Neurobiology of Normal Wakefulness

Hypocretin deficiency may partially explain certain comorbidities3-6

Interconnected wake-promoting neurons activate cortical and subcortical arousal regions and inhibit neurons primarily responsible for promoting rapid eye-movement (REM) sleep and non-REM (NREM) sleep.1,2 The neuropeptide hypocretin (or orexin) activates these wake-promoting neurons to help maintain wakefulness and muscle tone and inhibit REM sleep during the day.1,7

Narcolepsy: A Deeper Look

Narcolepsy type 1*(narcolepsy with cataplexy)

Narcolepsy type 2 (narcolepsy without cataplexy)

Narcolepsy type 1 is thought to be due to the permanent loss of hypocretin neurons. Patients with narcolepsy type 1 have low or undetectable levels of cerebrospinal fluid (CSF) hypocretin-1.3,†

Based on animal models, loss of hypocretin neurons is thought to lead to inconsistent signaling of wake-promoting neurons responsible for maintaining wakefulness and muscle tone and inhibit NREM and REM-sleep promoting neurons (eg, dopaminergic, noradrenergic, serotonergic neurons).1,7,‡

  • Wake-promoting neurons fail to activate cortical and subcortical arousal regions and fail to inhibit sleep-promoting neurons (ie, GABAergic neurons), resulting in excessive daytime sleepiness.7
  • Certain wake-promoting neurons that also suppress REM signaling fail to inhibit REM-promoting neurons, resulting in cataplexy and other abnormal manifestations of REM sleep such as hypnagogic/hypnopompic hallucinations and sleep paralysis.2,7
  • Disruption of mutually inhibitory sleep-wake circuits may also lead to unwanted transitions from sleep to wakefulness and to associated sleep disruption.2,8
Narcolepsy type 2 is likely a heterogeneous disorder.3 In patients with narcolepsy type 2, cataplexy is not present, and CSF hypocretin-1 levels are usually normal or unknown.3 One quarter to one third of patients diagnosed with narcolepsy type 2 may actually have hypocretin deficiency, which would classify them as narcolepsy type 1 if levels were known, and about 8% may have intermediate levels of CSF hypocretin-1.3,9 These patients are more likely to develop cataplexy over time than those with normal hypocretin levels.9 The exact cause of narcolepsy type 2 is unknown.3

Narcolepsy type 1* (narcolepsy with cataplexy)

Narcolepsy type 1 is thought to be due to the permanent loss of hypocretin neurons. Patients with narcolepsy type 1 have low or undetectable levels of cerebrospinal fluid (CSF) hypocretin-1.3,†

Based on animal models, loss of hypocretin neurons is thought to lead to inconsistent signaling of wake-promoting neurons responsible for maintaining wakefulness and muscle tone and inhibit NREM and REM-sleep promoting neurons (eg, dopaminergic, noradrenergic, serotonergic neurons).1,7,‡

  • Wake-promoting neurons fail to activate cortical and subcortical arousal regions and fail to inhibit sleep-promoting neurons (ie, GABAergic neurons), resulting in excessive daytime sleepiness.7
  • Certain wake-promoting neurons that also suppress REM signaling fail to inhibit REM-promoting neurons, resulting in cataplexy and other abnormal manifestations of REM sleep such as hypnagogic/hypnopompic and sleep paralysis.2,7
  • Disruption of mutually inhibitory sleep-wake circuits may also lead to unwanted transitions from sleep to wakefulness and to associated sleep disruption.2,8

Narcolepsy type 2 (narcolepsy without cataplexy)

Narcolepsy type 2 is likely a heterogeneous disorder.3 In patients with narcolepsy type 2, cataplexy is not present, and CSF hypocretin-1 levels are usually normal or unknown.3 One quarter to one third of patients diagnosed with narcolepsy type 2 may actually have hypocretin deficiency, which would classify them as narcolepsy type 1 if levels were known, and about 8% may have intermediate levels of CSF hypocretin-1.3,9 These patients are more likely to develop cataplexy over time than those with normal hypocretin levels.9 The exact cause of narcolepsy type 2 is unknown.3
*
Not all patients with narcolepsy type 1 experience all 5 symptoms.3,10
†
CSF hypocretin-1 levels typically are not obtained in clinical practice.
‡
Based on animal models. Other neuronal systems are also thought to be involved.1,7