Symptoms start usually during the second decade of life, peaking at 14 years of age, while a second peak is shown to be around age 35 [18] [20]. Additionally, patients that have a positive family history for narcolepsy have shown a significant predilection toward an early onset of the condition [20]. The first symptom is excessive daytime sleepiness accompanied by fragmented sleep during the night [26]. Cataplexy, defined as sudden and brief (ranging between 5 and 30 seconds) partial or total loss of muscle tone triggered by emotional stimuli (laughter, surprise or anger) [3], may appear together with narcolepsy, but its onset is sometimes delayed for years or even decades [18]. However, it is rarely the first symptom of this condition [18]. Cataplexy may involve isolated muscle groups or it can be generalized, resulting in falling and the collapse of the individual and in rare cases, prolonged loss of muscle tone is described, known as status cataplectic [3]. Hallucinations, both visual and auditory, are also an integral component of the clinical presentation, as both hypnagogic (at sleep onset) and hypnopompic (upon awakening) may be present [3]. A subjective sense of clumsiness, slurred speech, weakness, and muscle twitches are reported prior to the attack [3].

• Excessive Daytime Sleepiness

  The first symptom is excessive daytime sleepiness accompanied by fragmented sleep during the night. [symptoma.com]

  Narcolepsy means excessive daytime sleepiness. Most of us sometimes feel tired and sleepy during the day. [mydr.com.au]

  A 20-year-old male presented with a 12-year history of excessive daytime sleepiness and sudden muscle weakness caused by laughter and disturbed nocturnal sleep. He had never presented hypnagogic hallucinations or sleep paralysis. [ncbi.nlm.nih.gov]

  It most commonly manifests in teens and young adults with excessive daytime sleepiness. Primary narcolepsy is either caused by orexin deficiency (type 1) or is idiopathic (type 2). [amboss.com]

  Excessive daytime sleepiness (EDS) and cataplexy are considered the main symptoms of narcolepsy. Excessive daytime sleepiness is typically the first symptom that comes on, and other symptoms of narcolepsy may or may not develop later. [pulmonologyadvisor.com]

• Weakness

  This condition can be quite debilitating considering the primary symptoms include extreme drowsiness, falling asleep without warning, and sudden muscle weakness. [labovick.com]

  Partial weakness - specifically ask patients about partial weakness (eg, mild facial or jaw weakness), which they may not report. [patient.info]

  A 20-year-old male presented with a 12-year history of excessive daytime sleepiness and sudden muscle weakness caused by laughter and disturbed nocturnal sleep. He had never presented hypnagogic hallucinations or sleep paralysis. [ncbi.nlm.nih.gov]

  Without much warning, the person loses muscle tone and can have a slack jaw, broken speech, buckled knees or total weakness in their face, arms, legs, and trunk. [sleepfoundation.org]

• Hypersomnia

  Hypersomnias are subdivided into Idiopathic Hypersomnia (persistent sleepiness lasting more than 3 months without abnormal tendencies to enter REM sleep) and Recurrent Hypersomnia (recurrent episodes of sleepiness that are entirely reversible in between [stanfordhealthcare.org]

  Idiopathic hypersomnia without cataplexy or REM sleep abnormalities may represent a third phenotype, although most cases of idiopathic hypersomnia are probably unrelated to the HLA-D linked gene. [ncbi.nlm.nih.gov]

  Idiopathic hypersomnia. Sleep Med Rev 2001; 5 : 349–358. 19. Kawashima M, Ohashi J, Nishida N, Tokunaga K. [nature.com]

  One case of narcolepsy and two cases of idiopathic hypersomnia were identified. All the other 45 relatives were symptom‐free. [onlinelibrary.wiley.com]

• Fatigue

  Fatigue: A struggle to keep going Lack of energy. Fatigue is a self-reported lack of physical or mental energy. People with fatigue do not usually complain of excessive daytime sleepiness. [health.clevelandclinic.org]

