Narcolepsy

1R02 crystallography[1]

Narcolepsy is a chronic neurological disorder characterized by the classic tetrad of excessive daytime sleepiness, cataplexy, sleep paralysis and hypnagogic hallucinations. The first descriptions of narcolepsy-cataplexy were reported in Germany by Westphal and Fisher in 1877/1878.

The disorder is related to the following process: endocrine.

Presentation

The classic tetrad of narcolepsy consists of excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, and sleep paralysis. In very few cases it is seen that a child presents with all 4 symptoms [13].

EDS is the primary symptom of narcolepsy and must be present for at least 3 months to justify the diagnosis. In persons with narcolepsy, severe EDS leads to involuntary somnolence during activities that normally need attention, like driving, eating, or talking. Narcoleptic patient can suffer from severe and constant sleepiness, with bouts of falling asleep without any warning (i.e. sleep attacks).

Patients with narcolepsy tend to take short and refreshing naps (i.e. rapid eye movement (REM)-type naps) during the day. Sometimes dreams also accompany the daytime naps.

A significant number of narcolepsy patients have trouble sleeping at night [14]. In addition, patients may have nocturnal compulsive habits like, eating disorder in relation with sleep and smoking at night [15]. Obesity is commonly seen with narcolepsy.

Cataplexy is a brief and sudden loss of muscle tone and represents REM sleep intrusion during wakefulness. The most characteristic feature of cataplexy is that it usually is triggered by emotions (especially laughter and anger). Cataplexy is seen in about 70% of patients with narcolepsy. The presence of cataplexy along with EDS is strongly suggestive of narcolepsy.

Patients with narcolepsy may experience sleep paralysis, in which the patient is not able to move when he/she wakes up and sometimes when asleep with consciousness intact. Often hallucinations accompany it. Sleep paralysis occurs less frequently when patients sleep in uncomfortable positions. The person can be rescued from this condition by sensory stimuli, like touch or talking with that person.

Sleep-related hallucinations may be either hypnagogic (i.e. occurring at sleep onset) or hypnopompic (i.e. occurring at awakening). These hallucinations are usually vivid (dreamy) either tactile, visual or auditory in character.

At disease onset, children with narcolepsy and cataplexy may display a wide range of motor disturbances that do not corroborate with cataplexy as it is classically. The motor disturbances, can be negative (hypotonia) or active (e.g. perioral movements, dyskinetic-dystonic movements, or stereotypic movements), and are seen to settle later during the course of disease [16].

In children aged 5-10 years, inattentiveness is the most common initial complaint, followed by recurring sleepiness and later on by difficulty in morning arousal associated with aggressive behavior and abrupt falls in school [17]. These children often were misdiagnosed as having attention deficit hyperactivity disorder (ADHD), learning disability, depression, or another neurological disorder. In children aged 10-12 years, poor academic performance is a common complaint [17].

Physically, narcoleptic patients are normal.

