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]

• Disability

  If your RFC is determined to preclude all work, then you will be found disabled under the SSA’s regulations. Stress Less During the SSD Application Process As you can imagine, this is not an easy process. [labovick.com]

  Author information 1 Neurologie, CHU Montpellier Hôpital Gui-de-Chauliac and INSERM U888, Montpellier-France. [email protected] Abstract Narcolepsy with cataplexy is a disabling sleep disorder affecting 0.02% of adults worldwide. [ncbi.nlm.nih.gov]

  Prognosis Narcolepsy can severely disable scholarly and professional performances of the patients. [orpha.net]

• Cough

  Symptoms You may have a cough or be short of breath. You could also be wheezing heavily. These symptoms, while very uncomfortable, may seem like a cold or another breathing problem. [webmd.com]

  Are there clinical features of a sensitized cough reflex? Pulmon Pharmacol Ther2009;22:59-64.CrossRefMedlineWeb of Science ↵Williams CT. The pathology and treatment of spasmodic asthma. BMJ1874;1:769-72.FREE Full Text ↵Gillespie RD. [bionyt.s807.sureserver.com]

• Nausea

  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]

  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. [symptoma.com]

  Side effects include nausea, vomiting, dizziness, urinary incontinence (involuntary urination), and sleepiness. [merckmanuals.com]

  Adverse effects include headache, nausea, dizziness, nasopharyngitis, somnolence, vomiting, urinary incontinence, and sometimes sleepwalking. Sodium oxybate is a schedule III drug and has potential for abuse and dependence. [msdmanuals.com]

• Metallic Taste

  Medications for Insomnia Medication Onset of action (minutes) Half-life (hours) Dose (mg) Main indications Common adverse effects Cost* Benzodiazepine receptor agonists Eszopiclone (Lunesta) 10 5 to 7 1 to 3 Sleep maintenance insomnia Metallic taste in [aafp.org]

• 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]

• Hypotension

  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]

  Patients initially diagnosed with idiopathic RBD often later develop other neurological signs including parkinsonism (most frequently), orthostatic hypotension, anosmia, and cognitive impairment. [hindawi.com]

  Migraine associated hypotension and autonomic ganglionitis. Letter in Neurology, 1997, 49, 1186 Ishiyama A, Jacobson KM, Baloh RW. Migraine and benign positional vertigo. Ann Otol Rhinol Laryngol. 2000;109:377-380 Johnson GD. [dizziness-and-balance.com]

  Doral) 30 39 to 75 7.5 to 15 Sleep onset and maintenance insomnia Dyspepsia, xerostomia, dizziness, hangover, headache, fatigue NA ($32) Temazepam (Restoril) 30 to 60 8 to 15 7.5 to 30 Sleep onset and maintenance insomnia Somnolence, blurred vision, hypotension [aafp.org]

• Muscle Weakness

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

  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]

  People who have narcolepsy without cataplexy have sleepiness but no emotionally triggered muscle weakness, and generally have less severe symptoms. [healthysleep.med.harvard.edu]

  The muscle weakness, sleep paralysis, and hallucinations of narcolepsy resemble the loss of muscle tone, paralysis, and vivid dreaming that occur during REM sleep. [merckmanuals.com]

  NHS Choices defines cataplexy as a sudden, temporary muscle weakness or loss of muscular control. [youtube.com]

• Arthritis

  This rare clinical case carries five clustered, interlinked clinical disorders—three sleep disorders and two medical disorders (parkinsonism, rheumatoid arthritis)—with NC being considered to be an autoimmune disorder and rheumatoid arthritis being a [hindawi.com]

  […] of hypocretin, but scientists think this could be a result of the following: genetic mutations of a sleep gene, a family history, infections, brain injuries, contact with toxic substances (e.g., pesticides), and autoimmune diseases (e.g., rheumatoid arthritis [medbroadcast.com]

  […] susceptibility to Narcolepsy Variants of other HLA genes (HLA-DQA1, HLA-DQB1, HLA-DRB1) and some additional gene’ variants, all involved in immune function (TNF, TNFRSF1B, TRA, CHKB, CPT1B), have also been reported Autoimmune disorders, such as rheumatoid arthritis [dovemed.com]

  […] result of a wide range of medical conditions, including other sleep disorders such as sleep apnea, various viral or bacterial infections, mood disorders such as depression, and chronic illnesses such as anemia, congestive heart failure, and rheumatoid arthritis [msunites.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]

• 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]

• 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]

• 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]

• Hunger

  Disorders such as diabetes, Kleine-Levin Syndrome (a malfunction in the hypothalamus), the genetic disorders Prader-Willi Syndrome and Bardet Biedl Syndrome can cause hyperphagia (compulsive hunger). [diki.pl]

  Hypothalamus — A part of the forebrain that controls heartbeat, body temperature, thirst, hunger, body temperature and pressure, blood sugar levels, and other functions. [medical-dictionary.thefreedictionary.com]

  Hypothalamus —A part of the forebrain that controls heartbeat, body temperature, thirst, hunger, body temperature and pressure, blood sugar levels, and other functions. [healthofchildren.com]

• 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]

• Seizure

  We report a case of new-onset seizures and narcolepsy in a previously healthy 40-year-old man. He developed severe daytime somnolence and cataplexy over the course of a few months. [experts.umich.edu]

  Similar to one, you would replace dyscognitive seizures with narcolepsy. [labovick.com]

  Results All patients showed a major reduction in the number of seizures per week at an effective dose of 6–9 g, from a mean of 8.19 before treatment to a mean of 2.32 after treatment, although the significance was only borderline due to the small sample [ejhp.bmj.com]

  Cataplexy may be mistaken for seizures. [play.google.com]

• Excitement

  Laughter is the most typical trigger, but other triggers may include happiness, excitement, annoyance, surprise, fear, or a stressful event. [medicalnewstoday.com]

  Cataplexy attacks are usually triggered by an emotion, such as excitement, laughter, anger or surprise. Attacks can last from a few seconds to several minutes. [youtube.com]

  Cataplexy is a sudden and uncontrollable muscle weakness or paralysis that comes on during the day and is often triggered by a strong emotion, such as excitement or laughter. [sleepfoundation.org]

• Somnolence

  Because no cure for narcolepsy-cataplexy syndrome is currently available, the aim of treatment is to control symptoms by combining non-pharmacological treatment (sleep hygiene and short scheduled naps at times of greater somnolence) with pharmacological [ejhp.bmj.com]

  He developed severe daytime somnolence and cataplexy over the course of a few months. Brain MRI was normal, and polysomnography with multiple sleep latency testing confirmed a diagnosis of narcolepsy. [experts.umich.edu]

  Gélineau's definition was somewhat open ended, as he did not distinguish it from other forms of somnolence and some investigators spoke of ‘Narcolepsies'. [ispub.com]

  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]

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].

• Staphylococcus Aureus

  aureus and Gram-negative enteric bacilli perhaps because intravascular sickling of the bowel leads to patchy ischaemic infarction. [71] Acute papillary necrosis in the kidneys Leg ulcers [72] In eyes, background retinopathy, proliferative retinopathy [en.wikipedia.org]

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.

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