Sleep Disorders
Sleep Disorders
What You'll Learn
- N2 dominates sleep (45–55%); K-complexes + sleep spindles are the defining features
- Narcolepsy Type 1: CSF hypocretin-1 ≤110 pg/mL is diagnostic; autoimmune loss of orexin neurons. HLA-DQB1*06:02 is strongly associated but NOT diagnostic (12–25% of the general population also carry it).
- MSLT: mean sleep latency ≤8 min + ≥2 SOREMPs; must stop REM-suppressing meds ≥2 weeks before
- RBD: strongest prodromal marker for alpha-synucleinopathy — multicenter data (Postuma) show ~6% per year and ~73.5% at 12 years; risk continues to rise with longer follow-up
- RLS: check ferritin in ALL patients; supplement if <75 ng/mL; alpha-2-delta ligands are first-line (not dopamine agonists — augmentation risk)
- OSA: independent stroke risk factor; AHI ≥30 = severe; CPAP is first-line
- Fatal familial insomnia: PRNP D178N-129M, thalamic degeneration, progressive insomnia → death
HighYield Pearls
- Narcolepsy type 1 = cataplexy + CSF hypocretin-1 ≤110 pg/mL: autoimmune loss of lateral hypothalamic orexin neurons; HLA-DQB1*06:02 is strongly associated but NOT diagnostic (12–25% of general population are carriers); post-H1N1 Pandemrix vaccine link in Europe
- MSLT criteria: mean sleep latency ≤8 min + ≥2 SOREMPs (sleep-onset REM on overnight PSG counts as one); stop REM-suppressing meds (SSRIs, SNRIs, TCAs) ≥2 weeks before
- Idiopathic hypersomnia vs narcolepsy: both have MSLT ≤8 min, but IH has NO SOREMPs and unrefreshing long sleep
- RBD → α-synucleinopathy: ~6%/yr conversion and ~73.5% at 12 years (Postuma multicenter); risk continues to rise with longer follow-up; PSG shows REM sleep without atonia; melatonin first-line, clonazepam second + safety counseling
- NREM parasomnias (sleep terrors, sleepwalking, confusional arousals): first third of night out of N3 slow-wave, amnestic, family history — vs RBD which is late-night REM with recall
- RLS workup: check ferritin in ALL patients, repletion if <75 ng/mL; α-2-δ ligands (gabapentin enacarbil, pregabalin) first-line — dopamine agonists risk augmentation + impulse-control disorders
- OSA: AHI ≥5 mild, ≥15 moderate, ≥30 severe; independent risk for HTN, AF, stroke, MI; CPAP first-line
- ASV CONTRAINDICATED in symptomatic chronic HF with LVEF ≤45% AND moderate/severe predominant central sleep apnea (SERVE-HF trial — increased mortality)
- Insomnia: CBT-I is first-line (not benzos); DORAs (suvorexant, lemborexant), low-dose doxepin, ramelteon are safer chronic options
- Fatal familial insomnia: prion PRNP D178N-129M, thalamic degeneration, dysautonomia, fatal within 1–2 yr — vs anti-IgLON5 (tauopathy with parasomnia + bulbar + sleep-disordered breathing, immunotherapy-responsive)
🔍 Quick ReferenceClinical · PSG / MSLT · Treatment
Clinical phenotype
- Sudden loss of muscle tone triggered by laughter / emotion → cataplexy — narcolepsy type 1
- Dream enactment, punching / kicking bed partner, recalled dream content → REM sleep behavior disorder (RBD)
- Child screaming inconsolably in first third of night, amnestic next morning → sleep terrors (NREM N3 parasomnia)
- Urge to move legs at rest, relieved by movement, worse evening → restless legs syndrome (RLS)
- Adolescent with recurrent episodes of hypersomnia + hyperphagia + hypersexuality → Kleine-Levin syndrome
- Parasomnia + bulbar + sleep-disordered breathing + cognitive decline, tauopathy at autopsy → anti-IgLON5 disease