  Fatigue Completed NCT00678691 Phase 4 armodafinil;placebo 4 Slow-wave Sleep and Daytime Functioning in Chronic Fatigue Syndrome: Effects of Sodium Oxybate Completed NCT02055898 Phase 4 Sodium Oxybate 5 The Effect of Armodafinil (Nuvigil) on Fatigue and [malacards.org]

  A person with signs of narcolepsy will experience extreme fatigue and may fall asleep at odd and inappropriate times, such as during work or school. A brief nap is generally refreshing, but the sleepiness re-occur rapidly a few hours later. [stanfordhealthcare.org]

  If these movements are associated with sleep disturbance that results in daytime fatigue or sleepiness, it is then called periodic limb movement disorder. The disorder may be diagnosed only after other causes of daytime symptoms are excluded. [aafp.org]

  Even minor fatigue can impair judgement, making vehicles and heavy machinery dangerous. Controlling the symptoms of narcolepsy can go a long way towards preventing accidents. [medbroadcast.com]

• Nightmare

  Having an occasional strange dream isn’t unusual—but sometimes they can border on a nightmare, resulting in stress and lost sleep. If that sounds familiar, you’re not alone: More than 50 percent of adults have nightmares or intense visions at night. [sleepfoundation.org]

  He also developed hypnopompic hallucinations and nightmares. Multiple sleep latency test (MSLT) following full-night polysomnography (PSG) showed that the mean sleep latency was 0.6 minutes; and all of the naps had sleep-onset REM periods. [ncbi.nlm.nih.gov]

• Loss of Appetite

  The family reported that the patient developed complaints of withdrawal, decrease in speech, loss of appetite, and reluctance in the same period. Therefore, his academic success was also decreased. [ncbi.nlm.nih.gov]

• Palpitations

  These medications can produce side effects similar to that of caffeine, such as agitation, nervousness, and palpitations. They are generally started at a low dose and increased gradually as needed. [my.clevelandclinic.org]

  Autonomic symptoms have been reported in narcoleptic patients and include pupillary abnormalities, fainting spells, erectile dysfunction, night sweats, gastric problems, low body temperature, systemic hypotension, dry mouth, heart palpitations, headache [patient.info]

  They may cause side effects such as nervousness and heart palpitations. Selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs). [mayoclinic.org]

  Three months’ palpitation at twenty. N Engl J Med1928;198:585-9.CrossRef ↵Kadari R, Sarche MA, Krantz MJ. Fatal laughter. [bionyt.s807.sureserver.com]

• Muscle Twitch

  A subjective sense of clumsiness, slurred speech, weakness, and muscle twitches are reported prior to the attack. [symptoma.com]

• Blurred Vision

  Other complaints associated with narcolepsy may include eye disturbances due to sleepiness, such as blurred vision, double vision, and droopy eyelids. [medicinenet.com]

  Slurred speech and visual symptoms such as blurred vision or diplopia may be experienced. Hearing, awareness and consciousness are intact. [patient.info]

  […] insomnia Somnolence, blurred vision, hypotension, rebound insomnia† $4 to $43 ($90) Triazolam (Halcion) 15 to 30 2 to 5 0.125 to 0.25 Sleep onset and maintenance insomnia Somnolence, amnesia, ataxia, nausea and vomiting, dizziness, hepatotoxicity, rebound [aafp.org]

  vision, diplopia, ptosis Management Pre-planned 'catnaps' throughout day, analeptics–ie, long-term stimulants–eg, methylphenidate, dextroamphetamine or tricyclic antidepressants that inhibit re-uptake of norepinephrine and serotonin; MAOIs may eventually [medical-dictionary.thefreedictionary.com]

• Diplopia

  Slurred speech and visual symptoms such as blurred vision or diplopia may be experienced. Hearing, awareness and consciousness are intact. [patient.info]

  […] have HLA-DR2 and/or HLA-DQw1 Clinical Narcolepsy tetrad; if accompanied by cataplexy, Pt feels a sense of absolute urgency for sleep in often inappropriate situations–while standing, eating, carrying on conversations, accompanied by blurred vision, diplopia [medical-dictionary.thefreedictionary.com]

