Restless leg syndrome

Dr Parag MoonSenior resident,

Dept. Of NeurologyGMC, Kota.

Ekbom syndrome aka Anxietas tibiarum Leg jitters- colloquial term Periodic limb movements in sleep (PLMS) Motor counterpart of RLS Formerly nocturnal myoclonus and periodic

leg movements in sleep.

Restless leg syndrome

Affects about 10% of adults Approximately one third-symptoms prior to

age of 18 Prevalence-increases with age More common in females Family history-frequently in those who

experience early symptoms.

Epidemiology

Early-onset RLS-starts before age of 45 years, progress gradually.

Late-onset RLS-advances more quickly and occurs more often.

Primary RLS- occurs independently of other disorders.

Secondary RLS- precipitated by other disorders and resolves when other disorders treated.

Types

May be secondary to-◦ Iron deficiency, vit. B12 deficiency◦ Pregnancy◦ End stage renal disease (ESRD)◦ Diabetes◦ Hypothyroidism ◦ Rheumatoid arthritis◦ Sjogren syndrome◦ Peripheral neuropathy◦ Parkinson disease◦ Drugs (antidepressants, antipsychotics, lithium etc.)

Diphenhydramine Metoclopramide Prochlorperazine Chlordiazepoxide Traditional antipsychotics (phenothiazines) Atypical neuroleptics (olanzapine and risperidone) Antidepressants (especially norepinehrine or selective

serotonin reuptake inhibitors) Anticonvulsants (zonisamide, phenytoin,

methsuximide) Antihistamines Opiods

Drugs that exacerbrate RLS

Characterised-irresistible urge to move legs especially at rest.

Symptoms worsen in evening and night and improve with activity such as walking.

Sensations described as crawling, pins and needles, tingling, prickly, painful, or worming or other indescribable feelings in their legs.

May simply have a need to move. Sensation decreased by movement,

massaging.

Clinical features

Rarely occur on arms Can cause sleep disturbances Most have mild or intermittent symptoms 30 percent-moderate to severe symptoms. Severe-15 days or more per month. Often associated with depression and

anxiety Can have negative effect on quality of life.

Clinical features

Periodic limb movements of sleep (PLM or PLMS)

Brief repetitive movements Mostly of legs Occur every 20-40 seconds. Often present in RLS patients Initial jerk followed by tonic spasm. Dorsiflexion of big toe, foot and even leg Occurs during stage I and II of sleep

Clinical features

Underlying causes of RLS or PLMS remain unclear Central dopaminergic system, particularly

striatonigral system, implicated Hypothesis supported by beneficial effects of

dopaminergic agents SPECT and PET-reduced striatal D2 receptor

binding using123I-IBZM and 11C-raclopride. 18F-DOPA PET-decrease in striatal18F-DOPA uptake Decrease in cerebral blood flow in caudate nuclei

and increase in anterior cingulate gyrus-familial RLS.

Pathophysiology

Reduced CSF ferritin and increased transferrin concentrations in idiopathic RLS

Serum iron concentrations exhibit circadian variation with up to 50% drop in iron concentration at night

Iron-cofactor for hydroxylation of tyrosine hydroxylase-rate limiting enzyme for dopamine production.

Pathophysiology

PLMS and spinal flexor reflexes share common spinal origin

Disinhibition of reticulospinal excitatory responses may lead to pathological recruitment of spinal motor neurons.

Spinal flexor reflexes seem to be under partial dopaminergic control and levodopa depresses both facilitatory and inhibitory flexor reflex afferents.

Pathophysiology

Coexistence of RLS and Parkinson's disease is controversial

Increased PLM index-reported in untreated patients with Parkinson's disease.

Misdiagnosis of RLS-nocturnal dyskinesias and akathisia in PD

Genetic basis for RLS-positive family history in 63%-92% & autosomal dominant pattern of inheritance

Associated with spinocerebellar ataxia (type 3).

Pathophysiology

Panic attacks Akathisia Painful legs and moving toes syndrome-similar

distribution but not relieved by movement. “Vesper’s curse”-associated with congestive heart

failure, in which engorgement of lumbar veins at night brings transient stenosis of lumbar cord causing nocturnal pain in lower limbs extending to lumbosacral region.

Polyneuropathies Meralgia paraesthetica Sleep onset myoclonus and nocturnal myoclonus

Differential diagnosis

Essential criteria Urge to move or Urge to move legs, usually

accompanied/caused by uncomfortable/ unpleasant sensations in legs.

Unpleasant sensations begin or worsen during periods of rest or inactivity.

Urge to move or unpleasant sensations are partially/totally relieved by movement, at least as long as activity continues.

Urge to move or unpleasant sensations worse in evening/night than during day, or only occur in evening/night.

Diagnostic criteria

Positive family history of RLS. Positive response to dopaminergic Drugs. PLMS as assessed with polysomnography or

leg activity devices.

Supportive criteria

Natural clinical course of disorder. Sleep disorders-frequent but unspecific

symptom of the RLS. Medical evaluation/physical examination:

neurological examination usually normal. Probable causes for secondary RLS should

be excluded.

Associated features

POLYSOMNOGRAPHY Records PLMS Correlates strongly but indirectly with RLS Useful measure for diagnosing RLS and

monitoring of treatment. Tibialis anterior muscle-recorded PLM scoring-pathological value >five

PLM/hour of sleep. Evidence of arousal.

