Cvetikovic-Lopes, V. et al. Elevated Tribbles homolog-2-specific antibody levels in narcolepsy patients. J. Clin. Invest. 120 , 713–719 (2010).

Bergman, H. et al. Narcolepsy patients have antibodies that stain distinct cell populations in rat brain and influence sleep patterns. Proc. Natl Acad. Sci. USA 111 , E3735–E3744 (2014).

Kallweit, U. et al. Co-existing narcolepsy (with and without cataplexy) and multiple sclerosis: six new cases and a literature review. J. Neurol. 265 , 2071–2078 (2018).

Ekbom, K. Familial multiple sclerosis associated with narcolepsy. Arch. Neurol. 15 , 337–344 (1966).

Tsutsui, K. et al. Anti-NMDA-receptor antibody detected in encephalitis, schizophrenia, and narcolepsy with psychotic features. BMC Psychiatry 12 , 37 (2012).

Overeem, S. et al. Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis. Neurology 62 , 138–140 (2004).

Dauvilliers, Y. et al. Hypothalamic immunopathology in anti-Ma–associated diencephalitis with narcolepsy-cataplexy. JAMA Neurol. 70 , 1305–1310 (2013).

Peraita-Adrados, R. et al. A patient with narcolepsy with cataplexy and multiple sclerosis: two different diseases that may share pathophysiologic mechanisms? Sleep Med. 14 , 695–696 (2013).

Valko, P. O., Khatami, R., Baumann, C. R. & Bassetti, C. L. No effect of intravenous immunoglobulins in patents with narcolepsy with cataplexy. J. Neurol. 255 , 1900–1903 (2008).

Chen, W., Black, J., Call, P. & Mignot, E. Late-onset narcolepsy presenting as rapidly progressing muscle weakness: response to plasmapheresis. Ann. Neurol. 58 , 489–490 (2005).

Lecendreux, M., Maret, S., Bassetti, C., Mouren, M. C. & Tafti, M. Clinical efficacy of high-dose intravenous immunoglobulins near the onset of narcolepsy in a 10-year-old boy. J. Sleep Res. 12 , 347–348 (2003).

Black, J. L. 3rd et al. Analysis of hypocretin (orexin) antibodies in patients with narcolepsy. Sleep 28 , 427–431 (2005).

Tanaka, S., Honda, Y., Inoue, Y. & Honda, M. Detection of autoantibodies against hypocretin, HCRTR1, and HCRTR2 in narcolepsy: anti-Hcrt system antibody in narcolepsy. Sleep 29 , 633–638 (2006).

Giannoccaro, M. P. et al. Antibodies against hypocretin receptor 2 are rare in narcolepsy. Sleep 40 , zsw056 (2017).

Langdon, N. et al. Immune factors in narcolepsy. Sleep 9 , 143–148 (1986).

Fredrikson, S., Carlander, B., Billiard, M. & Link, H. CSF immune variables in patients with narcolepsy. Acta Neurol. Scand. 81 , 253–254 (1990).

Hartmann, F. J. et al. High-dimensional single-cell analysis reveals the immune signature of narcolepsy. J. Exp. Med. 213 , 2621–2633 (2016).

Ramberger, M. et al. CD4 + T cell reactivity to orexin/hypocretin in patients with narcolepsy type 1. Sleep 40 , zsw070 (2017).

Lecendreux, M. et al. Impact of cytokine in type 1 narcolepsy: role of pandemic H1N1 vaccination? J. Autoimmun. 60 , 20–31 (2015).

Lecendreux, M. et al. Narcolepsy type 1 is associated with a systemic increase and activation of regulatory T cells and with a systemic activation of global T cells. PLOS ONE 12 , e0169836 (2017).

Khatami, R. et al. The European Narcolepsy Network (EU-NN) database. J. Sleep Res. 25 , 356–364 (2016).

Kornum, B. R. et al. Narcolepsy. Nat. Rev. Dis. Primers 3 , 16100 (2017).

Guilleminault, C., Philips, R. & Dement, W. C. A syndrome of hypersomnia with automatic behaviour. Electroencephalogr. Clin. Neurophysiol. 38 , 403–413 (1975).

Valko, P. O., Bassetti, C. L., Bloch, K. E., Held, U. & Baumann, C. R. Validation of the fatigue severity scale in a Swiss cohort. Sleep 31 , 1601–1607 (2008).

Droogleever Fortuyn, H. A. et al. Severe fatigue in narcolepsy with cataplexy. J. Sleep Res. 21 , 163–169 (2012).

Overeem, S. et al. The clinical features of cataplexy: a questionnaire study in narcolepsy patients with and without hypocretin-1 deficiency. Sleep Med. 12 , 12–18 (2011).

Pizza, F. et al. The distinguishing motor features of cataplexy: a study from video-recorded attacks. Sleep 41 , zsy026 (2018).

Serra, L., Montagna, P., Mignot, E., Lugaresi, E. & Plazzi, G. Cataplexy features in childhood narcolepsy. Mov. Disord. 23 , 858–865 (2008).

Barateau, L. et al. Persistence of deep-tendon reflexes during partial cataplexy. Sleep Med. 45 , 80–82 (2018).

Antelmi, E., Vandi, S., Pizza, Liguori, F., R. & Plazzi, G. Parkinsonian tremor persisting during cataplexy. Sleep Med. 17 , 174–176 (2016).

Poryazova, R., Siccoli, M., Werth, E. & Bassetti, C. L. Unusually prolonged rebound cataplexy after withdrawal of fluoxetine. Neurology 65 , 967–968 (2005).

Gelb, M. et al. Stability of cataplexy over several months — information for the design of therapeutic trials. Sleep 17 , 265–273 (1994).

Rubboli, G. et al. A video-polygraphic analysis of the cataplectic attack. Clin. Neurophysiol. 111 , S120–S128 (2000).

Plazzi, G. et al. Complex movement disorders at disease onset in childhood narcolepsy with cataplexy. Brain 134 , 3477–3489 (2011).

Redlich, E. Epilegomena zur Narkolepsie-Frage [German]. Z. Ges. Neurol. Psychiatr. 136 , 129–173 (1931).

Roth, B. Narcolepsy and Hypersomnia (Karger, 1980).

Rüther, E., Meier-Ewert, K. & Gallitz, A. Zur Symptomatologie des narkoleptischen syndroms [German]. Nervenarzt 43 , 640–643 (1972).

Attarian, H. P., Schenck, C. H. & Mahowald, M. W. Presumed REM sleep behavior disorder arising from cataplexy and wakeful dreaming. Sleep Med. 1 , 131–133 (2000).

Poryazova, R., Khatami, R., Werth, E. & Bassetti, C. L. Weak with sex: sexual intercourse as a trigger for cataplexy. J. Sex. Med. 6 , 2271–2277 (2009).

Parkes, J. D., Chen, S. Y., Clift, S. J., Dahlitz, M. J. & Dunn, G. The clinical diagnosis of the narcoleptic syndrome. J. Sleep Res. 7 , 41–52 (1997).

Vgontzas, A. N., Sollenberger, S. E., Kales, A., Bixler, E. O. & Vela-Bueno, A. Narcolepsy-cataplexy and loss of sphincter control. Postgrad. Med. J. 72 , 493–494 (1996).

Fortuyn, H. A. et al. Psychotic symptoms in narcolepsy: phenomenology and a comparison with schizophrenia. Gen. Hosp. Psychiatry 31 , 146–154 (2009).

Wamsley, E., Donjacour, C. E., Scammell, T. E., Lammers, G. J. & Stickgold, R. Delusional confusion of dreaming and reality in narcolepsy. Sleep 37 , 419–422 (2014).

Roth, T. et al. Disrupted nighttime sleep in narcolepsy. J. Clin. Sleep Med. 9 , 955–965 (2013).

Gudden, H. Die physiologische und pathologische Schlaftrunkenheit [German]. Arch. Psychiat. 40 , 989–1015 (1905).

Mullington, J. & Broughton, R. Daytime sleep inertia in narcolepsy-cataplexy. Sleep 17 , 69–76 (1994).

Broughton, R., Dunham, W., Weisskopf, M. & Rivers, M. Night sleep does not predict day sleep in narcolepsy. Electroencephalogr. Clin. Neurophysiol. 91 , 67–70 (1994).

Harsh, J., Peszka, J., Hartwig, G. & Mitler, M. Night-time sleep and daytime sleepiness in narcolepsy. J. Sleep Res. 9 , 309–316 (2000).

Mayer, G. & Meier-Ewert, K. Motor dyscontrol in sleep of narcoleptic patients (a lifelong development?). J. Sleep Res. 2 , 143–148 (1993).

Nevsimalova, S., Prihodova, I., Kemlink, D., Lin, L. & Mignot, E. REM behavior disorder (RBD) can be one of the first symptoms of childhood narcolepsy. Sleep Med. 8 , 784–786 (2007).

Pizza, F., Tartarotti, S., Poryazova, R., Baumann, C. R. & Bassetti, C. L. Sleep-disordered breathing and periodic limb movements in narcolepsy with cataplexy: a systematic analysis of 35 consecutive patients. Eur. Neurol. 70 , 22–26 (2013).

Knudsen, S., Gammeltoft, S. & Jennum, P. J. Rapid eye movement sleep behaviour disorder in patients with narcolepsy is associated with hypocretin-1 deficiency. Brain 133 , 568–579 (2010).

Dauvilliers, Y. et al. Periodic leg movements during sleep and wakefulness in narcolepsy. J. Sleep Res. 16 , 333–339 (2007).

Plazzi, G. et al. Restless legs syndrome is frequent in narcolepsy with cataplexy patients. Sleep 33 , 689–694 (2010).

Franceschini, C. et al. Motor events during REM sleep in patients with narcolepsy-cataplexy: a video-polysomnographic pilot study. Sleep Med. 12 , S59–S63 (2011).

Nightingale, S. et al. The association between narcolepsy and REM behavior disorder (RBD). Sleep Med. 6 , 253–258 (2005).

Chokroverty, S. Sleep apnea in narcolepsy. Sleep 9 , 250–253 (1986).

Sansa, G., Iranzo, A. & Santamaria, J. Obstructive sleep apnea in narcolepsy. Sleep Med. 11 , 93–95 (2010).

Dodet, P., Chavez, M., Leu-Semenescu, S., Golmard, J. L. & Arnulf, I. Lucid dreaming in narcolepsy. Sleep 38 , 487–497 (2015).

Rak, M. et al. Increased lucid dreaming frequency in narcolepsy. Sleep 38 , 787–792 (2015).

Bladin, P. F. Narcolepsy-cataplexy and psychoanalytic theory of sleep and dreams. J. Hist. Neurosci. 9 , 203–217 (2000).

Willey, M. M. Sleep as an escape mechanism. Psychoanal. Rev. 11 , 181–183 (1924).

Missriegler, A. On the psychogenesis of narcolepsy. J. Nerv. Ment. Dis. 93 , 141–162 (1941).

Pai, M. N. Hypersomnia syndromes. Br. Med. J. 1 , 522–524 (1950).

Orellana, C. et al. Life events in the year preceding the onset of narcolepsy. Sleep 17 , S50–S53 (1994).

Broughton, R. et al. Life effects of narcolepsy in 180 patients from North America, Asia and Europe compared to matched controls. Can. J. Neurol. Sci. 8 , 299–304 (1981).

Roth, B. & Nevsimalova, S. Depression in narcolepsy and hypersomnia. Schweiz. Arch. Neurol. Neurochir. Psychiatr. 116 , 291–300 (1975).

Vourdas, A. et al. Narcolepsy and psychopathology: is there an association? Sleep Med. 3 , 353–360 (2002).

Ohayon, M. M. Narcolepsy is complicated by high medical and psychiatric comorbidities: a comparison with the general population. Sleep Med. 14 , 488–492 (2013).

Ruoff, C. M. et al. High rates of psychiatric comorbidity in narcolepsy: findings from the Burden of Narcolepsy Disease (BOND) study of 9,312 patients in the United States. J. Clin. Psychiatry 78 , 171–176 (2017).

Cohen, A., Mandrekar, J., St Louis, E. K., Silber, M. H. & Kotagal, S. Comorbidities in a community sample of narcolepsy. Sleep Med. 43 , 14–18 (2018).

Fortuyn, H. A., Mulders, P. C., Renier, Buitelaar, W. O., J. K. & Overeem, S. Narcolepsy and psychiatry: an evolving association of increasing interest. Sleep Med. 12 , 714–719 (2011).

Rosenthal, C. Über das Auftreten von halluzinatorisch-kataplektischen Angstsyndrom, Wachanfällen und ähnlichen Störungen bei Schizophrenen [German]. Monatschr. Psychiatr. Neurol. 102 , 11–38 (1939).

Nissen, C. et al. Transient narcolepsy-cataplexy syndrome after discontinuation of the antidepressant venlafaxine. J. Sleep Res. 14 , 207–208 (2005).

Plazzi, G., Khatami, R., Serra, Pizza, L., F. & Bassetti, C. L. Pseudocataplexy in narcolepsy-cataplexy. Sleep Med. 11 , 591–594 (2010).

Krahn, L. E., Hansen, M. R. & Shepard, J. W. Pseudocataplexy. Psychosomatics 42 , 356–358 (2001).

Ponz, A. et al. Abnormal activitiy in reward brain circuits in human narcolepsy with cataplexy. Ann. Neurol. 67 , 190–200 (2010).

Ponz, A. et al. Reduced amygdala activity during aversive conditioning in human narcolepsy. Ann. Neurol. 67 , 394–398 (2010).

Georgescu, D. et al. Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal. J. Neurosci. 23 , 3106–3111 (2003).

Broughton, R. J., Guberman, A. & Roberts, J. Comparison of the psychosocial effects of epilepsy and narcolepsy/cataplexy: a controlled study. Epilepsia 25 , 423–433 (1984).

Ohayon, M. M. et al. Increased mortality in narcolepsy. Sleep 37 , 439–444 (2014).

Pizza, F. et al. Car crashes and central disorders of hypersomnolence: a French study. PLOS ONE 10 , e0129386 (2015).

Blackwell, J. E., Alammar, H. A., Weighall, A. R., Kellar, I. & Nash, H. M. A systematic review of cognitive function and psychosocial well-being in school-age children with narcolepsy. Sleep Med. Rev. 34 , 82–93 (2017).

Szakacs, Z., Hallbook, T., Tideman, P., Darin, N. & Wentz, E. Psychiatric comorbidity and cognitive profile in children with narcolepsy with or without association to the H1N1 influenza vaccnination. Sleep 38 , 615–621 (2015).

Douglas, N. J. The psychosocial aspects of narcolepsy. Neurology 50 , S27–S30 (1998).

Goswami, M. The influence of clinical symptoms on quality of life in patients with narcolepsy. Neurology 50 , S31–S36 (1998).

Oosterloo, M., Lammers, G. J., Overeem, S., de Noord, I. & Kooij, J. J. Possible confusion between primary hypersomnia and adult attention-deficit/hyperactivity disorder. Psychiatry Res. 143 , 293–297 (2006).

Filardi, M. et al. Attention impairments and ADHD symptoms in adult narcoleptic patients with and without hypocretin deficiency. PLOS ONE 12 , e0182085 (2017).

Naumann, A., Bellebaum, C. & Daum, I. Cognitive deficits in narcolepsy. J. Sleep Res. 15 , 329–338 (2006).

Zamarian, L. et al. Subjective deficits of attention, cognition and depression in patients with narcolepsy. Sleep Med. 16 , 45–51 (2015).

Bayard, S. et al. Executive control of attention in narcolepsy. PLOS ONE 7 , e33525 (2012).

Jennum, J. et al. Cerebrospinal fluid biomarkers of neurodegeneration are decreased or normal in narcolepsy. Sleep 40 , zsw006 (2017).

Economou, N. T., Manconi, M., Ghika, J., Raimondi, M. & Bassetti, C. L. Development of Parkinson and Alzheimer diseases in two cases of narcolepsy-cataplexy. Eur. Neurol. 67 , 48–50 (2012).

Roberts, H. J. Obesity due to the syndrome of narcolepsy and diabetogenic hyperinsulinism: clinical and therapeutic observations on 252 patients. J. Am. Geriatr. Soc. 15 , 721–743 (1967).

Schuld, A., Hebebrand, J., Geller, F. & Pöllmächer, T. Increased body mass index in patients with narcolepsy. Lancet 355 , 1274–1275 (2000).