• Visual Impairment

  He had no fever, headache, seizures, nausea, vomiting, hearing or visual impairment or dizziness. He was not on any drug and neither smokes nor drinks alcohol. [ajns.paans.org]

• Night Sweats

  Autonomic symptoms have been reported in narcoleptic patients and include pupillary abnormalities, fainting spells, erectile dysfunction, night sweats, gastric problems, low body temperature, systemic hypotension, dry mouth, heart palpitations, headache [patient.info]

• Fear

  People who suffer from narcolepsy often also experience episodes of cataplexy, in which there is a dramatic reduction in muscle tone in association with emotional triggers such as laughing, joking, surprise, fear or anger. [isleephealth.com.au]

  It can feel very real, and trigger feelings of fear or dread. Other common visions may include being caught in a fire or flying through the air. [sleepeducation.org]

  It can occur spontaneously, but many people notice that it is triggered by sudden emotions, such as laughter, excitement fear or, anger. [mydr.com.au]

  The five core symptoms are: Excessive Daytime Sleepiness : An uncontrollable desire to sleep Muscle weakening or unexpected relaxation of knees, mouth, eyes drooping, especially when in conjunction with vivid emotions such as fear or laughter Striking [sleepassociation.org]

  The disease can also be quite frightening and the fear of falling asleep inappropriately often significantly alters life for people with narcolepsy. [msunites.com]

• Visual Hallucination

  Other features of the full narcolepsy/cataplexy syndrome include sleep paralysis, auditory and/or visual hallucinations and automatic behaviour. [isleephealth.com.au]

  We present a 7-year-old girl with ROHHAD who displayed the classic features of narcolepsy with cataplexy: excessive daytime sleepiness with daytime naps, visual hallucinations, and partial cataplexy reflected in intermittent loss of facial muscle tone [pediatrics.aappublications.org]

  Hypnagogic hallucinations — Dream-like auditory or visual hallucinations that occur while falling asleep. [medical-dictionary.thefreedictionary.com]

  The abnormal features of dream sleep experienced by people with narcolepsy type 1 include hallucinations, sleep paralysis, and cataplexy. Hypnagogic hallucinations are dream-like auditory or visual hallucinations upon falling asleep or dozing. [hypersomniafoundation.org]

  Abnormal vivid auditory or visual hallucinations that occur while falling asleep are known as hypnagogic hallucinations, but the more common hypnopompic hallucinations occur upon awakening. [pulmonologyadvisor.com]

• Auditory Hallucination

  Both visual and auditory hallucinations may appear, together with slurred speech and a sense of clumsiness that can precede the attack. [symptoma.com]

  Hallucinations. Some people have vivid, often frightening visual, tactile, or auditory hallucinations as they fall asleep, referred to as hypnagogic hallucinations. Sleep paralysis. [health.clevelandclinic.org]

  Hypnagogic hallucinations; (∼ 50% of cases): vivid, often frightening visual or auditory hallucinations that occur as the patient falls asleep Hypnopompic hallucinations: experienced while waking up (less common than hypnagogic hallucinations) Automatic [amboss.com]

  Hypnagogic hallucinations — Dream-like auditory or visual hallucinations that occur while falling asleep. [medical-dictionary.thefreedictionary.com]

  Abnormal vivid auditory or visual hallucinations that occur while falling asleep are known as hypnagogic hallucinations, but the more common hypnopompic hallucinations occur upon awakening. [pulmonologyadvisor.com]

• Compulsive Behavior

  Narcolepsy with cataplexy associated with nocturnal compulsive behaviors: a case-control study. Sleep 2011;34:1365-71. 42. [jtsm.org]

  Other features of PWS include gross motor delay, social delay, obsessive-compulsive behavior and rigid thinking. Her family history is notable for a number of members (including our patient’s father) who suffer from EDS. [jmedicalcasereports.biomedcentral.com]

  There have also been reports of increased tendency toward compulsive behaviors, such as gambling, in patients taking these medications. In patients with iron deficiency, iron supplementation may improve or resolve symptoms of restless legs syndrome. [aafp.org]

