Sleep–wake regulation
Two-process model
- Process S - homeostatic sleep drive; builds with wake time (adenosine), discharged by sleep
- Process C - circadian drive; suprachiasmatic nucleus, entrained by light via the retinohypothalamic tract -> pineal melatonin (rises ~2 h before habitual sleep onset, "dim light melatonin onset")
- Flip-flop switch - VLPO (GABA/galanin, sleep-promoting) vs ascending arousal system (orexin/hypocretin, histamine TMN, noradrenergic LC, serotonergic raphe, cholinergic PPT/LDT)
- Orexin from the lateral hypothalamus stabilises the switch - its loss (narcolepsy type 1) causes state instability in both directions: sleepiness by day, fragmented sleep at night
Sleep architecture
| Stage | EEG | Notes |
|---|---|---|
| N1 | Theta, vertex waves | Transition; ~5% |
| N2 | Sleep spindles, K complexes | ~50%; the bulk of sleep |
| N3 | Delta (slow-wave) | Front-loaded to the first half; growth hormone; parasomnias of arousal arise here |
| REM | Low-voltage mixed frequency, sawtooth waves | Muscle atonia, dreaming; back-loaded to the second half; ~20-25% |
- Cycle length ~90 min
- Ageing: dec N3, dec total sleep time, inc fragmentation, phase advance
Entities the investigations separate
Entities the investigations are used to separate
- Restless legs syndrome - an unpleasant or uncomfortable urge to move the legs (occasionally arms)
- Periodic limb movement disorder - stereotyped movements in sleep; only a disorder if it causes symptoms
- REM sleep behaviour disorder - loss of REM atonia -> dream enactment
- Narcolepsy type 1 (with cataplexy, orexin-deficient) and type 2
- OSA, central sleep apnoea, circadian rhythm sleep-wake disorders, insomnia
Epidemiology
- RLS: 5-10% of adults; F>M ~2:1; prevalence rises with age and in pregnancy (~20% third trimester)
- RBD: ~0.5-1%, M>>F (~4:1), onset >50
- Narcolepsy type 1: ~25-50 per 100,000; bimodal onset ~15 and ~35 yrs
- OSA: ~9-25% of adults by AHI criteria; symptomatic OSA far less
- Insomnia disorder ~6-10%
RLS - mechanism
RLS
- Central iron deficiency with dopaminergic dysfunction - low brain iron (a cofactor for tyrosine hydroxylase) despite sometimes normal peripheral stores
- Family history in ~50% (BTBD9, MEIS1, PTPRD)
- Secondary causes - always look
- Iron deficiency (the single most important), pregnancy, end-stage kidney disease/dialysis, peripheral neuropathy, spinal cord lesion
- Drugs that exacerbate RLS
- Antihistamines, especially sedating agents
- Dopamine antagonists - antipsychotics, metoclopramide, prochlorperazine
- Antidepressants - mirtazapine most strongly; also TCAs, SSRIs, SNRIs
- Bupropion is the antidepressant least likely to worsen RLS
- Caffeine, alcohol, nicotine
RBD - mechanism
RBD
- Loss of glutamatergic sublaterodorsal nucleus projections to the medullary magnocellular reticular formation -> REM without atonia
- An alpha-synucleinopathy in evolution in most idiopathic cases
- Secondary: narcolepsy (any age), antidepressants (SSRI, SNRI, TCA, mirtazapine), brainstem lesion, alcohol withdrawal
Narcolepsy type 1 - mechanism
Narcolepsy type 1
- Autoimmune destruction of hypothalamic orexin (hypocretin) neurones
- *HLA-DQB1\06:02 in >98%* (but present in 20-25% of the population - a poor screening test*)
- Triggers: Streptococcus, H1N1 infection and (historically) the Pandemrix vaccine
RLS - clinical diagnosis, 5 essential criteria
1. Urge to move the legs, usually with an uncomfortable sensation
2. Worse at rest or inactivity
3. Relieved by movement, at least partly, for as long as movement continues
4. Worse in the evening or at night
5. Not solely explained by another condition (leg cramps, positional discomfort, arthralgia, akathisia, neuropathy, venous stasis)
- Every patient: ferritin AND transferrin saturation (ferritin is an acute phase reactant - a "normal" ferritin with low TSAT still means iron deficiency)
- Polysomnography is NOT needed to diagnose RLS
Sleep investigations - which test answers which question
| Test | What it measures | Used for |
|---|---|---|
| Level 1 in-laboratory polysomnography | EEG, EOG, EMG (chin + limb), ECG, airflow, effort, oximetry, video | Suspected RBD (must include video + limb EMG), parasomnia, nocturnal seizure, central apnoea, OSA with comorbidity, PLMD |
| Home sleep apnoea test (level 3/4) | Airflow, effort, oximetry | Uncomplicated moderate-to-high-probability OSA only; cannot stage sleep, underestimates AHI, useless for anything but OSA |
| MSLT | 5 naps at 2-hourly intervals after a PSG night | Narcolepsy/hypersomnia: mean sleep latency <=8 min + >=2 sleep-onset REM periods (a SOREMP on the preceding PSG counts as one) |
| MWT | 4 x 40 min trials, instructed to stay awake | Fitness to drive/work - not diagnosis |
| Actigraphy (>=7-14 days) + sleep diary | Rest-activity pattern | Circadian rhythm disorders, insomnia, before MSLT to exclude sleep deprivation |
| Overnight oximetry | Desaturation | Screening only; a normal study does not exclude OSA |
- *Always exclude chronic sleep deprivation and shift work before an MSLT - insufficient sleep is the commonest cause of a "positive" test*
Key PSG numbers
Key PSG numbers
- AHI (apnoea-hypopnoea index): 5-15 mild, 15-30 moderate, >30 severe
- PLM index >15/h in adults is abnormal; only "PLMD" if it causes symptoms and no other cause
- REM without atonia = the defining PSG finding in RBD