Entire body system
  • Epilepsy Just like people with epilepsy, I can't control having a sleep attack or cataplexy any more than they can control having a seizure. [source] The disorder is sometimes confused with insomnia due to its characteristic disturbed night-time sleep and with epilepsy because of unexplained sudden falls caused by cataplexy. [source] Although, sever symptoms do have the potential to impact lifestyle quality similar to that of Parkinson’s or Epilepsy[source]
  • Excessive Daytime Sleepiness Narcolepsy, Hypersomnia and Excessive Daytime Sleepiness Narcolepsy and hypersomnias refer to a group of disorders for which excessive daytime sleepiness (ESD) is the core symptom, but when it is not due to insufficient sleep (sleep deprivation), disturbed [source] Narcolepsy is a chronic, neurological sleep disorder characterized by excessive daytime sleepiness (EDS), cataplexy and abnormal REM sleep. [source] In narcolepsy, other symptoms beside excessive daytime sleepiness are present as well and there is a tendency to falling asleep directly or extremely rapidly into Rapid Eye Movement (REM) Sleep (dreaming sleep). [source]
  • Falling Untreated narcolepsy increases the risk of motor vehicle collisions and falls[source] Sleep paralysis and vivid dreams can occur while falling asleep or waking up. [source] Again, people with narcolepsy fall asleep rapidly and enter REM sleep early. [source]
  • Fatigue Many medical conditions result in fatigue, thus physicians might not consider narcolepsy. [source] Symptoms Excessive Daytime Sleepiness (EDS), an overwhelming sense of tiredness and fatigue throughout the day Poor quality of sleep because the sleep wake patterns are disrupted Micro-naps (falling asleep for a few seconds) and sleep attacks (an overwhelming [source] 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. [source]
  • Hypersomnia The 2001 International Classification of Sleep Disorders (ICSD) divides primary hypersomnia syndromes between narcolepsy, idiopathic hypersomnia, and the recurrent hypersomnias (like Klein-Levin syndrome); it further divides narcolepsy into that with [source] Since the 2001 ICSD, the classification of primary hypersomnias has been steadily evolving, as further research has shown more overlap between narcolepsy and idiopathic hypersomnia[source] The other primary hypersomnias will remain subdivided based on the presence of SOREMPs. [source]
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neurologic
  • Automatic Behavior Automatic behavior Automatic behavior is the performance of routine tasks by a person who is not consciously controlling the activity. [source] Automatic behavior can be very dangerous if a person is involved in a potentially dangerous activity such as driving or cooking. [source] Other symptoms may include automatic behaviors and night-time wakefulness. [source]
  • Drop Attack Cataplexy - may mimic drop attacks, syncope , seizures/epilepsy , transient ischaemic attack , periodic paralysis (channelopathies), psychiatric disorder, or cataplectic-like episodes (the latter can occur in healthy people). [source]
  • Hyperactivity In the 1960s, fenethylline was widely recommended to people suffering from ailments like hyperactivity and narcolepsy . [source] Sleepiness doesn’t always LOOK sleepy Narcolepsy’s sleepiness may manifest as hyperactivity, irritability, moodiness, attention deficits, fogginess, or memory problems. [source] These children often were misdiagnosed as having attention deficit hyperactivity disorder (ADHD), learning disability, depression, or another neurological disorder.  [source]
  • Sleep Attack These sleep attacks can last from a few seconds to more than an hour. [source] Persistent sleepiness and sleep attacks are the hallmarks of this condition. [source] Amphetamine-like stimulant drugs are often prescribed to control drowsiness and sleep attacks[source]
  • Somnolence Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy: US Modafinil in Narcolepsy Multicenter Study Group. [source] It reclassifies narcolepsy without cataplexy as major somnolence disorder (MSD). [source] While cognitive impairment does occur, it may only be a reflection of the excessive daytime somnolence[source]
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respiratoric
  • Sleep Apnea apnea) disorders or medical issues. [source] refer to a group of disorders for which excessive daytime sleepiness (ESD) is the core symptom, but when it is not due to insufficient sleep (sleep deprivation), disturbed nocturnal sleep, insomnia , circadian rhythm disorders , sleep-related breathing (sleep [source] These include sleep apnea , circadian rhythm sleep disorders and restless legs syndrome . [source]
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musculoskeletal
psychiatrical
  • Aggressive Behavior In children aged 5-10 years, inattentiveness is the most common initial complaint, followed by recurring sleepiness and later on by difficulty in morning arousal associated with aggressive behavior and abrupt falls in school. [source]
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Eyes
  • Diplopia Occasionally there will be introductions of blurred vision or diplopia due to their sleepiness. [source] 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 [source] Slurred speech and visual symptoms such as blurred vision or diplopia may be experienced. [source]
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Workup

Sleep studies are an essential part of the evaluation of patients with probable chances narcolepsy. An overnight polysomnogram (PSG) followed by a multiple sleep latency test (MSLT) can provide strongly suggestive evidence of narcolepsy while excluding other sleep disorders.

Human leukocyte antigen (HLA) typing may provide collateral data, but it is more useful for excluding the diagnosis by documenting that the patient does not have either DQB1*0602 or DQA1*0602.

Measurement of hypocretin (orexin) levels in the cerebrospinal fluid (CSF) may help establish the diagnosis [9]. CSF hypocretin levels lower than 110 pg/mL are included in the diagnostic criteria for narcolepsy in the second edition of the International Classification of Sleep Disorders (ICSD-2).

Imaging studies such as MRI are useful for excluding rare causes of symptomatic narcolepsy. Idiopathic narcolepsy may be seen in cases where there are structural abnormalities of the brainstem and diencephalon. MRI of brain in patients suffering from secondary narcolepsy, may show different abnormalities that can be related to the underlying cause.

