Restless leg syndrome is a very common condition. it is a sleep related disorder.

1. Restless leg syndrome
Dr Anjum Ahamadi
Pharm.D

2. Overview
• Restless leg syndrome is a sleep related movement disorder characterized
by continuous urge to move legs during rest.
• It is a poorly recognized disorder because of the unclear pathophysiology
and relatively low morbidity, resulting in limited recognition by primary
care physicians and common misdiagnosis and under-diagnosis.
• RLS is considered as a common neurological sensorimotor disorder that
involves an irresistible urge to move the body to relieve the uncomfortable
sensations.
• And it commonly worsens at night.
• Classification: 2 types
1. primary RLS (unknown case)
2. secondary RLS
(known cause - neurological disorders, iron deficiency, pregnancy, or chronic
renal failure)

3. Epidemology
• Prevalence: Caucasians - 7–10%
Asian population - 0.1 to 12%
• RLS is most common in western countries the
prevalence of 10, 10–15, and 5.5% in United
States, Canada, and Europe (United Kingdom,
Spain, Germany, Italy), respectively.
• Prevalence of 0.96% among Japan.
• China revealed a prevalence rate of 1.4%.

4. • The prevalence and severity of the RLS both
increase with age , suggesting that the
neurodegenerative process may play an important
role in RLS.
• Life style of older people and the changes like
cardiovascular changes and metabolism changes is
also related to RLS
• Women is twice as prone as men, which may be
due to hormones (estrogen and progesterone)
and different social roles.
• Symptoms usually begins by 3rd decade of life.

5. Clinical features
• The classical presentation of RLS is the discomfort in the
legs that occurs at rest and is relieved by movements.
The unpleasant sensations are often described as
creeping, crawling, pulling, stretching type of pain, often
deep-seated and localised below the knee.
• These symptoms gets severe at night and force the
patient to get out of bed for relief of symptoms.
• The sensory and periodic limb movements of sleep
(PLMS) are stereotyped flexion movements of the lower,
and sometimes, upper extremities, which last for 0.5–5 s
and occur every 20–40 s throughout sleep and are
invariably diagnostic of RLS.

6. • The important clinical criterion is the presence of circadian pattern
of symptoms occurring in the evening or night and absent in the
daytime.
• The circadian pattern of symptoms are related to dopaminergic
activity that shows natural circadian fluctuations.
• In a study, a circadian rhythm for cerebrospinal fluid (CSF)
dopamine and homovanillic acid concentrations in humans was
demonstrated with higher levels in the daytime than at night time,
establishing the role of dopamine in the pathophysiology of the
disease.
• RLS has significant impact on the quality of life of patients. Severe
symptoms are associated with psychological impairments related to
sleep disruption; poor concentration; and difficulties with work,
travel and social events

8. Diagnosis
• Biochemistry : blood ferritin levels,
homovanillic acid levels in CSF.
• Imaging:
• A significant decrease in N-acetylaspartate, creatinine
ratio, and N-acetylaspartate concentrations were found
in the medial thalamus of RLS patients in a recent study
using proton magnetic resonance spectroscopy.
• Functional MRI and PET studies concluded an important
role of medial thalamic nuclei in RLS pathophysiology.
• The medial thalamic nuclei is modulated by
dopaminergic afferents.

9. Diagnosis
1. Essential clinical diagnostic criteria:
• The urge to move the legs that is usually accompanied
by unpleasant sensations of leg paraesthesia and
dysesthesias.
• The urge to move or unpleasant sensation totally
relieved by movements.
• The symptoms that appear are worse at rest and are
partially relieved by activity.
• The symptoms are worse in the evening and during the
night.

10. 2. Supportive diagnostic criteria:
• Presence of positive family history in primary restless legs syndrome
(seen in more than 50% of patients).
• Positive response to dopaminergic therapy.
• Sleep disturbances with periodic limb movements in sleep (seen in
85% of patients).
3.Differential diagnosis:
• Nocturnal leg cramps: Sudden involuntary muscle contractions
associated with palpable tightening of the leg muscles.
• Akathisia: An internal desire to move, most commonly related to the
use of neuroleptic medications; desire to move not necessarily
associated with discomfort in the legs; and the symptoms are not
worse at night.
• Polyneuropathy: Aetiologies include trauma, nerve compression,
diabetes, nutritional disorders, infections, others; mostly results in
sensory disturbance; may or may not be more noticeable at night;
not typically relieved by activity.
• Vascular insufficiency: Primarily a consequence of atherosclerosis;
cramping-type pains that are exacerbated by activity and improve
with rest; symptoms not worse at night.

