Def: chronic neurological dz caused by extensive loss of hypothalamic orexin (hypocretin) A and B neurons
Cardinal features
- Persistent EDS: mandatory
- Cataplexy: REM atonia of voluntary muscles intruding into wakefulness
Can be partial (face, limbs) or complete (whole body)
Triggered by positive or negative emotion: laughter, surprise, anger, frustration - Sleep paralysis: whole-body REM atonia at sleep onset, during arousal or on waking
- Hypnagogic (sleep onset) and hypnopompic (waking) hallucinations: dreaming while awake
Other features
Disturbed nighttime sleep with increased N1
Brief naps of minutes are usually refreshing
Comorbid sleep d/o: RBD, OSA, PLMS
Depression and anxiety, cause unclear: QoL impact or neurochemical changes
Epidemiology: Prevalence 1 per 2000-4000 (0.025-0.05%) worldwide
Bimodal onset: peak ~15 yrs, smaller peak at 30-40 yrs
Pathophysiology
Autoimmune destruction of orexin neurons in lateral hypothalamus
Genetic susceptibility HLA-DQB1*06:02 plus environmental trigger (infection, H1N1 vaccine)
CSF orexin-A (hypocretin-1) low (<110 pg/mL) or undetectable
Onset more common in spring after winter infections
Increase in NT1 after Pandemrix H1N1 vaccine
Dx criteria (ICSD-3, 1 and 2 required)
- Daily irrepressible need to sleep or daytime lapses into sleep for ≥3 months
- One or both of:
a. Cataplexy + MSLT with MSL ≤8 min and ≥2 SOREMPs
b. CSF hypocretin-1 ≤110 pg/mL or <1/3 of normal mean with same assay
SOREMP = REM within 15 min of sleep onset
A SOREMP on the preceding PSG can replace 1 MSLT SOREMP
ICSD-3-TR: cataplexy + nocturnal SOREMP on PSG alone can confirm NT1
MSLT protocol
Perform immediately after overnight PSG with ≥6 hrs sleep
Preceded by ≥1 wk of actigraphy or sleep diary to rule out sleep deprivation, shift work, circadian d/o
Off sleep-affecting meds ≥14 days, confirm with UDS
Treatment
Non-pharm: Sleep hygiene, Scheduled naps help EDS, but meds usually also needed. Liaise with schools with pt consent. Exam accommodations: supervision for sleepiness, breaks for short naps. Driving: allowed once sx well controlled
Pharm
AASM 2021 strong recs: modafinil, pitolisant, sodium oxybate, solriamfetol
Wake-promoting agents
Stimulants: methylphenidate, dextroamphetamine 10-60 mg/day in 2-3 divided doses or once daily ER
Solriamfetol 75-150 mg qAM, FDA approved for EDS in narcolepsy
Anticataplectic agents
Suppress REM, also help sleep paralysis and hypnagogic hallucinations
Venlafaxine 37.5-75 mg BID or ER 37.5-150 mg qAM
Agents for both EDS and cataplexy
Sodium oxybate: low-sodium oxybate (Xywav) and once-nightly sodium oxybate (Lumryz) also FDA approved
Pitolisant: H3 inverse agonist
Orexin receptor agonists in late-stage development
Differential dx
Pseudo-cataplexy: laughing hard, hypotension, psych d/o
Other causes of EDS: psych d/o, drug misuse, chronic fatigue syndrome
Central hypersomnias: all require daily EDS ≥3 months (except KLS) and not better explained by another condition or meds
- Oxford Handbook of Sleep Medicine 2022