Narcolepsy: Orexin Deficiency, Cataplexy, and REM Sleep Intrusion
Narcolepsy type 1 is caused by autoimmune destruction of 70,000–90,000 orexin-producing hypothalamic neurons; CSF hypocretin-1 falls below 110 pg/mL (normal >200 pg/mL) and MSLT shows mean sleep latency <8 min with ≥2 SOREMPs.
| Measure | Value | Unit | Notes |
|---|---|---|---|
| Orexin neuron loss in narcolepsy type 1 | 90–95 | % of neurons lost | Thannickal et al. 2000; 70,000–90,000 neurons in lateral hypothalamus destroyed |
| CSF hypocretin-1 diagnostic threshold | 110 | pg/mL (below = diagnostic) | Mignot et al. 2002; specificity 99.6%, sensitivity ~87% for type 1 |
| Mean sleep latency on MSLT in narcolepsy | <8 | minutes | ≤2 SOREMP also required; controls average 10–20 min |
| HLA-DQB1*06:02 prevalence in type 1 | 85–95 | % of patients | vs 12–38% in general population; supports autoimmune etiology |
| Prevalence of narcolepsy type 1 | 0.025–0.05 | % of population | 25–50 per 100,000; under-diagnosed; average 8–10 year delay to diagnosis |
Orexin/Hypocretin System
The orexin system — ~70,000–90,000 neurons in the lateral hypothalamus projecting throughout the brain — is the primary stabilizer of wake states. Orexin neurons fire during wake, suppress REM-promoting cells in the brainstem, and reinforce arousal circuits (locus coeruleus, raphe nuclei, tuberomammillary nucleus, basal forebrain).
In narcolepsy type 1, these neurons are selectively destroyed — almost certainly by autoimmune T-cells, triggered in genetically susceptible individuals (HLA-DQB1*06:02) by an environmental trigger. The 2009 H1N1 pandemic vaccination with AS03-adjuvanted Pandemrix in Scandinavia produced a 5–14× increase in narcolepsy incidence in children — strong evidence for infectious/immune triggering.
The Flip-Flop Switch — Broken
Saper et al. (2001) proposed that wake and sleep are controlled by a bistable “flip-flop switch” with orexin providing the stabilizing drive. Without orexin, the switch becomes unstable:
| State | Normal | Narcolepsy |
|---|---|---|
| Wakefulness | Stable hours | Interrupted by EDS, sleep attacks |
| NREM sleep | Stable | SOREMPs (direct REM onset) |
| REM | Stable atonia | Cataplexy intrudes into wake |
Diagnostic Criteria (ICSD-3)
Narcolepsy type 1: Either (A) CSF hypocretin-1 ≤110 pg/mL OR (B) MSLT showing mean sleep latency ≤8 minutes with ≥2 SOREMPs, plus symptoms of EDS for ≥3 months. Cataplexy should be present.
Narcolepsy type 2: MSLT criteria met, CSF hypocretin normal, no cataplexy. Pathophysiology less clear; smaller orexin neuron loss hypothesized.
Treatment
No treatment restores orexin. Management is symptomatic:
- Sodium oxybate (GHB): First-line for cataplexy and EDS; consolidates nighttime sleep and reduces daytime sleep attacks by unknown mechanism
- Modafinil/armodafinil: Wake-promoting; reduces EDS; less effective for cataplexy
- Pitolisant: Histamine H3 receptor antagonist; increases endogenous histamine; approved for EDS and cataplexy
- Venlafaxine: Off-label; suppresses cataplexy via noradrenergic effect on REM atonia circuits
- Stimulants (methylphenidate, amphetamines): Older standard; effective for EDS; not for cataplexy
Related Pages
Sources
- Thannickal TC et al. — Reduced number of hypocretin neurons in human narcolepsy. Neuron (2000)
- Mignot E et al. — The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy. Arch Neurol (2002)
- Scammell TE — Narcolepsy. N Engl J Med (2015)
- Kornum BR et al. — Narcolepsy. Nat Rev Dis Primers (2017)
Frequently Asked Questions
What causes cataplexy in narcolepsy?
Cataplexy — sudden bilateral muscle weakness triggered by strong emotions (laughter, surprise, anger) — is the pathognomonic symptom of narcolepsy type 1. Normally, orexin stabilizes the flip-flop switch between wake and REM sleep states. Without orexin, the REM atonia mechanism (inhibition of motor neurons via brainstem glycinergic/GABAergic pathways) can be triggered while awake, especially when strong emotions activate the amygdala and limbic circuits. The result is tone loss ranging from jaw weakness to complete collapse, with preserved consciousness — identical to the atonia that prevents acting out dreams during REM.
How is narcolepsy diagnosed?
Diagnosis requires overnight polysomnography (to rule out other disorders like sleep apnea causing sleepiness) followed by a Multiple Sleep Latency Test (MSLT) the next day. The MSLT involves 5 nap opportunities spaced 2 hours apart. Narcolepsy type 1 diagnosis: mean sleep latency <8 minutes AND ≥2 sleep-onset REM periods (SOREMPs) OR confirmed low CSF hypocretin-1 (<110 pg/mL). The lumbar puncture for CSF is now considered sufficient for diagnosis without MSLT if cataplexy is also present.