Narcolepsy

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness (EDS) and difficulty maintaining both sleep and wakefulness.   The International Classification of Sleep Disorders, third edition (ICSD-3), divides narcolepsy into two subtypes, narcolepsy type 1 and narcolepsy type 2.

Narcolepsy type 1 is caused by a hypocretin (orexin) deficiency, and definitive diagnosis is based on the presence of cataplexy (sudden episodes of muscle weakness triggered by strong emotions) or a hypocretin deficiency confirmed through laboratory testing (although this testing is not always available). The pathophysiology for narcolepsy type 2 is uncertain, and it can be diagnosed by clinical history and sleep studies.

Because of the strong association between narcolepsy and the presence of the HLA-DQB1*06:02 allele, genetic testing for HLA-DQB1*06:02 can help rule out narcolepsy.

Quick Answers for Clinicians

What are the different classifications of narcolepsy?

Previously, narcolepsy was divided into two types: narcolepsy with cataplexy (a sudden loss of muscle tone brought on by strong emotions) and narcolepsy without cataplexy. However, patients who initially present without cataplexy often develop cataplexy after the initial diagnosis, and 25-30% of individuals with narcolepsy who do not experience cataplexy have hypocretin deficiencies. As a result, the International Classification of Sleep Disorders, third edition (ICSD-3), updated the narcolepsy classifications to narcolepsy type 1, which requires either the presence of cataplexy or documentation of lower than normal levels of hypocretin-1, and narcolepsy type 2, which does not. 

What causes narcolepsy?

Narcolepsy type 1 is generally presumed to be an autoimmune-mediated disease in which a loss of hypocretin-producing neurons results in a decrease in hypocretin (orexin).  Hypocretin deficiency is often, but not always, accompanied by cataplexy. The pathophysiology of narcolepsy type 2 (formerly narcolepsy without cataplexy) is uncertain, but it may be caused by less extensive damage to hypocretin-producing neurons. 

Does the diagnosis of narcolepsy differ for pediatric populations?

Although the criteria for diagnosis in children are the same as for adults, narcolepsy does often present differently in children, which can lead to misdiagnosis. The following symptoms may be present in children:

  • Hyperactivity during the day
  • Cataplexy without an obvious emotional trigger
  • Increased time spent sleeping over a 24-hour period

Indications for Testing

Testing for narcolepsy should be considered when an individual has experienced EDS regularly for at least 3 months and after other common causes of persistent sleepiness (eg, other sleep disorders, insufficient sleep, medication use, depression) have been ruled out. 

Laboratory Testing

Sleep assessments are more important to the diagnosis of narcolepsy than are standard laboratory tests. Typically, an individual with narcolepsy experiences sleep fragmentation during a nocturnal polysomnography (PSG) and several short sleep-onset rapid-eye-movement (REM) periods (SOREMPs) during a Multiple Sleep Latency Test (MSLT).  If the findings of these tests are indicative of narcolepsy (see Diagnostic Criteria below), further laboratory testing may be performed to differentiate between narcolepsy type 1 and type 2. 

Sleep tests should not be administered when the patient is under the influence of medications that affect REM sleep, such as psychoactive medications, stimulants, and antidepressants. 

HLA-DQB1*06:02 Genotyping

The HLA-DQB1*06:02 allele is strongly associated with narcolepsy and is present in over 98% of individuals with narcolepsy type 1 and about 50% of individuals with narcolepsy type 2,  representing one of the strongest HLA-disease associations.   However, 15-25% of individuals in the general population also carry the allele, which suggests that it is necessary but not sufficient for development of the disorder, and additional genetic and environmental factors may be involved.  

HLA testing in a patient has an excellent negative predictive value and is useful to rule out narcolepsy in patients with unexplained sleepiness.  However, the positive predictive value is low; a positive test for HLA-DQB1*06:02 does not establish a diagnosis on its own.

Because an individual without HLA-DQB1*06:02 almost never has a hypocretin deficiency, some clinicians suggest testing for the allele before performing a lumbar puncture to assess hypocretin-1 concentrations in patients. 

Recent studies indicate a gene dose effect for HLA-DQB1*06:02: homozygosity doubles the risk of narcolepsy. Other HLA alleles in trans position have been described as dominantly protective, including HLA-DQB1*06:03, 06:01, 05:01, 06:09, and DQB1*02 alleles.  However, currently available clinical tests do not provide information on gene dose; they only report the presence or absence of HLA-DQB1*06:02 allele (positive or negative).

Hypocretin-1 Testing

Hypocretin deficiency is diagnostic for narcolepsy type 1.  After a positive test for HLA-DQB1*06:02, a test for hypocretin-1 in cerebrospinal fluid (CSF), if available, may be performed.  A value of ≤110 pg/mL is sufficient for a diagnosis of narcolepsy type 1 in patients suffering from EDS.  However, because hypocretin testing is not always available, narcolepsy type 1 and type 2 may be differentiated based solely on the presence or absence of cataplexy. 

Diagnostic Criteria

ICSD-3

Narcolepsy Type 1

Both of the following criteria must be met for a diagnosis of type 1:

  • Lapses into daytime sleep or episodes of irrepressible need to sleep occurring each day for 3 months or more
  • At least one of the following:
    • Cataplexy along with a mean sleep latency of ≤8 minutes, plus two or more SOREMPs on a standard MSLT (one SOREMP may be replaced by a SOREMP within 15 minutes of sleep onset on the nocturnal PSG)
    • Hypocretin deficiency (CSF hypocretin-1 value of ≤110 pg/mL)

Narcolepsy Type 2

All five of the following criteria must be met for a diagnosis of type 2:

  • Lapses into daytime sleep or episodes of irrepressible need to sleep occurring each day for 3 months or more
  • Mean sleep latency of ≤8 minutes, plus two or more SOREMPs on a standard MSLT (one SOREMP may be replaced by a SOREMP within 15 minutes of sleep onset on the nocturnal PSG)
  • Absence of cataplexy
  • CSF hypocretin-1 concentration either not measured or >110 pg/mL
  • Hypersomnolence or sleep latency observations that are not better explained by a different cause

DSM-5

Criteria from the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), for a diagnosis of narcolepsy (not subdivided by type), include the following:

  • Several periods of irrepressible need to sleep or lapses into sleep occurring on the same day, at least three times a week for 3 months
  • At least one of the following:
    • Several episodes of cataplexy per month, characterized as either:
      • Brief episodes of muscle tone loss, triggered by laughter or joking, with maintained consciousness (in individuals with long-term disease)
      • Spontaneous grimaces, jaw opening with tongue thrusting, or global hypotonia without any emotional triggers (in children or individuals with disease onset in last 6 months)
    • Hypocretin deficiency (CSF hypocretin-1 value of ≤110 pg/mL not attributable to another cause such as brain infection, injury, or inflammation)
    • REM sleep latency ≤15 minutes on nocturnal PSG or a mean sleep latency of ≤8 minutes with two or more SOREMPs on a standard MSLT

ARUP Laboratory Tests

Diagnosis

Rule out narcolepsy type 1

May help determine if hypocretin-1 CSF should be tested in an individual

Does not rule out narcolepsy type 2

Diagnose narcolepsy type 1

Hypocretin-1 CSF (not performed at ARUP Laboratories)

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