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Narcolepsy

Narcolepsy is a neurological sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep disorder marked by daytime sleepiness and associated with cataplexy, hypnagogic hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia, and sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep paralysis. There are 2 types of narcolepsy: type 1 Type 1 Spinal Muscular Atrophy is associated with cataplexy and type 2 Type 2 Spinal Muscular Atrophy has no association with cataplexy. A decreased level of orexin is noted in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with type 1 Type 1 Spinal Muscular Atrophy narcolepsy. Diagnostic criteria are made using sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep studies that show a decrease in REM latency. Management includes good sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep hygiene. Medications that act as CNS stimulants Stimulants Stimulants are used by the general public to increase alertness and energy, decrease fatigue, and promote mental focus. Stimulants have medical uses for individuals with ADHD and sleep disorders, and are also used in combination with analgesics in pain management. Stimulants and antidepressants are used to target the cataplexy. Narcolepsy is a life-long disorder with no definitive cure.

Last updated: Nov 10, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Narcolepsy is a neurological disorder affecting the normal sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep–wake cycle, resulting in daytime sleepiness. The disorder is associated with cataplexy (emotionally triggered loss of muscle tone Muscle tone The state of activity or tension of a muscle beyond that related to its physical properties, that is, its active resistance to stretch. In skeletal muscle, tonus is dependent upon efferent innervation. Skeletal Muscle Contraction), hypnagogic hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia ( hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia that occur while falling asleep), and sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep paralysis (brief immobility upon awakening).

Epidemiology

  • Narcolepsy type 1 Type 1 Spinal Muscular Atrophy:
    • Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: 25–50 in 100,000 people
    • Men = women
    • Begins in adolescence to early 20s (onset can range from 5–40 years of age)
  • Narcolepsy type 2 Type 2 Spinal Muscular Atrophy:
    • 20–35 in 100,000 people
    • Less well studied

Etiology

Narcolepsy type 1 Type 1 Spinal Muscular Atrophy:

  • Orexin (hypocretin) deficiency:
    • Orexin: neurotransmitter produced by lateral hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus
    • Produces excitatory effect of wakefulness by acting at the:
      • Locus Locus Specific regions that are mapped within a genome. Genetic loci are usually identified with a shorthand notation that indicates the chromosome number and the position of a specific band along the P or Q arm of the chromosome where they are found. For example the locus 6p21 is found within band 21 of the P-arm of chromosome 6. Many well known genetic loci are also known by common names that are associated with a genetic function or hereditary disease. Basic Terms of Genetics coeruleus
      • Raphe Raphe Testicles: Anatomy nuclei
      • Tuberomemmillary gland
    • In narcolepsy 1: loss of neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology in lateral hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus
  • Genetic factors:
    • Certain forms are familial.
    • 95% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship have DQB1*0602 haplotype (subtype of DQB1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics).
    • 96% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with this haplotype also have orexin deficiency. 
  • Environmental triggers:
    • Neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology that produce orexin may be destroyed due to autoimmune processes triggered after streptococcal pharyngitis Streptococcal Pharyngitis Rheumatic Fever or influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza.

Narcolepsy type 2 Type 2 Spinal Muscular Atrophy:

  • Orexin levels normal
  • Etiology unknown

Secondary narcolepsy:

  • Lesions affecting posterior hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus and midbrain Midbrain The middle of the three primitive cerebral vesicles of the embryonic brain. Without further subdivision, midbrain develops into a short, constricted portion connecting the pons and the diencephalon. Midbrain contains two major parts, the dorsal tectum mesencephali and the ventral tegmentum mesencephali, housing components of auditory, visual, and other sensorimotor systems. Brain Stem: Anatomy (e.g., tumors, strokes, vascular malformations, inflammatory processes such as sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis)
  • Associated with syndromes ( Prader-Willi syndrome Prader-Willi syndrome Prader-Willi syndrome (PWS) is a rare autosomal neurodevelopmental genetic disorders mapped to a specific region of chromosome 15 attributed to genomic imprinting. A paternally derived chromosome 15 with this deletion results in 15q11-13 paternal deletion syndrome, or PWS. Prader-Willi Syndrome and Angelman Syndrome)

