Basics
Description
- Lifelong neurologic disorder that often initially manifests in childhood or adolescence and can cause significant functional impairment and disability
- Excessive daytime sleepiness and inappropriate transitions from wakefulness into rapid eye movement (REM) sleep
- Narcolepsy may occur with or without cataplexy.
- Other associated features include hypnagogic hallucinations, sleep paralysis, and nighttime sleep fragmentation.
General Prevention
- Narcolepsy is not preventable.
- Narcolepsy is underrecognized, especially in children.
- Physicians should screen for sleep dysfunction and excessive sleepiness as part of anticipatory guidance.
Epidemiology
- Prevalence in the United States is reported to range from 25 to 50 per 100,000; prevalence may be higher in the Japanese population.
- An estimated 200,000 Americans have narcolepsy, but fewer than 50,000 of these individuals have been diagnosed with the disorder.
- Approximately half of patients with narcolepsy have symptoms before age 15 years and <10% with symptoms <age 5 years, but often, diagnosis may lag 10 " �15 years after onset of symptoms.
- Cataplexy is present in 50 " �70% of adult patients and perhaps at least as many pediatric patients but may be initially sporadic or difficult to identify.
Risk Factors
- 1st-degree relatives of patients with narcolepsy with cataplexy have a 1 " �2% risk (which is 10- to 40-fold more than the general population) of developing narcolepsy.
- Both genetic and environmental factors may be involved in the development of narcolepsy.
- There is an association between narcolepsy with cataplexy and histocompatibility leukocyte antigens (HLA) subtypes, specifically DQB1*0602 in 85 " �95% and DR2 antigens. About 40% of cases of narcolepsy without cataplexy are also DQB1*0602 positive.
- Increased risk of narcolepsy after H1N1 vaccination has been a topic of interest.
Pathophysiology
- Hypocretin (also known as orexin) is a neuropeptide produced by neurons in the perifornical area of the lateral hypothalamus that is supplied to several areas of the brain that promote wakefulness. It may also inhibit REM sleep. It mediates appetite.
- To better reflect pathophysiology, the American Academy of Sleep Medicine has categorized narcolepsy into type 1 and type 2. Type 1 involves hypocretin deficiency, such as would be detected in cerebrospinal fluid (CSF) via lumbar puncture, or manifested clinically by the presence of cataplexy. Type 2 does not involve hypocretin deficiency, and in the absence of CSF testing would be the presumptive diagnosis for a patient who had not manifested cataplexy. Onset of cataplexy would herald a change in diagnosis from type 1 to type 2.
- Narcolepsy type 1 is caused by selective loss of the hypocretin-producing neurons in the hypothalamic region.
- The association between narcolepsy and specific HLA antigens has suggested autoimmune pathogenesis; however, this has yet to be definitively established.
Commonly Associated Conditions
- Secondary narcolepsy may be seen with CNS trauma, strokes, brain tumors, and demyelinating diseases, particularly involving the lateral and posterior hypothalamus, midbrain, and the pons.
- Genetic syndromes such as Prader-Willi syndrome, myotonic dystrophy, and Niemann-Pick type C syndrome may be associated with secondary narcolepsy.
Diagnosis
History
- Excess daytime sleepiness starting with recurrence of naps may be early signs of disease.
- In adults, naps tend to be restorative but are more likely to be described as "unrefreshing " � in children.
- Cataplexy, the abrupt loss of muscle tone provoked by laughter or strong emotions such as surprise, sadness, or anger, is almost pathognomonic for narcolepsy. Loss of muscle tone can range from sagging of face, eyelids, or jaw; blurred vision; and knee buckling to complete collapse but with preserved consciousness.
- Hypnagogic (on sleep onset) and hypnopompic (on awakening) hallucinations involve vivid auditory or visual hallucinations during transitions between sleep and wakefulness. Such hallucinations can also be experienced infrequently by normal individuals.
- Sleep paralysis is the inability to move or speak for a few seconds or minutes at sleep onset or offset. Normal individuals can also experience sleep paralysis, often in the context of sleep deprivation.
Physical Exam
- Normal in most idiopathic cases; children with narcolepsy are often overweight/obese.
- Vertical gaze palsy, confusion, poor memory, developmental regression, impaired thermoregulation, and signs of endocrine dysfunction may be present in cases of secondary narcolepsy.
Diagnostic Tests & Interpretation
Lab
- Levels of CSF hypocretin ≤110 pg/mL (30% of mean control value) are strongly indicative of narcolepsy with cataplexy. CSF testing is usually reserved for complicated or ambiguous cases.
- HLA antigen typing with HLA DQB*0602 and DR2 are strongly associated with narcolepsy with cataplexy but also present in 12 " �38% of the normal population. A negative result can be helpful in ruling out the condition, and HLA testing should be considered supportive rather than diagnostic.
Imaging
Brain MRI is indicated with sudden onset of sleepiness, recent head injury, or an abnormal neurologic exam. � �
Diagnostic Procedures/Other
- Overnight polysomnography (PSG) and multiple sleep latency test (MSLT) are considered standard of care for diagnosis.
