Restless Leg Syndrome

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Restless Leg Syndrome
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Disclosure

• Speaker for the following companies
• Jazz Pharmaceutical
• Sanofi
• Cephalon, Inc.
• GlaxoSmithKline

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Overview

• Epidemiology of RLS
• PLMS and it association to RLS
• Clinical features of RLS/PLMS
• Treatment of RLS/PLMS

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Sir Thomas Willis described RLS in the 17th
Century

• When being in a bed, they betake themselves
  to sleep, presently in the arms and legs,
  leapings and contractions of the tendons, and so
  great a restlessness and tossings of their
  members ensue, that the diseased are no more able
  to sleep, than if they were in a place of the
  greatest torture.
• -Willis T. The Practice of Physick, 1692

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Epidemiology of Restless Legs Syndrome

• Prevalence1,2
• Affects approximately 10 of US adults
• Increases with age
• Peaks above age 50
• Age of onset varies widely2,3
• Common onset 40 years of age
• Present in both men and women, with greater
  prevalence in women2,4
• 15 report feelings of creeping, crawling, or
  tingling in the legs5.

1. Phillips et al. Arch Intern Med.
20001602137-2141. 2. Hening et al. Sleep Med.
20045237-246. 3. Walters et al. Neurology.
19964692-95. 4. Nichols et al. Arch Intern Med.
20031632323-2329.
1. Phillips et al. Arch Intern Med.
20001602137-2141. 2. Hening et al. Sleep Med.
20045237-246. 3. Walters et al. Neurology.
19964692-95. 4. Nichols et al. Arch Intern Med.
20031632323-2329. 5. National Sleep Foundation
2000 Omnibus Sleep in America Poll.
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Healthcare and Sleep

• 61 have not been asked by a doctor how well they
  sleep.
• 80 have never initiated a discussion about sleep
  problems.
• Only 5 of insomniacs, 2 of sleep apnea, and 2
  of restless leg syndrome patients have been
  diagnosed.
• When experiencing difficulty sleeping, 53 will
  do nothing about it.
• 19 have used alcohol to help them sleep during
  the past year.

National Sleep Foundation 2000 Omnibus Sleep in
America Poll
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How Much Caffeine?

• Only oil ranks above coffee in the amount traded
  on the commodities market.
• 60 of Americans drink coffee.
• 6.3 billion gallons of coffee are consumed a
  year.
• Average consumes 3.4 cups(8-20 oz)/day.
• 2.4 billion gallons of tea.
• 15.3 billion gallons of soft drink (70 are
  caffeinated). 574 cans/yr for every man, women,
  and child.

Time Magazine 12/20/04
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Clinical Features of Restless Leg Syndrome
Diagnostic criteria developed by the
International RLS (IRLS) Study Group in
collaboration with the National Institutes of
Health (NIH).
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Criterion 1 Urge to Move Legs Accompanied or
Caused by Uncomfortable/Unpleasant Sensations

• Creepy, crawly, tingly
• Like worms or bugs crawling under the skin
• Painful, burning, or achy
• Like water running over the skin
• Sometimes indescribable

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Criterion 2 Urge to Move Legs/Sensations
Partially or Wholly Relieved by Movement
Temporarily

• Activity variably, temporarily, and partially
  relieves the discomfort
• Patients develop habits and behaviors to relieve
  discomfort (Nightwalkers)

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Criterion 3 Urge to Move Legs/Unpleasant
Sensations Begin or Worsen During Inactivity or
Rest

• Increasing duration of rest associated with
  greater
• Probability of symptoms
• Intensity of symptoms
• Symptoms not associated with any particular body
  position during rest

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Criterion 4 Urge to Move Legs/Sensations Worsen
or Occur Solely in the Evening or at Night

• Symptoms typically peak between midnight and 4
  A.M.
• Circadian rhythm of symptoms persists even in
  unconventional sleep /wake cycles

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International RLS (IRLS) Rating Scale

• Disease-specific, 10-item rating scale
• Measures disease severity through subjective
  assessment of primary sensorimotor features,
  associated sleep problems, and impact on
  patients mood, daily life, and activities
• Questions rated by patient on 0 to 4 point scale
  (0none, 1mild, 2moderate, 3severe, 4very
  severe)
• Total score ranges from 0 (no symptoms) to 40
  (very severe symptoms)

Hening et al. Sleep Med. 2003495-97. IRLS Study
Group. Sleep Med. 20034121-132.
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REST Study Time Required for Patients to Fall
Asleep
68.6
250
35.9
200
150
22.3
Number of patients
17.4
100
8.5
8.0
7.3
50
0.5
0
lt15mins
1530mins
3060mins
12hours
23 hours
gt3hours
Noanswergiven

• Difficulty falling asleep may frequently be
  associated with moderate-to-severe RLS.
• n551.
• Indicates the range of values considered
  abnormal and representing insomnia.

