RespiratoryTier 2Disease (DEADMAN)

Sleep disorders - restless legs syndrome and periodic limb movements of sleep

Description

Restless legs syndrome (RLS, Willis-Ekbom disease)

A clinical, sensorimotor diagnosis. URGE mnemonic - all five essential criteria required:

U - Urge to move the legs, usually with an unpleasant sensation ("crawling", "electric", "fizzy" - not pain, not paraesthesia)
R - Rest worsens it (inactivity, sitting, lying)
G - Gets better with movement, at least partially, for as long as movement continues
E - Evening/night worsening (circadian, independent of activity)
Plus: not solely explained by another condition (leg cramps, positional discomfort, arthralgia, neuropathy, akathisia)

Periodic limb movements of sleep (PLMS)

Repetitive stereotyped limb movements during sleep - dorsiflexion of the great toe and ankle, sometimes knee/hip
Duration 0.5-10 s, recurring every 5-90 s, in runs of >=4
A polysomnographic finding, not a diagnosis
- PLM index (PLMI) = movements per hour of sleep; >15/h in adults is abnormal
*Periodic limb movement disorder (PLMD) = PLMS + sleep disturbance or daytime impairment with no other cause (a diagnosis of exclusion; rare*)
*PLMS occur in 80-90% of RLS - but PLMS is common and usually asymptomatic. Do not call every PLMI >15 a disorder*

Epidemiology

RLS prevalence 5-10% of adults of European ancestry; lower in Asian populations
F>M (~2:1); rises with age; ~2-3% have clinically significant symptoms requiring treatment
Familial in ~50% of early-onset cases (<45 yr) - autosomal dominant with variable penetrance
PLMS prevalence: ~5-6% of young adults, >45% of people over 65 - age alone explains most of it
Pregnancy: RLS in ~20%, usually third trimester, resolves after delivery

Aetiopathogenesis

The central mechanism: brain iron deficiency -> dopaminergic dysfunction

Iron is the rate-limiting cofactor for tyrosine hydroxylase (the rate-limiting enzyme in dopamine synthesis)
Low brain iron (substantia nigra, putamen) -> altered striatal D2 receptor function and circadian dopamine variation
-> explains the evening worsening (dopamine is lowest at night) and the response to dopaminergic drugs and to iron
*Brain iron deficiency can exist with normal peripheral iron stores - and ferritin can be normal-range and still too low*
Additional: glutamatergic hyperarousal (the basis of alpha-2-delta ligand efficacy), spinal cord hyperexcitability, genetic loci (BTBD9, MEIS1, MAP2K5, PTPRD)

Secondary causes - screen for every one

*Iron deficiency - including low ferritin without anaemia*; the single most important reversible cause
Chronic kidney disease / dialysis (prevalence 20-30%; improves after transplant)
Pregnancy (third trimester)
Peripheral neuropathy, radiculopathy, spinal cord lesions
Diabetes, thyroid disease, rheumatoid arthritis, Parkinson disease, MS
Drugs
- Antidepressants - SSRIs, SNRIs, TCAs, mirtazapine (mirtazapine is the worst offender)
- Antipsychotics and antiemetics - dopamine antagonists (metoclopramide, prochlorperazine)
- Antihistamines (sedating, e.g. diphenhydramine)
- Lithium, tramadol withdrawal
- Bupropion and desvenlafaxine are the least likely to worsen RLS
Caffeine, alcohol, nicotine, sleep deprivation

Diagnosis

Diagnosis is clinical - no test confirms RLS

Apply the five URGE criteria
Assess severity: International RLS Study Group Rating Scale (IRLS); frequency, impact on sleep and daytime function
Suggested immobilisation test rarely needed

Investigations - to find the secondary cause

*Iron studies: ferritin AND transferrin saturation* - the mandatory test
- Treat if ferritin <=75 micrograms/L or transferrin saturation <20%
- Note the threshold is far above the usual "iron deficiency" cutoff - RLS is a brain iron problem
- Ferritin is an acute phase reactant - interpret with CRP
UEC, eGFR, glucose/HbA1c, TSH, B12, folate
Full medication review - the highest-yield step
Polysomnography only if: OSA is suspected, the diagnosis is uncertain, symptoms are refractory, or in medico-legal/occupational assessment
- Not needed to diagnose RLS

Differential

Condition	Discriminator
Akathisia	Generalised inner restlessness, not confined to legs, no circadian pattern, no relief with movement; drug-induced (antipsychotics)
Nocturnal leg cramps	Painful, palpable muscle contraction, relieved by stretching, focal
Peripheral neuropathy	Burning/numbness, no urge to move, no circadian pattern, stocking distribution
Positional discomfort	Relieved by a single position change
Vascular claudication	Brought on by exercise, relieved by rest - the opposite pattern
Anxiety/fidgeting	No sensory component
Hypnic jerks	Single, at sleep onset