Clinical Presentation

  • Daytime sleepiness:
    • Most common symptom
    • Sleeping at inappropriate times (not excessive)
    • Sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep attacks”: no warning sign and lasting < 30 minutes
    • Usually wake up well rested in the morning 
  • Cataplexy (60%–70%):
    • Emotionally triggered (e.g., laughing) transient muscle weakness
    • Begins in face and may progress to full drop attacks Drop Attacks Seizures in Children.
    • Patient is conscious. 
    • Usually lasts 2 minutes
    • 60% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present within 5 years of onset of disease.
  • Hypnagogic hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia (< 5%):
    • Frightening and vivid visual, tactile, or auditory hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia that occur as the individual is falling asleep
  • Sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep paralysis (< 5%):
    • Inability to move upon awakening
    • Lasts approximately 2 minutes
  • Comorbidities Comorbidities The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. St. Louis Encephalitis Virus:
    • Restless legs syndrome Restless legs syndrome Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome
    • Obstructive sleep apnea Sleep apnea Repeated cessation of breathing for > 10 seconds during sleep and results in sleep interruption, fatigue, and daytime sleepiness. Obstructive Sleep Apnea (mild obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity is common in narcolepsy patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship)
    • Depression
    • Anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder
    • ADHD ADHD Attention deficit hyperactivity disorder is a neurodevelopmental disorder characterized by a pattern of inattention and/or hyperactivity-impulsivity that occurs in at least 2 different settings for more than 6 months. Although the patient has normal intelligence, the disease causes functional decline. Attention Deficit Hyperactivity Disorder

Diagnosis

Investigations

  • Sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep studies:
    • Polysomnography Polysomnography Simultaneous and continuous monitoring of several parameters during sleep to study normal and abnormal sleep. The study includes monitoring of brain waves, to assess sleep stages, and other physiological variables such as breathing, eye movements, and blood oxygen levels which exhibit a disrupted pattern with sleep disturbances. Physiology of Sleep (PSG) reveals:
      • Spontaneous awakenings
      • Reduced sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep efficiency
      • Increased light non-REM sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep
      • REM sleep REM sleep A stage of sleep characterized by rapid movements of the eye and low voltage fast pattern eeg. It is usually associated with dreaming. Physiology of Sleep within 15 minutes (versus 80–100 minutes in healthy individuals)
    • Multiple sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep latency test (MSLT):
      • Performed the morning after PSG
      • Patient is placed in sleep-inducing environment and allowed to fall asleep spontaneously.
      • Each nap session continues for 15 minutes after sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep onset to detect REM sleep REM sleep A stage of sleep characterized by rapid movements of the eye and low voltage fast pattern eeg. It is usually associated with dreaming. Physiology of Sleep.
      • Repeated at 2-hour intervals until patient has had 4–5 opportunities to nap
      • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with narcolepsy take < 8 minutes to fall asleep (versus 10–15 minutes in healthy patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship).
  • Laboratory investigations:
    • CSF analysis CSF analysis Meningitis:
      • Measures orexin levels 
      • Low levels (< ⅓ of normal value) suggestive of narcolepsy
      • Done when sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep testing cannot be performed
    • Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies for DQB1*0602:
      • Nonspecific

Diagnostic criteria

Narcolepsy type 1 Type 1 Spinal Muscular Atrophy:

  • Daily periods of irrepressible need to sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep:
    • 3x/week
    • For ≥ 3 months
  • 1 or both of the following:
    • Low levels of orexin/hypocretin in CSF
    • Cataplexy and MSLT ≤ 8 minutes 

Narcolepsy type 2 Type 2 Spinal Muscular Atrophy:

All criteria must be met MET Preoperative Care.

  • Daily periods of irrepressible need to sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep:
    • 3x/week
    • For ≥ 3 months
  • Mean sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep latency of ≤ 8 minutes (MSLT)
  • Cataplexy is absent.
  • Normal levels of orexin in CSF
  • Findings not better explained by other causes, such as:
    • Insufficient sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep
    • Obstructive sleep apnea Sleep apnea Repeated cessation of breathing for > 10 seconds during sleep and results in sleep interruption, fatigue, and daytime sleepiness. Obstructive Sleep Apnea
    • Delayed sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep phase disorder
    • Effect of medication, illicit substances, or their withdrawal

Management

The goal of therapy is to improve alertness, so performance and safety are adequate for important activities such as school or work.