Test Results

EEG
  • Multiple Sleep Latency Test Testing in a sleep laboratory, with polysomnography and multiple sleep latency testing, is needed to confirm the diagnosis. [source] Sleep testing in a sleep laboratory consists of polysomnography , done overnight, and multiple sleep latency testing , done the next day. [source] Diagnosis of Narcolepsy Polysomnography Multiple sleep latency testing Doctors suspect narcolepsy when people with excessive daytime sleepiness have had episodes of muscle weakness. [source]
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Other Test Results

Laboratory

HLA Type
  • HLA-DQ1 DQ1[source] been published in the Lancet providing strong evidence suggesting that some cases of narcolepsy might be caused by autoimmune disease. [1] Narcolepsy is strongly associated with HLA DQB1*0602 genotype . [2] There is also an association with HLA DR2 and HLA [source]
  • HLA-DR2 driving or while at work and prefer shift work as 'drowsiness' is more socially acceptable; it may also be accompanied by sleep paralysis Prevalence 1:600–Japan, 1:2400–US, 1:500, 000–Israel, : ratio 1:1, onset age 15– 35; 98-100% of narcoleptics have HLA-DR2 [source] DR2 and HLA DQ1. [source] research has been published in the Lancet providing strong evidence suggesting that some cases of narcolepsy might be caused by autoimmune disease. [1] Narcolepsy is strongly associated with HLA DQB1*0602 genotype . [2] There is also an association with HLA [source]
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Treatment

Treatment of narcolepsy has two components i.e medical and auxiliary management. Good sleep hygiene is a must. Improvement is seen when the patients have a regular sleep schedule, which is generally 7.5-8 hours of sleep every night. Scheduled naps during the day also may help [18].

Pharmacologic treatment of narcolepsy involves the use of central nervous system (CNS) stimulants such as amphetamine, methylphenidate, modafinil, methamphetamine, and dextroamphetamine sulfate. With the help of these medicines daytime sleepiness can be reduced, thereby improving the symptoms in 65-85% of patients.

Tricyclic antidepressants such as protriptyline, imipramine and clomipramine, are effective for cataplexy. Sodium oxybate is highly effective for cataplexy, as it helps in improving night time sleep, which is often poor in narcolepsy. Selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs) suppress REM sleep, thus helping to alleviate the symptoms of cataplexy, hypnotic hallucinations and sleep paralysis. They include fluoxetine and venlafaxine.

Prognosis

If the disease is managed and treated properly, then patients suffering from narcolepsy can have good life at home and work too. But if not treated, then it can be psychosocially disastrous [12].

Narcoleptic children may suffer from bad performance in school, social impairment, mocked by the colleagues, and there would be flaws in various activities seen in normal childhood development.

