narcolepsy
NARCOLEPSY

Narcolepsy is a chronic neurologic sleep disorder wherein the patient have excessive daytime sleepiness and rapid eye movement sleep is dysregulated.

It affects 1 in 1000 individuals, with prevalence of about 0.04% of general population.
The exact cause remains unclear.
Studies suggest a combination of genetic predisposition, abnormal neurotransmitter functioning and abnormal immune modulation.
Symptoms include excessive daytime sleepiness, cataplexy, sleep paralysis, sleep-related hallucinations, automatic behavior, fragmented nocturnal sleep and insomnia.

Diagnosis

  • Identify all symptoms that suggest narcolepsy
    • Presence of both excessive daytime sleepiness & cataplexy highly suggest narcolepsy
  • Obtain structured sleep history
    • Determine whether main complaint is sleepiness or fatigue
    • Timing, quantity & quality of sleep
    • Snoring or difficulty in breathing
    • Relevant medication or drug use including alcohol intake
  • According to DSM-5 criteria, narcolepsy is the daily occurrence of uncontrollable need to sleep, daytime lapses or napping for at least 3 times per week for the past 3 months with the presence of any of the following:
    • Cataplexy episodes, that occur at least a few times in a month, can be defined as either:
      • Occurrence in patients with long-standing disease of sudden bilateral loss of muscle tone with intact consciousness for a few seconds to minutes triggered by laughter or joking
      • Presence of unprovoked grimaces or jaw-opening episodes with tongue thrusting or global hypotonia without any obvious emotional triggers in children or adult patients within the past 6 months
    • Inadequate hypocretin as measured using cerebrospinal fluid hypocretin-1 immunoreactivity values (≤1/3 of values obtained in healthy individuals tested using the same assay or ≤110 pg/mL). Low CSF levels should not be due to acute brain injury, inflammation or infection
    • Nocturnal sleep polysomnography shows ≤15 minutes of rapid eye movement sleep latency or a multiple sleep latency test of ≤8 minutes mean sleep latency & ≥2 sleep-onset rapid eye movement periods
  • Based on DSM-5 criteria, narcolepsy can be subclassified as:
    • Narcolepsy without cataplexy but with hypocretin deficiency if the patient has low CSF hypocretin-1 levels& positive results in polysomnography/multiple sleep latency test but there is no cataplexy
    • Narcolepsy with cataplexy but without hypocretin deficiency if the patient has normal CSF hypocretin-1levels but with cataplexy & positive results in polysomnography/multiple sleep latency test, this is a rare type of narcolepsy
    • Autosomal dominant cerebellar ataxia, deafness, & narcolepsy if the patient has narcolepsy at the age of 30-40 years (late-onset) with low or intermediate CSF hypocretin-1 levels, deafness, cerebellar ataxia, & eventually dementia caused by exon 21 DNA (cytosine-5)-methyltransferase-1 mutations
    • Autosomal dominant narcolepsy, obesity & type 2 diabetes if the patient has narcolepsy, obesity, & type 2 diabetes & low CSF hypocretin-1 levels associated with a mutation in the myelin oligodendrocytes glycoprotein gene
    • Narcolepsy secondary to another medical condition if the patient has narcolepsy due to medical conditions that cause infectious (eg, Whipple’s disease, sarcoidosis), traumatic or tumoral destruction of hypocretin neurons
  • Severity of narcolepsy based on DSM-5 criteria can be classified as:
    • Mild if cataplexy occurs <1/week, the need for naps is only once or twice per day, & with less disturbing nocturnal sleep
    • Moderate if cataplexy occurs once daily or every few days, with daily need for multiple naps, & with disturbed nocturnal sleep
    • Severe if the patient has multiple attacks of drug-resistant cataplexy daily, almost constant sleepiness, &disturbed nocturnal sleep

Evaluation

Diagnostic Exams

  • Confirm the diagnosis, determine severity & exclude other sleep disorders

Polysomnography (PSG)

  • Overnight test for concurrent sleep disorders
  • Helps to exclude other conditions that produce sleepiness such as obstructive sleep apnea, periodic limb movement disorder & rapid eye movement (REM) sleep behavior disorders
  • Accurately documents fragmented sleep patterns with a normal amount of rapid eye movement sleep but a pattern of sleep-onset rapid eye movement
  • A short latency rapid eye movement sleep can be an evidence for narcolepsy esp if multiple sleep latency test (MSLT) results are vague

Multiple Sleep Latency Test (MSLT)

  • Helps to confirm the diagnosis
  • Useful in determining the severity of daytime sleepiness
  • Performed one day after the nocturnal polysomnography
  • ≤8 minutes of MSLT & ≥2 sleep-onset REM (SOREM) periods indicate pathological sleepiness in narcolepsy
    • Narcoleptics usually fall asleep & enter rapid eye movement sleep within 15 minutes of sleep onset

Maintenance of Wakefulness Test (MWT)

  • Objective test that measures the ability to resist falling asleep
  • Narcoleptics usually have short sleep latencies in maintenance of wakefulness test
  • This test does not necessarily confirm diagnosis but only indicates that the patient is sleepy

Assessment

Epworth Sleepiness Scale

  • Subjective test in which patients are asked to rate their level of sleepiness in normal daytime situations
  • Total score of  ≥11 suggests a high probability of sleep disturbance
  • Most commonly used index of sleepiness in adults
Stanford Sleepiness Scale
  • A 7-point scale that quantifies subjectively the sleepiness of the patient throughout the day

Laboratory Tests

Cerebrospinal Fluid Hypocretin

  • Absence of low levels of cerebrospinal fluid hypocretin-1 can confirm the presence of narcolepsy with cataplexy
    • ≤110 pg/mL CSF hypocretin-1 level has a high positive predictive value of 94%
  • Most accurate diagnostic technique
  • Its use in narcolepsy without cataplexy needs to be determined
    • Normal levels of CSF hypocretin-1 have been found in narcolepsy without cataplexy & idiopathic hypersomnia

Human Leukocyte Antigen (HLA) Testing

  • The clinical use of HLA subtype DQB1*0602 & DQA1*0602 is limited because of genetic variation
  • Should not be used for the diagnosis of narcolepsy without cataplexy

Imaging

Magnetic Resonance Imaging (MRI)

  • Useful in patients with atypical symptoms or focal findings on neurological exam to identify structural lesions of the brainstem & diencephalon which can cause narcolepsy

Classification

Types of Narcoplepsy

Narcolepsy w/ cataplexy

  • ≥3 months of excessive daytime sleepiness
  • Presence of definitive history of cataplexy
  • May be confirmed by:
    • Polysomnography to rule out other causes of disrupted nocturnal sleep & demonstrating at least 6 hours of sleep followed by multiple sleep latency test showing ≤8 minutes of sleep latency & ≥2 SOREM; or
    • ≤110 pg/mL CSF hypocretin-1 level

Narcolepsy without cataplexy

  • ≥3 months of excessive daytime sleepiness
  • No cataplexy or questionable/atypical cataplexy-like episodes
  • Must be confirmed by polysomnography & multiple sleep latency test

Narcolepsy caused by a medical condition

  • ≥3 months of excessive daytime sleepiness
  • Significant underlying medical or neurologic condition accounts for the daytime sleepiness
  • Presence of definitive history of cataplexy; or
  • Positive polysomnography & multiple sleep latency test when cataplexy or questionable/atypical cataplexy-like episode is not present
  • <110 pg/mL CSF hypocretin-1 level (or 30% of normal control values) if there is absence of cataplexy or negative polysomnography & multiple sleep latency test
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