Kok, S. W. et al. Reduction of plasma leptin levels and loss of its circadian rhythmicity in hypocretin (orexin)-deficient narcoleptic humans. J. Clin. Endocrinol. Metab. 87 , 805–809 (2002).

Donjacour, C. E. et al. Glucose and fat metabolism in narcolepsy and the effect of sodium oxybate: a hyperinsulinemic-euglycemic clamp study. Sleep 37 , 795–801 (2014).

Poli, F. et al. High prevalence of precocious puberty and obesity in childhood narcolepsy with cataplexy. Sleep 36 , 175–181 (2013).

van Holst, R. J. et al. Aberrant food choices after satiation in human orexin-deficient narcolepsy type 1. Sleep 39 , 1951–1959 (2016).

Nishino, S. et al. Low cerebrospinal fluid hypocretin (orexin) and altered energy homeostasis in human narcolepsy. Ann. Neurol. 50 , 381–388 (2001).

Kok, S. W. et al. Altered setting of the pituitary-thyroid ensemble in hypocretin-deficient narcoleptic men. Am. J. Physiol. Endocrinol. Metab. 288 , E892–E899 (2005).

Plazzi, G. et al. Autonomic disturbances in narcolepsy. Sleep Med. Rev. 15 , 187–196 (2011).

Stiasny-Kolster, K. et al. Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for alpha-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 128 , 126–137 (2005).

Bayard, S. et al. Olfactory dysfunction in narcolepsy with cataplexy. Sleep Med. 11 , 876–881 (2010).

Black, J. et al. Medical comorbidity in narcolepsy: findings from the Burden of Narcolepsy Disease (BOND) study. Sleep Med. 33 , 13–18 (2017).

Lecendreux, M. Pediatric narcolepsy: clinical and therapeutical approach. Handb. Clin. Neurol. 112 , 839–845 (2013).

Vandi, S. et al. A standardized test to document cataplexy. Sleep Med. 53 , 197–204 (2017).

Baumann, C. R., Khatami, R., Werth, E. & Bassetti, C. L. Hypocretin (orexin) deficiency predicts severe objective excessive daytime sleepiness in narcolepsy with cataplexy. J. Neurol. Neurosurg. Psychiatry 77 , 402–404 (2006).

Gerashchenko, D. et al. Hypocretin-2-saporin lesions of the lateral hypothalamus produce narcoleptic-like sleep behavior in the rat. J. Neurosci. 21 , 7273–7283 (2001).

Baumann, C. R. & Bassetti, C. L. Hypocretins (orexins) and sleep-wake disorders. Lancet Neurol. 10 , 673–682 (2005).

Baumann, C. R., Dauvilliers, Y., Mignot, E. & Bassetti, C. L. Normal CSF hypocretin-1 (orexin-A) levels in dementia with Lewy bodies. Eur. Neurol. 52 , 73–76 (2004).

Mayer, G. & Lammers, G. J. The MSLT: more objections than benefits as a diagnostic gold standard? Sleep 37 , 1027–1028 (2014).

Sakai, N., Matsumura, M., Lin, L., Mignot, E. & Nishino, S. HLPC analysis of CSF hypocretin-1 in type 1 and 2 narcolepsy. Sci. Rep. 9 , 477 (2019).

Mignot, E. et al. Correlates of sleep-onset REM periods during the Multiple Sleep Latency Test in community adults. Brain 129 , 1609–1623 (2006).

Goldbart, A. et al. Narcolepsy and predictors of positive MSLTs in the Wisconsin sleep cohort. Sleep 37 , 1043–1051 (2014).

Zhang, Z. et al. Exploring the clinical features of narcolepsy type 1 versus narcolepsy type 2 from European Narcolepsy Network database with machine learning. Sci. Rep. 8 , 10628 (2018).

Bassetti, C. & Aldrich, M. S. Idiopathic hypersomnia. A series of 42 patients. Brain 120 , 1423–1435 (1997).

Berti Ceroni, G., Coccagna, G., Gambi, D. & Lugaresi, E. Considerazioni clinico-poligrafiche sulla narcolessia essenziale “a sonno lento” [Italian]. Sist. Nerv. 2 , 81–89 (1967).

Hishikawa, Y. et al. The nature of sleep attack and other symptoms of narcolepsy. Electroencephalogr. Clin. Neurophysiol. 24 , 1–10 (1968).

Melberg, A. et al. Autosomal dominant cerebellar ataxia deafness and narcolepsy. J. Neurol. Sci. 134 , 119–129 (1995).

Moghadam, K. K. et al. Narcolepsy is a common phenotype in HSAN IE and ADCA-DN. Brain 137 , 1643–1655 (2014).

D’Cruz, O. F., Vaughn, B. V., Gold, S. H. & Greenwood, R. S. Symptomatic cataplexy in pontomedullary lesions. Neurology 44 , 2189–2191 (1994).

Kanbayashi, T. Symptomatic narcolepsy in patients with neuromyelitis optica and multiple sclerosis: new neurochemical and immunological implications. Arch. Neurol. 66 , 1563–1566 (2009).

Mathis, J., Hess, C. W. & Bassetti, C. Isolated mediotegmental lesion causing narcolepsy and rapid eye movement sleep behaviour disorder: a case evidencing a common pathway in narcolepsy and rapid eye movement sleep behaviour disorder. J. Neurol. Neurosurg. Psychiatry 78 , 427–429 (2007).

Schwartz, W. J., Stakes, J. W. & Hobson, J. A. Transient cataplexy after removal of a craniopharyngioma. Neurology 34 , 1372–1375 (1984).

Bonduelle, M. & Degos, C. in Narcolepsy: Proceedings of the First International Symposium on Narcolepsy (eds Guilleminault, C. et al.) 313–332 (Spectrum, 1976).

Stahl, S. M., Layzer, R. B., Aminoff, M. J., Townsend, J. J. & Feldon, S. Continuous cataplexy in a patient with a midbrain tumor: the limp man syndrome. Neurology 30 , 1115–1118 (1980).

Fernandez, J. M., Sadaba, F., Villaverde, F. J., Alvaro, L. C. & Cortina, C. Cataplexy associated with midbrain lesion. Neurology 45 , 393–394 (1995).

Roehrs, T., Zorick, F., Sicklesteel, J., Wittig, R. & Roth, T. Excessive daytime sleepiness associated with insufficient sleep. Sleep 6 , 319–325 (1983).

Baumann, C., Ferini-Strambi, L., Waldvogel, D., Werth, E. & Bassetti, C. L. Parkinsonism with excessive daytime sleepiness — a narcolepsy-like disorder? J. Neurol. 252 , 139–145 (2005).

Kaplan, K. A. & Harvey, A. G. Hypersomnia across mood disorders: a review and synthesis. Sleep Med. Rev. 13 , 275–285 (2009).

McLeod, S., Ferrie, C. & Zuberi, S. M. Symptoms of narcolepsy in children misinterpreted as epilepsy. Epileptic Disord. 7 , 13–17 (2005).

Paskind, H. A. Effect of laughter on muscle tone. Arch. Neurol. Psychiatry 28 , 623–628 (1932).

Partinen, M. Sleeping habits and sleep disorders of Finnish men before, during and after military service. Ann. Med. Milit. Fenn. 57 (Suppl. 1), 1–96 (1982).

Overeem, S., Lammers, G. J. & van Dijk, J. G. Weak with laughter. Lancet 354 , 838 (1999).

Kim, L. J. et al. Frequencies and associations of narcolepsy-related symptoms: a cross-sectional study. J. Clin. Sleep Med. 11 , 1377–1384 (2015).

Parkes, J. D. Genetic factors in human sleep disorders with special reference to Norrie disease, Prader–Willi syndrome and Moebius syndrome. J. Sleep Res. 8 (Suppl. 1), 14–22 (1999).

Iranzo, A. & Santamaria, J. Hyperkalemic periodic paralysis associated with multiple sleep onset REM periods. Sleep 22 , 1123–1124 (1999).

Hartse, K. M., Zorick, F., Sicklesteel, J. & Roth, T. Isolated cataplexy: a familial study. Henry Ford Hosp. Med. J. 36 , 24–27 (1988).

Kishi, Y. et al. Schizophrenia and narcolepsy: a review with a case report. Psychiatry Clin. Neurosci. 58 , 117–124 (2004).

Bassetti, C. L. in Handbook of Clinical Neurology 169–190 (Elsevier, 2014).

Antelmi, E., Pizza, F., Vandi, S. & Plazzi, G. Stereotyped episodes of aphasia and immobility: how cataplexy mimics stroke in an elderly patient. Sleep Med. 36 , 122–124 (2017).

Leu-Semenscu, S. et al. Hallucinations in narcolepsy with and without cataplexy: contrasts with Parkinson’s disease. Sleep Med. 12 , 497–504 (2011).

Cheyne, J. A., Newby-Clark, I. R. & Rueffer, S. D. Relations among hypnagogic and hypnopompic experiences associated with sleep paralysis. J. Sleep Res. 8 , 313–318 (1999).

Dahmen, N., Kasten, M., Müller, M. J. & Mittag, K. Frequency and dependence on body posture of hallucinations and sleep paralysis in a community sample. J. Sleep Res. 11 , 179–180 (2002).

Ohayon, M. M. & Smirne, S. Prevalence and consequences of insomnia disorders in the general population of Italy. Sleep Med. 3 , 115–120 (2002).

Kallweit, U., Schmidt, M. & Bassetti, C. L. Patient-reported measures of narcolepsy: the need for better assessment. J. Clin. Sleep Med. 13 , 737–744 (2017).

Sturzenegger, C. et al. Swiss Narcolepsy Scale: a simple screening tool for hypocretin-deficient narcolepsy with cataplexy. Clin. Transl Neurosci. 2 , 1–5 (2018).

Aldrich, M. S., Chervin, R. D. & Malow, B. A. Value of the multiple sleep latency test (MSLT) for the diagnosis of narcolepsy. Sleep 20 , 620–629 (1997).

Dauvilliers, Y. et al. Effect of age on MSLT results in patients with narcolepsy-cataplexy. Neurology 62 , 46–50 (2004).

Singh, M., Drake, C. L. & Roth, T. The prevalence of multiple sleep-onset REM periods in a population-based sample. Sleep 29 , 890–895 (2016).

Huang, Y. S. et al. Multiple sleep latency test in narcolepsy type 1 and narcolepsy type 2: a 5-year follow-up study. J. Sleep Res. 27 , e12700 (2018).

Marti, I., Valko, P. O., Khatami, R., Bassetti, C. L. & Baumann, C. R. Multiple sleep latency measures in narcolepsy and behaviourally insufficient sleep syndrome. Sleep Med. 10 , 1146–1150 (2009).

Drakatos, P. et al. First rapid eye movement sleep periods and sleep-onset rapid eye movement periods in sleep-stage sequencing of hypersomnias. Sleep Med. 14 , 897–901 (2013).

Cairns, A. & Bogan, R. Prevalence and clinical correlates of a short onset REM period (SOREMP) during routine PSG. Sleep 38 , 1575–1581 (2015).

Pizza, F. et al. Spectral electroencephalography profile of rapid eye movement sleep at sleep onset in narcolepsy type 1. Eur. J. Neurol. 24 , 334–340 (2017).

Pizza, F. et al. Nocturnal sleep dynamics identify narcolepsy type 1. Sleep 38 , 1277–1284 (2015).

Sakai, N., Mastsumura, M., Lin, L., Mignot, E. & Nishino, S. HPLC analysis of CSF hypocretin-1 in type 1 and 2 narcolepsy. Sci. Rep. 9 , 477 (2019).

Bassetti, C., Aldrich, M. S. & Quint, D. J. MRI findings in narcolepsy. Sleep 20 , 630–631 (1997).

Plazzi, G. et al. Pontine lesions in idiopathic narcolepsy. Neurology 46 , 1250–1254 (1996).

Kaufmann, C., Schuld, A., Pöllmächer, T. & Auer, D. P. Reduced cortical gray matter in narcolepsy: preliminary findings with voxel-based morphometry. Neurology 58 , 1852–1855 (2002).

Overeem, S. et al. Voxel-based morphometry in hypocretin-deficient narcolepsy. Sleep 26 , 44–46 (2003).

Poryazova, R. et al. Magnetic resonance spectroscopy in narcolepsy [abstract]. Sleep 29 , A222 (2006).

Schaer, M., Poryazova, R., Schwartz, S., Bassetti, C. L. & Baumann, C. R. Cortical morphometry in narcolepsy with cataplexy. J. Sleep Res. 21 , 487–494 (2012).

Wada, M. et al. Neuroimaging correlates of narcolepsy with cataplexy: a systematic review. Neurosci. Res. https://doi.org/10.1016/j.neures.2018.03.005 (2018).

Meletti, S. et al. The brain correlates of laugh and cataplexy in childhood narcolepsy. J. Neurosci. 35 , 11583–11594 (2015).

Schwartz, S. et al. Abnormal activity in hypothalamus and amygdala during humour processing in human narcolepsy with cataplexy. Brain 131 , 514–522 (2008).

Reiss, A. L. et al. Anomalous hypothalamic response to humor in cataplexy. PLOS ONE 3 , e2225 (2008).

Siegel, J. M. et al. Neuronal-activity in narcolepsy: Identification of cataplexy-related cells in the medial medulla. Science 252 , 1315–1318 (1991).

Aldrich, M. Narcolepsy. N. Engl. J. Med. 323 , 389–394 (1990).

Apergis-Schoute, J. et al. Optogenetic evidence for inhibitory signaling from orexin to MCH neurons via local microcircuits. J. Neurosci. 35 , 5435–5441 (2015).

Schöne, C., Apergis-Schoute, J., Sakurai, T., Adamantidis, A. & Burdakov, D. Coreleased orexin and glutamate evoke nonredundant spike outputs and computations in histamine neurons. Cell Rep. 7 , 697–704 (2014).

van den Top, M., Lee, K., Whyment, A. D., Blanks, A. M. & Spanswick, D. Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus. Nat. Neurosci. 7 , 493–494 (2004).

Belle, M. D. et al. Acute suppressive and long-term phase modulation actions of orexin on the mammalian circadian clock. J. Neurosci. 34 , 3607–3621 (2014).

Lee, M. G., Hassani, O. K. & Jones, B. E. Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. J. Neurosci. 25 , 6716–6720 (2005).

Chemelli, R. M. et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98 , 437–451 (1999).

Lin, L. et al. The sleep disorder of canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98 , 365–376 (1999).

Hasegawa, E., Yanagisawa, M., Sakurai, T. & Mieda, M. Orexin neurons suppress narcolepsy via 2 distinct efferent pathways. J. Clin. Invest. 124 , 604–616 (2014).

Irukayama-Tomobe, Y. et al. Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models. Proc. Natl Acad. Sci. USA 114 , 5731–5736 (2017).

Kaushik, M. K. et al. Continuous intrathecal orexin delivery inhibits cataplexy in a murine model of narcolepsy. Proc. Natl Acad. Sci. USA 115 , 6046–6051 (2018).

Black, S. W. et al. Partial ablation of the orexin field induces a sub-narcoleptic phenotype in a conditional mouse model of orexin neurodegeneration. Sleep 41 , zsy116 (2018).

Lin, J. S. Brain structures and mechanisms involved in the control of cortical activation and wakefulness, with emphasis on posterior hypothalamus and histaminergic neurons. Sleep Med. Rev. 4 , 471–503 (2000).

Kanbayashi, T. et al. CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome. Sleep 32 , 181–187 (2009).

Nishino, S. et al. Decreased CSF histamine in narcolepsy with and without low CSF hypocretin-1 in comparison to healthy controls. Sleep 32 , 175–180 (2009).

Bassetti, C. L. et al. Cerebrospinal fluid histamine levels are decreased in patients with narcolepsy and excessive daytime sleepiness of other origin. J. Sleep Res. 19 , 620–623 (2010).

Dauvilliers, Y. et al. Normal cerebrospinal fluid histamine and tele-methylhistamine levels in hypersomnia conditions. Sleep 35 , 1359–1366 (2012).

Lin, J. S. et al. An inverse agonist of the histamine H 3  receptor improves wakefulnesss in narcolepsy: studies in orexin −/− mice and patients. Neurobiol. Dis. 30 , 74–83 (2008).