11. Pathophysiology
1. IRON:
• The local brain iron level plays an important role in RLS pathophysiology, however,
the mechanism is still unclear.
• Blood brain barrier contain endothelial cells which serves as reservoir for storage
of iron, hence disruption of this or any interference may cause iron deficiency in
brain.
• A dysfunction of iron regulatory protein in the microvasculature causes
dysregulation of iron transport across the BBB, resulting in a decrease of iron
storage in endothelial cells.
• Biochemical studies on the effect of iron in brain indicated that several iron
containing proteins were included in various processes like oxidative
phosphorylation, oxygen transportation, myelin production and the synthesis and
metabolism of neurotransmitters.
• Therefore, iron deficiency can lead to cellular damage by oxidation and
modification of cellular compounds such as lipids, carbohydrates, protein, and
DNA from hydroxyl radical production.
• Hence the impairment in neuronal iron uptake and the functions of the
neuromelanin-containing cells and dopamine-producing cells play an important
role in pathophysiology of RLS.
• Iron deficiency leads to decreased extracellular dopamine, DAT, D1 and D2
receptors, indicating that iron affect the brain dopaminergic transmission in
different ways.

12. 2. Gene:
• Studies demonstrate a strong relationship between genetic
predisposition and early-onset RLS, of which more than 60%
reveal a positive familial history.
• Moreover, inheritance was found to be related to late-onset RLS
and secondary RLS MEIS1 (chromosome
2p14), BTBD9 (chromosome 6p21.2), PTPRD (chromosome
9p24.1-p23), MAP2K5/SCOR1 (chromosome 15q23) and
chromosome 16q12.1.
• Main function of these genes was related to embryonic
neuronal development and limb development.
• In RLS autopsy cases, MEIS1 gene was found to be associated
with an increase in H-ferritin, L-ferritin and divalent metal
transporter-1 RNA expression in the thalamus
suggesting MEIS1 gene mutants predisposed to lower iron
condition.

13. 3. Dopamine:
• Tyrosine hydroxylase is An enzyme responsible for the conversion of thyrosine
to levodopa.
• It is a rate limiting step.
• As iron is a cofactor of this enzyme, iron deficiency can alter the dopaminergic
activity in the brain.
• The dopaminergic dysfunction might lead to an impairment of the medial pain
system and causes the uncomfortable symptoms of RLS.
• Pharmacological studies also demonstrated that opioids had a protective effect
in some RLS patients.
• Iron deficiency can cause cell death, mainly dopaminergic cells in substantia
nigra.
• Opiates shows protective action and prevent them from cell death under the
condition of iron deprivation.
• An intact endogenous opioid system and opioid treatment could prevent the
dopamine system from dysfunction in iron deficiency patients.

15. 4. Neurotransmitters:
• Hypocretin-1 (orexin A) are neurotransmitters produced by the
hypothalamus that are essential for normal control of the sleep cycle.
• They increase arousal and are found to interact with the dopamine
system. A study by Allen et al has identified that there is an increase in
the hypocretin levels in the cerebrospinal fluid in the early onset RLS.
• This was the first study that demonstrated the true difference
between patients with early-onset and late-onset RLS.
• Hence by this study it was conclude that elevated levels of hypocretin
are responsible for the rare manifestations of sleep deprivation
symptoms often observed in these patients.
• But in further study theirnwas no such observation about relationship
between hypocretin levels between early-onset and late-onset RLS
and the levels at 6 PM.

16. 5. Inflamation:
• The role of inflammation and immune dysfunction was suggested by
studies reporting increased prevalence of small intestinal bacterial
overgrowth and the case reports of RLS in the presence of infection
such as HIV, Streptococcus, mycoplasma, Borrelia and hepatitis C
infection and connective tissue diseases such as systemic lupus
erythematosus and Sjogren's syndrome.
• The three gastrointestinal disorders, namely, Crohn's disease, irritable
bowel disease and celiac disease are also associated with RLS.
• It has been observed that increase in hepcidin levels may trigger central
nervous system (CNS) iron deficiency.
• Hepcidin is a hormone produced by the liver involved in iron regulation.
• It binds with ferroportin (that export the iron from cells into
circulation) and results in its degradation.
• This creates a state of systemic iron deficiency explaining the decreased
iron levels in CSF in these patients.

17. Treatment
Treatment goals:
• To reduce or cure the troublesome symptoms
during rest or sleep.
• Reduce the associated sleep disturbance.
• Reduce daytime fatigue or somnolence.
• Improving the quality of life.