Management

A. Non-pharmacological and reversible causes - always first

Correct iron deficiency (see below) - may resolve symptoms entirely
Stop or substitute the offending drug - antidepressants, antipsychotics, antihistamines, dopamine antagonists
Reduce caffeine, alcohol, nicotine; regular sleep schedule; moderate exercise (not late at night)
Treat coexisting OSA - improves RLS
Counter-stimulation: massage, stretching, hot/cold, pneumatic compression, walking

B. Iron repletion - a first-line treatment, not just a correction

Oral iron if ferritin <=75 and tolerated: elemental iron with vitamin C, on alternate days, on an empty stomach - alternate-day dosing avoids hepcidin-mediated blockade
IV iron (ferric carboxymaltose) where oral iron fails, is not tolerated, in CKD, or where rapid response is needed
- Recommended in the 2024 AASM guideline; effect may take 4-6 weeks
Recheck ferritin at 3 months

C. Pharmacotherapy - *the recommendations reversed in 2024*

	Agent	Status
First-line	Gabapentin enacarbil (then gabapentin, pregabalin)	Strong recommendation. Alpha-2-delta calcium channel ligands
	IV and oral iron	Recommended
*Recommended AGAINST for long-term use*	Pramipexole, ropinirole, rotigotine, levodopa	*Conditional recommendation against - unacceptable augmentation* risk
Selected refractory	Low-dose opioid (methadone, oxycodone)	Specialist use only, in a monitored program
Other	Dipyridamole, bilateral high-frequency peroneal nerve stimulation	Emerging

This is a genuine reversal: dopamine agonists were first-line for two decades and are now discouraged for chronic use
Alpha-2-delta ligands: start low at night, titrate; adverse effects - sedation, dizziness, weight gain, ankle oedema, cognitive slowing; reduce dose in renal impairment
In CKD/dialysis - alpha-2-delta ligands need substantial dose reduction; consider IV iron and treat the uraemia

D. *Augmentation* - the key concept to know

Paradoxical worsening of RLS caused by long-term dopaminergic therapy:

Earlier onset in the day
Shorter latency to symptoms at rest
Spread to arms and trunk
Greater intensity, and a paradoxical worsening with each dose increase
Incidence ~7-10% per year of dopamine agonist use; higher with levodopa and higher doses
Management: exclude and correct iron deficiency, then cross-taper to an alpha-2-delta ligand; withdraw the dopamine agonist slowly (expect a rebound period of 1-2 weeks); low-dose opioid may be needed as a bridge
Do not escalate the dopamine agonist dose in response to worsening symptoms - that is the trap

E. Pregnancy

Non-pharmacological measures plus iron repletion are the mainstay
Most drugs avoided; usually resolves within days of delivery

F. PLMS/PLMD

Treat only if the movements are genuinely causing sleep disruption and no other cause is found
Same agents as RLS; the evidence base is much weaker
Reducing the PLM index is not itself a therapeutic goal

Associations

Iron deficiency (incl. blood donors, coeliac disease, menorrhagia, GI blood loss - investigate the cause**)
Chronic kidney disease and dialysis
Pregnancy
Peripheral neuropathy, radiculopathy, spinal cord disease, multiple sclerosis
Parkinson disease - coexists but is a distinct entity; RLS does not predict PD, unlike RBD
ADHD in children - shared dopaminergic mechanism; screen for iron deficiency in both
Cardiovascular disease and hypertension - PLMS cause repetitive nocturnal sympathetic surges with BP and heart rate rises (association; causality unproven)
Obstructive sleep apnoea - PLMS often emerge or are unmasked after CPAP starts
Depression and insomnia - bidirectional; and their treatments worsen RLS

Natural history & complications

Early-onset (<45 yr) familial disease: slowly progressive over decades, often with long remissions
Late-onset disease: more rapidly progressive, more often secondary
Secondary RLS (iron deficiency, pregnancy, CKD post-transplant): resolves when the cause is corrected
Spontaneous remissions of months are common - do not attribute every improvement to the drug

Complications

Chronic sleep-onset and sleep-maintenance insomnia -> daytime fatigue, impaired concentration, reduced quality of life
Depression and anxiety
Augmentation from dopaminergic therapy - the commonest iatrogenic complication
Impulse control disorders from dopamine agonists (pathological gambling, hypersexuality, compulsive shopping - ask directly; patients do not volunteer this)
Opioid dependence in refractory disease
Bed-partner sleep disruption

Monitoring

IRLS score and sleep quality at each review
Ferritin annually (and with any symptom change)
Actively ask about augmentation features in anyone still taking a dopamine agonist

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