• Aggressive Behavior

  EMEA0.3 EMEA0.3 It would explain the aggressive behavior, the cataplexy, the memory loss, even the twitching. [pl.glosbe.com]

  These occur more rarely, but may include: Dependency or abuse Psychosis Mania Aggressive behavior Tourette’s syndrome (rare) Irregular heart rhythms Heart attack Stroke Sudden death Seizures Growth suppression with long-term use Allergic reaction Exfoliative [verywell.com]

• Oligomenorrhea

  Her PCOS was diagnosed based on the presence of oligomenorrhea approximately one menstruation a year since her menarche at age 18, infertility indicating oligo or an-ovulation, obesity, hirsutism, elevated testosterone (134.2 ng/dl) and increased insulin [clinmedjournals.org]

• Sleep Attack

  […] of www.dovepress.com ) Symptomatic Sleep Attacks Sleep attacks may be defined as an inevitably strong urge to go to sleep regardless of the circumstance or time or location one may be in, and the sleep attack often strikes the patient in rather inappropriate [bedroom.solutions]

  Sometimes sleepiness occurs so suddenly and with such overwhelming power that it is referred to as a 'sleep attack'. [nodss.org.au]

  Sleep attacks Sleep attacks – falling asleep suddenly and without warning – are also common in people with narcolepsy. They may occur at any time. The length of time a sleep attack lasts will vary from person to person. [nhs.uk]

  Daytime sleep attacks repeated 6–7 times during the daytime and lasted approximately for 30–60 min. [ncbi.nlm.nih.gov]

  Amphetamine-like stimulant drugs are often prescribed to control drowsiness and sleep attacks. [medical-dictionary.thefreedictionary.com]

• Headache

  Headache 21:110-112, 1981 Kuritsky A, Ziegler D, Hassanein R. Vertigo, motion sickness and migraine. Headache 21, 227-231, 1981 Lipton RB and others. Migraine in the United States. Epidemiology and patterns of health care use. [dizziness-and-balance.com]

  The editors and contributing authors are internationally recognized authorities who cover everything from sleep and ADHD, headaches, restless leg syndrome, parasomnias, hypersomnias, autism, brain tumors, epilepsy, traumatic brain injury, and other primary [books.google.de]

  Adverse effects included nausea, dizziness, headaches, anxiety and depression. An association was found between development of the disease and the presence of allele DQB1*0602. [ejhp.bmj.com]

  BOEHRINGER INGELHEIM UZGLABĀŠANA en Although the clinical trial experience with sodium oxybate in narcolepsy/cataplexy patients at therapeutic doses does not show clear evidence of a withdrawal syndrome, in rare cases, adverse events such as insomnia, headache [lv.glosbe.com]

• Automatic Behavior

  Definition: A condition characterized by recurrent episodes of daytime somnolence and lapses in consciousness (microsomnias) that may be associated with automatic behaviors and AMNESIA. [hon.ch]

  behavior Hallucinations that are hypnagogic in nature Impaired sleep at night ( Narcolepsy and Halllucinations – Image Courtesy of journal.frontiersin.org ) Cataplexy is typically characterised by a prompt loss of muscle tone in all of the patient’s [bedroom.solutions]

  Automatic behavior – a person continues to function or talk while being half asleep, and awakens with no memory of doing these activities. Difficulties maintaining sleep – Nighttime sleep is disturbed. [stanfordhealthcare.org]

  Automatic behavior: You fall asleep during a regular activity like driving, walking, or talking. You continue the activity while asleep and wake up with no memory of what you did. [webmd.com]

• Irritability

  […] to novieto atpakaļ tajā pašā vietā, lai tās apakša būtu tajā pašā temperatūrā kā iepriekš, ko samazina picai cepoties absorbētais karstums en Common: agitation, depression, emotional lability/mood swings, hostility/aggression, insomnia, nervousness/irritability [lv.glosbe.com]

  Employer thinks it's an excuse, friends are irritated, I'm at my wits end. Life is spent sleeping more than awake. A. Narcolepsy cannot yet be cured. [medical-dictionary.thefreedictionary.com]

