Key Facts

Narcolepsy is a chronic, debilitating condition often diagnosed years after onset. Type 1 is caused by autoimmune loss of hypocretin neurones. Appropriate pharmacological management can significantly improve quality of life.

Epidemiology

Prevalence ~25-50 per 100,000. Onset typically 10-20 years (bimodal: peak at 15 and 35). Equal sex distribution. Significant diagnostic delay (~8-10 years from onset to diagnosis).

Aetiology

• Type 1: autoimmune destruction of hypocretin (orexin)-producing neurones in the lateral hypothalamus
• Strong HLA association: HLA-DQB106:02 (>98% of type 1; necessary but not sufficient — only ~0.04% of HLA-DQB106:02 carriers develop narcolepsy)
• Environmental trigger: H1N1 influenza infection, Pandemrix vaccine (adjuvanted H1N1 vaccine — increased incidence in 2009-2010)
• T-cell mediated destruction of hypocretin neurones (CD8+ T cells targeting hypocretin peptides)
• Type 2: normal CSF hypocretin; pathophysiology less clear

Pathophysiology

Hypocretin (orexin) is produced by ~70,000 neurones in the lateral hypothalamus. These neurones stabilise the sleep-wake switch (flip-flop model). Loss of hypocretin → unstable boundary between wake and sleep states → intrusion of REM sleep phenomena into wakefulness (cataplexy = REM atonia while awake; hallucinations = REM dreams while awake; sleep paralysis = REM atonia during wake transition). Also causes fragmented nocturnal sleep.

Excessive Daytime Sleepiness (100%)

• Overwhelming, irresistible urge to sleep; inappropriate sleep attacks
• Brief naps (10-20 min) are refreshing (vs non-refreshing in other hypersomnias)
• Impairs work, education, social function, driving

Cataplexy (~70% of Type 1)

• Sudden loss of muscle tone triggered by strong emotions (laughter, surprise, anger)
• Ranges from subtle (jaw drop, head nod, knee buckling) to complete collapse
• Consciousness preserved throughout
• Duration: seconds to minutes
• Pathognomonic for narcolepsy type 1

Sleep Paralysis (~25-50%)

• Inability to move on waking or falling asleep; lasts seconds-minutes
• Often frightening; may occur with hallucinations
• Also occurs in ~8% of general population (isolated sleep paralysis)

Hypnagogic/Hypnopompic Hallucinations (~30-60%)

• Vivid, often frightening hallucinations at sleep onset (hypnagogic) or on waking (hypnopompic)
• Visual, auditory, or tactile

Other

• Fragmented nocturnal sleep
• Automatic behaviours (continuing activities in semi-sleep state)
• Weight gain (hypocretin deficiency → metabolic effects)
• Depression, anxiety (common comorbidity)

Red Flags

• Excessive sleepiness in young person → consider narcolepsy
• Cataplexy triggered by emotions → diagnostic of type 1
• Secondary narcolepsy: hypothalamic lesion (tumour, sarcoidosis, MS) → MRI brain

Sleep Studies

• Polysomnography (PSG): overnight; excludes OSA; demonstrates fragmented sleep; may show sleep-onset REM period
• Multiple Sleep Latency Test (MSLT): performed day after PSG; 5 nap opportunities at 2-hour intervals; diagnostic: mean sleep latency ≤8 minutes + ≥2 SOREMPs (sleep-onset REM periods within 15 minutes)

CSF

• Hypocretin-1 (orexin-A): <110 pg/mL (or <1/3 of mean normal) — diagnostic for narcolepsy type 1; >90% sensitivity and specificity; does not require sleep study

Bloods

• HLA typing: HLA-DQB1*06:02 — supportive (not diagnostic; present in 25% general population)

Imaging

• MRI brain: exclude hypothalamic lesion (secondary narcolepsy)

Questionnaires

• Epworth Sleepiness Scale: ≥11/24 = excessive sleepiness (non-specific)
• Stanford Narcolepsy Questionnaire: cataplexy-specific questions

Non-Pharmacological

• Sleep hygiene: regular sleep schedule, adequate nocturnal sleep (7-9 hours)
• Scheduled daytime naps (10-20 min): reduces sleep attacks
• Workplace/school accommodations
• Driving: must notify DVLA; may be able to drive if well-controlled (specialist assessment)
• Patient education: Narcolepsy UK support

Pharmacological — EDS

• Modafinil 100-400mg/day (morning ± midday): first-line wake-promoting agent; mechanism unclear; NICE recommended
• Pitolisant 4.5-36mg OD: histamine H3 inverse agonist; promotes wakefulness; NICE TA764
• Sodium oxybate (Xyrem) 4.5-9g/night in 2 divided doses: consolidated nocturnal sleep → reduced EDS; also treats cataplexy; controlled drug; NICE TA761
• Dexamfetamine 5-60mg/day: if modafinil ineffective; controlled drug
• Solriamfetol: DRIS (dopamine/norepinephrine reuptake inhibitor); emerging

Pharmacological — Cataplexy

• Sodium oxybate: most effective for cataplexy (dose-dependent response)
• Antidepressants: venlafaxine 37.5-225mg/day, clomipramine 10-75mg/day (suppress REM → reduce cataplexy); off-label
• Pitolisant: also reduces cataplexy

Referral Criteria

• All suspected narcolepsy: sleep medicine specialist/neurology
• Driving: occupational health/DVLA assessment
• Paediatric: specialist paediatric sleep centre

Narcolepsy is a lifelong condition with no cure. Symptoms typically stabilise after onset but do not remit. EDS is the most disabling symptom. Cataplexy may decrease in frequency over decades. With appropriate treatment, most patients can lead productive lives. Driving restrictions apply (DVLA Group 1: may drive if controlled and satisfactory specialist report). Psychosocial impact is significant — depression in ~30%, social stigma, employment difficulties.

Narcolepsy Type 1 vs Type 2

MSLT Interpretation