18. Non pharmacological treatment
• The non-pharmacological approach includes lifestyle
modifications such as avoidance of aggravating factors like
alcohol, caffeine and nicotine.
• Mental alertness exercises (video games and reading books);
stretching exercises for the posterior leg muscles.
• Application of heat with warm baths or heating pad.
• Iron replacement therapy (Ferrous sulfate 325 mg three times
daily) can be suggested for patients with low serum ferritin
levels (less than 50 ng/ml).
• Sleep hygiene should be corrected before all the
pharmacological treatment.
• Sleep deprivation, sleep disturbances and factors that can
result in insomnia should all be avoided.

19. Pharmacological treatment
1. Treatment with iron (oral and IV)

21. 2. Dopaminergic agonists:
• The dopamine agonists available for the treatment of RLS include
pramipexole, ropinirole, rotigotine, cabergoline and pergolide.
• They directly stimulate the dopamine receptors and are generally the
drug of choice in view of their lower side effects compared to the
dopamine precursors.
• Augumentation is the condition in which symptoms appears 2houres
prior to pain onset.
• Augmentation is also diagnosed in the presence of any of the two
following symptoms: increase in symptoms with increase in dosage,
decrease in symptoms with decrease in dosage, shortening of
therapeutic benefit compared to initiation of therapy and periodic legs
movements while awake either presenting or worsening.
• This phenomenon is probably attributed to excessive dopamine
concentration in the CNS resulting in the overstimulation of D1
receptors compared to that of D2 receptors in the spinal cord resulting
in D1-related pain and periodic limb movements.
• Low serum ferritin levels may affect the dopamine transporter and may
predispose to augmentation.

22. • If a patient is on levodopa then manage augmentation by gradually
tapering the dose or shifting to dopamine agonists such as ropinirole,
pramipexole that may cause augmentation but with less frequency and
low intensity.
• The other options include dividing the drug and providing the lower dose
at the earlier time of the day or increasing the total dose and providing
the standard dose 1–2 h prior to the symptom onset, or if unsuccessful
with the above strategies, to change to long-acting, high-potency drugs
such as methadone or levorphanol.
• The dopamine agonist pergolide is currently not recommended in USA
due to its reported toxicity of restrictive valvular heart disease and
retroperitoneal fibrosis. Hence usage of pergolide in the treatment of RLS
is contraindicated.
• Cabergoline showed high efficacy but its risk of valvular heart disease
precludes its recommendation in the routine clinical practice.
• Carbidopa a decarboxylase inhibitor that inhibits the peripheral
breakdown of levodopa.
• It does not cross the blood-brain barrier.
• Although it is proven to be effective in RLS, the problems encountered
with these agents include augmentation and rebound recurrence of
symptoms.

23. 3. Benzodiazepines:
• Clonazepam is one of the first few earlier drugs that were considered in the
treatment of RLS.
• It tends to improve sleep and reduce arousals due to PLMS but it was not
effective in reducing the motor and sensory abnormalities associated with RLS.
• Hence it had therapeutic effect on insomnia but not on the limb movements.
• Short-acting agents like triazolam, zalepon and temazepam, zolpidem were
effective for sleep onset insomnia but the intermediate acting agent like
temazepan was recommended if the patient awakens later at night.
• Overall, evidence recommends clonazepam as an option as an adjunctive
medication.
4. Opioids:
• Opioids decrease the release of neurotransmitters resulting in analgesic effect.
• There is low level of evidence reporting the benefit of opioids as first-line
treatment for RLS.
• They require monitoring for sleep apnoea either clinically or by
polysomnography.
• The major side effects are nausea and constipation.
• The opioids can be used as second-line agents in patients with augmentation,
non-responders to dopamine therapy and in refractory RLS.

24. 5. Anticonvulsants:
• Gabapentin was effective in the treatment of mild-to-moderate RLS.
• Studies showed significant improvement in the PLMS and sleep
architecture.
• It was identified that patients with pain, experienced relief with
gabapentin.
• However, there were concerns regarding the side effects such as sedation,
dizziness and suicidal tendencies.
• Further Studies demonstrated improvement in the symptoms of RLS
including sleep architecture and mood with gabapentin enacarbil.
• The common adverse effects observed were mild somnolence and
dizziness.
• Two studies on the use of pregabalin (α2 delta ligand) demonstrated its
effectiveness in the treatment of moderate-to-severe RLS.
• One of them reported a 90% reduction in RLS symptoms and the
other reported that patients on pregabalin (300 mg/day) had a 2.1%
incidence of augmentation.
• The latter study revealed that a non-dopaminergic drug had a low
incidence of augmentation.

