undetectable in up to 95% of patients with type 1 narcolepsy. the system which regulates sleep, arousal, and transitions between these states in humans is composed of three interconnected subsystems: the orexin projections from the lateral hypothalamus, the reticular activating system, and the ventrolateral preoptic nucleus. in narcoleptic individuals, these systems are all associated with impairments due to a greatly reduced number of hypothalamic orexin projection neurons and significantly fewer orexin neuropeptides in cerebrospinal fluid and neural tissue, compared to non-narcoleptic individuals. those with narcolepsy generally experience the rem stage of sleep within five minutes of falling asleep, while people who do not have narcolepsy (unless they are significantly sleep deprived) do not experience rem until after a period of slow-wave sleep, which lasts for about the first hour or so of a sleep cycle. disturbed sleep states the neural control of normal sleep states and the relationship to narcolepsy are only partially understood. in humans, narcoleptic sleep is characterized by a tendency to go abruptly from a waking state to rem sleep with little or no intervening non-rem sleep. the changes in the motor and proprioceptive systems during rem sleep have been studied in both human and animal models. during normal rem sleep, spinal and brainstem alpha motor neuron hyperpolarization produces almost complete atonia of skeletal muscles via an inhibitory descending reticulospinal pathway. acetylcholine may be one of the neurotransmitters involved in this pathway. in narcolepsy, the reflex inhibition of the motor system seen in cataplexy has features normally seen only in normal rem sleep. diagnosis the third edition of the international classification of sleep disorders (icsd-3) differentiates between narcolepsy with cataplexy (type 1) and narcolepsy without cataplexy (type 2), while the fifth edition of the diagnostic and statistical manual of mental disorders (dsm-5) uses the diagnosis of narcolepsy to refer to type 1 narcolepsy only. the dsm-5 refers to narcolepsy without cataplexy as hypersomnolence disorder. the most recent edition of the international classification of diseases, icd-11, currently identifies three types of narcolepsy: type 1 narcolepsy, type 2 narcolepsy, and unspecified narcolepsy. icsd-3 diagnostic criteria posits that the individual must experience "daily periods of irrepressible need to sleep or daytime lapses into sleep" for both subtypes of narcolepsy. this symptom must last for at least three months. for a diagnosis of type 1 narcolepsy, the person must present with either cataplexy, a mean sleep latency of less than 8 minutes, and two or more sleep-onset rem periods (soremps), or they must present with a hypocretin-1 concentration of less than 110 pg/ml. a diagnosis of type 2 narcolepsy requires a mean sleep latency of less than 8 minutes, two or more soremps, and a hypocretin-1 concentration of more than 110 pg/ml. in addition, the hypersomnolence and sleep latency findings cannot be better explained by other causes. dsm-5 narcolepsy criteria requires that the person to display recurrent periods of "an irrepressible need to sleep, lapsing into sleep, or napping" for at least three times a week over a period of three months. the individual must also display one of the following: cataplexy, hypocretin-1 concentration of less than 110 pg/ml, rem sleep latency of less than 15 minutes, or a multiple sleep latency test (mslt) showing sleep latency of less than 8 minutes and two or more soremps. for a diagnosis of hypersomnolence disorder, the individual must present with excessive sleepiness despite at least 7 hours of sleep as well as either recurrent lapses into daytime sleep, nonrestorative sleep episodes of 9 or more hours, or difficulty staying awake after awakening. in addition, the hypersomnolence must occur at least three times a week for a period of three months, and must be accompanied by significant distress or impairment. it also cannot be explained by another sleep disorder, coexisting mental or medical disorders, or medication. tests diagnosis is relatively easy when all the symptoms of narcolepsy are present, but if the sleep attacks are isolated and cataplexy is mild or absent, diagnosis is more difficult. three tests that are commonly used in diagnosing narcolepsy are polysomnography (psg), the multiple sleep latency test (mslt), and the epworth sleepiness scale (ess). these tests are usually performed by a sleep specialist. polysomnography involves the continuous recording of sleep brain waves and a number of nerve and muscle functions during night time sleep. when tested, people with narcolepsy fall asleep rapidly, enter rem sleep early, and may often awaken during the night. the polysomnogram also helps to detect other possible sleep disorders that could cause daytime sleepiness. the epworth sleepiness scale is a brief questionnaire that is administered to determine the likelihood of the presence of a sleep disorder, including narcolepsy. the multiple sleep latency test is performed after the person undergoes an overnight sleep study. the person will be asked to sleep once every 2 hours, and the time it takes for them to do so is recorded. most individuals will fall asleep within 5 to 8 minutes, as well as display rem sleep faster than non-narcoleptic people. measuring orexin levels in a person's cerebrospinal fluid sampled in a spinal tap may help in diagnosing narcolepsy, with abnormally low levels serving as an indicator of the disorder. this test can be useful when mslt results are inconclusive or difficult to interpret. treatment orexin replacement people with narcolepsy can be substantially helped, but not cured. however, the technology exists in early form such as experiments in using the prepro-orexin transgene via gene editing restored normal function in mice models by making other neurons produce orexin after the original set have been destroyed, or replacing the missing orexinergic neurons with hypocretin stem cell transplantation, are both steps in that direction for fixing the biology effectively permanently once applied in humans. additionally effective ideal non-gene editing and chemical-drug methods involve hypocretin treatments methods such as future drugs like hypocretin agonists (such as danavorexton) or hypocretin replacement, in the form of hypocretin 1 given intravenous (injected into the veins), intracisternal (direct injection into the brain), and intranasal (sprayed through the nose), the latter being low in efficacy, at the low amount used in current experiments but may be effective at very high doses in the future. behavioral general strategies like people and family education, sleep hygiene and medication compliance, and discussion of safety issues for example