- CSF orexin-1 <110 pg/mL confirms narcolepsy type 1 where MSLT is equivocal
Bedside tools
- Epworth Sleepiness Scale (>10 = excessive daytime sleepiness), STOP-BANG (OSA screening), International RLS Study Group severity scale
Restless legs syndrome - management
A. Restless legs syndrome
- Step 1 - correct iron and remove exacerbants
- Iron replacement if ferritin <=75 micrograms/L OR transferrin saturation <20%
- This threshold has risen - the older cutoff of 45-50 undertreats. Oral iron with vitamin C on alternate days; IV ferric carboxymaltose if oral fails, malabsorption, or dialysis
- Stop or substitute the offending drugs above
- Sleep hygiene, exercise, reduce caffeine/alcohol/nicotine
- Iron replacement if ferritin <=75 micrograms/L OR transferrin saturation <20%
- Step 2 - alpha-2-delta ligands are FIRST-LINE
- Gabapentin, pregabalin (or gabapentin enacarbil where available)
- Non-inferior to pramipexole for efficacy and do not cause augmentation**
- Caution: sedation, ataxia, weight gain, falls in the elderly; dose reduce in renal impairment
- *Dopamine agonists (pramipexole, ropinirole, rotigotine) and levodopa are NO LONGER first-line and are conditionally recommended AGAINST for routine long-term use - because of augmentation* and impulse control disorders
- Reserve for selected patients; use the lowest dose; rotigotine patch has the lowest augmentation rate
- Refractory disease - IV iron, combination therapy, low-dose methadone or oxycodone in specialist hands
- Augmentation management - symptoms earlier in the day, more intense, spreading to arms, shorter latency at rest
- Occurs after >=6 months of stable dopaminergic therapy
- Check and replete iron -> cross-taper to an alpha-2-delta ligand and withdraw the dopamine agonist; expect a transient worsening
REM sleep behaviour disorder - management
B. REM sleep behaviour disorder
- Bedroom safety first and always - remove sharp objects and firearms, pad or lower the bed, move furniture away, partner may need to sleep separately
- Stop or reduce precipitating antidepressants where possible
- Melatonin 3-12 mg nocte - first choice; better tolerated
- Clonazepam 0.25-1 mg nocte - effective but falls, sedation, cognitive impairment, worsens comorbid OSA
- Counselling about neurodegenerative risk - do it, but at the patient's pace; offer surveillance and research/trial enrolment
Narcolepsy - management
C. Narcolepsy
- Scheduled naps + regular sleep schedule in everyone
- Alerting agents: modafinil/armodafinil first-line; solriamfetol, pitolisant (H3 inverse agonist), dexamfetamine/methylphenidate
- Sodium oxybate for cataplexy + disrupted nocturnal sleep + sleepiness (the only agent that treats all three)
- Cataplexy - sodium oxybate, pitolisant, venlafaxine or clomipramine (never stop abruptly - status cataplecticus)
- Driving and workplace safety - mandatory discussion and reporting per Austroads criteria
General
D. General
- Treat comorbid OSA before attributing residual sleepiness to anything else
- Circadian disorders: timed light exposure + timed melatonin; shift-work planning
- Chronic insomnia: CBT-I is first-line, not hypnotics
Associations
- RLS - iron deficiency, pregnancy, end-stage kidney disease, peripheral neuropathy, Parkinson disease, MS, coeliac disease, ADHD
- RBD - Parkinson disease, dementia with Lewy bodies, multiple system atrophy, narcolepsy, antidepressant use, brainstem lesions
- Narcolepsy type 1 - *HLA-DQB1\06:02**, obesity, precocious puberty, ADHD, depression
- OSA - obesity, hypertension (esp. resistant), AF, stroke, T2DM, pulmonary hypertension, retinopathy, acromegaly, hypothyroidism
- Circadian disruption - shift work; associated with metabolic syndrome and breast/colorectal cancer risk
RBD - the most examinable prognostic fact in sleep medicine
- Phenoconversion to a neurodegenerative synucleinopathy
- ~18-35% at 5 years
- ~40-75% at 10 years
- Continues to rise thereafter (>80% at 12-14 years in cohort studies)
- Most often Parkinson disease, dementia with Lewy bodies, or multiple system atrophy
- *RBD is currently the strongest clinical prodromal marker of synucleinopathy - a tauopathy such as PSP or Alzheimer disease is NOT the expected outcome*
- Markers of earlier conversion: olfactory loss, subtle motor signs, colour vision impairment, constipation, orthostatic hypotension, abnormal DaT scan
RLS - course
RLS
- Chronic, fluctuating, generally progressive; remits after delivery in pregnancy-related disease and after transplantation in ESKD
- Augmentation is the major iatrogenic complication - the reason the guideline changed
- Consequences: sleep-onset insomnia, daytime fatigue, depression, hypertension
Narcolepsy - course
Narcolepsy
- Lifelong; sleepiness stable, cataplexy may lessen with age
- Weight gain, depression and social/occupational impairment are major morbidities
Monitor
- RLS: severity score, ferritin/TSAT annually, specifically screen for augmentation and impulse control disorders at every visit if on a dopamine agonist
- RBD: injuries to patient or partner, annual motor/cognitive/autonomic review
- Narcolepsy: MWT for driving, BP and weight on stimulants, sodium load on oxybate
🔒
19 more sections, plus exam facts
Premium unlocks every note across every specialty, and the full exam fact library behind it.
Get premium access