- MSLT is a protocol consisting of four or five 20-minute nap opportunities 2 hours apart after an overnight PSG to determine mean sleep latency (MSL) and sleep-onset REM periods (SOREMPs) within 15 minutes of falling asleep. PSG is performed to ensure adequate nighttime sleep and exclude other sleep disorders that could cause daytime sleepiness. On MSLT, MSL <8 minutes and ≥2 SOREMPs are diagnostic of narcolepsy. SOREMP at the beginning of the preceding night 's PSG can now be substituted for a SOREMP on the MSLT. Two or more SOREMPs tend to be specific for narcolepsy, whereas up to 30% of the general population may have MSL <8 minutes. Other factors influencing sleepiness such as chronic sleep deprivation or sedating medications must provide context for test interpretation.
Differential Diagnosis
- Chronic insufficient sleep
- Poor sleep hygiene (particularly nighttime electronics use)
- Delayed sleep phase disorder (manifesting as daytime sleepiness)
- Idiopathic CNS hypersomnia (without cataplexy, SOREMPs, or other REM intrusion phenomena in wakefulness or sleep)
- Primary sleep disorders such as obstructive sleep apnea, restless legs syndrome, periodic limb movement disorder
- Kleine-Levin syndrome (cyclical episodes of hypersomnolence, classically also with overeating and hypersexuality lasting days to weeks with normal intervals in between)
- Psychiatric disorders/depression
- Medication side effects, drug/alcohol abuse
- Atonic drop attacks associated with childhood epilepsy syndromes such as Lennox-Gastaut syndrome
- Cataplexy can be associated with Coffin-Lowry syndrome or Norrie syndrome, both rare and involving other deficits including intellectual disability.
Treatment
Medication
- Daytime sleepiness
- Methylphenidate, 5 " �30 mg/24 h (max 60 mg/24 h). Consider other long-acting formulations such as Concerta, Ritalin LA, Metadate CD, Focalin XR, etc.
- Dextroamphetamine (Dexedrine) 5 " �40 mg/24 h (max 60 mg/24 h)
- Mixed amphetamine salts (Adderall XR) 10 " �30 mg/24 h
- Modafinil (Provigil), 100 " �400 mg/24 h. FDA Pediatric Advisory Committee warning; recommends use only if 1st- and 2nd-line treatments have failed and the benefits outweigh the risks of serious dermatologic and psychiatric side effects
- Cataplexy
- Sodium oxybate (Xyrem): treats both hypersomnia and cataplexy. Dose is given at bedtime while in bed and again 2 � � " �4 hours later due to profound sedating effects.
- Venlafaxine (Effexor) starting at 12.5 " �25 mg
- Selective serotonin reuptake inhibitors: fluoxetine (Prozac) 5 " �30 mg/24 h or sertraline (Zoloft) 25 " �100 mg/24 h
- Clomipramine (Anafranil) 25 " �100 mg /24 h
- Imipramine (Tofranil) 25 " �75 mg /24 h
Additional Therapies
- Regular sleep schedule
- Short scheduled naps
- Regular physical exercise
Ongoing Care
Prognosis
Children with narcolepsy can be expected to have normal life expectancy and normal intellectual functioning. Lifestyle and medication treatments to reduce sleepiness and cataplexy improve academic performance, quality of life, and ability to participate. � �
Additional Reading
- Aran � �A, Einen � �M, Lin � �L, et al. Clinical and therapeutic aspects of childhood narcolepsy-cataplexy: a retrospective study of 51 children. Sleep. 2010;33(11):1457 " �1464. � �[View Abstract]
- Dauvilliers � �Y, Arnulf � �I, Mignot � �E. Narcolepsy with cataplexy. Lancet. 2007;369(9560):499 " �511. � �[View Abstract]
- Kotagal � �S. Narcolepsy in children. In: Sheldon � �S, Kryger � �M, Ferber � �R, eds. Principles and Practice of Pediatric Sleep Medicine. Philadelphia, PA: Elsevier; 2005:171 " �179.
- Nevsimalova � �S. Narcolepsy in childhood. Sleep Med Rev. 2009;13(2):169 " �180. � �[View Abstract]
Codes
ICD09
- 347.00 Narcolepsy, without cataplexy
- 347.01 Narcolepsy, with cataplexy
- 347.10 Narcolepsy in conditions classified elsewhere, without cataplexy
- 347.11 Narcolepsy in conditions classified elsewhere, with cataplexy
ICD10
- G47.419 Narcolepsy without cataplexy
- G47.411 Narcolepsy with cataplexy
- G47.429 Narcolepsy in conditions classified elsewhere w/o cataplexy
- G47.421 Narcolepsy in conditions classified elsewhere with cataplexy
SNOMED
- 60380001 Narcolepsy (disorder)
- 193042000 Cataplexy and narcolepsy (disorder)
- 91521000119104 Narcolepsy without cataplexy (disorder)
- 434251000124109 Secondary narcolepsy without cataplexy (disorder)
- 434261000124106 Secondary narcolepsy with cataplexy (disorder)
FAQ
- Q: What is the chance that a sibling of the patient may develop narcolepsy?
- A: There is a 1% possibility that siblings and offspring could be affected.
- Q: Will a patient with narcolepsy be able to drive a car?
- A: Patients with narcolepsy can legally drive, provided they are on the appropriate medications to keep them from falling asleep at the wheel.
- Q: Is there a cure for narcolepsy?
- A: No. Treatment is symptomatic.