Complications

  • Auditory Hallucination hallucinations at the onset of sleep. [source] sometimes accompanied by paralysis and hallucinations. nar′co·lep′tic (-lĕp′tĭk) adj. narcolepsy [när′kəlep′sē] Etymology: Gk, narke, stupor, lambanein, to seize a syndrome characterized by sudden sleep attacks, cataplexy, sleep paralysis, and visual or auditory [source] Auditory hallucinations may include random sounds or elaborate melodies. [source]
  • Cataplexy Cataplexy is seen in about 70% of patients with narcolepsy. [source] Narcolepsy with cataplexy affects 0.02% of adults worldwide. [source] The first descriptions of narcolepsy-cataplexy were reported in Germany by Westphal and Fisher in 1877/1878. [source]
  • Depression Although it has been linked with blood pressure management and depression, the genesis of narcolepsy is unknown. [source] These episodes can be frightening, and you may become depressed because of the sudden lack of control. [source] Narcolepsy treatment: counseling and support groups It’s very common for those with narcolepsy to suffer from depression[source]
  • Dyskinesia 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 cause tardive dyskinesia [source]
  • Hallucinations Often hallucinations accompany it. [source] The classic tetrad of narcolepsy consists of excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, and sleep paralysis. [source] Sleep-related hallucinations may be either hypnagogic (i.e. occurring at sleep onset) or hypnopompic (i.e. occurring at awakening). [source]
  • Hypnagogic Hallucination Hypnagogic hallucinations Hypnagogic hallucinations are vivid dreamlike experiences that are difficult to distinguish from reality. [source] The four most common symptoms are: excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations[source] Cataplexy, sleep paralysis, and hypnagogic hallucinations are similar to the loss of muscle tone that accompanies normal dreaming in a stage of sleep called REM. [source]
  • Narcolepsy The exact cause of narcolepsy isn't known. [source] Narcolepsy affects about 1 in 2,000 people. [source] The male-to-female ratio in narcolepsy is 1.64:1. [source]
  • Obesity Since 2009, clinicians have observed greater rates of abrupt onset in young children who are obese and likely to experience premature puberty. [source] Accompanying Physical Problems Obesity[source] Evidence suggests that people with narcolepsy are at high risk for obesity compared to the general population. [source]
  • Obstructive Sleep Apnea Emerging drugs for common conditions of sleepiness: obstructive sleep apnea and narcolepsy. [source] Narcolepsy also can be associated with other sleep disorders, such as obstructive sleep apnea , restless legs syndrome , and insomnia . [source] sleep apnea syndrome. [25] The CSF histamine level may serve as a biomarker reflecting the degree of hypersomnia of central origin. [ 24 , 25] CNS nuclei for wakefulness and the relevant neurotransmitters generated in those nuclei include the following [source]
  • Schizophrenia Misdiagnoses include epilepsy, depression, and schizophrenia. 4. [source] For more insider perspectives, check out 5 Ridiculous Myths You Probably Believe About Schizophrenia and 4 Things You Learn Having A Disease Doctors Can't Diagnose . [source] The hallucinations can sometimes be so strong that this symptom can be mistaken for schizophrenia[source]
  • Sleep Apnea Syndrome apnea syndrome. [25] The CSF histamine level may serve as a biomarker reflecting the degree of hypersomnia of central origin. [ 24 , 25] CNS nuclei for wakefulness and the relevant neurotransmitters generated in those nuclei include the following: Locus [source] they are also seen in narcolepsy patients with normal CSF hypocretin levels and in patients with idiopathic hypersomnia. [24, 25 ] It is noteworthy that low CSF histamine levels have not been found in patients with hypersomnia secondary to obstructive sleep [source] Sleep paralysis and similar hallucinations occasionally occur in otherwise healthy adults, in people who have been sleep deprived, and in people with sleep apnea syndrome or depression. [source]
  • Sleep Paralysis Sleep paralysis occurs less frequently when patients sleep in uncomfortable positions. [source] The classic tetrad of narcolepsy consists of excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, and sleep paralysis[source] It is characterized by the classic tetrad of excessive sleepiness during the daytime, cataplexy, hypnotic hallucinations, and sleep paralysis[source]
  • Tactile Hallucination Hypnagogic hallucinations: dreamlike visual, auditory or tactile hallucinations in which elements of the waking world are incorporated just before falling asleep. [source] Sometimes accompanied by visual, auditory or tactile hallucinations as REAL as reality. [source] Thomas Kilkenny, he laughed and assured her she wasn’t going crazy, but that, given her past sleeping problems and recent visual, auditory, and tactile hallucinations, she most likely had narcolepsy. [source]
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Etiology

The exact cause of narcolepsy isn't known. Narcolepsy has a genetic component and tends to run in families. An estimated 8 to 10% of people with narcolepsy have a close relative who has the disorder. Narcolepsy most likely involves a combination of genetics and one or more environmental provoking factors like infection, trauma, hormonal changes, immune system disorders, or stress.

Causes

Epidemiology

Narcolepsy affects about 1 in 2,000 people. The prevalence of narcolepsy in the US is 0.02-0.18%, which is comparable to that of multiple sclerosis [2] [3]. The frequency among first-degree relatives is 1-2%. Narcolepsy with cataplexy affects 0.02% of adults worldwide [4].

The male-to-female ratio in narcolepsy is 1.64:1. The disease has highest peak of occurrence at 15 years and a less marked peak at 36 years.

Sex distribution
Age distribution

Pathophysiology

Narcolepsy is considered to be an outcome of susceptible genes, defective neurotransmitter functioning and sensitivity, and aberrant immune modulation. Recent studies blame some human leukocyte antigen (HLA) subtypes and abnormal hypocretin (orexin) neurotransmission, that causes unexpected changes in monoamine and acetylcholine synaptic transmissions, and more accurately in the reticular activating system of the pons [5] [6].

The centrality of hypocretin transmission in the pathophysiology of narcolepsy was demonstrated when hypocretin knockout mice displayed cataplexy and sleepiness [7] [8]. Further evidence for impaired hypocretin functioning in humans was found with the discovery of low levels of hypocretin in the cerebrospinal fluid (CSF) of narcoleptic patients [9].