  Poor performance in school and difficulty making friends as a result of irritability or embarrassment over sleep attacks can have a lasting impact on a child's chances of preparation for college or the choice of a challenging and satisfying line of work [healthofchildren.com]

  Without modafinil use, our patient became tired and irritable by early afternoon. With modafinil therapy, our patient no longer required naps after school and was more social, alert, and less irritable. [jmedicalcasereports.biomedcentral.com]

  In the latter case, irritability, heart rhythm problems and disruptions to nighttime sleep can occur, and, as noted by NINDS, “the potential for abuse is high with any amphetamine.” 13 Antidepressants are another drug class sometimes given to people with [articles.mercola.com]

• Slurred Speech

  Typical symptoms include: Jaw dropping, the head slumping down, legs collapsing uncontrollably, slurred speech, finding it difficult to focus, or double vision. [youtube.com]

  A subjective sense of clumsiness, slurred speech, weakness, and muscle twitches are reported prior to the attack. [symptoma.com]

  Typical symptoms are: the jaw dropping the head slumping down legs collapsing uncontrollably slurred speech double vision or finding it difficult to focus Cataplexy attacks are usually triggered by an emotion, such as excitement, laughter, anger or surprise [nhs.uk]

  Cataplexy: This can cause problems ranging from slurred speech to total body collapse, depending on the muscles involved. It’s often triggered by intense emotions such as surprise, laughter, or anger. [webmd.com]

  This condition, called cataplexy (KAT-uh-plek-see), can cause a number of physical changes, from slurred speech to complete weakness of most muscles, and may last up to a few minutes. [mayoclinic.org]

The diagnostic workup comprises a meticulous patient history that includes the onset of symptoms and their features, as well as tests that evaluate sleeping patterns. Current guidelines recommend that every patient suffering from excessive daytime sleepiness accompanied by cataplexy should conduct the multiple sleep latency test (MSLT), a diagnostic procedure composed of five scheduled 20-minutes naps every two hours during the day in hospital conditions [14]. Presence or absence of REM sleep and the time necessary to fall asleep is recorded during this time and criteria for the diagnosis are: falling asleep within eight minutes across five naps and onset of REM during the first 15 minutes of sleep (termed sleep-onset REM, or SOREM) on two separate occasions [14]. Prior to initiation of MSLT, nocturnal polysomnography is performed to assess features such as sleeping time, movements, heart rate, and breathing, while actigraphy and sleeping logs may provide useful information as well [14]. If results from sleep studies, together with clinical signs and symptoms, point to the narcolepsy-cataplexy syndrome, CSF levels of hypocretin should be determined, as they are universally reduced in these patients [21] [22]. Finally, genetic studies confirming HLA-DQB1 mutations solidify the diagnosis, but it must be kept in mind that other comorbid conditions harboring HLA-DQB1 mutations should be excluded, most importantly MS, which is why physicians must perform a detailed physical examination and all necessary diagnostic procedures to rule out other conditions that have a similar clinical presentation [14]. Major depression, obstructive sleep apnea, bipolar and mood disorders, Parkinson's and Alzheimer's diseases and schizophrenia must be ruled out on the basis of their criteria [14].

Current therapeutic principles focus on the resolution of symptoms, which is performed by using various pharmacologic agents. Namely, drugs that act on the monoaminergic system and thus promote the activity of dopamine and noradrenaline are used for managing excessive daytime sleepiness and the two most commonly used drugs are amphetamines and methylphenidate [10] [14]. Depending on the formulation, daily doses range between 10-60 mg, but various side-effects have been documented, including hypertension, production or exacerbation of psychiatric conditions such as anxiety, mania and psychosis, weight loss and tics [14]. Addiction can be a significant issue, which is why careful assessment and monitoring of patients is necessary [14]. In addition to these agents, modafinil, approved in the United States for the treatment of excessive sleepiness related to narcolepsy, has shown to be an effective agent by promoting wakefulness, but its exact mechanism of action is unknown [15]. Dry mouth, nausea, anxiety, headaches, and insomnia are most common adverse effects, while serious drug-induced rashes - Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in rare cases [14]. Gamma-hydroxybutyric acid salt, known as sodium oxybate, may be used for cataplexy as well [10]. In lower doses, it inhibits the GABAergic system, whereas stimulation of dopamine release occurs at higher doses [14]. Because of the presumed role of serotonin, noradrenaline and dopamine in the pathogenesis of narcolepsy-cataplexy syndrome, various antidepressants including selective serotonin reuptake inhibitors (SSRIs) and tricyclics (TCAs), but also monoamine-oxidase (MAO) inhibitors have been used in therapy as well, with variable success [14].