  • Safety:
    • Commercial drivers or workplace injury must be discussed.
    • Appropriate authorities notified
  • Sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep hygiene:
    • Maintain regular Regular Insulin and adequate sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep schedule.
    • Scheduled daytime naps
    • Avoid substances that may affect sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep schedule, e.g., caffeine Caffeine A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine’s most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. Stimulants.
  • Avoid medications/drugs that may worsen sleepiness:
    • Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines
    • Opiates Opiates Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
    • Antipsychotics 
    • Alcohol
    • Prazosin Prazosin A selective adrenergic alpha-1 antagonist used in the treatment of heart failure; hypertension; pheochromocytoma; raynaud disease; prostatic hypertrophy; and urinary retention. Antiadrenergic Drugs
  • Monitoring co-morbidities (psychiatric and obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity)

Pharmacological treatment

In patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with excessive daytime sleepiness and impaired daily functioning (majority of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship), medical intervention may be indicated. More than 1 medication may be needed to combat symptoms.

  • Daytime sleepiness:
    • Modafinil Modafinil Stimulants:
      • 1st line
      • Non-amphetamine CNS stimulant 
      • Well tolerated with low abuse potential
    • Amphetamines Amphetamines Analogs or derivatives of amphetamine. Many are sympathomimetics and central nervous system stimulators causing excitation, vasopressin, bronchodilation, and to varying degrees, anorexia, analepsis, nasal decongestion, and some smooth muscle relaxation. Stimulants and methylphenidate Methylphenidate A central nervous system stimulant used most commonly in the treatment of attention deficit disorder in children and for narcolepsy. Its mechanisms appear to be similar to those of dextroamphetamine. Stimulants:
      • 2nd line
      • Preferred in children
      • Higher risk of adverse effects (e.g., hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children, psychosis, anorexia Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa, abuse)
      • Newer options for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship not tolerating other options:
        • Solriamfetol (approved in 2019): selective dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS and norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS reuptake inhibitor
        • Pitolisant Pitolisant Stimulants (approved in 2020): oral histamine H₃ receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors inverse agonist
  • Cataplexy:
    • Aim is to suppress REM sleep REM sleep A stage of sleep characterized by rapid movements of the eye and low voltage fast pattern eeg. It is usually associated with dreaming. Physiology of Sleep by increasing norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS and serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS.
    • Serotonin-norepinephrine reuptake inhibitor (SNRI):
    • Selective norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS reuptake inhibitor:
      • Atomoxetine
      • Reboxetine
    • Selective serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS reuptake inhibitor (SSRI):
    • Tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants ( TCAs TCAs Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants):
      • Protriptyline Protriptyline Tricyclic antidepressant similar in action and side effects to imipramine. It may produce excitation. Tricyclic Antidepressants or clomipramine Clomipramine A tricyclic antidepressant similar to imipramine that selectively inhibits the uptake of serotonin in the brain. It is readily absorbed from the gastrointestinal tract and demethylated in the liver to form its primary active metabolite, desmethylclomipramine. Tricyclic Antidepressants 
      • Used when triggers are known and short term (e.g., stress)
      • Have anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs side effects
    • Sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia oxybate:
      • Drug of choice for severe cataplexy
      • Mediates effect via GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
    • Pitolisant Pitolisant Stimulants
Table: Comparison of medications used to manage narcolepsy
Medication Mechanism of action Side effects
Modafinil Modafinil Stimulants
  • Not well known
  • May work as a dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS reuptake inhibitor
  • Well tolerated
  • May cause headaches, anorexia Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics
