Restless leg syndrome (RLS) is a neurological disorder characterized by uncomfortable sensations in the legs and an irresistible urge to move them. It was first described in 1685 and termed RLS in 1945. RLS can be primary/idiopathic or secondary to conditions like iron deficiency, end-stage renal disease, and pregnancy. Diagnosis is based on clinical criteria including worsening symptoms at rest relieved by movement. Treatment involves lifestyle modifications and medications like dopaminergics, gabapentin, or opioids which provide symptom relief.

1. Restless leg syndrome
DR. MUNISH KUMAR
MD (MEDICINE), DM Neurology
G b pant, new delhi

2. Restless leg syndrome
• The first description of RLS is attributed to Thomas Willis
in 1685.
• Ekbom coined the term restless legs.
• In 1945, Ekbom gave a full description of the syndrome
based on a large series of patients.
• This condition is sometimes referred to as Ekbom's
syndrome.

3. Restless leg syndrome
• Periodic limb movement (PLM) and Restless leg syndrome (RLS)
are types of sleep disorders.
• While RLS is a clinical diagnosis, the diagnosis of PLM is made by
polysomnography.
• They share the same pathophysiology and often respond to the same
treatment.
• The epidemiological studies have reported the prevalence between
2% and 15%.
• Rangarajan et al. (2007) found a prevalence of 2% from the door-to-
door survey in Bangalore, India.

4. Restless leg syndrome
• RLS is a lifelong sensory-motor neurological
disorder that often begins at a very young age
but is mostly diagnosed in the middle or later
years.
• Prevalence of RLS increases with age.

5. Restless leg syndrome
• The prevalence is greater in women than in men, and the
disease is gradually progressing.
• Family studies of RLS suggest an increased incidence (≈40%-
50%) in first-degree relatives of idiopathic cases.
• Autosomal dominant mode of inheritance (Hening et al.,
2009).
• Linkage analysis documented significant linkage to at least six
different chromosomes (12q, 14q, 9p, 2q, and 20p).

6. Types of RLS
• There are two types of RLS:
1. Early onset: Age of onset is less than 45 years, tends to cluster in
families and progresses slowly with a female to male ratio of 2 : 1.
2. Late-onset : Age of onset over 45, has an equal male to female
ratio, more rapid progression, more severe and more frequent
symptoms, no familial clustering and are more commonly associated
with radiculopathy, neuropathy or myelopathy.

7. Diagnostic criteria
• The diagnosis rests entirely on clinical features and is based on
the International Restless Legs Syndrome Study Group
(IRLSSG) criteria first established in 1995 (Walters, 1995) and
modified slightly in 2003 (Allen et al., 2003).
• These criteria include essential, supportive, and associated
features.
• All four essential diagnostic criteria are needed for establishing
the diagnosis.

8. Clinical Diagnostic Criteria for Idiopathic Restless Legs Syndrome
• Essential Criteria
 An urge to move the legs, usually accompanied by or caused by uncomfortable
sensations in the legs.
 The urge to move or unpleasant sensations beginning or worsening during periods
of rest or inactivity, such as lying or sitting.
 The urge to move or unpleasant sensations are partially or totally relieved by
movement such as walking or stretching, at least as long as the activity continues.
 The urge to move or unpleasant sensations are worse in the evening or night than
during the day or only occur in the evening or night.

9. Clinical Diagnostic Criteria for Idiopathic Restless Legs Syndrome
• Supportive Features
 Dopaminergic responsiveness
 Presence of periodic limb movements in sleep or wakefulness
 Positive family history
• Associated Features
 Usually progressive clinical course
 Normal neurological examination in the idiopathic form
 Sleep disturbance

10. Symptoms
• The sensory manifestations of RLS include intense disagreeable
feelings described as creeping, crawling, tingling, burning,
aching, cramping, knifelike, or itching sensations.
• These creeping sensations occur mostly between the knees and
ankles.
• Sometimes, similar symptoms occur in the arms or other parts of
the body, particularly in advanced stages of the disease.
• Approximately 15% to 20% of patients complain of actual pain.

11. Symptoms
• Most of the movements, particularly in the early stages,
are noted in the evening while the patients are resting in
bed.
• In severe cases, however, movements may be noted in
the daytime while subjects are sitting or lying down.
• At least 80% of RLS patients have PLMS, and many
also have periodic limb movements in wakefulness.

12. Secondary RLS
• The term secondary RLS is used whenever this condition is found in
association with another medical condition.
• The most frequently found associations are renal failure, iron deficiency and
pregnancy.
• RLS can be associated with pregnancy typically after 20th week and the
incidence is estimated to be around 20%.
• RLS in association with hemodialysis population is estimated to be around
20% and the disease is usually more severe than primary RLS.
• Lower levels of ferritin have been noted in patients with RLS in comparison
with controls.

13. Causes of Symptomatic or Comorbid Restless Legs Syndrome
• Neurological Disorders
o Polyneuropathies
o Lumbosacral radiculopathies
o Amyotrophic lateral sclerosis
o Myelopathies
o Multiple sclerosis
o Parkinson disease
o Poliomyelitis
o Isaacs syndrome
o Hyperekplexia (startle disease)
• Medical Disorders
o Anemia: iron and folate deficiency
o Diabetes mellitus
o Amyloidosis
o Uremia
o Gastrectomy
o Cancer
o Chronic obstructive pulmonary disease
o Peripheral vascular (arterial or venous)
disorder
o Rheumatoid arthritis
o Hypothyroidism
• Drugs and Chemicals
o Caffeine
o Neuroleptics
o Withdrawal from sedatives or narcotics
o Lithium, nifedipine