Investigations

ACTIGRAPHY Muscle activity monitored by small portable

meter Usually worn at ankle. Allows monitoring in patient’s own home Actigraphical devices do not differentiate

between PLM and other involuntary movements associated with apnoea.

IMMOBILISATION TESTS Suggested immobilisation test (SIT)-Patients

attempt to maintain seated posture without moving their legs

Forced immobilisation test (FIT)-legs are physically restrained while anterior tibial EMGs record PLM

Discomfort of patients.

Primary RLS-require treatment throughout their lives

Secondary RLS -remit underlying condition resolved

RLS treatment symptomatic, not preventive. Non-pharmacological measures-advice on

improvement of sleep hygiene and avoidance of stimulants or aggravating drugs (caffeine, alcohol, hot baths).

Treatment

Levodopa In primary RLS and at short-term follow-up-

effective in reducing symptoms of RLS and improving sleep quality and quality of life and reducing PLMS (level A rating).

Adverse events minor (level A). In long-term follow-up its still effective 30–70% dropped out due to adverse events

or lack of efficacy (level C).

Dopaminergic drugs

Augmentation-20-82% In RLS secondary to uraemia, at short-term

follow-up, levodopa probably effective in reducing symptoms, improving quality of life and reducing PLMS (level B).

Ergot derivatives In primary RLS pergolide effective at mean

dosages of 0.4–0.55 mg/day (level A) Possibly effective in long term (level C). Cabergoline effective at 0.5–2 mg/day

(level A) and possibly effective in long term (level C).

Bromocriptine 7.5 mg probably effective (level B).

Dopamine agonist

In secondary RLS associated with chronic haemodialysis, pergolide probably ineffective at 0.25 mg/day (level B).

Adverse events- nausea, headache, nasal congestion, dizziness and orthostatic hypotension

Augmentation not assessed with pergolide in class I studies

Non ergot derivatives Primary RLS ropinirole effective 1.5–4.6 mg/day

(level A) Rotigotine transdermal patch delivery effective in

short term (level A) Pramipexole probably effective (level B). In RLS secondary to uraemia ropinirole probable

effective (level B). Augmentation-7% with ropinirole (class I evidence). Insufficient evidence about use of non-ergot in

PLMD.

Gabapentin 800–1800 mg/day effective in primary RLS (level A) and probably effective in secondary RLS after haemodialysis (level B).

Carbamazepine 100–300 mg and valproate slow release 600 mg/day-probably effective in primary RLS (level B).

Pregabalin also effective.

Antiepileptics

Clonidine-probably effective in reducing symptoms and sleep latency in primary RLS at short term (level B).

Mean dosage 0.5 mg 2 h before onset of symptoms) for 2–3 weeks

Adverse events (dry mouth, decreased cognition and libido, lightheadedness, sleepiness, headache

Other drugs-talipexole, propranolol and phenoxybenzamine

Drugs acting on adrenoreceptors

Clonazepam -probably effective for improving symptoms in primary RLS when given at 1 mg before bedtime

Probably ineffective when given at four doses (level B).

For PLMD, clonazepam at 0.5–2 mg/daily probably effective (level B)

Triazolam (0.125–0.50 mg/day)-probably effective in ameliorating sleep efficiency and probably ineffective in reducing PLMS (level B).

Benzodiazapines/hypnotics

Adverse events-morning sedation, memory dysfunction, daytime somnolence and muscle weakness

No recommendation for other benzodiazepines/hypnotics and in secondary RLS.

BZD/hypnotics

Primary RLS oxycodone at 11.4 mg probably effective in improving RLS symptoms, PLMS and sleep efficiency on short-term basis (level B).

Adverse events-mild sedation and rare nocturnal respiratory disturbances on long-term use

Insufficient evidence about morphine, tramadol, codeine and dihydrocodeine, tilidine, and

methadone and intrathecal route Insufficient evidence in secondary RLS.

Opioids

Primary RLS iron sulphate at daily dose 325mg probably ineffective (level B).

Insufficient evidence to about use of intravenous iron dextran, magnesium oxide and amantadine.

In RLS secondary to uraemia, iron dextran 1000 mg in single intravenous dose is probably effective in short term (<1 month) (level B).

Iron sucrose ineffective.

Other therapies

PLMS- transdermal oestradiol ineffective (level A)

Modafinil and 1-day nocturnal haemodialysis probably ineffective(level B)

Cognitive-behavioural therapy as effective as clonazepam (level B).

5-OH-tryptophan, trazodone possibly ineffective

Apomorphine and physical exercise (in myelopathy) possibly effective (level C).

Thank you

Algorithms for the diagnosis and treatment of restless legs syndrome in primary care; Garcia-Borreguero et al. BMC Neurology 2015, 11:28

Hornyak M et al; What treatment works best for restless legs syndrome? Meta-analyses of dopaminergic and non-dopaminergic medications. Sleep Med Rev. 2014 Apr;18(2):153-64.

Rios R. Et al; Treatment of restless legs syndrome. Curr Treat Options Neurol. 2013 Aug;15(4):396-409.

The Treatment of Restless Legs Syndrome and Periodic Limb Movement Disorder in Adults—An Update for 2012: Practice Parameters with an Evidence-Based Systematic Review and Meta-Analyses; SLEEP, Vol. 35, No. 8, 2012

EFNS guidelines on management of restless legs syndrome and periodic limb movement disorder in sleep; European Journal of Neurology 2010, 13: 1049–1065

References