  • Sympathomimetic Sympathomimetic Sympathomimetic drugs, also known as adrenergic agonists, mimic the action of the stimulators (α, β, or dopamine receptors) of the sympathetic autonomic nervous system. Sympathomimetic drugs are classified based on the type of receptors the drugs act on (some agents act on several receptors but 1 is predominate). Sympathomimetic Drugs side effects ( tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children, hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension)
  • Rare abuse potential
Sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia oxybate
  • Not well known
  • May work through GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS B receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
  • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics and dizziness Dizziness An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. Lateral Medullary Syndrome (Wallenberg Syndrome)
  • Weight loss Weight loss Decrease in existing body weight. Bariatric Surgery
  • Urinary incontinence Urinary incontinence Urinary incontinence (UI) is involuntary loss of bladder control or unintentional voiding, which represents a hygienic or social problem to the patient. Urinary incontinence is a symptom, a sign, and a disorder. The 5 types of UI include stress, urge, mixed, overflow, and functional. Urinary Incontinence
  • Mood swings, worsening of depression, or psychosis
  • Sleepwalking Sleepwalking A parasomnia characterized by a partial arousal that occurs during stage IV of non-rem sleep. Affected individuals exhibit semipurposeful behaviors such as ambulation and are difficult to fully awaken. Children are primarily affected, with a peak age range of 4-6 years. Parasomnias
  • Abuse: restrictive prescription
Amphetamines Amphetamines Analogs or derivatives of amphetamine. Many are sympathomimetics and central nervous system stimulators causing excitation, vasopressin, bronchodilation, and to varying degrees, anorexia, analepsis, nasal decongestion, and some smooth muscle relaxation. Stimulants Increase catecholamines Catecholamines A general class of ortho-dihydroxyphenylalkylamines derived from tyrosine. Adrenal Hormones in synaptic cleft Synaptic cleft Synapses and Neurotransmission
  • Nervousness, agitation Agitation A feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions. St. Louis Encephalitis Virus, tics Tics Habitual, repeated, rapid contraction of certain muscles, resulting in stereotyped individualized actions that can be voluntarily suppressed for only brief periods. They often involve the face, vocal cords, neck, and less often the extremities. Examples include repetitive throat clearing, vocalizations, sniffing, pursing the lips, and excessive blinking. Tics tend to be aggravated by emotional stress. When frequent they may interfere with speech and interpersonal relations. Conditions which feature frequent and prominent tics as a primary manifestation of disease are referred to as tic disorders. Tics and Tourette Syndrome, anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder, or psychosis
  • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
  • Anorexia Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa
  • Sympathomimetic Sympathomimetic Sympathomimetic drugs, also known as adrenergic agonists, mimic the action of the stimulators (α, β, or dopamine receptors) of the sympathetic autonomic nervous system. Sympathomimetic drugs are classified based on the type of receptors the drugs act on (some agents act on several receptors but 1 is predominate). Sympathomimetic Drugs side effects ( tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children, hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension)
  • Higher risk of abuse
Methylphenidate Methylphenidate A central nervous system stimulant used most commonly in the treatment of attention deficit disorder in children and for narcolepsy. Its mechanisms appear to be similar to those of dextroamphetamine. Stimulants Blocks dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS and norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS reuptake by neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology
  • Sympathomimetic Sympathomimetic Sympathomimetic drugs, also known as adrenergic agonists, mimic the action of the stimulators (α, β, or dopamine receptors) of the sympathetic autonomic nervous system. Sympathomimetic drugs are classified based on the type of receptors the drugs act on (some agents act on several receptors but 1 is predominate). Sympathomimetic Drugs side effects ( tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children, hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension)
  • Arrhythmias
Solriamfetol Selective dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS and norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS reuptake inhibitor with wake-promoting effects Similar to modafinil Modafinil Stimulants
Pitolisant Pitolisant Stimulants Histamine H3 receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors inverse agonist
  • Well tolerated
  • May cause headaches, insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, and QT prolongation