Jordan, W. et al. Prostaglandin D synthase (beta-trace) in healthy human sleep. Sleep 27 , 867–874 (2004).

Jordan, W. et al. Narcolepsy increased L-PGDS (beta-trace) levels correlate with excessive daytime sleepiness but not with cataplexy. J. Neurol. 252 , 1372–1378 (2005).

Bassetti, C. L., Hersberger, M. & Baumann, C. R. CSF prostaglandin D synthase is reduced in excessive daytime sleepiness. J. Neurol. 253 , 1030–1033 (2006).

Peyron, C. et al. Neurons containing hypocretin (orexin) project to multiple neuronal system. J. Neurosci. 18 , 9996–10015 (1998).

Boissard, R. et al. The rat ponto-medullary network responsible for paradoxical sleep onset and maintenance: a combined microinjection and functional neuroanatomical study. Eur. J. Neurosci. 16 , 1959–1973 (2002).

Lu, J., Sherman, D., Devor, M. & Saper, C. B. A putative flip-flop switch for control of REM sleep. Nature 441 , 589–594 (2006).

Okura, M., Riehl, J., Mignot, E. & Nishino, S. Sulpiride, a D2/D3 blocker reduces cataplexy but not REM sleep in canine narcolepsy. Neuropsychopharmacology 23 , 528–538 (2000).

Vu, M. H., Hurni, C., Mathis, J., Roth, C. & Bassetti, C. L. Selective REM sleep deprivation in narcolepsy. J. Sleep Res. 20 , 50–56 (2011).

Overeem, S., Lammers, G. J. & van Dijk, J. G. Cataplexy: ‘tonic immobility’ rather than ‘REM-sleep atonia’? Sleep Med. 3 , 471–477 (2002).

Hishikawa, Y. et al. Characteristics of REM sleep accompanied by sleep paralysis and hypnagogic hallucinations in narcoleptic patients. Waking Sleeping 2 , 113–123 (1978).

Terzaghi, M., Ratti, P. L., Manni, F. & Manni, R. Sleep paralysis in narcolepsy: more than just a motor dissociative phenomenon? Neurol. Sci. 33 , 169–172 (2012).

Snow, M. B. et al. GABA cells in the central nucleus of the amygdala promote cataplexy. J. Neurosci. 37 , 4007–4022 (2017).

Mahoney, C. E., Agostinelli, L. J., Brooks, J. N., Lowell, B. B. & Scammell, T. E. GABAergic neurons of the central amygdala promote cataplexy. J. Neurosci. 37 , 3995–4006 (2017).

Gulyani, S., Wu, M. F., Nienhuis, R., John, J. & Siegel, J. M. Cataplexy-related neurons in the amygdala of the narcoleptic dog. Neuroscience 112 , 355–365 (2002).

Burgess, C. R., Oishi, Y., Mochizuki, T., Peever, J. H. & Scammell, T. E. Amygdala lesions reduce cataplexy in orexin knock-out mice. J. Neurosci. 33 , 9734–9742 (2013).

Hong, S. B., Tae, W. S. & Joo, E. Y. Cerebral perfusion changes during cataplexy in narcolepsy patients. Neurology 66 , 1747–1749 (2006).

Tucci, V. et al. Emotional information processing in patients with narcolepsy: a psychophysiologic investigation. Sleep 26 , 558–564 (2003).

Khatami, R., Birkmann, S. & Bassetti, C. L. Amygdala dysfunction in narcolepsy-cataplexy. J. Sleep Res. 16 , 226–229 (2007).

Oishi, Y. et al. Role of the medial prefrontal cortex in cataplexy. J. Neurosci. 33 , 9743–9751 (2013).

Vassalli, A. et al. Electroencephalogram paroxysmal θ characterizes cataplexy in mice and children. Brain 136 , 1592–1608 (2013).

van der Heide, A. et al. Comparing treatment effect measurements in narcolepsy: the sustained attention to response task, Epworth sleepiness scale and maintenance of wakefulness test. Sleep 38 , 1051–1058 (2015).

Bogan, R. et al. Evaluation of quality of life in patients with narcolepsy treated with sodium oxybate: use of the 36-item short-form health survey in a clinical trial. Neurol. Ther. 5 , 203–213 (2016).

Filardi, M. et al. Physical activity and sleep/wake behavior, anthropometric, and metabolic profile in pediatric narcolepsy type 1. Front. Neurol. 9 , 707 (2018).

Yoss, R. E. & Daly, D. Treatment of narcolepsy with ritalin. Neurology 9 , 171–173 (1959).

Hishikawa, Y., Ida, H., Nakai, K. & Kaneko, Z. Treatment of narcolepsy with imipramine (tofranil) and desmethylimipramine (pertofran). J. Neurol. Sci. 3 , 453–461 (1966).

Frey, J. & Darbonne, C. Fluoxetine suppresses human cataplexy: a pilot study. Neurology 44 , 707–709 (1994).

Kallweit, U. & Bassetti, C. L. Pharmacological management of narcolepsy with and without cataplexy. Expert Opin. Pharmacother. 18 , 809–817 (2017).

Broughton, R. et al. Randomized, double blind, placebo-controlled cross-over trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy. Neurology 49 , 444–451 (1997).

US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann. Neurol. 43 , 88–97 (1998).

US Xyrem Multicenter Study Group. Sodium oxybate demonstrates long-term efficacy for the treatment of cataplexy in patients with narcolepsy. Sleep Med. 5 , 119–123 (2004).

US Xyrem Multicenter Study Group. A 12-month, open-label, multicenter extension trial of orally administered sodium oxybate for the treatment of narcolepsy. Sleep 26 , 31–35 (2003).

Dauvilliers, Y. et al. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 12 , 1068–1075 (2013).

Szakacs, Z. et al. Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 16 , 200–207 (2017).

Thannickal, T. C. et al. Opiates increase the number of hypocretin-producing cells in human and mouse brain and reverse cataplexy in a mouse model of narcolepsy. Sci. Transl Med. 10 , eaao4953 (2018).

Article   PubMed   CAS   PubMed Central   Google Scholar  

Harper, J. M. Gelineau’s narcolepsy relieved by opiates. Lancet 10 , 92 (1981).

Fry, J. M., Pressman, M. R., DiPhilippo, M. A. & Forst-Paulus, M. Treatment of narcolepsy with codeine. Sleep 9 , 269–274 (1986).

Billiard, M. et al. EFNS guidelines on management of narcolepsy. Eur. J. Neurol. 13 , 1035–1048 (2006).

Mignot, E. J. A practical guide to the therapy of narcolepsy and hypersomnia syndromes. Neurotherapeutics 9 , 739–752 (2012).

Bogan, R. K., Roth, T., Schwartz, J. & Miloslavsky, M. Time to response with sodium oxybate for the treatment if excessive daytime sleepiness and cataplexy in patients with narcolepsy. J. Clin. Sleep Med. 11 , 427–432 (2015).

Thorpy, M. J. et al. A randomized study of solriamfetol for excessive sleepiness in narcolepsy. Ann. Neurol. 85 , 359–370 (2019).

Ruoff, C. et al. Effect of oral JZP-110 (ADX-N05) on wakefulness and sleepiness in adults with narcolepsy: a phase 2b study. Sleep 39 , 1379–1387 (2016).

Mitler, M. M., Hajdukovic, R. & Erman, M. K. Treatment of narcolepsy with methamphetamine. Sleep 16 , 306–317 (1993).

Jin, L. et al. Antidepressants for the treatment of narcolepsy: a prospective study of 148 patients in northern China. J. Clin. Neurosci. https://doi.org/10.1016/j.jocn.2019.02.014 (2019).

Lehert, P. & Falissard, B. Multiple treatment comparison in narcolepsy: a network meta-analysis. Sleep 41 , zsy185 (2018).

Article   PubMed Central   Google Scholar  

Roth, T. et al. Effect of sodium oxybate on disrupted nighttime sleep in patients with narcolepsy. J. Sleep Res. 26 , 407–414 (2016).

Plazzi, G. et al. Treatment of paediatric narcolepsy with sodium oxybate: a double-blind, placebo-controlled, randomised-withdrawal multicentre study and open-label investigation. Lancet Child Adolesc. Health 2 , 483–494 (2018).

Calvo-Ferrandiz, E. & Peraita-Adrados, R. Narcolepsy with cataplexy and pregnancy: a case–control study. J. Sleep Res. 27 , 268–272 (2017).

Maurovich-Horvat, E. et al. Narcolepsy and pregnancy: a retrospective European evaluation of 249 pregnancies. J. Sleep Res. 22 , 496–512 (2013).

Dauvilliers, Y., Carlander, B., Rivier, F., Touchon, J. & Tafti, M. Successful management of cataplexy with intravenous immunoglobulins at narcolepsy onset. Ann. Neurol. 56 , 905–908 (2004).

Miyata, R., Hayashi, M., Kohyama, J. & Honda, M. Steroid therapy ameliorated cataplexy in three children with recent-onset of narcolepsy. Sleep Med. 29 , 86–87 (2017).

Donjacur, C. E. & Lammers, G. J. A remarkable effect of alemtuzumab in a patient suffering from narcolepsy with cataplexy. J. Sleep Res. 21 , 479–480 (2012).

Liblau, R. S., Vassalli, A., Seifinejad, A. & Tafti, M. Hypocretin (orexin) biology and the pathophysiology of narcolepsy with cataplexy. Lancet Neurol. 14 , 318–328 (2015).

Bernard-Valnet, R. et al. CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice. Proc. Natl Acad. Sci. USA 113 , 10956–10961 (2016).

Krahn, L. E., Boeve, B. F., Olson, E. J., Herold, D. L. & Silber, M. H. A standardized test for cataplexy. Sleep Med. 1 , 125–130 (2000).

Olsen, A. V. et al. Diagnostic value of sleep stage dissociation as visualized on a 2-dimensional sleep state space in human narcolepsy. J. Neurosci. Methods 282 , 9–19 (2017).

Hirtz, C. et al. From radioimmunoassay to mass spectrometry: a new method to quantify orexin-A (hypocretin-1) in cerebrospinal fluid. Sci. Rep. 6 , 25162 (2016).

Stephansen, J. B. et al. Neural network analysis of sleep stages enables efficient diagnosis of narcolepsy. Nat. Commun. 9 , 5229 (2018).

Rosenberg, R. & Kim, A. Y. The AWAKEN survey: knowledge of narcolepsy among physicians and the general population. Postgrad. Med. 126 , 78–86 (2014).

Maski, K. et al. Listening to the patient voice in narcolepsy: diagnostic delay, disease burden, and treatment efficacy. J. Clin. Sleep Med. 13 , 419–425 (2017).

Chaplin, J. E., Szakács, A. & Hallböök, Darin, T. N. The development of a health-related quality-of-life instrument for young people with narcolepsy: NARQoL-21. Health Qual. Life Outcomes 15 , 135 (2017).

Dauvilliers, Y. et al. Measurement of narcolepsy symptoms: the Narcolepsy Severity Scale. Neurology 88 , 1358–1365 (2017).

Download references

Acknowledgements

The authors thank the Klaus-Grawe Foundation and the European Sleep Foundation (formerly the Alpine Sleep Summer School) for enabling the Think Tank, which formed the basis of this article. They also thank A. Blank of Inselspital Bern for preparation of the original figures accompanying this article.

Reviewer information

Nature Reviews Neurology thanks M. Honda, G. Plazzi, M. Partinen and other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Authors and affiliations.

Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Claudio L. A. Bassetti, Antoine Adamantidis, Ulf Kallweit & Ramin Khatami

The Francis Crick Institute, London, UK

Denis Burdakov

Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

Department of Health Sciences and Technology, Swiss Federal Institute of Technology/ETH Zürich, Zurich, Switzerland

Department of Pulmonary Medicine, Beijing University People’s Hospital, Beijing, China

Department of Rheumatology, University Hospital, Zurich, Switzerland

Steffen Gay

University of Witten/Herdecke, Institute of Immunology, Clinical Sleep and Neuroimmunology, Witten, Germany

Ulf Kallweit

Centre of Sleep Medicine and Sleep Research, Klinik Barmelweid AG, Barmelweid, Switzerland

Ramin Khatami

Department of Immunohaematology, and Blood Transfusion, Leiden University Medical Centre, Leiden, Netherlands

Frits Koning

Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark

Brigitte R. Kornum

Neurology Department, Leiden University Medical Centre, Leiden, Netherlands

Gert Jan Lammers

Sleep Wake Centre, Stichting Epilepsie Instellingen Nederland, Heemstede, Netherlands

INSERM U1043 — Centre National de la Recherche Scientifique UMR 5282, Centre de Physiopathologie Toulouse-Purpan, Université Toulouse III, Toulouse, France

Roland S. Liblau

Centre de Recherche en Neurosciences de Lyon (CRNL), INSERM, Lyon, France

Pierre H. Luppi

Université Claude Bernard Lyon 1, Lyon, France

Hephata-Klinik, Schwalmstadt, Philipps-Universität Marburg, Department of Neurology, Marburg, Germany

Geert Mayer

Zentrum für psychische Gesundheit, Klinikum Ingolstadt, Ingolstadt, Germany

Thomas Pollmächer

Faculty of Medicine, University of Tsukuba, Ibaraki, Tsukuba, Japan

Takeshi Sakurai

Center of Medical Immunology, Institute for Research in Biomedicine, Bellinzona, Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland

Federica Sallusto

Institute of Microbiology, Eidgenössische Technische Hochschule, Zurich, Switzerland

Department of Neurology, Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

Thomas E. Scammell

Department of Physiology, University of Lausanne, Lausanne, Switzerland

Mehdi Tafti

Center for Investigation and Research in Sleep, Vaud University Hospital, Lausanne, Switzerland

Sleep-Wake Disorders Center, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Montpellier, France

Yves Dauvilliers

National Reference Network for Narcolepsy, Montpellier, France

Institut National de la Santé et de la Recherche Médicale (INSERM) U1061, Montpellier, France

You can also search for this author in PubMed   Google Scholar

Contributions

All authors contributed to researching data for the article and discussions of its content. C.L.A.B. and Y.D. prepared the first draft of the manuscript. All authors participated in review and revision of the manuscript before submission.

Corresponding author

Correspondence to Claudio L. A. Bassetti .

Ethics declarations

Competing interests.

C.L.A.B. declares that he is a member of the advisory boards of Idorsia, Jazz, Takeda and UCB. R.K. and M.T. declare that they are members of the advisory board of UCB. G.J.L. and G.M. declare that they are members of the advisory boards of Bioproject and UCB. T.S. declares that he is a member of the advisory board of Jazz. Y.D. declares that he is a member of the advisory boards of Bioproject, Harmony Biosciences, Idorsia, Jazz, Takeda and UCB. R.L. has received a research grant from GSK. UK declares that he is a member of the advisory boards of AOP Orphan Pharmaceuticals, Bioprojet, Harmony Biosciences, Jazz, and UCB. T.E.S. has received research grant support from Takeda and Merck. T.E.S. declares that he is a member of the advisory board of Avadel, Harmony Biosciences, Idorsia, Jazz and Takeda. The other authors declare no competing interests.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Cite this article.

Bassetti, C.L.A., Adamantidis, A., Burdakov, D. et al. Narcolepsy — clinical spectrum, aetiopathophysiology, diagnosis and treatment. Nat Rev Neurol 15 , 519–539 (2019). https://doi.org/10.1038/s41582-019-0226-9

Download citation

Accepted : 04 April 2019

Published : 19 July 2019

Issue Date : September 2019

DOI : https://doi.org/10.1038/s41582-019-0226-9

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

This article is cited by

Navigating narcolepsy: exploring coping strategies and their association with quality of life in patients with narcolepsy type 1.