Numerous complications may occur during daily life, as sudden onset of sleep can happen during driving, working with dangerous equipment at work, or during class in school, resulting in severe socio-occupational difficulties [18]. Significant adjustments are necessary to minimize the risk of adverse events, as some of them may even be life-threatening. Unfortunately, the diagnosis of the narcolepsy-cataplexy syndrome is often delayed for a significant period of time [19], which can significantly affect the quality of the patient's life.

Several theories regarding the etiology of the narcolepsy-cataplexy syndrome exist, but most recent studies suggest a multifactorial model [3] [6]. The loss of a small subset of neurons that synthesize hypocretin in the postero-lateral aspect of the hypothalamus is confirmed as the principal event in narcolepsy-cataplexy syndrome [3]. Namely, hypocretin is shown to be one of the most important mediators of sleep, wakefulness, energy homeostasis and feeding behavior [15]. The mechanisms that lead to this phenomenon, however, remains to be elucidated. A strong association between HLA-DQB1*0602 mutations and this condition has been discovered throughout the past few decades [5], which supports the autoimmune origin of neuronal loss in the hypothalamus. Additional research has confirmed T-cell receptor α (the major receptor for HLA-peptide presentation) polymorphisms [7], reduced expression of purinergic receptor subtype 2Y11 (P2RY11) gene involved in modulating the activity of CD8+ T-lymphocytes and natural killer (NK) cells, but also the presence of anti-streptolysin O (ASO) antibodies, which implies that the streptococcal antigen may be the trigger of narcolepsy [9]. Furthermore, anti-tribbles homolog 2 (TRIB2) autoantibodies are detected in patients who develop cataplexy shortly after narcolepsy, suggesting that they play an important role in the pathogenesis of this syndrome as well [6] [16].

Prevalence rates of the narcolepsy-cataplexy syndrome are estimated between 0.02%-0.05% in the general population [10]. In Europe, a prevalence rate of 47 per 100,000 individuals has been established (corresponding to a 0.00047%) [11]. A significant ethnic predisposition has been proposed in studies that further determined a prevalence rate of 0.59% and 0.00023% in the Japanese and Israeli Jews, respectively [12]. Reports from Hong Kong indicate that 0.034% of the local population suffers from this disorder [14]. Family history has shown to be the most important risk factor for narcolepsy-cataplexy, as prevalence rates are 10-40 times higher in families with members suffering from this condition compared to the general population [17]. At this moment, gender predilection is not established [18].

Loss of neuronal circuits that secrete hypocretins 1 and 2 (or orexins A and B) is the hallmark of the narcolepsy-cataplexy syndrome [3]. Hypocretins are peptides secreted from the postero-lateral aspect of the hypothalamus and act through monoamine G-coupled receptors in various brain regions, including the locus coeruleus, the raphe and tuberomammillary nuclei and the tegmental areas responsive to various neurotransmitters [3]. It is hypothesized that the loss of hypocretins has a profound effect on the dopaminergic, histaminergic, serotonergic and noradrenergic systems [3], which leads to the appearance of various signs and symptoms associated with sleep and muscle tone. The most probable cause of neuronal loss is an autoimmune reaction, having in mind the fact that virtually all patients have HLA-DQB1*0602 mutations, while the roles of ASO and anti-TRIB2 antibodies, as well as increased expression of P2RY11, remain to be confirmed [6] [9] [16].

Current preventive strategies are unknown.