Narcolepsy in Children

Etiology and diagnosis of narcolepsy in children is the same as in adults.

Epidemiology

  • ↑ Trend in incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency 
  • Age of onset is typically 5–7 years.

Clinical presentation

  • Daytime sleepiness:
    • Sleeping during sedentary activities (e.g., sitting in classroom, reading a book)
    • Lasts 20–30 minutes
    • Doesn’t refresh the child
    • Habitual napping is uncommon in healthy children > 6 years of age and should raise suspicion. 
  • Cataplexy (80%):
    • More specific symptom
    • Characterized by oculo-bucco-facial weakness (“cataplectic facies”)
      • Jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint: Anatomy dropping open
      • Ptosis Ptosis Cranial Nerve Palsies
      • Head rolling Rolling Movement of tethered, spherical leukocytes along the endothelial surface of the microvasculature. The tethering and rolling involves interaction with selectins and other adhesion molecules in both the endothelium and leukocyte. The rolling leukocyte then becomes activated by chemokines, flattens out, and firmly adheres to the endothelial surface in preparation for transmigration through the interendothelial cell junction. Inflammation
  • Hypnagogic hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia and sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep paralysis (50%–60%)

Management

Behavioral modification:

  • Education about disorder being life long; no cure
  • Planned naps are essential.
  • Regularly scheduled bedtimes 
  • Optimize schooling with special accommodation Accommodation Refractive Errors.
  • Caution while swimming
  • Psychosocial support to detect development of anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder or depression

Medical management:

  • Amphetamines Amphetamines Analogs or derivatives of amphetamine. Many are sympathomimetics and central nervous system stimulators causing excitation, vasopressin, bronchodilation, and to varying degrees, anorexia, analepsis, nasal decongestion, and some smooth muscle relaxation. Stimulants and methylphenidate Methylphenidate A central nervous system stimulant used most commonly in the treatment of attention deficit disorder in children and for narcolepsy. Its mechanisms appear to be similar to those of dextroamphetamine. Stimulants:
    • 1st line for children
    • Monotherapy
  • Sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia oxybate: if cataplexy is presenting complaint

Clinical Relevance

The following conditions are other types of sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep disorders:

  • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia: sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep disorder marked by symptoms that interfere with duration and/or quality Quality Activities and programs intended to assure or improve the quality of care in either a defined medical setting or a program. The concept includes the assessment or evaluation of the quality of care; identification of problems or shortcomings in the delivery of care; designing activities to overcome these deficiencies; and follow-up monitoring to ensure effectiveness of corrective steps. Quality Measurement and Improvement of sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep despite adequate opportunity for sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep
  • Circadian rhythm Circadian Rhythm The regular recurrence, in cycles of about 24 hours, of biological processes or activities, such as sensitivity to drugs or environmental and physiological stimuli. Cranial Nerve Palsies sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep–wake disorder: recurrent patterns of sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep disruption due to alteration of circadian system or misalignment between individual’s inner circadian rhythm Circadian Rhythm The regular recurrence, in cycles of about 24 hours, of biological processes or activities, such as sensitivity to drugs or environmental and physiological stimuli. Cranial Nerve Palsies and sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep–wake cycle. Subtypes include delayed sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep phase disorder, advanced sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep phase disorder, shift-work disorder Shift-work disorder Circadian Rhythm Sleep–Wake Disorder, and jet lag disorder.
  • Parasomnias Parasomnias Parasomnias are a pattern of sleep disorders marked by unusual actions, activities, or physiological events that occur during sleep or sleep-wake transitions. Parasomnias are divided into which sleep phase the symptoms occur, either rapid eye movement (REM) or non-REM (NREM). Parasomnias: pattern of sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep disorder marked by unusual actions, activities, or physiological events that occur during sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep or sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep–wake transitions. Symptoms may include abnormal movements, emotions, dreams, and autonomic activity.
  • Restless legs syndrome Restless legs syndrome Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome: condition marked by overwhelming urge to move one’s legs, accompanied by unpleasant sensations, which are relieved with movement. Patient complaint occurs during evening and is associated with sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep disturbance.
  • Obstructive sleep apnea Sleep apnea Repeated cessation of breathing for > 10 seconds during sleep and results in sleep interruption, fatigue, and daytime sleepiness. Obstructive Sleep Apnea: episodic apnea, or cessation of breathing during sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep, in which period of apnea lasts for more than 10 seconds. Usually due to partial or complete collapse of upper airway Airway ABCDE Assessment and is associated with snoring, restlessness, daytime headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, and somnolence.

References

  1. Scammell TE. Narcolepsy (2015). N Engl J Med;373:2654. https://pubmed.ncbi.nlm.nih.gov/26716917/
  2. Nishino S, Ripley B, Overeem S, et al. (2000). Hypocretin (orexin) deficiency in human narcolepsy. Lancet. https://pubmed.ncbi.nlm.nih.gov/10615891/
  3. Carskadon MA, Dement WC, Mitler MM, et al. (1986). Guidelines for the multiple sleep latency test (MSLT): a standard measure of sleepiness. https://pubmed.ncbi.nlm.nih.gov/3809866/
  4. Dauvilliers Y, Bassetti C, Lammers GJ, et al. (2013). Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomized trial. Lancet Neurol. https://pubmed.ncbi.nlm.nih.gov/24107292/
  5. Ganti et al. (2016). First Aid for the Psychiatry Clerkship, 4th ed. (p. 165).
  6. Le T, Bhusan V, Sochat M, et al. (Eds.) (2020). First Aid for the USMLE Step 1, 30th ed. (p. 556).

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