Restless Legs Syndrome

“The Most Common Condition You’ve Never Heard of”

Ayman Krayem, MBChB, ABIM, FCCP

Consultant in Pulmonary & Sleep Medicine

Chair, Jeddah Sleep Medicine Club

KAMC-Jeddah

Restless Legs Syndrome

“the most common condition you’ve never heard of”

www.rls.org

RLS Excludes PLMD

RLS Includes PLMS

RLS PLMD

RLS PLMD

Definitions

RLS = Restless Legs Syndrome PLM = Periodic Limb Movements PLMS = PLM in sleep: characteristic movement that occur during sleep.

PLMW = PLM in wake (usually seen as part of a nocturnal PSG)

PLMD = PLM disorder: a sleep disorder based on a finding of PLMS (Usually < 5/hr of sleep) with an associated sleep dysfunction that cannot be otherwise explained.

Willis T. The London practice of physick London: Bassett and Crooke; 1685.

Historical References for RLS

“Therefore to some, on being a bed, they

betake themselves to sleep, presently in the

arms and legs, leaping and contractions of

the tendons, and so great a restlessness and

tossing of their members ensue that the

diseased are no more able to sleep than if

they were in the place of the greatest

torture.”

Wittmaack T. Pathologie und therapie der sensibilitat neurosen Liepzig: Schafer; 1861.

“anxietas tibiarum” - Felt to be of hysterical origin.

Ekbom K. Acta Med Scand. 1944;118:197-209. Asthenia crurum paraesthetica (irritable

legs).

Historical References

Common Characteristics OfRestless Legs Syndrome

Unpleasant sensations in the legs (sometimes the arms as well).

often described as creeping, crawling, tingling, pulling, or rarely painful.

Leg sensations are relieved by walking, stretching, knee bends, massage, or hot or cold baths.

Leg discomfort occurs when lying down or sitting for prolonged periods of time.

Common Characteristics OfRestless Legs Syndrome

The symptoms are worse in the evening and during the night.

Involuntary leg (and occasionally arm) movements while asleep;

Difficulty falling asleep or staying asleep; Sleepiness or fatigue during the daytime; Cause of discomfort not detected by medical

tests;

Family members with similar symptoms.

Terms Used to Describe RLS Sensations

Creeping Aching Restless

Crawling Pulling Painful

Itching Drawing Indescribable

Burning Electric current-like

Searing Like water flowing

Tugging Like worms or bugs crawling under the skin

Primary Features of RLS Essential for Diagnosis

A sensation of an urge to move the limbs (usually legs) accompanied by uncomfortable or unpleasant sensation .

Motor restlessness to reduce sensation.

Onset or worsening of symptoms when at rest.

Marked circadian variation in occurrence or severity of symptoms (night time)

No other identifiable cause

Sleep Med 2003; 4: 101–19.

Symptoms of RLS Follow Circadian Rhythm Hening W et al, Sleep 22:901-915 1999

Associated Features

Periodic Limb Movements in sleep

Sleep disturbance, especially difficulty in sleep initiation.

Positive family history

Onset at any age

Chronic and progressive course with remissions.

RLS Severity Scale

10 Questions– Specific to leg discomfort, movement– Effects on sleep

– Overall quality of life

0-4 rating of various symptoms for each

question; 0= none – 4 = very severe

0-10 mild 11-20 moderate

21-30 severe 31-40 very severe

Distribution of RLS Scores

Neurology 2005;65:239–246

n = 731

Differential Diagnosis of RLS

Leg cramps

Peripheral neuropathy

Varicose veins

Intermittent claudication

Neuroleptic-induced akathisia

Symptomatic Restless Legs

Iron deficiency – Hemoglobin Normal but Low Ferritin

Uremia, Caffeine, Nicotine Diabetes Peripheral neuropathy or radiculopathy Fibromyalgia Rheumatoid arthritis Pregnancy Vitamin D Deficiency

RLS Epidemiology

Affects 5-10% of population.

? Increased in French Canadians

(Lavigne G & Montplaisir J Sleep 1994; 17:739-43)

Prevalence increase with age

Women more affected than men

RLS Prevalence in Francen = 10,263

Neurology 2005;65:239–246

RLS Prevalence in Francen = 10,263

Men Women

Prevalence in Germanyn = 431

Arch Intern Med 2004; 164: 196–202.

Symptoms in a US population

Arch Intern Med 2000; 160: 2137–41.

Genetics of Restless Legs Syndrome

Familial nature first described by Ekbom

Complex inheritance

3 major loci identified

– 12q - French Canadian

– 14q - Italian, Canadian

– 9p - 2 US Families

RLS Pathophysiology

Central Nervous system dysfunction– Cortical

– subcortical

– spinal cord

Brain Dopaminergic function.