driving license can be useful. potential side effects of medication can also be addressed. regular follow-up is useful to be able to monitor the response to treatment, to assess the presence of other sleep disorders like obstructive sleep apnea, and to discuss psychosocial issues. in many cases, planned regular short naps can reduce the need for pharmacological treatment of the eds, but only improve symptoms for a short duration. a 120-minute nap provided benefit for 3 hours in the person's alertness whereas a 15-minute nap provided no benefit. daytime naps are not a replacement for night time sleep. ongoing communication between the health care provider, person, and their family members is important for optimal management of narcolepsy. medications the main treatment of excessive daytime sleepiness in narcolepsy is central nervous system stimulants such as methylphenidate, amphetamine, dextroamphetamine, modafinil, and armodafinil. in late 2007 an alert for severe adverse skin reactions to modafinil was issued by the fda. pemoline was previously used but was withdrawn due to toxicity. another drug that is used is atomoxetine, a non-stimulant and a norepinephrine reuptake inhibitor (nri), which has no addiction liability or recreational effects. other nris like viloxazine and reboxetine have also been used in the treatment of narcolepsy. additional related medications include mazindol and selegiline. another fda-approved treatment option for narcolepsy is sodium oxybate, also known as sodium gamma-hydroxybutyrate (ghb). it can be used for cataplexy associated with narcolepsy and excessive daytime sleepiness associated with narcolepsy. several studies also showed that sodium oxybate is effective to treat cataplexy. solriamfetol is a new molecule indicated for narcolepsy of type 1 and 2. solriamfetol works by inhibiting the reuptake of the monoamines via the interaction with both the dopamine transporter and the norepinephrine transporter. this mechanism differs from that of the wake-promoting agents modafinil and armodafinil. these are thought to bind primarily at the dopamine transporter to inhibit the reuptake of dopamine. solriamfetol also differs from amphetamines as it does not promote the release of norepinephrine in the brain. narcolepsy has sometimes been treated with selective serotonin reuptake inhibitors and tricyclic antidepressants, such as clomipramine, imipramine, or protriptyline, as well as other drugs that suppress rem sleep. venlafaxine, an antidepressant which blocks the reuptake of serotonin and norepinephrine, has shown usefulness in managing symptoms of cataplexy, however, it has notable side-effects including sleep disruption. the antidepressant class is used mainly for the treatment of cataplexy, for people with narcolepsy without cataplexy these are usually not used. children common behavioral treatments for childhood narcolepsy include improved sleep hygiene, scheduled naps, and physical exercise. many medications are used in treating adults and may be used to treat children. these medications include central nervous system stimulants such as methylphenidate, modafinil, amphetamine, and dextroamphetamine. other medications, such as sodium oxybate or atomoxetine may also be used to counteract sleepiness. medications such as sodium oxybate, venlafaxine, fluoxetine, and clomipramine may be prescribed if the child presents with cataplexy. epidemiology estimates of frequency range from 0.2 per 100,000 in israel to 600 per 100,000 in japan. these differences may be due to how the studies were conducted or the populations themselves. in the united states, narcolepsy is estimated to affect as many as 200,000 americans, but fewer than 50,000 are diagnosed. the prevalence of narcolepsy is about 1 per 2,000 persons. narcolepsy is often mistaken for depression, epilepsy, the side effects of medications, poor sleeping habits or recreational drug use, making misdiagnosis likely. while narcolepsy symptoms are often confused with depression, there is a link between the two disorders. research studies have mixed results on co-occurrence of depression in people with narcolepsy, as the numbers quoted by different studies are anywhere between 6% and 50%. narcolepsy can occur in both men and women at any age, although typical symptom onset occurs in adolescence and young adulthood. there is about a ten-year delay in diagnosing narcolepsy in adults. cognitive, educational, occupational, and psychosocial problems associated with the excessive daytime sleepiness of narcolepsy have been documented. for these to occur in the crucial teen years when education, development of self-image, and development of occupational choice are taking place is especially devastating. while cognitive impairment does occur, it may only be a reflection of the excessive daytime somnolence. society and culture in 2015, it was reported that the british department of health was paying for sodium oxybate medication at a cost of £12,000 a year for 80 people who are taking legal action over problems linked to the use of the pandemrix swine flu vaccine. sodium oxybate is not available to people with narcolepsy through the national health service. name the term "narcolepsy" is from the french narcolepsie. the french term was first used in 1880 by jean-baptiste-édouard gélineau, who used the greek νάρκη (narkē), meaning "numbness", and λῆψις (lepsis) meaning "attack". research histamine-directed medications it remains to be seen whether h3 antagonists (i.e., compounds such as pitolisant that promote the release of the wakefulness-promoting molecule amine histamine) will be particularly useful as wake-promoting agents. however, usage now does exist in various nations such as in france, united kingdom's (nhs as of september 2016) after being given marketing authorisation by european commission on the advice of the european medicines agency and in the united states by the approval of the food and drug administration (fda) as of august 2019. gaba-directed medications given the possible role of hyper-active gabaa receptors in the primary hypersomnias (narcolepsy and idiopathic hypersomnia), medications that could counteract this activity are being studied to test their potential to improve sleepiness. these currently include clarithromycin and flumazenil. flumazenil flumazenil is the only gabaa receptor antagonist on the market as of jan 2013, and it is currently manufactured only as an intravenous formulation. given its pharmacology, researchers consider it to be a promising medication in the treatment of primary hypersomnias. results of a small, double-blind, randomized, controlled clinical trial were published in november 2012. this research showed that flumazenil provides relief for most people whose csf contains the unknown "somnogen" that enhances the function of