Initially described almost 150 years ago [1] [2], the narcolepsy-cataplexy syndrome is a clinical entity in which sudden and brief attacks of sleep and loss of muscle tone occurs, while excessive daytime sleepiness and hallucinations appear in the clinical presentation as well [3]. The cause seems to be multifactorial, involving genetic, environmental, but also autoimmune factors [3] [4]. Current theories propose that autoimmune-mediated loss of a small group of hypothalamic neurons that produce hypocretin, a neuropeptide involved in regulation of sleep and wakefulness, is the principal cause of this syndrome, while mutations of HLA-DQB1*0602 (seen in 95% of cases), aberrations in t-cell receptors and presence of antistreptolysin O antibodies further solidify this hypothesis [5 [6] [7] [8] [9]. The overall prevalence is estimated at 0.02-0.05%, with significant differences across world [10], varying from 0.00047% in Europe to 0.54% in Japan [11] [12]. Because hypocretin is involved in numerous physiological processes regarding sleep, wakefulness and other neurological functions, its absence cause significant changes in the dopaminergic, noradrenergic and histaminergic neurotransmitter systems [3]. The appearance of narcolepsy - excessive daytime sleepiness (accompanied by fragmented nocturnal sleep and the presence of limb movements during sleep), and cataplexy - sudden but brief loss of muscle tone after severe emotional stimuli such as laughter, are consequences of hypocretin deficiency [3] [10]. Symptoms most frequently appear before age 20, but the onset may occur during the third, fourth and fifth decade of life as well [13]. Both visual and auditory hallucinations may appear, together with slurred speech and a sense of clumsiness that can precede the attack [14]. The diagnosis is made through evaluation of sleep by polysomnography and multiple sleep latency test (MSLT), while cerebrospinal fluid levels of hypocretin and genetic testing for HLA mutations further solidify the diagnosis [14]. It must be noted that other comorbid conditions, mainly of psychiatric nature, may be present concomitantly, whereas HLA mutations may be seen in multiple sclerosis (MS) [14], which suggests that the workup of patients must be thorough. The goal of therapy is to reduce the burden of symptoms in daily life and amphetamine, methylphenidate, modafinil and sodium-oxybate are used to promote wakefulness through various mechanisms [14]. Because significant adverse events may occur in daily life (falling asleep when driving or handling equipment during work), timely recognition and treatment are necessary.

The narcolepsy-cataplexy syndrome is a condition characterized by excessive daytime sleepiness, fragmented night sleep and attacks of sleep (narcolepsy) accompanied by sudden loss of muscle tone lasting between 5 and 30 seconds, medically termed cataplexy. The cause seems to stem from the deficiency of hypocretin, one of the most important mediators of wakefulness and sleep that are released from the brain. Most recent discoveries suggest that an autoimmune reaction to the nerves that release hypocretin occurs and causes the syndrome, but the exact mechanism remains unknown. However, almost 95% of patients possess genetic mutations of molecules involved in regulation of the immune system (known as a human leukocytic antigen, or HLA), suggesting that the disease may have a multifactorial origin. The disorder affects approximately 0.02-0.05% of the general population, but significant ethnic predilections have been established. Namely, a much higher rate of the disease is seen in Japan compared to Europe and people of Jewish ancestry and the explanation is yet to be discovered. Because hypocretin plays such an important role in regulating sleep, its deficiency leads to symptoms such as excessive daytime sleepiness, disturbed night sleep, fatigue and the eventual appearance of sleep attacks simultaneously with sudden loss of either isolated muscle groups or the whole body. These attacks are brief and may be triggered by an excessive emotional stimulus (anger, humor, surprise), while both visual and auditory hallucinations can appear either before or after the attack. To make the diagnosis, procedures that evaluate sleep are performed. Nocturnal polysomnography, which serves to assess breathing, heart rate, movement, and brain activity of the patient during sleep and multiple sleep latency test are used. Once a presumptive diagnosis is made based on the obtained results, levels of hypocretin in cerebrospinal fluid and presence of specific HLA mutations should be determined, so that appropriate treatment may be initiated. The role of therapy is to alleviate symptoms of excessive sleepiness and drugs that are recommended for narcolepsy-cataplexy syndrome are amphetamines, methylphenidate, modafinil, and sodium-oxybate, but because drugs possess various side effects (hypertension, rash, addiction, dry mouth, nausea, but also induction of psychiatric symptoms such as mania and anxiety), careful evaluation and long-term monitoring of patients is vital. This syndrome may significantly impair the quality of life of patients, primarily because these attack can occur when performing tasks that require a high level of focus (driving, working with delicate equipment, or during classes), which forces them to make major adjustments in their occupation, but also education. For this reason, early recognition of the disease is essential.