• Giorgia Varallo
• Christian Franceschini
• Giuseppe Plazzi

Scientific Reports (2024)

Role of sleep in neurodegeneration: the consensus report of the 5th Think Tank World Sleep Forum

• Luigi Ferini-Strambi
• Claudio Liguori
• Claudio Bassetti

Neurological Sciences (2024)

Estimating the prevalence and clinical causality of obstructive sleep apnea in paediatric narcolepsy patients

• Chaofan Geng

Sleep and Breathing (2024)

Large-scale genome sequencing redefines the genetic footprints of high-altitude adaptation in Tibetans

• Wangshan Zheng

Genome Biology (2023)

Comparison of the clinical and electrophysiological characteristics between type 1 and type 2 narcolepsy: a cross-sectional study

• Kuniyuki Niijima
• Masakazu Wakai

Sleep Science and Practice (2023)

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

• Corpus ID: 73996875

Case Study of a Narcoleptic Patient with a Family History of Narcolepsy

• Y. Shin , Seung-Chul Hong , +3 authors Sung-Pil Lee
• Published 2007

7 References

Hla haplotypes, polysomnography, and pedigrees in a case series of patients with narcolepsy., occurrence of sleep disorders in the families of narcoleptic patients, family studies in narcolepsy., familial aspects of narcolepsy-cataplexy in the czech republic., familial patterns of narcolepsy, age at onset of narcolepsy in two large populations of patients in france and quebec, genetic study of narcoleptic syndrome., related papers.

Showing 1 through 3 of 0 Related Papers

CASE REPORT article

Case report: cases of narcolepsy misdiagnosed as other psychiatric disorders.

• 1 School of Medicine, Southeast University, Nanjing, China
• 2 Sleep Medical Center, Huzhou Third Municipal Hospital, The Affiliated Hospital of Huzhou University, Huzhou, China
• 3 Department of Psychiatry, Wenzhou Medical University, Wenzhou, China

Narcolepsy is characterized by uncontrollable excessive daytime sleepiness, paroxysmal cataplexy, sleep paralysis, and hallucinations. It is often misdiagnosed as psychiatric disorders such as depression and schizophrenia, resulting from the overlap in symptoms and a lack of understanding of narcolepsy. In the present study, three cases of narcolepsy misdiagnosed as depression, dissociative disorder, and schizophrenia are presented to emphasize the high occurrence of the misdiagnosis of narcolepsy in clinical practice. The main reasons for this dilemma are attributed to the lack of adequate sleep, medicine, education, as well as specialized professional technicians. A multi-disciplinary team composed of psychiatrists and sleep specialists should be established to deal with this problem.

Introduction

Narcolepsy is a lifelong sleep disorder characterized by intermittent arousal in rapid eye movement (REM) sleep with the symptoms of excessive daytime sleepiness (EDS), sleep fragmentation, sleep-related hallucinations, sleep paralysis, and cataplexy ( 1 , 2 ); patients with narcolepsy also share the symptoms of eating disorders, affective symptoms, and anxiety. These symptoms are not confined to just one cluster but span several domains with high comorbidity psychiatric disorders such as depression, anxiety, and schizophrenia ( 2 ). Narcolepsy is often misdiagnosed as other psychiatric disorders resulting from the overlap in symptoms and a lack of understanding of sleep disorders ( 2 , 3 ). There is still little understanding of narcolepsy in clinical practice; misdiagnosis and missed diagnosis are common, and the peak period of onset is in childhood ( 2 ). Therefore, correct understanding, early diagnosis, and reasonable treatment can significantly improve growth, development, and quality of life. In this study, we introduced three cases of narcolepsy that were misdiagnosed as psychiatric disorders in the early stages of life and explored the potential reasons for misdiagnosis.

Case presentation

Chief complaints.

A 17-year-old woman visited a psychiatry outpatient service with EDS and depression for 6 years.

History of present illness

The patient gradually developed EDS, inattention in class, and began sleeping in class about 6 years ago without any obvious inducement. Her parents thought she was too tired to study and asked her to go to bed before 21:00 every day, but more than 8 h of sound sleep at night could not make her perform better during the day. Meanwhile, she ate more and had significant weight gain. Because of continued EDS, the patient was unable to study, which led to a decline in academic performance. She would often attempt to keep herself awake but fall asleep even while studying, chatting, and eating. Over the next 6 years, the symptoms continued to aggravate. These symptoms led to significant socio-occupational dysfunction, and she became distressed. She visited multiple physicians, including neurologists and psychiatrists. After repeated examination of thyroid function, electroencephalography (EEG), computed tomography, and cerebrospinal fluid analysis, viral encephalitis and other nervous system diseases, such as epilepsy, were excluded. Her family thought that she might have psychological problems, so she was brought to the psychological department of our hospital for treatment. She was diagnosed with “Major Depressive Disorder” and was treated with sertraline (100 mg qd) but showed poor improvement. After entering high school, the patient again experienced the same pattern of sleepiness. As a result, she was so distressed that she lost interest in everyday life. After a comprehensive physical examination and supplementary examination, such as repeated EEG and head magnetic resonance imaging, the diagnosis of “depression” was confirmed. However, the effect of antidepressant treatment (including venlafaxine 150 mg qd and bupropion 150 mg qd) was not satisfactory.

History of past illness and family history

The patient had no major physical and mental illnesses in the past. There was no positive family history of any sleep disorders or mental disorders.

Diagnostic assessment and treatment

The patient was hospitalized in the sleep medical center. Tests for liver function, renal function, serum electrolytes, thyroid function, and dynamic EEG revealed no abnormalities. After multiple sleep latency test (MSLT) examinations, a diagnosis of “narcolepsy” was considered. Overnight polysomnography (PSG) in our sleep medical center indicated that the total sleep time (TST) was 7:42:0, sleep efficiency (SE; TST/time in bed [TIB]) was 90%, the N3 duration was 93 min, and the REM phase duration was 94.5 min; obstructive sleep apnea was excluded. Repeated MSLT examination during five naps showed three REM episodes and three sleep-onset REM periods (SOREMPs), the mean sleep latency was 7.1 min, and the mean sleep latency of REM was 8.8 min during daytime. Combined with a comprehensive mental examination, according to the International Classification of Disease 10th Revision (ICD-10), she was diagnosed with narcolepsy (G47.4); thus, antidepressants were stopped, and modafinil (100 mg qd) was prescribed to treat the narcolepsy.

Outcome and follow-up

One week after the treatment, the symptoms of EDS disappeared, with continuous improvement in academic performance after modafinil treatment; depressive symptoms also subsided, with the caveat that the patient will still have EDS symptoms if she stopped meds over the weekends. So far, she continues treatment with modafinil (100 mg qd) with no obvious side effects.

A 14-year-old female student was hospitalized due to ‘having “paroxysmal cataplexy” for more than 2 years, with her condition being aggravated during the past 6 months'.

The patient had an acute onset of illness after being frightened for more than 2 years ago. She had sudden dizziness with no change in body position for several days. Her head felt heavy and she had visual rotation, but there was no nausea and vomiting, chest tightness, or fever. Since then, the patient's sleep had been irregular, and day and night sleep patterns were reversed. In the beginning, the patient was treated in a local hospital. EEG and transcranial Doppler ultrasound showed mild abnormalities, and no noticeable abnormalities were found during head CT. The patient went to the pediatric hospital, and no apparent abnormalities were found after relevant examinations. She was diagnosed with “dizziness” and was treated with traditional Chinese medicine (the specific details are unknown), without desired effects. The patient went to a psychiatric hospital and was diagnosed with “sleep-wake rhythm disorder, epilepsy.” After treatment with lorazepam (0.75 mg qn), fluoxetine (20 mg qd), olanzapine (5 mg qn), and topiramate (0.1 qd), intermittent dizziness persisted and, sometimes, there were occurrences of even “cataplexy” not accompanied by convulsions. Dynamic EEG was performed, but no epileptic waves were found. More than 1 year before this case presentation, the patient suffered from paroxysmal dizziness and fell slowly to the ground when she was in school but did not sustain a physical injury. When responders opened her eyes, they found that her eyes were turned up, her face and lips remained unchanged, and she had no limb convulsions. After 2–5 min, the patient was awake and lucid. The patient dropped out of school due to paroxysmal cataplexy. After quarreling with her mother, the episodes gradually increased in occurrence to 1–4 times/day, with the same manifestation. Therefore, the patient went to another pediatric hospital and was diagnosed with “cataplexy, dissociative disorder,” her original drug treatments were stopped, and she was switched to sertraline (50 mg qd). After treatment, her condition improved mildly, and episodes of cataplexy decreased significantly to a frequency of about 1–2 per month. Six months before this case presentation, the condition of the patient worsened for no apparent reason, with similar symptoms as in her prior presentation, but attacks were more frequent, at more than 10 times per day. Therefore, the patient went to the pediatric hospital again and resumed sertraline (50 mg qd), but the treatment was ineffective. She then went to another pediatric hospital and was diagnosed with “viral encephalitis” after a cerebrospinal fluid examination. Cataplexy still occurred frequently after antiviral treatment, so the patient was transferred to a hospital in Beijing. During hospitalization, cerebrospinal fluid was rechecked. No obvious abnormalities were found, so she was transferred to the department of psychology for further treatment.

The patient had no major physical and mental illnesses in the past. Her parents (now divorced) were busy with work and her grandfather provided primary care. The patient had no positive family history of any sleep disorders or mental disorders in her family.

The patient experienced many laboratory examinations, and we only listed the following subset here. Transcranial Doppler ultrasound, video EEG, and evoked potential EEG showed no obvious abnormalities (July 2019; Children's Hospital of Fudan University). Head MRI showed that a deep choroidal cyst in the right temporal lobe was possible, and there was minor inflammation in the right posterior ethmoid sinus group; head MRA indicated that the posterior cerebral artery on the cephalic side was not displayed, and there were no obvious abnormal signs in the others; cerebrospinal fluid was found to be colorless and transparent, leukocytes were 29 × 10 6 /l, mainly multinucleated, with no obvious biochemical abnormalities and a negative culture (May 2021; Zhoushan Women's and Children's Hospital). The lying and sitting position test was negative; the dynamic electrocardiogram showed sinus rhythm, occasional ventricular premature contractions, intermittent ST-segment and T-wave changes, and a normal QT interval (20 September 2021; the First Hospital of Peking University).

Overnight PSG performed in our sleep medical center showed a TST of 8:13:0, an SE (TST/TIB) of 92%, an N3 duration of 105 min, and a REM duration of 90.0 min; obstructive sleep apnea was excluded. MSLT examination during five naps showed three REM episodes and three SOREMPs, a mean sleep latency of 3.7 min, and a mean sleep latency of REM of 4.7 min in the daytime. The diagnosis of the patient was corrected to “narcolepsy” after MLST examinations. Treatment with modafinil (100 mg qd) was prescribed to treat cataplexy syndrome, while treatment with sertraline (50 mg qd) continued. Zopiclone (7.5 mg qn) was prescribed to treat delayed sleepiness.

After 1 week of pharmaceutical treatment, the cataplexy syndrome disappeared and EDS improved, but the sleep rhythm disorder persisted with a presentation of late sleep and late waking up. The patient still cannot return to school. Her medication adherence is not very good, and she occasionally has cataplexy attacks when her mood changes, such as while quarreling with her mother.

An 18-year-old woman presented to our department with a chief complaint of “Too much sleep, depression, and hallucination for 6 years.”

The patient began to gradually feel sleepier during the daytime, and she always felt fatigued during the daytime 6 years prior without any obvious inducement. The quieter the environment, the easier it was to fall asleep. Sometimes the patient even could fall asleep when walking. Due to her symptoms, the patient suffered a decline in academic performance and was misunderstood by her parents, causing emotional distress. She always felt exhausted and lost interest in almost everything except food. The patient experienced multimodal hallucinations while falling asleep. She would see an unknown person standing near her or terrible scenes that others could not see. She experienced the olfactory hallucination of the smell of honey and auditory hallucinations of her mother. She stated that sometimes she had the feeling that her “whole brain was filled with porridge”. She attributed this to some parts of her brain having been disconnected from others, and she stated that sometimes some of her thoughts were not hers. While experiencing these hallucinations, the patient could not move her limbs or speak; this phenomenon always happened before falling asleep or after coming out of sleep, daytime or night. Therefore, she often felt nervous and insecure and was afraid of being alone. She felt that the problem was out of her control and she had no future. After 3 months of symptom onset, she was diagnosed with “schizophrenia” in a local psychiatric hospital. She received treatment with sertraline and olanzapine during a 2-month hospitalization; symptoms slightly improved, but the details are obscure. The EDS symptoms of the patient became more serious and hallucinations persisted, and the patient could not continue her normal studies. Three years prior to the case presentation, she went to another psychiatric hospital in Shanghai for treatment. The diagnosis of schizophrenia was confirmed, and the patient successively received symptomatic treatment with olanzapine (5 mg qn) and aripiprazole (5 mg qd). The response to treatment was unsatisfactory, and the patient experienced worsened sleepiness. She became less confident and sometimes overate; the patient also presented with obesity. The patient denied that she had negative thoughts. Since the onset of her symptoms, she had no prominent periods of remission. Due to the impairment of social functions, she dropped out of school and could not perform her usual housework duties.

The patient had been in good health history and denied that other members of the family had a history of mental disorders.

The patient was admitted to the sleep medical center of our hospital. Overnight PSG examination showed a TST of 7:38:16, SE (TST/TIB) of 93%, an N3 duration of 89 min, and a REM duration of 92.0 min; obstructive sleep apnea was excluded. MSLT examination during five naps reported five REM episodes and three SOREMPs; the mean sleep latency was 5.9 min, and the mean sleep latency of REM was 1.0 min during the daytime. Combined with a comprehensive mental examination, the patient was diagnosed with “narcolepsy” according to ICD-10 criteria. Her treatment was adjusted, treatment with aripiprazole was stopped, and bupropion (150 mg qd) was prescribed; after treatment for 1 week, the symptoms of hallucination subsided, but she still felt fatigued, had slow responses, and experienced occasional dizziness. The bupropion prescription (150 mg qd) was changed to modafinil (100 mg qd).

After 2 weeks of treatment with modafinil, EDS symptoms were significantly relieved; at the same time, hallucination symptoms completely disappeared, other manifestations were also significantly improved, and night sleep returned to normal. One month after being discharged from the hospital, the patient behaved normally and was able to perform her daily housework tasks.

Narcolepsy is frequently misdiagnosed as a psychiatric disorder in clinical practice, which occurred in the cases reported above, causing a delay in accurate diagnosis and treatment. Lee et al. ( 4 ) reported that more than 50% of patients with narcolepsy had been diagnosed with depression prior to narcolepsy ( 4 ). More than one-third of patients with narcolepsy have various forms of hallucinations even during daytime naps ( 5 ), which is easy to confuse with schizophrenia ( 2 ). Anxiety disorders, such as panic disorder, have been reported in as many as 53% of patients with narcolepsy ( 6 ). Furthermore, more than 23% of patients with narcolepsy had a comorbid clinical eating disorder ( 7 ). As concluded by John Khoury ( 1 ), an accurate diagnosis of narcolepsy will not be established until an average of 10 years after the onset of this disorder ( 1 ). Patients with narcolepsy display the symptoms of eating disorders, affective symptoms, and hallucinations ( 1 ).

Narcolepsy seriously damages the social functioning and quality of life of patients, which causes a high socioeconomic burden ( 8 ). The three patients reported herein were teenage students; EDS disabled their studies, and, if misdiagnosed as schizophrenia, the maintenance of anti-psychotics may cause a more difficult life if the diagnosis is not corrected in time. Peers, parents, teachers, patients themselves, and doctors often confused EDS with laziness or lack of motivation, which was reflected in these three reported cases. Meanwhile, substantial medical resources are used when the correct diagnosis is delayed, which was also reflected in these three cases. The main case characteristics of the three patients are listed in Table 1 .

Table 1 . Main characteristics of all three patients.

The diagnosis of narcolepsy must be confirmed by overnight PSG, followed by an MSLT. PSG is performed to ensure adequate nocturnal sleep and excludes other sleep disorders. To establish the diagnosis, the average MSLT sleep latency should be 8 min or less and patients should show REM episodes during at least two nap opportunities or in one nap opportunity if PSG of the previous night revealed the onset of REM sleep within 15 min of sleep onset ( 9 , 10 ). Nowadays, only a few psychiatrists or psychologists in China received adequate education and training in sleep medicine for cases of suspected narcolepsy in patients. In fact, many psychiatric hospitals or departments in China have no PSG instruments. Even if the doctors are aware of the presence of narcolepsy, they have to consider the manifestation of psychiatric syndromes. Performing the MSLT requires professional technicians, as it is more than a simple PSG instrument. There are few hospitals that can test for narcolepsy-related biomarkers, such as hypocretin levels in cerebrospinal fluid ( 11 ).