Iron Metabolism

Brain Iron Insufficiency

Brain Iron InsufficiencyRestless Legs Syndrome

CNS Dopamine Abnormalities

Iron-Dopamine Model of RLS

Ferritin Levels: Correlate with RLS but not PLMS

0 25 50 75 100 125 150 175 200 225

Ferritin mcg/l

0

1

2

3

RLS

sev

erity

r=0.43

0 25 50 75 100 125 150 175 200 225 250

Ferritin mcg/l

-200

20406080

100120140160180200

PLM

/hr

r=0.13

Iron-Dopamine Model of RLS

Earley CJ et al Neurology 2000; 54:1698-1700

contro

l

RLS

MRI Measurement of Brain Iron in RLS Patients

Iron content is reduced in both red nucleus and substantia nigra for RLS patients compared to controls • Allen RP et al; Neurology 2001;56:263-65

Neurology 2003;61:304–309

Impaired Brain Iron Acquisition inRestless Legs Syndrome:

Neuropathologic Examination

Control RLS

Marked reduction in ferritin in substantia nigra of RLS brain

5 secs

15 secs

30 secs

Periodic Limb Movements Characteristic limb movements 0.5 – 10 sec duration movements Recur periodically (every 4 to 90 sec) Must occur in a series of 4 or more in any

sleep or wake state.

Diagnosis of PLMD with the above and: - > 5 h in children, >15/h in adults- Clinical Sleep Disturbance or Daytime Fatigue- Not better explained by another disorder- Cannot diagnose RLS and PLMD at same time

(ICSD)

Disease of Conditions Associated with PLMS

• Narcolepsy• REM Sleep Behavior

Disorder• Neurodegenerative

Disorders• Tourette’s Syndrome• Peripheral

Neuropathy

• End Stage Renal Disease

• Pregnancy• Post Traumatic Stress

Disorder• Obstructive Sleep

Apnea• Antidepressants

(exceptions: bupropion trazodone)

Most people are asymptomatic

Poor association between PLMS and sleepiness

One third of patients with PLMS have RLS

Needs PSG for diagnosis

Periodic Limb Movement Syndrome

Treatment of RLS and PLMS

Varies according to the clinical course.

Co-morbid medical conditions.

Presence or absence of associated pain.

Individualize Therapy!!

Pharmacologic Rx for RLS

Dopamine receptor agonists and dopamine precusors.

Opioids

Benzodiazepines

Anticonvulsants

Other

Pharmacologic Rx for RLS

Agent Advantages Disadvantages

Dopaminergic Carbidopa- Levadopa

Use as required; Good for intermittent RLS

Symptom augmentation; GI upset; Insomnia Take without food

Dopamine agonists Pramipexole Ropinirole

Good for moderate to severe RLS; highly effective

GI upset, dizziness, extreme sleepiness

Agent Advantages Disadvantages

OpioidsCodeinePropoxypheneoxycodone

Use as required;Good forintermittent RLS

Constipation, urinaryretention, nausea;tolerance andaddiction

BenzodiazepinesClonazepamTemazepam

May improve sleep;useful when othermedications nottolerated

Daytime sleepiness;cognitive impairment(esp elderly)

Agent Advantages Disadvantages

Anticonvulsants Gabapentin Carbamazepine Prigabalin (Lyrica)

Use when dopamine agonists not working; Good in augmentation and if pain is present

Constipation, urinary retention, nausea; sleepiness, tolerance and addiction

Opiates / Benzodiazepines

Alternate meds Pain control

Constipation, Sedation Tolerance

Iron supplements as Rx for RLS

Check serum ferritin levels

Add iron in patients with serum ferritin < 50mg/L

Ideal supplement not known

May take several months to be effective

May be poorly tolerated

Vitamin D deficiency is associated with Restless Legs Syndrome.

Ayman Krayem, FCCP, Siraj Wali, FCCP, Afnan Shukr, MBBS, Ayah Boudal, MBBS, Ahmad Alsaiari, MBBS. (Abstract)

Poster # 704. American Academy of Sleep Medicine annual meeting, June 1-5, 2013, Biltmore, USA.

26

10

0

5

10

15

20

25

30

RLS Score

Pre Treatment

Post Treatment

Manifestations of Augmentation

Increase in RLS symptom severity during treatment:- Frequency of symptoms or earlier symptoms. - Duration of symptoms- Number of body parts affected- Intensity

Most commonly during treatment with L-DOPA and estimated to occur in 27-82% of cases.

Not reported during treatment with opiates, anticonvulsants or other dopaminergic drugs.

Conclusion

RLS is common but under-diagnosed

Consequences: Insomnia, bed partners separation, depression & sexual dysfunction

Diagnosis: History

Workup: Iron, Vitamin D, Folic Acid, Vitamin B12

Management: Replacement, Specific Drug Therapy (Dopanergic)