1. Westphal C. Eigentümliche mit Einschlafen verbundene Anfälle. Archiv für Psychiatrie und Nervenkrankheiten. 1877;7:631–5.
2. Gélineau J. De la narcolepsie. Gazette des Hôpitaux. 1880;53:626–8.
3. Plazzi G, Pizza F, Palaia V, et al. Complex movement disorders at disease onset in childhood narcolepsy with cataplexy. Brain. 2011;134(12):3477-3489.
4. Palaia V, Poli F, Pizza F, et al. Narcolepsy with cataplexy associated with nocturnal compulsive behaviors: a case-control study. Sleep. 2011;34(10):1365-1371.
5. Mignot E, Lin L, Rogers W, et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet. 2001;68:686–699.
6. Kawashima M, Lin L, Tanaka S, et al. Anti-Tribbles homolog 2 (TRIB2) autoantibodies in narcolepsy are associated with recent onset of cataplexy. Sleep. 2010;33:869–874.
7. Hallmayer J, Faraco J, Lin L, et al. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nat Genet. 2009;41:708–711.
8. Kornum BR, Kawashima M, Faraco J, et al. Common variants in P2RY11 are associated with narcolepsy. Nat Genet. 2011;43:66–71.
9. Aran A, Lin L, Nevsimalova S, Plazzi G, Hong SC, Weiner K. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep. 2009;32:979–983.
10. Billiard M. Narcolepsy: current treatment options and future approaches. Neuropsychiatr Dis Treat. 2008;4(3):557-566.
11. Cvetkovic-Lopes V, Bayer L, Dorsaz S, et al. Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients. J Clin Invest. 2010;120:713–719.
12. Wing YK, Li RH, Lam CW, et al. The prevalence of narcolepsy among Chinese in Hong-Kong. Ann Neurol. 2002;51:578–584.
13. Ohayon MM, Ferini-Strambi L, Plazzi G, Smirne S, Castronovo V. How age influences the expression of narcolepsy. J Psychosom Res. 2005;59:399–405.
14. Peacock J, Benca RM. Narcolepsy: clinical features, co-morbidities & treatment. Indian J Med Res. 2010;131:338-349.
15. Schwartz JR, Nelson MT, Schwartz ER, et al. Effects of modafinil on wakefulness and executive function in patients with narcolepsy experiencing late-day sleepiness. Clin Neuropharmacol. 2004;27:74–79.
16. Ohayon MM, Priest RG, Zulley J, et al. Prevalence of narcolepsy symptomatology and diagnosis in the European general population. Neurology. 2002;58:1826–1833.
17. Ohayon MM, Ferini-Strambi L, Plazzi G, Smirne S, Castronovo V. Frequency of narcolepsy symptoms and other sleep disorders in narcoleptic patients and their first-degree relatives. J Sleep Res. 2005;14:437–445.
18. American Academy of Sleep Medicine. International classification of sleep disorders: Diagnostic and coding manual, 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.
19. Morrish E, King MA, Smith IE, Shneerson JM. Factors associated with a delay in the diagnosis of narcolepsy. Sleep Med. 2004;5:37–41.
20. Dauvilliers Y, Montplaisir J, Molinari N, et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology. 2001;57:2029–2033.
21. Black J, Houghton WC. Sodium oxybate improves excessive daytime sleepiness in narcolepsy. Sleep. 2006;2:939–46.
22. Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002;59(10):1553-1562.