A diagnosis of narcolepsy should be considered in atypical and refractory psychiatric illnesses, especially in children and adolescents. More importantly, psychiatrists and psychologists need further education in sleep medicine. Education plays a crucial role in the management of these patients. Considering the high comorbidity of narcolepsy and psychiatric illness, multi-disciplinary teams composed of psychiatrists and sleep specialists should be established to deal with this dilemma. Furthermore, in the three cases of narcolepsy reported above, all patients responded quickly to modafinil with good tolerance, as is reported by other studies ( 12 ). This suggested that it was not likely to be too late to administer proper medication for narcolepsy, and an optimistic prognosis can be expected with the maintenance of medication. Future studies should focus on exploring more practical approaches to identifying patients with narcolepsy and psychiatric illness.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

Ethics statement

The studies involving human participants were reviewed and approved by the Ethics Committee of Huzhou Third Municipal Hospital. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.

Author contributions

ZS, YShu, SM, YShe, and XS contributed to the treatment and information record of the case report. ZS and SY contributed to the medical treatment of the patient, conceptualization of the case report, and manuscript writing and editing. All authors have read and approved the final version.

This study was partly supported by the Huzhou Public Welfare Research Project Social Development Category (2018GYB49, ZS) and the Social Development Project of Public Welfare Technology Application in Zhejiang Province in 2019 (LGF19H090002, ZS).

Acknowledgments

The authors would like to express thanks to Benhong Wang of Sleep Medical Center, Huzhou Third Municipal Hospital, PR China, for the operation and analysis of MSLT.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

1. Khoury J, Doghramji K. Primary sleep disorders. Psychiatr Clin North Am. (2015) 38:683–704. doi: 10.1016/j.psc.2015.08.002

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Morse AM, Sanjeev K. Narcolepsy and psychiatric disorders: comorbidities or shared pathophysiology? Med Sci. (2018) 6:16. doi: 10.3390/medsci6010016

3. Dunne L, Patel P, Maschauer E, Morrison I, Riha RL. Misdiagnosis of narcolepsy. Sleep Breath . (2016) 20:1277–84. doi: 10.1007/s11325-016-1365-5

4. Lee MJ, Lee SY, Yuan SS, Yang CJ, Yang KC, Lee TL, et al. Comorbidity of narcolepsy and depressive disorders: a nationwide population-based study in Taiwan. Sleep Med. (2017) 39:95–100. doi: 10.1016/j.sleep.2017.07.022

5. Han F, Lin L, Li J, Aran A, Dong SX, An P, et al. Presentations of primary hypersomnia in Chinese children. Sleep. (2011) 34:627–32. doi: 10.1093/sleep/34.5.627

6. Fortuyn HA, Lappenschaar MA, Furer JW, Hodiamont PP, Rijnders CA, Renier WO, et al. Anxiety and mood disorders in narcolepsy: a case-control study. Gen Hosp Psychiatry. (2010) 32:49–56. doi: 10.1016/j.genhosppsych.2009.08.007

7. Fortuyn HA, Swinkels S, Buitelaar J, Renier WO, Furer JW, Rijnders CA, et al. High prevalence of eating disorders in narcolepsy with cataplexy: a case-control study. Sleep. (2008) 31:335–41. doi: 10.1093/sleep/31.3.335

8. Black J, Reaven NL, Funk SE, McGaughey K, Ohayon MM, Guilleminault C, et al. Medical comorbidity in narcolepsy: findings from the Burden of Narcolepsy Disease (BOND) study. Sleep Med. (2017) 33:13–8. doi: 10.1016/j.sleep.2016.04.004

9. American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic and Coding Manual . Westchester, IL: American Academy of Sleep Medicine (2005), p. 297.

Google Scholar

10. Arand D, Bonnet M, Hurwitz T, Mitler M, Rosa R, Sangal RB. The clinical use of the MSLT and MWT. Sleep. (2005) 28:123–44. doi: 10.1093/sleep/28.1.123

11. Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. (2002) 59:1553–62. doi: 10.1001/archneur.59.10.1553

12. Sonka K, Susta M. Diagnosis and management of central hypersomnias. Ther Adv Neurol Disord. (2012) 5:297–305. doi: 10.1177/1756285612454692

Keywords: narcolepsy, misdiagnosis, psychiatric disorder, case report, excessive daytime sleepiness (EDS)

Citation: Shen Z, Shuai Y, Mou S, Shen Y, Shen X and Yang S (2022) Case report: Cases of narcolepsy misdiagnosed as other psychiatric disorders. Front. Psychiatry 13:942839. doi: 10.3389/fpsyt.2022.942839

Received: 13 May 2022; Accepted: 20 June 2022; Published: 03 November 2022.

Reviewed by:

Copyright © 2022 Shen, Shuai, Mou, Shen, Shen and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Xinhua Shen, shenxinhuasun@sina.com ; Shengliang Yang, ysl7250@126.com

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• Shanghai Arch Psychiatry
• v.26(4); 2014 Aug

Language: English | Chinese

Case report of narcolepsy in a six-year-old child initially misdiagnosed as atypical epilepsy

1例发作性睡病的6岁孩子最初误诊为不典型癫痫的病例报告.

This report describes a case of first-onset narcolepsy in a six-year-old female that was misdiagnosed as atypical epilepsy and other diagnoses at eight different hospitals over a period of 10 months before the correct diagnosis was made. The diagnosis of narcolepsy is more difficult in children because very few of them experience all four cardinal symptoms of narcolepsy – paroxysmal sleep, cataplexy, hypnagogic hallucination, and sleep paralysis – and they often have a more prolonged onset and diverse symptoms. To decrease the time lag between initial presentation and accurate diagnosis, we recommend that in all cases in which children report excessive sleep of unknown etiology – regardless of the associated symptoms – that sleep monitoring and sleep latency tests be conducted to rule out the possibility of narcolepsy. The case highlights the wide variety of presentations of uncommon psychiatric conditions, particularly in children, and the need for clinicians to be aware of the atypical presentations of these conditions when collecting medical histories.

概述

本文报告1例6岁女童首次发生发作性睡病被 误诊为不典型癫痫。之后10个月在8家不同医院被误 诊为其他疾病，最后才得以确诊。发作性睡病的诊断 在小儿中比较困难，因为睡眠发作、猝倒、入睡前幻 觉和睡眠麻痹四个主要症状都存在的病例在儿童中极 少见到。患儿往往发作期更长、症状多样化。为了缩 短从首次发病到确诊的时间，我们建议对所有不明原 因过度睡眠的患儿监测睡眠并进行睡眠潜伏期试验， 以排除发作性睡病的可能，而不论其相关症状如何。 该病例凸显出罕见精神障碍的表现可以是多种多样的， 特别是儿童。这就需要临床医生在采集病史时要充分 考虑这些病例的非典型表现。

1. Background

Narcolepsy is a chronic neurodegenerative disease caused by autoimmune destruction of hypocretinproducing neurons. [1] Its primary clinical manifestations are excessive daytime sleep and cataplexy -- loss of muscle tone which is typically triggered by strong emotional stimuli. Less common symptoms include hypnagogic or hypnopompic hallucinations, sleep paralysis, vivid dreams and frequent nocturnal awakening, behavioral changes, obesity, and cognitive impairment. [2] About 10% of individuals with narcolepsy have the four core symptoms of narcolepsy: paroxysmal sleep, cataplexy, hypnagogic hallucination, and sleep paralysis. [3] , [4] Because narcolepsy is relatively rare, it is often misdiagnosed, particularly in primary care hospitals. Misdiagnosis of children with narcolepsy can interfere with their normal growth and puts them at increased risk of life-threating accidents.

2. Clinical history

The patient was a 6-year old female who was hospitalized with the written consent of her parents because of visual hypnagogic hallucinations and other symptoms that had gradually exacerbated over the last 10 months.

She reported initially seeing various ghosts when falling asleep at night; on some nights she shouted, was agitated, and was unable to fall asleep. After one month of these nocturnal symptoms other symptoms started to occur during the day; her teacher found her asleep in class and she sometimes collapsed when standing, walking, watching television, or eating. Her parents initially attributed these daytime symptoms to her poor sleep. Then other symptoms started while she was sleeping: 2 to 10-minute episodes during the night when she was unresponsive and her limbs were flaccid followed by agitation when she woke.

The number of these episodes gradually increased to 10 times per day so her parents sought treatment at the general medical and neurological departments of eight different hospitals before coming to our hospital. A wide range of tests and examinations were conducted at these hospitals and many diagnoses were considered, but in most cases she was diagnosed as having some form of atypical epilepsy that did not have EEG evidence. She was treated with anti-epileptics but her symptoms gradually worsened. Over the course of time she became more irritable and less active. She gained 7kg within 10 months despite having a normal diet and normal elimination.

On admission to our hospital the family reported no prior mental disorder and no family history of mental disorders. She was 112cm tall and weighed 23kg. On mental status examination she was irritable and had difficulty concentrating but was fully conscious and orientated. Her behavior was appropriate and wellcoordinated. She had normal intelligence and insight appropriate for a 6-year-old child. She reported no current hallucinations or delusions at the time of the examination. She had slurred speech and at times during the examination her eyes closed and she was not responsive to loud noises.

Blood tests including complete blood count, blood chemistry, blood concentration of sodium valproate, and assessment of muscle enzymes were normal. Cranial CT, chest radiograph, electrocardiogram, cardiac ultrasound, and spinal fluid pressure examinations were also normal. Skull MRI demonstrated that the right hippocampal sulcus was slightly widened.

Video-EEG while awake identified occasional low amplitude Beta activity in the background of irregular 5-8Hz 20-80uv intertwined Alpha and Theta activity. The two hemispheres were symmetrical. Hyperventilation and visual responses were normal. Sleep-wake cycle was disordered. No epileptiform discharges were found. Nocturnal polysomnography (PSG) showed reduced average sleep latency at 6 to 8 minutes, increased number of awakenings, disturbed sleep-wake cycle, shortened REM latency (the patient entered REM sleep immediately), and increased proportion of REM. After getting enough sleep (≥6h), daytime the Multiple Sleep Latency Test (MSLT) revealed two incidents of sleeponset REM periods with reduced sleep latency.

Children with narcolepsy usually show shortened average sleep latency on their EEG and sleep onset REM periods. The video EEG of this patient showed disturbed sleep-wake cycles. Based on her medical history, PSG results, and MSLT results she was diagnosed as having narcolepsy and was given methylphenidate 5mg/d for 5 days. Her symptoms resolved and her diurnal sleep was significantly reduced, particularly at school. At 1-year follow-up, she had no significant difficulties in daily life or attending school.

3. Discussion

According to the American Academy of Sleep Medicine (2005), [5] symptoms of narcolepsy with cataplexy include: (a) recurrent daytime naps or lapses into sleep that occur almost daily for at least three months and; (b) sudden bilateral loss of postural muscle tone in association with intense emotion- cataplexy. Administering the Multiple Sleep Latency Test (MSLT) after overnight polysomnography (PSG) can assist in making the diagnosis of narcolepsy with cataplexy. The presence of one or both of the following confirms the diagnosis: (a) a mean sleep latency of <8 minutes and two or more sleep onset REM periods (SOREMPs) based on MSLT performed after at least six hours of sleep during the previous night. (A SOREMP on the preceding nocturnal PSG may replace one of the SOREMPs on the MSLT.) (b) Hypocretin-1 concentration, measured by immunoreactivity of either <110 pg/ml or <1/3 of the mean values obtained in normal subjects with the same standardized assay. Finally, the symptoms are not explained by other sleep disorders, nervous system diseases, mental disorders, or drug or substance abuse.

Based on reports from other countries, the prevalence of narcolepsy is about 0.2 to 0.9% with no discernible male-female differences. Most cases have their first onset after 10 years of age. Cases with onset before 10 years of age account for about 5% of all cases. Some patients have a family history. Studies have shown that the lack of orexin (hyopcretin) or the dysfunction of its receptors in the brain may lead to narcolepsy. [6] Other reports suggest that narcolepsy is related to hypofunction of the ascending reticular activating system or hyperfunction of the caudal pontine reticular nucleus. The cardinal symptoms include paroxysmal sleep (100%), cataplexy (70%), hypnagogic hallucination (25%), and sleep paralysis (5%). [6] , [7] , [8] Usually, patients experience some, but not all, of these four symptoms. About two-thirds of patients experience transient paroxysmal sleep only, and one-third of patients have one of the other three symptoms in addition to paroxysmal sleep. It is accompanied by nocturnal sleep disturbances or mood problems in some patients. Pathophysiological changes of narcolepsy mainly include sleep-wake cycle disturbances, and shortened REM latency (<8 minutes after falling asleep). [6] , [7] , [8]

The patient reported here initially presented with hypnagogic hallucination but no dreams. Her diurnal sleep increased and she experienced cataplexy. Her EEG demonstrated disrupted sleep cycles, and her PSG indicated shortened sleep latency. In addition, she had obvious weight gain (7kg within 10 months) and personality changes, symptoms that are sometimes seen in patients with narcolepsy. [4] It was not difficult to make the diagnosis based on these typical clinical manifestations and the results of the polysomnography and EEG monitoring.

The diagnosis of narcolepsy is more difficult in children because very few of them experience all four cardinal symptoms and they often have a more prolonged onset and more diffuse symptoms. The initial or prodromal symptoms may be atypical which can result in delayed diagnosis and treatment. Lack of clinical awareness about the different presentations of narcolepsy in children can result in misdiagnosis, as occurred at eight different hospitals in this case. The financial and emotional costs for the patient and the family of such a protracted process of arriving at the correct diagnosis can be substantial.

To decrease the time lag between initial presentation and accurate diagnosis, we recommend that in all cases in which children report excessive sleep of unknown etiology – regardless of the associated symptoms – that sleep monitoring and sleep latency tests be conducted to rule out the possibility of narcolepsy. In this case the initial presentation of hypnagogic hallucinations and clinicians’ failure to understand the relevance of the patient’s reports (and her parents’ report) of excessive sleep lead to the repeated incorrect diagnosis of different types of atypical epilepsy and to inappropriate treatment with antiepileptic medications, despite the absence of EEG evidence of epilepsy. Accurate diagnosis and treatment depends on taking detailed medical histories and being sensitive to the atypical presentations of uncommon psychiatric conditions, particularly in children.

Jinquan Zhou obtained his bachelor’s degree in Clinical Medicine from Kunming Medical School in 1993. He is a chief psychiatrist and director of the Department of Psychiatry at the Dali Prefecture Second People’s Hospital. He is responsible for clinical care, teaching, research, and health care management. He also serves as the secretary of the second party branch of the Communist Party at the hospital. He has won the Level Two Award of the State Government Scientific and Technological Progress Award once and the Level Two Award of the Dali Health System New Technology Projects twice.

Funding Statement

There was no funding support provided for the preparation of this case report.

Conflict of interest: The authors declare that they have no competing interests.

Informed consent: The patient’s parents signed an informed consent form and agreed to the publication of this case report.

• Patient Care & Health Information
• Diseases & Conditions

Narcolepsy is a sleep disorder that makes people very drowsy during the day. People with narcolepsy find it hard to stay awake for long periods of time. They fall asleep suddenly. This can cause serious problems in their daily routine.

Sometimes narcolepsy also causes a sudden loss of muscle tone, known as cataplexy (KAT-uh-plek-see). This can be triggered by strong emotion, especially laughter. Narcolepsy is divided into two types. Most people with type 1 narcolepsy have cataplexy. Most people who don't have cataplexy have type 2 narcolepsy.

Narcolepsy is a life-long condition for which there's no cure. However, medicines and lifestyle changes can help manage the symptoms. Support from others — family, friends, employers and teachers — can help people cope with the disorder.

Products & Services

• A Book: Mayo Clinic Family Health Book
• Newsletter: Mayo Clinic Health Letter — Digital Edition

The symptoms of narcolepsy may get worse during the first few years of the disorder. Then they continue for life. They include:

Excessive daytime sleepiness. People with narcolepsy fall asleep without warning. It can happen anywhere and at any time. It may happen when you're bored or during a task. For example, you may be working or talking with friends and suddenly fall asleep. It can be especially dangerous if you fall asleep while driving. You might fall asleep for only a few minutes or up to a half-hour. After waking, you'll often feel refreshed but you'll get sleepy again.

You also may experience a decrease in how alert and focused you feel during the day. Daytime sleepiness often is the first symptom to appear. Feeling sleepy makes it hard to focus and function.