14. Conditions That Mimic Restless Legs Syndrome
• Presenting with Excess Restlessness
o Akathisia
o Degenerative disease
o Disorders of abnormal muscular
activity
o Myokymia
o Hypnic jerks
o Essential myoclonus
o Orthostatic tremor
o Anxiety/depression
o Periodic limb movement disorder
o Restlessness due to orthostatic
hypotension
o Attention-deficit hyperactivity
disorder
• Presenting with Nocturnal Leg
Discomfort
o Small-fiber neuropathies
o Claudication
o Venous stasis/varicose veins
o Myalgias
o Arthritis
o Radiculopathies
• Presenting with Unusual Motor Activity
Combined with Leg Discomfort
o Painful muscle cramps including nocturnal
leg cramps
o Syndrome of painful legs and moving toes
o Causalgia-dystonia syndrome
o Muscular pain-fasciculation syndrome

15. Pathophysiology
• The pathophysiology and the site of CNS dysfunction in idiopathic or primary RLS
remains unclear.
• Abnormalities in the body’s use and storage of iron and dopamine dysfunction,
which could involve changes in dopamine receptors or dopamine uptake .
• Iron is a necessary cofactor for tyrosine hydroxylase, the rate-limiting enzyme in
dopamine synthesis, and iron deficiency may decrease the number of dopamine D2
receptor binding sites, so the most exciting and current research focus is centered
on iron-dopamine dysfunction.
• Functional MRI (fMRI) points to locations in the brainstem, cerebellum, and
thalamus.
• CSF analysis, special MRI, and neuropathological studies demonstrate reduction in
CNS iron or ferritin or both.

16. Periodic Limb Movements in Sleep
• Periodic limb movements in sleep is a PSG finding.
• PLMS appears most commonly in RLS but may also occur in a other
medical, neurological, and sleep disorders and with ingestion of
medications (e.g., SSRIs, tricyclic antidepressants)
• Can occur in normal individuals, particularly in those older than age 65.
• Currently PLMD characterized by PSG findings of PLMS without
associated RLS causing repeated awakenings and sleep fragmentations.
• There is a growing body of evidence that PLMS may simply be a PSG
observation and may have no specific clinical significance

17. Features of Periodic Limb Movements in Sleep
• Repetitive, often stereotyped movements during NREM sleep.
• Usually noted in legs and consisting of extension of great toe, dorsiflexion
of ankle, and flexion of knee and hip; sometimes seen in arms.
• Periodic or quasi-periodic at an average interval of 20-40 sec (range, 5-90
sec) with a duration of 0.5-10 sec and as part of at least 4 consecutive
movements.
• Occurs at any age, but prevalence increases with age.
• May occur as an isolated condition or may be associated with a large
number of other medical, neurological, or sleep disorders and medications.
• Seen in at least 80% of patients with restless legs syndrome.

18. Treatment
• Patients who present with RLS should, in addition to a
thorough physical examination, also get a complete blood
count and an iron level.
• It is generally recommended that ferritin level less than 50
mcg/l should be taken as a cut-off for treatment with oral
iron.
• Caffeine, alcohol, nicotine and medications that aggravate
RLS should be avoided.

19. Treatment
• Akpinar in 1982 accidentally came across the
beneficial effects of levodopa on RLS.
• The most commonly used dopaminergic agents are
levodopa, dopamine agonist such as ropinirole,
pramipexole, pergolide.
• The efficacy of dopaminergic agents has been shown
to be 90% in randomized placebo-controlled trials.

20. Treatment
• They are generally effective in not only relieving symptoms
but also actually decreasing the number of movements at
night.
• Levodopa/carbidopa generally works better for intermittent
symptoms and as prophylaxis prior to car rides and plane trips.
• For daily symptoms, either ropinirole or pramipexole can be
used.

21. Treatment
• They should be administered at least 2 hr prior to the onset of symptoms.
• For RLS symptoms that occur mostly in the early part of the night, taking
these medications with dinner maybe helpful.
• In cases of PLMs, they should be given an hour prior to going to sleep.
• Both pramipexole and ropinirole can be started at 0.25 mg and increased as
tolerated.
• The maximum dose of these medications is generally 3 mg.
• In patients who are intolerant to dopaminergic medications, the ergot-
derivative pergolide can be used. The starting dose is a 0.025 mg and
increased up to 0.5 mg.

22. Treatment
• Augmentation is the most common side effect with long-term
use of levodopa in RLS.
• After initial improvement, symptoms worsen with use of
Levodopa.
• Augmentation has also been reported with other dopaminergic
agents and the incidence with these agents is probably around
20%.
• When augmentation occurs drug should be withheld rather
than increased.

23. Treatment
• Stopping the medications usually result in rebound
symptoms and that they can be managed effectively with
benzodiazepine receptor agonists (zolpidem, zaleplon) .
• Antiepileptic agents such as gabapentin and lamotrigine
have been effectively used as second line agents in the
treatment of RLS.

24. Recommended Drug Management of Restless Legs Syndrome.
Frequency
or Quality
of Symptoms
First choice Second choice Third choice
Nightly Dopamine agonist Opiates Gabapentin,
sedative–
hypnotic agent
Frequent (3 to 5
times per week)
Sedative–hypnotic
agent
Opiate Levodopa
Occasional Levodopa Sedative–hypnotic
agent
Opiates
Painful Gabapentin,
opiates
Dopamine agonist Sedative–hypnotic
agent

25. Thanks….

26. • Review of periodic limb movement and
restless leg syndrome. R Natarajan. JPGM
2010
Department of Pulmonary and Critical Care
Medicine, and Sleep Medicine, University of
Massachusetts, Worcester, USA