25. Si
no.
Drug Class Class Average
dose
(mg/day)
1. Pramipexole Non ergot derivative Dopaminergic agonist 0.125 –
0.75
2. Ropinirole Non ergot derivative Dopaminergic agonist 0.25 – 4.0
3. Rotigotine Non ergot derivative Dopaminergic agonist 0.5, 1, 2
or 3
4. Pergolide Ergot derivative Dopaminergic agonist 3
5. Levodopa Dopamine precursor Dopaminergic agonist <200
6. Gabapentin
enacarbil
- Alpha 2 delta agonists 600 – 800
7. Pregabalin - Alpha 2 delta agonists 300

26. Management in pregnancy
1. Dopaminergic agents:
• There is paucity of data on the use of dopamine agonists in pregnancy. However, in
one of the case the use of pramipexole in pregnancy with parkinsonism did not
show any adverse outcome.
• Levodopa appears to be safe in pregnancy according to the scanty evidences
available.
2. Opioids:
• There is evidence supporting the use and safety of opioids in pregnancy.
• The concerns are neonatal respiratory depression, especially if used in late
pregnancy.
• These agents are proven to be effective for long term treatment without any
addiction.

27. 3. Benzodiazepines:
• Benzodiazepines are considered to be effective in treating RLS in pregnancy.
• The concerns of risk of cleft palate, especially if used after first trimester, were
shown to be negligible in a meta-analysis.
• Although of rare occurrence, neonatal withdrawal syndrome has been
reported.
• The benzodiazepine of choice is clonazepam.
• Others such as temazepam and triazolam were also found to be effective.
4. Anticonvulsants:
• Carbamazepine is the first anticonvulsant evaluated in the treatment of RLS.
• With the safety data and proven efficacy in RLS, it is a reasonable option to be
considered in pregnancy.
• The data on gabapentin were also reassuring in terms of safety to the mother
and foetus.
• It is to be noted that all anticonvulsants are associated with risk of neural tube
defects in pregnancy, and hence, there is a need for continuing folic acid
(5 mg) supplementation from the first trimester onwards.

28. Women during pregnancy Women during lactation
Carbidopa 25 – 50 mg or Levodopa
100 -200 mg in the evening or night.
Reassess iron status.
Clonazepam 0.25 – 1 mg in the
evening.
Gabapentin 300 – 900 mg in the
evening or at night.
In severe case or refractory case:
low dose Oxycodone.
Clonazepam 0.25 – 1 mg in evening
or at night.
Reassess need for medication
periodically and at delivery.
In severe case or refractory case:
low dose Tramadol.

29. Maternal and foetal problems
• Research concluded that secondary RLS was associated
low haemoglobin levels than idiopathic RLS.
• However, duration of sleep and birth weight of neonates
were significantly reduced in idiopathic RLS.
• However there was no significant impact in terms of
positive family history, parity, duration of pregnancy and
rate of Caesarean section.
• Idiopathic RLS can have a negative effect during
pregnancy, and hence, require screening for the
condition to optimise outcome.

30. Management of other secondary RLS
• The prevalence of RLS in haemodialysis patient is 6–60%.
• And it appears to be more severe than primary RLS and is a predictor of mortality in these
patients.
• RLS in ESRD may be related to anaemia as benefit was observed with low-dose
erythropoietin and renal transplantation.
• In a randomised control study considerable benefits were observed with gabapentin.
• The prevalence of RLS is highest among patients with parkinsonism.
• The long-term anti-parkinsonism treatment results in development of RLS.
• This may be attributed to the wearing-off episodes of levodopa that mimics symptoms of RLS
or the augmentation effects of levodopa.
• Varicose veins are associated with RLS and sclerotherapy in these patients was associated
with relief in 98% of these patients.
• Treatment with hydroxyethylrutoside in these patients demonstrated relief although not as
dramatic as with sclerotherapy.
• Assessing serum ferritin levels and treatment of iron deficiency is of value.
• It is prudent to also incorporate lifestyle changes such as exercise, avoidance of caffeine and
appropriate sleep habits along with the drugs.

31. Referances
• Brendon Yee MBChB, PhD, FRA, Restless leg
syndrome, time sleep
• Kavitha Nagandla, Somsubhra De, Restless legs
syndrome: pathophysiology and modern
management, BMJ – PG journal.
• Shiyi Guo,Jinsha Huang,Restless Legs
Syndrome: From Pathophysiology to Clinical
Diagnosis and Management, Front Aging
Neurosci, 2017 Jun 2.