Some people with narcolepsy continue doing a task when they fall asleep briefly. For example, you may fall asleep while writing, typing or driving. You might continue to perform that task while asleep. When you awaken, you can't remember what you did, and you probably didn't do it well.

Sudden loss of muscle tone. This condition is called cataplexy. It can cause slurred speech or complete weakness of most muscles. Symptoms may last up to a few minutes.

Cataplexy can't be controlled. It's triggered by intense emotions. Often the emotions that cause cataplexy are positive. Laughter or excitement may cause the symptoms. But sometimes fear, surprise or anger can cause the loss of muscle tone. For example, when you laugh, your head may drop without your control. Or your knees may suddenly lose strength, causing you to fall.

Some people with narcolepsy experience only one or two episodes of cataplexy a year. Others have several episodes a day. Not everyone with narcolepsy has these symptoms.

Sleep paralysis. People with narcolepsy often experience sleep paralysis. During sleep paralysis, you can't move or speak while falling asleep or upon waking. It's usually brief — lasting a few seconds or minutes. But it can be scary. You may be aware of it happening and can recall it afterward.

Not everyone with sleep paralysis has narcolepsy.

• Hallucinations. Sometimes people see things that aren't there during sleep paralysis. Hallucinations also may happen in bed without sleep paralysis. These are called hypnagogic hallucinations if they happen as you fall asleep. They're called hypnopompic hallucinations if they happen upon waking. For example, you might feel as if there is a stranger in your bedroom. These hallucinations may be vivid and frightening because you may not be fully asleep when you begin dreaming.
• Changes in rapid eye movement (REM) sleep. REM sleep is when most dreaming happens. Typically, people enter REM sleep 60 to 90 minutes after falling asleep. But people with narcolepsy often move more quickly to REM sleep. They tend to enter REM sleep within 15 minutes of falling asleep. REM sleep also can happen at any time of the day.

Other characteristics

People with narcolepsy may have other sleep disorders. They might have obstructive sleep apnea, in which breathing starts and stops during the night. Or they may act out their dreams, known as REM sleep behavior disorder. Or they may have trouble falling asleep or staying asleep, called insomnia.

When to see a doctor

See your health care provider if you experience excessive daytime sleepiness that affects your personal or professional life.

There is a problem with information submitted for this request. Review/update the information highlighted below and resubmit the form.

From Mayo Clinic to your inbox

Sign up for free and stay up to date on research advancements, health tips, current health topics, and expertise on managing health. Click here for an email preview.

Error Email field is required

Error Include a valid email address

To provide you with the most relevant and helpful information, and understand which information is beneficial, we may combine your email and website usage information with other information we have about you. If you are a Mayo Clinic patient, this could include protected health information. If we combine this information with your protected health information, we will treat all of that information as protected health information and will only use or disclose that information as set forth in our notice of privacy practices. You may opt-out of email communications at any time by clicking on the unsubscribe link in the e-mail.

Thank you for subscribing!

You'll soon start receiving the latest Mayo Clinic health information you requested in your inbox.

Sorry something went wrong with your subscription

Please, try again in a couple of minutes

The exact cause of narcolepsy is unknown. People with type 1 narcolepsy have low levels of hypocretin (hi-poe-KREE-tin), also called orexin. Hypocretin is a chemical in the brain that helps control being awake and when you enter REM sleep.

Hypocretin levels are low in people who experience cataplexy. Exactly what causes the loss of hypocretin-producing cells in the brain isn't known. But experts suspect it's due to an autoimmune reaction. An autoimmune reaction is when the body's immune system destroys its own cells.

It's also likely that genetics plays a role in narcolepsy. But the risk of a parent passing this disorder to a child is very low — only about 1% to 2%.

Research also indicates that in some cases narcolepsy may be linked to exposure to the swine flu (H1N1 flu) virus. It also may be linked to a certain form of the H1N1 vaccine. The vaccine was administered in Europe.

Typical sleep pattern vs. narcolepsy

The typical process of falling asleep begins with a phase called non-rapid eye movement (NREM) sleep. During this phase, brain waves slow. After an hour or so of NREM sleep, brain activity changes and REM sleep begins. Most dreaming occurs during REM sleep.

In narcolepsy, you may suddenly enter REM sleep without going through NREM sleep. This can happen both at night and during the day. Cataplexy, sleep paralysis and hallucinations are similar to changes that occur in REM sleep. But in narcolepsy they happen while you're awake or drowsy.

Risk factors

There are only a few known risk factors for narcolepsy, including:

• Age. Narcolepsy typically begins between ages 10 and 30.
• Family history. Your risk of narcolepsy is 20 to 40 times higher if you have a close family member who has it.

Complications

• Public misconception of the condition. Narcolepsy can cause problems at work or in your personal life. Your performance may suffer at school or work. Others might see people with narcolepsy as lazy or lethargic.
• Effects on intimate relationships. Intense feelings, such as anger or joy, can trigger cataplexy. This can cause people with narcolepsy to withdraw from emotional interactions.
• Physical harm. Falling asleep suddenly may result in injury. You're at increased risk of a car accident if you fall asleep while driving. Your risk of cuts and burns is greater if you fall asleep while cooking.
• Obesity. People with narcolepsy are more likely to be overweight. Sometimes weight rapidly increases when sleepiness symptoms start.

Narcolepsy care at Mayo Clinic

• Kryger M, et al., eds. Principles and Practice of Sleep Medicine. 7th ed. Elsevier; 2022. https://www.clinicalkey.com. Accessed Dec. 19, 2022.
• Martin VP, et al. Sleepiness in adults: An umbrella review of a complex construct. Sleep Medicine Reviews. 2022; doi:10.1016/j.smrv.2022.101718.
• Ferri FF. Narcolepsy. In: Ferri's Clinical Advisor 2023. Elsevier; 2023. https://www.clinicalkey.com. Accessed Dec. 19, 2022.
• Ropper AH, et al. Sleep and its abnormalities. In: Adams and Victor's Principles of Neurology. 11th ed. McGraw Hill; 2019. https://accessmedicine.mhmedical.com. Accessed Dec. 19, 2022.
• Narcolepsy fact sheet. National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Narcolepsy-Fact-Sheet. Accessed Dec. 19, 2022.
• Chien P-Y, et al. Pharmacological interventions for excessive daytime sleepiness in adults with narcolepsy: A systematic review and network meta-analysis. Journal of Clinical Medicine. 2022; doi:10.3390/jcm11216302.
• Narcolepsy following 2009 Pandemrix influenza vaccination in Europe. Centers for Disease Control and Prevention. https://www.cdc.gov/vaccinesafety/concerns/history/narcolepsy-flu.html. Accessed Dec. 30, 2022.
• Justinussen JL, et al. How hypocretin agonists may improve the quality of wake in narcolepsy. Trends in Molecular Medicine. 2023; doi:10.1016/j.molmed.2022.10.008.
• Sodium oxybate oral. Facts & Comparisons eAnswers. https://fco.factsandcomparisons.com. Accessed Jan. 4, 2023.
• Oxybate salts (calcium, magnesium, potassium and sodium). Facts & Comparisons eAnswers. https://fco.factsandcomparisons.com. Accessed Jan. 4, 2023.
• Ami TR. Allscripts EPSi. Mayo Clinic. July 6, 2022.

Associated Procedures

• Polysomnography (sleep study)
• Symptoms & causes
• Diagnosis & treatment
• Doctors & departments
• Care at Mayo Clinic

Mayo Clinic does not endorse companies or products. Advertising revenue supports our not-for-profit mission.

• Opportunities

Mayo Clinic Press

Check out these best-sellers and special offers on books and newsletters from Mayo Clinic Press .

• Mayo Clinic on Incontinence - Mayo Clinic Press Mayo Clinic on Incontinence
• The Essential Diabetes Book - Mayo Clinic Press The Essential Diabetes Book
• Mayo Clinic on Hearing and Balance - Mayo Clinic Press Mayo Clinic on Hearing and Balance
• FREE Mayo Clinic Diet Assessment - Mayo Clinic Press FREE Mayo Clinic Diet Assessment
• Mayo Clinic Health Letter - FREE book - Mayo Clinic Press Mayo Clinic Health Letter - FREE book

5X Challenge

Thanks to generous benefactors, your gift today can have 5X the impact to advance AI innovation at Mayo Clinic.

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings
• My Bibliography
• Collections
• Citation manager

Save citation to file

Email citation, add to collections.

• Create a new collection
• Add to an existing collection

Add to My Bibliography

Your saved search, create a file for external citation management software, your rss feed.

• Search in PubMed
• Search in NLM Catalog
• Add to Search

Anxiety and mood disorders in narcolepsy: a case-control study

Affiliation.

• 1 Department of Psychiatry, Nijmegen Centre for Evidence-Based Practice, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. [email protected]
• PMID: 20114128
• DOI: 10.1016/j.genhosppsych.2009.08.007

Introduction: Narcolepsy is a primary sleeping disorder with excessive daytime sleepiness and cataplexy as core symptoms. There is increasing interest in the psychiatric phenotype of narcolepsy. Although many authors suggest an overrepresentation of mood disorders, few systematic studies have been performed and conflicting results have been reported. Anxiety disorders in narcolepsy have only received little attention.

Methods: We performed a case-control study in 60 narcolepsy patients and 120 age- and sex-matched controls from a previous population study. The Schedules for Clinical Assessment in Neuropsychiatry were used to assess symptoms and diagnostic classifications of mood and anxiety disorders.

Results: Symptoms of mood disorders were reported by about one third of patients. However, the prevalence of formal mood disorder diagnoses - including major depression - was not increased. In contrast, more than half of the narcolepsy patients had anxiety or panic attacks. Thirty-five percent of the patients could be diagnosed with anxiety disorder (odds ratio=15.6), with social phobia being the most important diagnosis. There was no influence of age, sex, duration of illness or medication use on the prevalence of mood or anxiety symptoms and disorders.

Discussion: Anxiety disorders, especially panic attacks and social phobias, often affect patients with narcolepsy. Although symptoms of mood disorders are present in many patients, the prevalence of major depression is not increased. Anxiety and mood symptoms could be secondary complications of the chronic symptoms of narcolepsy. Recent studies have shown that narcolepsy is caused by defective hypocretin signaling. As hypocretin neurotransmission is also involved in stress regulation and addiction, this raises the possibility that mood and anxiety symptoms are primary disease phenomena in narcolepsy.

Copyright 2010 Elsevier Inc. All rights reserved.

PubMed Disclaimer

Similar articles

• Cataplexy in anxious patients: is subclinical narcolepsy underrecognized in anxiety disorders? Flosnik DL, Cortese BM, Uhde TW. Flosnik DL, et al. J Clin Psychiatry. 2009 Jun;70(6):810-6. doi: 10.4088/JCP.08m04272. Epub 2009 May 5. J Clin Psychiatry. 2009. PMID: 19422758
• The Manitoba IBD cohort study: a population-based study of the prevalence of lifetime and 12-month anxiety and mood disorders. Walker JR, Ediger JP, Graff LA, Greenfeld JM, Clara I, Lix L, Rawsthorne P, Miller N, Rogala L, McPhail CM, Bernstein CN. Walker JR, et al. Am J Gastroenterol. 2008 Aug;103(8):1989-97. doi: 10.1111/j.1572-0241.2008.01980.x. Am J Gastroenterol. 2008. PMID: 18796096
• Anxiety disorders in 318 bipolar patients: prevalence and impact on illness severity and response to mood stabilizer. Henry C, Van den Bulke D, Bellivier F, Etain B, Rouillon F, Leboyer M. Henry C, et al. J Clin Psychiatry. 2003 Mar;64(3):331-5. J Clin Psychiatry. 2003. PMID: 12716276
• The differential diagnosis of anxiety. Psychiatric and medical disorders. Cameron OG. Cameron OG. Psychiatr Clin North Am. 1985 Mar;8(1):3-23. Psychiatr Clin North Am. 1985. PMID: 3887337 Review.
• Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Nishino S, Kanbayashi T. Nishino S, et al. Sleep Med Rev. 2005 Aug;9(4):269-310. doi: 10.1016/j.smrv.2005.03.004. Sleep Med Rev. 2005. PMID: 16006155 Review.
• Navigating narcolepsy: exploring coping strategies and their association with quality of life in patients with narcolepsy type 1. Varallo G, Franceschini C, Rapelli G, Zenesini C, Baldini V, Baccari F, Antelmi E, Pizza F, Vignatelli L, Biscarini F, Ingravallo F, Plazzi G. Varallo G, et al. Sci Rep. 2024 May 23;14(1):11837. doi: 10.1038/s41598-024-62698-5. Sci Rep. 2024. PMID: 38783152 Free PMC article.
• Alexithymia, impulsiveness, emotion, and eating dyscontrol: similarities and differences between narcolepsy type 1 and type 2. Del Bianco C, Ulivi M, Liguori C, Pisani A, Mercuri NB, Placidi F, Izzi F. Del Bianco C, et al. Sleep Biol Rhythms. 2022 Sep 5;21(1):39-50. doi: 10.1007/s41105-022-00414-4. eCollection 2023 Jan. Sleep Biol Rhythms. 2022. PMID: 38468909 Free PMC article.
• Comparison of Solriamfetol and Modafinil on Arousal and Anxiety-Related Behaviors in Narcoleptic Mice. Sakai N, Nishino S. Sakai N, et al. Neurotherapeutics. 2023 Mar;20(2):546-563. doi: 10.1007/s13311-022-01328-2. Epub 2022 Dec 21. Neurotherapeutics. 2023. PMID: 36544071 Free PMC article.
• Case report: Cases of narcolepsy misdiagnosed as other psychiatric disorders. Shen Z, Shuai Y, Mou S, Shen Y, Shen X, Yang S. Shen Z, et al. Front Psychiatry. 2022 Nov 3;13:942839. doi: 10.3389/fpsyt.2022.942839. eCollection 2022. Front Psychiatry. 2022. PMID: 36405899 Free PMC article.
• Exploring Addictive Online Behaviors in Patients with Narcolepsy Type 1. Varallo G, Musetti A, D'Anselmo A, Gori A, Giusti EM, Pizza F, Castelnuovo G, Plazzi G, Franceschini C. Varallo G, et al. Healthcare (Basel). 2022 Oct 30;10(11):2169. doi: 10.3390/healthcare10112169. Healthcare (Basel). 2022. PMID: 36360510 Free PMC article.

Publication types

• Search in MeSH

Related information

Linkout - more resources, full text sources.

• Elsevier Science

Other Literature Sources

• The Lens - Patent Citations
• Genetic Alliance
• MedlinePlus Consumer Health Information
• MedlinePlus Health Information

Research Materials

• NCI CPTC Antibody Characterization Program
• Citation Manager

NCBI Literature Resources

MeSH PMC Bookshelf Disclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

What is narcolepsy?

Narcolepsy is a chronic neurological disorder that affects the brain's ability to control sleep-wake cycles. People with narcolepsy may feel rested after waking, but then feel very sleepy throughout much of the day. Many individuals with narcolepsy also experience uneven and interrupted sleep that can involve waking up frequently during the night.

Narcolepsy can greatly affect daily activities. People may unwillingly fall asleep even if they are in the middle of an activity like driving, eating, or talking. Other symptoms may include sudden muscle weakness while awake that makes a person go limp or unable to move (cataplexy), vivid dream-like images or hallucinations, and total paralysis just before falling asleep or just after waking up (sleep paralysis).

In a normal sleep cycle, a person enters rapid eye movement (REM) sleep after about 60 to 90 minutes. Dreams occur during REM sleep, and the brain keeps muscles limp during this sleep stage, which prevents people from acting out their dreams. People with narcolepsy frequently enter REM sleep rapidly, within 15 minutes of falling asleep. Also, the muscle weakness or dream activity of REM sleep can occur during wakefulness or be absent during sleep. This helps explain some symptoms of narcolepsy.

If left undiagnosed or untreated, narcolepsy can interfere with psychological, social, and cognitive function and development and can inhibit academic, work, and social activities.