Subsequently, abnormal immune modulation was associated with the clinical development of narcolepsy in children in Scandinavia and Finland. It was found that the chances of narcolepsy increased to 8-12 folds in Finnish children after vaccination against the H1N1 influenza virus with a vaccine that used a potent ASO3 adjuvant. Every affected child who went through HLA typing was seen having the HLA DQB*0602 allele [10] [11].

Prevention

Narcolepsy cannot be prevented but the frequency of the narcolepsy episodes can be reduced in those suffering from it by avoiding the triggering factors or the conditions that causes the attack.

Summary

Narcolepsy is a chronic sleep disorder characterized by overwhelming daytime drowsiness and sudden bouts of sleep. It is difficult for a person suffering from narcolepsy to stay awake for long periods of time, whatever be the circumstances. It is characterized by the classic tetrad of excessive sleepiness during the daytime, cataplexy, hypnotic hallucinations, and sleep paralysis. It is also known as hypnolepsy, defined as a chronic neurological disorder caused by autoimmune destruction of hypocretin-producing neurons inhibiting the brain's ability to regulate sleep-wake cycles normally.[1]

Patient Information

Narcolepsy is a medical disorder characterized by excessive, sudden bouts of uncontrollable sleep during the day. These patients cannot sleep well at night and a polysomnogram is used to diagnose the condition.

The condition cannot be prevented as the exact cause is not understood but the symptoms can be controlled very well lifelong with medications like antidepressants, and stimulants. It is not a fatal condition but it can lead to accidents that are life-threatening.

Patients with narcolepsy should avoid heavy meals and alcohol. Patients should take scheduled short naps and participate in an exercise programs. They must avoid driving, operating heavy machinery, or any other activity that can have detrimental effect when sleepy. In one survey, almost 75% of patients with narcolepsy reported falling asleep while driving, and 56% reported nearly having accidents. In addition to these accidents, there are various other accidents that associated with narcolepsy like burns due to coming in close contact with hot objects, cuts from handling sharp objects, and breaking things. Patients with narcolepsy with cataplexy should wear a life preserver when engaged in water activities. They should not do water activities all by themselves. They should inform and also educate others about their cataplectic attacks.

People with narcolepsy have problems with memory, thinking, and attention. They suffer from emotional and social difficulties caused by their uncontrollable sleep episodes and cataplexy. They are prone to suffer from depression, severe emotional and social dysfunction in all areas, be it work, relationships or any relaxing activity. Generally it is seen that men with narcolepsy suffer from sexual problems.

Self-assessment

References

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  3. Silber MH, Krahn LE, Olson EJ, Pankratz VS. The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. Sleep. 2002 Mar 15;25(2):197-202
  4. Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet. 2007 Feb 10;369(9560):499-511.
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  7. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 1999 Aug 20;98(4):437-51.
  8. Diniz Behn CG, Klerman EB, Mochizuki T, Lin SC, Scammell TE. Abnormal sleep/wake dynamics in orexin knockout mice. Sleep. 2010 Mar;33(3):297-306.
  9. Mignot E, Lammers GJ, Ripley B, Okun M, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002 Oct;59(10):1553-62.
  10. Partinen M, Saarenpää-Heikkilä O, Ilveskoski I, Hublin C, et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS One. 2012;7(3):e33723.
  11. Nohynek H, Jokinen J, Partinen M, Vaarala O, et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS One. 2012;7(3):e33536.
  12. Douglas NJ. The psychosocial aspects of narcolepsy. Neurology. 1998 Feb;50(2 Suppl 1):S27-30.
  13. Vendrame M, Havaligi N, Matadeen-Ali C, Adams R, Kothare SV. Narcolepsy in children: a single-center clinical experience. Pediatr Neurol. 2008 May;38(5):314-20.
  14. Plazzi G, Serra L, Ferri R. Nocturnal aspects of narcolepsy with cataplexy. Sleep Med Rev. 2008 Apr;12(2):109-28.
  15. Palaia V, Poli F, Pizza F, Antelmi E, et al. Narcolepsy with cataplexy associated with nocturnal compulsive behaviors: a case-control study. Sleep. 2011 Oct 1;34(10):1365-71.
  16. Plazzi G, Pizza F, Palaia V, Franceschini C, et al. Complex movement disorders at disease onset in childhood narcolepsy with cataplexy. Brain. 2011 Dec;134:3480-92.
  17. Guilleminault C, Pelayo R. Narcolepsy in prepubertal children. Ann Neurol. 1998 Jan;43(1):135-42.
  18. 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.

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Media References

  1. 1R02 crystallography, Public Domain

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