- Progressive insomnia + dysautonomia + ataxia, fatal within 1–2 yr, family history → fatal familial insomnia (PRNP D178N)
- Delayed sleep phase adolescent — can’t fall asleep until 2–3 AM, sleeps in late → DSPD
PSG / MSLT / labs
- CSF hypocretin-1 ≤110 pg/mL → narcolepsy type 1
- MSLT: mean sleep latency ≤8 min + ≥2 SOREMPs → narcolepsy
- MSLT ≤8 min with 0 SOREMPs + long unrefreshing sleep → idiopathic hypersomnia
- REM sleep without atonia on PSG → RBD
- Periodic limb movements >15/hr with arousals → PLMD
- AHI ≥5 with obstructive events + daytime sleepiness → OSA
- Crescendo-decrescendo breathing with central apneas in HFrEF / post-stroke → Cheyne-Stokes CSA
- Ferritin <75 ng/mL in patient with leg restlessness → iron-deficient RLS
- HLA-DQB1*06:02 positive → strongly associated with narcolepsy type 1, but NOT diagnostic (12–25% of general population carry it)
Treatment / pearls
- Modafinil / armodafinil / pitolisant (H3 inverse agonist) / solriamfetol → narcolepsy daytime sleepiness
- Sodium oxybate / low-sodium oxybate (night-dosed ×2) and pitolisant (≥6 yr) → FDA-labeled for BOTH EDS and cataplexy in narcolepsy
- Melatonin first-line, clonazepam second + bedroom safety → RBD
- CPAP first-line; oral appliance / weight loss / upper-airway surgery → OSA
- ASV CONTRAINDICATED if LVEF ≤45% AND moderate/severe predominant central sleep apnea (SERVE-HF) → chronic symptomatic HF with predominant CSA
- Gabapentin enacarbil / pregabalin first-line; avoid dopamine agonists (augmentation, ICD) → RLS
- CBT-I first-line; DORAs (suvorexant, lemborexant), low-dose doxepin, ramelteon → chronic insomnia — avoid chronic benzodiazepines
- Bright light AM + melatonin PM → delayed sleep phase disorder (DSPD)
- Immunotherapy → anti-IgLON5 disease
Normal Sleep Architecture
Sleep Stages
| Stage | EEG Pattern | Key Features | % Total Sleep |
|---|---|---|---|
| Wake | Alpha (8–13 Hz, posterior) & Beta (>13 Hz) | Eyes open = beta; eyes closed = alpha | — |
| N1 | Theta (4–7 Hz) | Vertex sharp waves; easy to arouse | 5% |
| N2 | Theta background | K-complexes + sleep spindles (11–16 Hz, typically 12–14 Hz) | 45–55% |
| N3 (SWS) | Delta (0.5–2 Hz, ≥75 μV peak-to-peak) | N3 = ≥20% of epoch with slow-wave activity | 15–20% |
| REM | Low-voltage mixed frequency | Sawtooth waves, muscle atonia, REMs | 20–25% |
Sleep Cycle & Distribution
- Sleep cycles last ~90 minutes, 4–6 cycles per night
- N3 predominates early night (first 1–2 cycles); REM predominates late night (last 1–2 cycles)
- REM periods lengthen across the night; N3 periods shorten
Sleep Regulation: Two-Process Model
| Process | Mechanism | Key Molecule/Structure |
|---|---|---|
| Process S (Homeostatic) | Sleep pressure builds with waking | Adenosine accumulation (caffeine = adenosine antagonist) |
| Process C (Circadian) | ~24-hour internal clock | SCN → pineal gland → melatonin |
Key Neurotransmitters
| Function | Neurotransmitters | Source |
|---|---|---|
| Wake-promoting | Orexin/hypocretin | Lateral hypothalamus |
| Histamine | Tuberomammillary nucleus (TMN) | |
| Norepinephrine | Locus coeruleus (LC) | |
| Serotonin | Dorsal raphe | |
| Acetylcholine | Basal forebrain, PPT/LDT | |
| Dopamine | VTA, vPAG | |
| Sleep-promoting | GABA, galanin | VLPO (ventrolateral preoptic area) |
REM Switch
| REM-On | REM-Off |
|---|---|