Narcolepsy is a lifelong problem, but it does not usually worsen as the person ages. Symptoms can partially improve over time, but they will never disappear completely. The most typical symptoms are:

• Excessive daytime sleepiness (EDS)—All individuals with narcolepsy have EDS, and it is often the most obvious symptom. EDS is characterized by persistent sleepiness, regardless of how much sleep an individual gets at night. However, sleepiness in narcolepsy is more like a “sleep attack,” where an overwhelming sense of sleepiness comes on quickly. In between sleep attacks, individuals have normal levels of alertness, particularly if doing activities that keep their attention.
• Cataplexy—This sudden loss of muscle tone while a person is awake leads to weakness and a loss of voluntary muscle control. It is often triggered by sudden, strong emotions such as laughter, fear, anger, stress, or excitement. The symptoms of cataplexy may appear weeks or even years after the onset of EDS. Some people may only have one or two attacks in a lifetime, while others may experience many attacks a day. In about 10 percent of cases of narcolepsy, cataplexy is the first symptom to appear and can be misdiagnosed as a seizure disorder. Attacks may be mild and involve only a momentary sense of minor weakness in a limited number of muscles, such as a slight drooping of the eyelids. The most severe attacks result in a total body collapse during which individuals are unable to move, speak, or keep their eyes open. But even during the most severe episodes, people remain fully conscious, a characteristic that distinguishes cataplexy from fainting or seizure disorders. The loss of muscle tone during cataplexy resembles paralysis of muscle activity that naturally occurs during REM sleep. Episodes last a few minutes at most and resolve almost instantly on their own. While scary, the episodes are not dangerous as long as the individual finds a safe place in which to collapse.
• Sleep paralysis—The temporary inability to move or speak while falling asleep or waking up usually lasts only a few seconds or minutes and is similar to REM-induced inhibitions of voluntary muscle activity. Sleep paralysis resembles cataplexy except it occurs at the edges of sleep. As with cataplexy, people remain fully conscious. Even when severe, cataplexy and sleep paralysis do not result in permanent dysfunction—after episodes end, people rapidly recover their full capacity to move and speak.
• Hallucinations—Very vivid and sometimes frightening images can accompany sleep paralysis and usually occur when people are falling asleep or waking up. Most often the content is primarily visual, but any of the other senses can be involved.

Additional symptoms include:

• Fragmented sleep and insomnia—While individuals with narcolepsy are very sleepy during the day, they usually also experience difficulties staying asleep at night. Sleep may be disrupted by insomnia, vivid dreaming, sleep apnea, acting out while dreaming, and periodic leg movements.
• Automatic behaviors—Individuals with narcolepsy may experience temporary sleep episodes that can be very brief, lasting no more than seconds at a time. A person falls asleep during an activity (e.g., eating, talking) and automatically continues the activity for a few seconds or minutes without conscious awareness of what they are doing. This happens most often while people are engaged in habitual activities such as typing or driving. They cannot recall their actions, and their performance is almost always impaired. Their handwriting may, for example, degenerate into an illegible scrawl, or they may store items in bizarre locations and then forget where they placed them. If an episode occurs while driving, individuals may get lost or have an accident. People tend to awaken from these episodes feeling refreshed, finding that their drowsiness and fatigue has temporarily subsided.

There are two major types of narcolepsy:

• Type 1 narcolepsy (previously known as narcolepsy with cataplexy)—This diagnosis is based on the individual either having low levels of a brain hormone (hypocretin) or reporting cataplexy and having excessive daytime sleepiness on a special nap test.
• Type 2 narcolepsy (previously known as narcolepsy without cataplexy)—People with this condition experience excessive daytime sleepiness but usually do not have muscle weakness triggered by emotions. They usually also have less severe symptoms and have normal levels of the brain hormone hypocretin.

A condition known as secondary narcolepsy can result from an injury to the hypothalamus, a region deep in the brain that helps regulate sleep. In addition to experiencing the typical symptoms of narcolepsy, individuals may also have severe neurological problems and sleep for long periods (more than 10 hours) each night.

Who is more likely to get narcolepsy?

Narcolepsy affects both males and females equally. Symptoms often start in childhood, adolescence, or young adulthood (ages 7 to 25), but can occur at any time in life. Since people with narcolepsy are often misdiagnosed with other conditions, such as psychiatric disorders or emotional problems, it can take years for someone to get the proper diagnosis.

Narcolepsy may have several causes. Nearly all people with narcolepsy who have cataplexy have extremely low levels of the naturally occurring chemical hypocretin, which promotes wakefulness and regulates REM sleep. Hypocretin levels are usually normal in people who have narcolepsy without cataplexy.

Although the cause of narcolepsy is not completely understood, current research suggests that narcolepsy may be the result of a combination of factors working together to cause a lack of hypocretin. These factors include:

• Autoimmune disorders—When cataplexy is present, the cause is most often the loss of brain cells that produce hypocretin. Although the reason for this cell loss is unknown, it appears to be linked to abnormalities in the immune system. Autoimmune disorders occur when the body's immune system turns against itself and mistakenly attacks healthy cells or tissue. Researchers believe that in individuals with narcolepsy, the body's immune system selectively attacks the hypocretin-containing brain cells because of a combination of genetic and environmental factors.
• Family history—Most cases of narcolepsy are sporadic, meaning the disorder occurs in individuals with no known family history. However, clusters in families sometimes occur—up to 10 percent of individuals diagnosed with narcolepsy with cataplexy report having a close relative with similar symptoms.
• Brain injuries—Rarely, narcolepsy results from traumatic injury to parts of the brain that regulate wakefulness and REM sleep or from tumors and other diseases in the same regions.

In the past few decades, scientists have made considerable progress in understanding narcolepsy and identifying genes strongly associated with the disorder. Groups of neurons in several parts of the brain interact to control sleep, and the activity of these neurons is controlled by a large number of genes. The loss of hypocretin-producing neurons in the hypothalamus is the primary cause of type 1 narcolepsy. These neurons are important for stabilizing sleep and wake states.

The human leukocyte antigen (HLA) system of genes plays an important role in regulating the immune system. This gene family provides instructions for making a group of related proteins called the HLA complex, which helps the immune system distinguish between good proteins from an individual's own body and bad ones made by foreign invaders like viruses and bacteria.

One of the genes in this family is HLA-DQB1. A variation in this gene, called HLA-DQB1*06:02, increases the chance of developing narcolepsy, particularly the type of narcolepsy with cataplexy and a loss of hypocretins (also known as orexins). HLA-DQB1*06:02 and other HLA gene variations may increase susceptibility to an immune attack on hypocretin neurons, causing these cells to die. Most people with narcolepsy have this gene variation and may also have specific versions of closely related HLA genes.

However, it is important to note that these gene variations are common in the general population and only a small portion of the people with the HLA-DQB1*06:02 variation will develop narcolepsy. This indicates that other genetic and environmental factors are important in determining if an individual will develop the disorder.

Narcolepsy follows a seasonal pattern and is more likely to develop in the spring and early summer after the winter season, a time when people are more likely to get sick. By studying people soon after they develop the disorder, scientists have discovered that individuals with narcolepsy have high levels of anti-streptolysin O antibodies, indicating an immune response to a recent bacterial infection such as strep throat. Also, the H1N1 influenza epidemic in 2009 resulted in a large increase in the number of new cases of narcolepsy. Together, this suggests that individuals with the HLA-DQB1*06:02 variation are at risk for developing narcolepsy after they are exposed to a specific trigger, like certain infections that trick the immune system to attack the body.

How is narcolepsy diagnosed and treated?

Diagnosing narcolepsy

A clinical examination and detailed medical history are essential for diagnosis and treatment of narcolepsy. Individuals may be asked by their doctor to keep a sleep journal noting the times of sleep and symptoms over a one- to two-week period. A physical exam can rule out or identify other neurological conditions that may be causing the symptoms.

Two specialized tests, which can be performed in a sleep disorders clinic, are required to establish a diagnosis of narcolepsy:

• Polysomnogram (PSG or sleep study)—The PSG is an overnight recording of brain and muscle activity, breathing, and eye movements. A PSG can help reveal whether REM sleep occurs early in the sleep cycle and if an individual's symptoms result from another condition such as sleep apnea.
• Multiple sleep latency test (MSLT)—The MSLT assesses daytime sleepiness by measuring how quickly a person falls asleep and whether they enter REM sleep.

Occasionally, it may be helpful to measure the level of hypocretin in the fluid that surrounds the brain and spinal cord. To perform this test, a doctor will withdraw a sample of the cerebrospinal fluid using a lumbar puncture (also called a spinal tap) and measure the level of hypocretin-1.

Treating narcolepsy

Although there is no cure for narcolepsy, some of the symptoms can be treated with medicines and lifestyle changes.

Medications

• Modafinil—The initial line of treatment is usually a central nervous system stimulant such as modafinil. Modafinil is usually prescribed first because it is less addictive and has fewer side effects than older stimulants. For most people these drugs are generally effective at reducing daytime drowsiness and improving alertness.
• Amphetamine-like stimulants—In cases where modafinil is not effective, doctors may prescribe amphetamine-like stimulants such as methylphenidate to alleviate EDS. However, these medications must be carefully monitored because they can have side effects.
• Antidepressants—Two classes of antidepressant drugs have proven effective in controlling cataplexy in many individuals: tricyclics (including imipramine, desipramine, clomipramine, and protriptyline) and selective serotonin and noradrenergic reuptake inhibitors (including venlafaxine, fluoxetine, and atomoxetine).
• Sodium oxybate—Sodium oxybate (also known as gamma hydroxybutyrate or GHB) has been approved by the U.S. Food and Drug Administration (FDA) to treat cataplexy and excessive daytime sleepiness in individuals with narcolepsy. Due to safety concerns associated with the use of this drug, the distribution of sodium oxybate is tightly restricted.
• Histamine 3 receptor antagonist/inverse agonist—Pitolisant was recently approved by FDA as the only non-scheduled product for treating excessive daytime sleepiness or cataplexy in adults with narcolepsy and treating excessive daytime sleepiness in pediatric patients 6 years of age and older with narcolepsy. Pitolisant, which has been commercially available in the U.S. since 2019, is thought to increase histamine levels in the brain. The most common adverse reactions to Pitolisant in adults are insomnia, nausea, and anxiety, while most common adverse reactions in pediatric patients 6 years and older include headache and insomnia.

Lifestyle changes

Drug therapy should accompany various lifestyle changes. Remembering the following seven tips may be helpful:

• Take short naps. Many individuals take short, regularly scheduled naps at times when they tend to feel sleepiest.
• Maintain a regular sleep schedule. Going to bed and waking up at the same time every day, even on the weekends, can help people sleep better.
• Avoid caffeine or alcohol before bed. Individuals should avoid alcohol and caffeine for several hours before bedtime.
• Avoid smoking, especially at night.
• Exercise daily. Exercising for at least 20 minutes per day at least four or five hours before bedtime also improves sleep quality and can help people with narcolepsy avoid gaining excess weight.
• Avoid large, heavy meals right before bedtime. Eating very close to bedtime can make it harder to sleep.
• Relax before bed. Relaxing activities such as a warm bath before bedtime can help promote sleepiness. Also make sure the sleep space is cool and comfortable.

Safety precautions, particularly when driving, are important for everyone with narcolepsy. Suddenly falling asleep or losing muscle control can transform actions that are ordinarily safe, such as walking down a long flight of stairs, into hazards.

The Americans with Disabilities Act (ADA) requires employers to provide reasonable accommodations for all employees with disabilities. Adults with narcolepsy can often negotiate with employers to modify their work schedules so they can take naps when necessary and perform their most demanding tasks when they are most alert.

Similarly, children and adolescents with narcolepsy may be able to work with school administrators to accommodate special needs, like taking medications during the school day, modifying class schedules to fit in a nap, and other strategies.

Additionally, support groups can be extremely beneficial for people with narcolepsy.

What are the latest updates on narcolepsy?

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. The NINDS, a component of the National Institutes of Health (NIH), along with several other NIH Institutes and Centers, supports research on narcolepsy and other sleep disorders through grants to medical institutions across the country.

Additionally, the National Heart, Lung, and Blood Institute (NHLBI) manages the National Center on Sleep Disorders Research (NCSDR) , which coordinates federal government sleep research activities, promotes doctoral and postdoctoral training programs, and educates the public and health care professionals about sleep disorders. 

Genetics and biochemicals NINDS-sponsored researchers are conducting studies devoted to further clarifying the wide range of genetic—both HLA genes and non-HLA genes—and environmental factors that may cause narcolepsy. Other investigators are using animal models to better understand hypocretin and other chemicals such as glutamate that may play a key role in regulating sleep and wakefulness. Researchers are also investigating wake-promoting compounds to widen the range of available therapeutic options and create treatment options that reduce undesired side effects and decrease the potential for abuse. A greater understanding of the complex genetic and biochemical bases of narcolepsy will eventually lead to new therapies to control symptoms and may lead to a cure.

Immune system Abnormalities in the immune system may play an important role in the development of narcolepsy. NINDS-sponsored scientists have demonstrated the presence of unusual immune system activity in people with narcolepsy. Further, strep throat and certain varieties of influenza are now thought to be triggers in some at-risk individuals. Other NINDS researchers are also working to understand why the immune system destroys hypocretin neurons in narcolepsy in the hopes of finding a way to prevent or cure the disorder.

Sleep biology NINDS continues to support investigations into the basic biology of sleep, such as examining the brain mechanisms involved in generating and regulating REM sleep and other sleep behaviors. Since sleep and circadian rhythms are controlled by networks of neurons in the brain, NINDS researchers are also examining how neuronal circuits function in the body and contribute to sleep disorders like narcolepsy. A more comprehensive understanding of the complex biology of sleep will give scientists a better understanding of the processes that underlie narcolepsy and other sleep disorders.

How can I or my loved one help improve care for people with narcolepsy?

The NeuroBioBank serves as a central point of access to collections that span neurological, neuropsychiatric, and neurodevelopmental diseases and disorders. Tissue from individuals with narcolepsy is needed to enable scientists to study this disorder more intensely. Participating groups include brain and tissue repositories, researchers, NIH program staff, information technology experts, disease advocacy groups, and, most importantly, individuals seeking information about opportunities to donate.

Additionally, NINDS supports genetic and immunological research in narcolepsy at the Stanford University Center for Narcolepsy . Blood samples from individuals with narcolepsy can be sent by mail and are needed to enable scientists to study this disorder more intensely.

Consider participating in a clinical trial so clinicians and scientists can learn more about narcolepsy and related disorders. Clinical research uses human volunteers to help researchers learn more about a disorder and perhaps find better ways to safely detect, treat, or prevent disease.

All types of volunteers are needed—those who are healthy or may have an illness or disease—of all different ages, sexes, races, and ethnicities to ensure that study results apply to as many people as possible, and that treatments will be safe and effective for everyone who will use them.

For information about participating in clinical research visit NIH Clinical Research Trials and You . Learn about clinical trials currently looking for people with narcolepsy at Clinicaltrials.gov .

Where can I find more information about narcolepsy?

Information may be available from the following organizations:

Narcolepsy Network Phone: 401-667-2523 or 888-292-6522

National Heart, Lung, and Blood Institute (NHLBI) Phone: 301-592-8573 or 800-575-9355

National Library of Medicine Phone: 301-594-5983 or 888-346-3656

National Sleep Foundation Phone: 703-243-1697

Wake Up Narcolepsy Phone: 978-751-3693

• Case report
• Open access
• Published: 31 August 2024

Does gait influence biomechanics in a distal femoral osteotomy? An early post operative fracture after DFO above a Tomofix ® plate in a multiple sclerosis and low-density bone affected patient: choose a longer plate—a case report

• Antongiulio Favero 1 ,
• Domenico Alesi 1 , 2 ,
• Vito Gaetano Rinaldi 1 , 2 ,
• Tosca Cerasoli 1 ,
• Stefano Zaffagnini 1 &
• Giulio Maria Marcheggiani Muccioli 1 , 2  

Journal of Medical Case Reports volume  18 , Article number:  400 ( 2024 ) Cite this article

Metrics details

Distal femur osteotomies are a well known and valuable treatment option to manage valgus malalignment with unicompartmental arthritis. Early postoperative complications are well known, and risk factors, such as pulmonary diseases, smoke, high dependent functional status, and body mass index, have been studied, but no study is available about osteotomies when gait is abnormal because of neurodegenerative conditions or when mineral density is below the normal rate.

Case presentation

We report the case of a 44 year-old female Mediterranean patient who underwent a biplanar distal femur opening wedge osteotomy surgery following a lateral meniscus total removal, which led to the subsequent development of lateral compartment osteoarthritis and pain, despite general comorbidities, such as multiple sclerosis. Additionally, 2 months later a supracondylar femur fracture above the previously applied Tomofix ® plate was reported. Fracture was treated by applying a LCP condylar 16 hole (336 mm) plate, a structural fibular graft, and strut fibular graft on the opposite side.

The overall aim of this case report is to provide a lesson to surgeons who want to perform a realignment surgery of the lower limb in patients with abnormal gait. Not only mechanical axes are to be considered, but also bone density, patient’s gait, and load force distribution along the bone stock. Emerging literature on three-dimensional cutting guides fails to account for these factors, thus promoting a standardized approach to surgery across all patients. The present case highlights a patient with low bone density and abnormal force distribution resulting from a pathologic neurodegenerative gait. In such cases, treatment decisions must carefully consider the biomechanical vulnerabilities of the native bone and the distribution of vector forces. These conditions must lead the choice toward a longer plate if an osteotomy is indicated, because surgery is more likely to fail.

Peer Review reports

Introduction

Varus and valgus malalignment with isolated medial or lateral wear of knee compartments can be treated in young and active patients by performing a high tibial osteotomy (HTO) or a distal femoral osteotomy (DFO), shifting the mechanical axis of the lower limb, and thus distributing load equally on knee compartments.

Early postoperative complications include recurrence of deformity, infection, joint contracture, hemartrosis, loss of posterior slope, compartment syndrome, neurovascular injury, hardware failure, delayed union, nonunion, and fractures [ 4 ]. The latter ones are among the rarest complications, and usually occur after falls [ 2 ].

Preoperative planning of osteotomies should include anterior–posterior weight bearing X-rays of the lower limbs and lateral projections of the knee [ 1 , 2 , 4 , 6 , 7 ], but no study is available regarding the correlation between gait, distribution of forces, and mechanical axis surgical adjustments.

A 44 year-old Mediterranean woman (weight of 81 kg, height of 178 cm, body mass index of 25,6 kg/m 2 ) affected by a relapsing remitting form of multiple sclerosis in an initial phase, first presented to our outpatient clinic complaining of lateral left knee pain. Nothing relevant was found in the family history. In 2021, the patient underwent an arthroscopic subtotal lateral meniscectomy of the knee owing to a nonspecified lateral meniscal tear; in 2022 she then underwent an arthroscopic meniscal regularization because of residual pain. Physical examination revealed lateral pain during walking and lateral compartment tenderness at palpation and in response to valgus stress; ligaments were stable at stress maneuvers; range of movement (ROM) reported was 0–110°, limited by pain. Radiographs (Fig.  1 , left) revealed lateral compartment knee osteoarthritis and valgus femoral deformity. Therefore, an opening wedge DFO with an allograft wedge was scheduled. Initial planning showed lateral distal femoral angle (mLDFA) of 86,71° and medial proximal tibial angle (MPTA) of 87,01°; we therefore estimated a 5 mm medial opening cut to restore a neutral axis (Fig.  2 ).

X rays showing preoperative imaging, postoperative imaging, and post fracture imaging

From left to right: preoperative standing X-ray imaging, post distal femoral osteotomy standing X-ray imaging, and posttraumatic fracture fixation non-weight bearing panoramic X ray of the lower limb

Surgery was performed without any intraoperative complications. The patient developed postoperative anemia requiring a transfusion. No other complications were reported. The patient was discharged after 4 days. The rehabilitation program consisted in a knee brace blocked in extension for 30 days, which was removable to perform mobilization exercises; isometry exercises were allowed after 10 days, along with passive leg mobilization with kinetec device (starting with 0–35°). Flexion over 90° was not permitted in the first month. Finally, no weight bearing walking was allowed on the operated limb, and the blocked brace had to always remain on.

The patient came to visit as scheduled 30 days later in our outpatient clinic: knee ROM was 0–90°, X-rays were taken (Fig.  1 center), and she was prescribed progressive weight bearing for 30 days, physiotherapy (muscular reinforcement) two times a week, and maximum permitted-kinetec-assisted passive flexion for 45 days.

Then, 20 days later the patient presented to our emergency room (ER) referring a sudden failure of the knee while walking, followed by pain, swelling, and functional impotence. X-rays (Fig.  1 , right) revealed a displaced distal femur fracture. The patient was therefore hospitalized, and surgery was scheduled. The patient also brought to our attention a recent preoperative dual-energy X-ray absorptiometry (DEXA) scan showing a −2,5 T score, which was not considered before, because of her young age.

At 6 days after admission, surgery was performed. By laterally accessing the femur, after retracting fascia lata, muscular fascia, and lateral vastus, a multifragmentary displaced fracture, proximal to the previously applied plate was reported. By protecting the previous osteotomy site with k-wires, we removed the plate and its screws. A structural fibular graft was then placed inside the femoral canal. A LCP condylar 16 hole (336 mm) plate was placed after anatomical reduction of the stumps. We placed both locking and nonlocking screws, using a second contralateral fibular graft. Surgery was performed without any complications.

During hospitalization venous bleeding led to multiple transfusions. No other complications were reported. Physiotherapy started 3 days later: no weight bearing on the affected limb and knee brace blocked in extension.

The patient was dismissed 5 days after surgery.

The patient came to visit in our outpatient clinic after 21 days. Stitches were removed and the surgical wound had healed properly. She was given indication to start rehabilitation: progressive weight bearing with crutches. Postoperative X-rays at 1 month showed good progression in bone healing and good positioning of the plate (Fig.  3 ). The patient was very satisfied with the result. After 6 months from the first surgery, the patient would like to correct the other limb alignment too.

X-ray imaging showing plate fixation at 1 month follow up

Discussion and conclusion

No superiority between opening and closing wedge DFO has been found in literature; however, Rosso et al . [ 7 ] reported higher intraoperative precision regarding correction and less postoperative plate intolerance with open wedge techniques. Literature reports high variability in complications after opening wedge DFO procedures, ranging from 0% to 30%, the main consisting of hardware related issues [ 2 ]. This one is included among early postoperative complications and can compromise surgery, because, as Chahla et al . [ 2 ] reported in his systematic review, bone healing time can range from 3 to 6 months. Berk et al . (2023) reported higher rates of early complications in DFO when compared with HTO (11.6% versus 21.5%), suggesting that this procedure may need a strict follow up, especially in the first months. This may be because DFO are performed closer to diaphyseal bone when compared with HTO, and growth potential differs between these areas [ 6 ]. We presented the case of a distal femoral fracture after an opening wedge DFO, which occurred only 2 months after the procedure. Despite that, alignment, and healing of the bone in the site of osteotomy were not compromised; still, this complication must be defined as early and hardware related, because the length of the plate caused anomalous distribution of force vectors along the bone stock, defining a locus minoris resistantiae just above the plate itself. According to a 2013 systematic review of Vena et al . analyzing complications after osteotomies, fractures usually happen around the site of wedge opening or just below, with the fracture line directed toward the articular portion and are seen intraoperatively or as late complications. To our knowledge, there are no other cases describing an early fracture above the opening wedge in a low-density bone patient. No studies considered the link between osteoporosis and osteotomies owing to the relatively young age of patients undergoing this procedure (better outcomes in patients < 60 years) [ 9 ]. This study could suggest that bone density should be considered in patients who are at risk of osteoporosis. Our case lacked the recognition of preoperative preexisting osteoporosis, which is well known to be linked to multiple sclerosis, such as some fracture patterns, as Yazdan Panah et al . [ 11 ] highlighted. Moreover, we must consider that the population is growing progressively older in first world countries and patients might refuse a knee replacement asking for an axis correction (as in osteotomies) if their functional requests are high.

Well known associated risk factors are age > 45 years, diabetes mellitus, chronic obstructive pulmonary disease, and smoking [ 4 ] and are related to failure of the procedure, mainly influencing soft tissue healing but also favoring infection. Moreover, high body mass index, hypertension, and dependent functional status were found to be risk factors [ 3 ]. Our patient did not present any of these risk factors, apart from dependent functional status. This evidence could suggest that we should improve our knowledge in this field to avoid complications such as in this case.

According to Berk et al . The most common complications after DFO are anemia requiring transfusion (14%) and readmission (4%). Our patient developed both.

Existing literature already evaluated outcomes of DFO in patients affected by monocompartimental osteoarthritis. Gait analysis is a valuable tool in this field. Regarding valgus correction, it is known that it can cause an increase in the abduction moment and a lateral shift in the dynamic knee joint loading. Varus osteotomies have less literature regarding these aspects, but recent studies seem to suggest that knee adduction moment can increase similarly. It is also well known that the peak knee flexion moment is strongly related to walking speed [ 10 ]. No literature exists regarding abnormal distribution of forces on the bone stock after surgeries in patients affected by neurodegenerative diseases. More specifically, no studies evaluated the link between abnormal gait and complications after DFO. Current literature suggests that coronal forces could prevail on other plane vectors during normal gait, above all when a slow gait or an intra-external rotated lower limb axis is considered. In our case, we had both a slow and wide gait, which could have led coronal forces to strongly overcome bone elastic module. Moreover, out patient’s bone was osteoporotic. We chose a Tomofix ® plate, because, as Rosso et al . [ 7 ] reported that, despite no clinical superiority being found, biomechanically it has greater axial and torsional stability. Positioning a too short plate, such as Tomofix ® ones commonly used for osteotomies, on an osteoporotic bone, can elicit peri-implant fractures. Abnormal gait, including poor coordination and balance issues, eventual spasticity, and widening of the docking station typical of neurodegenerative condition affected patients, may add a further risk factor. In these cases, we suggest applying a longer plate and eventually, if other risk factors are highlighted, a contralateral fibular strut on the other side primarily favoring bone regrowth.

Custom guides for osteotomies are becoming more and more popular among orthopedic surgeons, focusing above all on axis realignment, leaving aside how force vectors will distribute after our cuts. New vectors could destabilize previous bone deficiencies leading to surgical failures.

Increasing literature is emerging about distal femur fractures treated with fibular grafts and plating, showing promising results. Wen Chin Su [ 8 ] and Ibrahim [ 5 ] show that this application may have lower bone healing time and postoperative nonunion or femur collapse in varus rates, particularly when patients are older than 50 years, with a lower bone density (not necessarily pathological). Our patient resembled these risk factors; therefore, we applied the same type of cautions.

The overall aim of this case report is to provide a lesson to surgeons who want to perform a realignment surgery of the lower limb in patients with abnormal gait. Not only mechanical axes are to be considered, but also bone density, patient’s gait and load force distribution along the bone stock. Emerging literature on three-dimensional cutting guides fail to account for these factors, thus promoting a standardized approach to surgery across all patients. The present case highlights a patient with low bone density and abnormal force distribution resulting from a pathologic neurodegenerative gait. In such cases, treatment decisions must carefully consider the biomechanical vulnerabilities of the native bone and the distribution of vector forces. These conditions must guide the choice toward a longer plate if an osteotomy is indicated, because surgery is more likely to fail.

This case report has some limitations. First, follow up time is limited: a long-term follow could provide better clinical and radiographical data. Moreover, we expect this patient to experience a progressive neurological decay, which will affect our outcome in a nonpredictable and measurable way. We also did not report clinical scores prior to surgery.

Availability of data and materials

All the data discussed in the manuscript are in the databases of Istituto Ortopedico Rizzoli.

Brouwer RW, Huizinga MR, Duivenvoorden T, van Raaij TM, Verhagen AP, Bierma-Zeinstra MA. Osteotomy for treating knee osteoarthritis. Cochrane Database Syst Rev. 2014. https://doi.org/10.1002/14651858.CD004019.pub4 .

Article   PubMed   PubMed Central   Google Scholar  

Chahla J, Mitchell JJ, Liechti DJ, Moatshe G, Menge TJ, Dean CS. Opening- and closing-wedge distal femoral osteotomy. Orthopaedic J Sports Med. 2016. https://doi.org/10.1177/2325967116649901 .

Article   Google Scholar  

Cotter EJ, Gowd AK, Bohl DD, Getgood A, Cole BJ, Frank RM. Medical comorbidities and functional dependent living are independent risk factors for short-term complications following osteotomy procedures about the knee. Cartilage. 2020. https://doi.org/10.1177/1947603518798889 .

Article   PubMed   Google Scholar  

Early Postoperative Complications and Associated Variables After High Tibial Osteotomy and Distal Femoral Osteotomy—Cerca con Google. Consultato 5 ottobre 2023. https://www.google.com/search?q=Early+Postoperative+Complications+and+Associated+Variables+After+High+Tibial+Osteotomy+and+Distal+Femoral+Osteotomy&oq=Early+Postoperative+Complications+and+Associated+Variables+After+High+Tibial+Osteotomy+and+Distal+Femoral+Osteotomy&gs_lcrp=EgZjaHJvbWUyBggAEEUYOTIGCAEQRRg80gEHMjgyajBqN6gCALACAA&sourceid=chrome&ie=UTF-8 .

Ibrahim FM, El Ghazawy AK, Hussien MA. Primary fibular grafting combined with double plating in distal femur fractures in elderly patients. Int Orthopaedic. 2022. https://doi.org/10.1007/s00264-022-05441-x .

Jacobi M, Wahl P, Bouaicha S, Jakob RP, Gautier E. Distal femoral varus osteotomy: problems associated with the lateral open-wedge technique. Archiv Orthopaedic Trauma Surg. 2011. https://doi.org/10.1007/s00402-010-1193-1 .

Rosso F, Margheritini F. Distal femoral osteotomy. Current Rev Musculoskeletal Med. 2014. https://doi.org/10.1007/s12178-014-9233-z .

Su WC, Tzai-Chiu Y, Peng CH, Liu KL, Wen-Tien W, Chen IH, Wang JH, Yeh KT. Use of an intramedullary allogenic fibular strut bone and lateral locking plate for distal femoral fracture with supracondylar comminution in patients over 50 years of age. Medicina. 2022. https://doi.org/10.3390/medicina59010009 .

Vena G, D’Adamio S, Amendola A. Complications of osteotomies about the knee. Sports Med Arthrosc Rev. 2013. https://doi.org/10.1097/JSA.0b013e3182900720 .

van Egmond N, et al . Gait analysis before and after corrective osteotomy in patients with knee osteoarthritis and a valgus deformity. Knee Surg Sports Traumatol Arthrosc Off J ESSKA. 2017. https://doi.org/10.1007/s00167-016-4045-x .

Panah MY, Vaheb S, Ghaffary EM, Shaygannejad V, Zabeti A, Mirmosayyeb O. Bone loss and fracture in people with multiple sclerosis a systematic review and meta analysis. Multiple Sclerosis Related Disorders. 2024. https://doi.org/10.1016/j.msard.2024.105773 .

Download references

Acknowledgements

Not applicable.

Author information

Authors and affiliations.

II Clinica Ortopedica, IRCCS Istituto Ortopedico Rizzoli, Via Pupilli 1, 40137, Bologna, Italy

Antongiulio Favero, Domenico Alesi, Vito Gaetano Rinaldi, Tosca Cerasoli, Stefano Zaffagnini & Giulio Maria Marcheggiani Muccioli

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

Domenico Alesi, Vito Gaetano Rinaldi & Giulio Maria Marcheggiani Muccioli

You can also search for this author in PubMed   Google Scholar

Contributions

Each author contributed to the article: GMMM performed the surgery, conceived and designed the paper, and revised the paper; AF contributed data and wrote the paper; SZ conceived and designed the paper and revised the paper.

Corresponding author

Correspondence to Antongiulio Favero .

Ethics declarations

Ethical approval and consent to participate.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ .

Reprints and permissions

About this article

Cite this article.

Favero, A., Alesi, D., Rinaldi, V.G. et al. Does gait influence biomechanics in a distal femoral osteotomy? An early post operative fracture after DFO above a Tomofix ® plate in a multiple sclerosis and low-density bone affected patient: choose a longer plate—a case report. J Med Case Reports 18 , 400 (2024). https://doi.org/10.1186/s13256-024-04739-1

Download citation

Received : 16 January 2024

Accepted : 03 August 2024

Published : 31 August 2024

DOI : https://doi.org/10.1186/s13256-024-04739-1

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Distal femoral osteotomy
• Knee fracture
• Distal femur fracture
• Low density bone
• Neurodegenerative gait
• Lateral compartment osteoarthritis
• Fibular strut
• Lower limb malalignment
• Gait analysis

Journal of Medical Case Reports

ISSN: 1752-1947

• Submission enquiries: Access here and click Contact Us
• General enquiries: [email protected]