| Cholinergic — PPT/LDT (pedunculopontine/laterodorsal tegmentum) | Noradrenergic — locus coeruleus |
| Glutamatergic — sublaterodorsal nucleus (SLD) | Serotonergic — dorsal raphe |
💎 Board Pearl
- K-complexes + sleep spindles = N2 — the most common sleep-staging question on boards
- Sawtooth waves are specific to REM; vertex sharp waves = N1
- VLPO is the “sleep switch” — lesions cause insomnia (flip-flop model with orexin stabilization)
Narcolepsy
Type 1 vs Type 2
| Feature | Narcolepsy Type 1 | Narcolepsy Type 2 |
|---|---|---|
| Cataplexy | Present (pathognomonic) | Absent |
| CSF hypocretin-1 | ≤110 pg/mL (or <1/3 normal) | Normal (>110 pg/mL) |
| HLA-DQB1*06:02 | Strongly associated (very common in narcolepsy-cataplexy cohorts); NOT diagnostic — 12–25% of general population are carriers | ~50% |
| MSLT | ≤8 min + ≥2 SOREMPs | ≤8 min + ≥2 SOREMPs |
| Pathophysiology | Autoimmune loss of orexin neurons (lateral hypothalamus) | Unknown; partial orexin deficiency? |
| Prognosis | Lifelong; does not remit | May remit or evolve to Type 1 |
Classic Pentad (Type 1)
- Excessive daytime sleepiness — most common and earliest symptom (100%)
- Cataplexy — sudden loss of muscle tone triggered by emotion (especially laughter); consciousness preserved
- Hypnagogic/hypnopompic hallucinations — vivid, dream-like imagery at sleep onset/offset
- Sleep paralysis — inability to move at sleep-wake transitions
- Disrupted nocturnal sleep — frequent awakenings
Diagnosis
- CSF hypocretin-1 ≤110 pg/mL: diagnostic for Type 1 regardless of MSLT result (most specific test)
- MSLT criteria: mean sleep latency ≤8 min + ≥2 SOREMPs
- A SOREMP on preceding nocturnal PSG counts as one of the required 2
- Must stop REM-suppressing medications (SSRIs, SNRIs, TCAs) ≥2 weeks prior (longer for fluoxetine due to norfluoxetine half-life — up to 4–6 weeks)
- HLA-DQB1*06:02 is sensitive but NOT specific (~12–25% of general population positive) — not used for diagnosis
Treatment
| Target | Medications | Notes |
|---|---|---|
| EDS | Modafinil/armodafinil | First-line; dopamine reuptake inhibitor |
| Solriamfetol | Dual dopamine/NE reuptake inhibitor | |
| Pitolisant | H3 receptor inverse agonist (promotes histamine release) | |
| Methylphenidate, amphetamines | Traditional stimulants; second-line | |
| Cataplexy | Sodium oxybate (Xyrem) | Also improves EDS + nocturnal sleep; given at bedtime + 2.5–4 h later |
| Venlafaxine / other SNRIs | REM-suppressing; off-label for cataplexy | |
| TCAs (clomipramine) | Anticholinergic side effects limit use | |
| Both EDS + cataplexy | Sodium oxybate (Xyrem) | FDA-labeled for both EDS and cataplexy; Schedule III controlled |
| Low-sodium oxybate (Xywav) | FDA-labeled for both; same efficacy, less sodium | |
| Pitolisant (Wakix) | H3 inverse agonist; FDA-labeled for both EDS and cataplexy in patients ≥6 years with narcolepsy |
💎 Board Pearl
- Low CSF hypocretin-1 (≤110 pg/mL) is the most specific test for narcolepsy Type 1 — diagnostic even without MSLT
- Sodium oxybate, low-sodium oxybate, and pitolisant are FDA-labeled for both EDS and cataplexy in narcolepsy (pitolisant ≥6 years); solriamfetol and modafinil are EDS-only; antidepressants are commonly used off-label for cataplexy
- Cataplexy triggered by laughter in a young patient = narcolepsy Type 1 until proven otherwise
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