Hening et al. Sleep Med. 20045237246.
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Additional Features

• Sleep disturbance
• Often the primary reason the patient seeks
  medical attention
• Difficulty falling asleep may frequently be
  associated with moderate-to-severe RLS
• Generally chronic course
• May be progressive or static
• Remissions occur only in 15

Allen et al. Sleep Med. 20034101-119.
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Insomnia Clinic
Do you have dark circles under your eyes?
Do you stay awake all night?
We can help. Call the Midwest Center for Sleep
Medicine at 309-662-9997
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Types of RLS

• Primary or idiopathic
• Secondary

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Primary RLS

• No identifiable predisposing factor
• Accounts for most of the RLS cases
• Tends to occur in families in 33-55 of cases
• May be genetic Probable autosomal dominant with
  variable penetrance.

1. Allen Earley. J Clin Neurophysiol.
200118128-147. 2. NHLBI Working Group on
Restless Legs Syndrome. Am Fam Physician.
200062108-114.
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Secondary RLS

• Iron-deficiency anemia B12, folate, iron,
  ferritin levels less than 45 ng/ml.
• Uremia (20-40 of dialysis patients)
• Pregnancy (up to 27)
• Exercise after 700pm
• Neurological lesions
• both spinal cord and peripheral nerve lesions
• Drug/Diet-induced
• tricyclics, SSRIs, lithium, Reglan, dopamine
• blockers (e.g., Haldol, Thorazine), xanthines,
  EtOH caffeine, nicotine, chocolate, MSG,
  decongestants, ?nutrasweet.

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Associated Conditions

• Depression
• Parkinsons disease
• End stage renal disease
• Hypothyroidism

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Depression and RLS

• Depression symptoms are common in RLS.
• RLS has a prevalence of 26 in untreated patients
  presenting to a psychiatric clinic with unipolar
  depression symptoms.
• Most antidepressants can aggravate RLS.

Leutgeb, U. et al. Europ J Med Research. 2002
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Antidepressants and RLS, PLMS

• SSRIs (75 of people have some feelings of RLS),
  tricyclics, and lithium have all been associated
  with inducing or aggravating RLS/PLMS.
• Most SSRIs reduce dopamine
• Bupropion and trazodone decrease PLMS.
• Pramipexole may have antidepressant effects in
  addition to treatment of RLS/PLMS.

Saletu.M, et al. Europ Arch of Psych and Clinical
Neuroscience. 2002
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Parkinsons Disease and Its Relationship to RLS

• RLS is common in patients with Parkinsons
  Disease (20).
• Unless there is a familial relationship of RLS,
  it appears to be low ferritin levels associated
  with development of RLS in patients with
  Parkinsons Disease.
• In patients without a family history of RLS, PD
  always preceded RLS.

Ondo, WG. Arch, Neurol. 2001
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Ondo, WG. Arch, Neurol. 2001
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End Stage Renal Disease

• RLS is common in ESRD (20-35)
• Elimination of RLS with transplantation
• Role of iron deficiency is unclear
• There is a significant increased risk of
  mortality at 2.5 years in ESRD patients with RLS
  due to higher rate of discontinuation of
  dialysis1.
• Survival of ESRD patients with an PLMI lt20 was
  90 vs gt20 was 50 at 20 months2.

1. Winkelman, JW. Am J of Kidney Disease. 1996
2. Benz, RL et al. Am J of Kidney Disease. 2000
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Differential Diagnosis

• Neuropathy
• Lumbar disk disease/spinal stenosis
• Diabetic neuropathy
• Depression and other causes of insomnia
• Arthritis
• Vascular disease

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Differential Diagnosis

• Nocturnal Leg Cramps
• Neuroleptic-Induced Akathisia
• Painful Legs and Moving Toes

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Akathisia vs. RLS

• Akathisia
• Entire body
• More of an inner sense of restlessness not
  referable to the extremeties
• Not made worse by laying down
• No family history
• Associated with dopamine antagonists
• Mildly worse at night
• Associated with Parkinsonsism
• Associated with low iron

• RLS
• Worse in the limbs
• Worse at night
• Normal neurological exam
• Positive familial history

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Painful Legs and Moving Toes

• Condition often associated with peripheral
  trauma, isolated peripheral nerve lesions, or
  rediculopathy.
• It consists of severe pain in the affected foot
  or leg accompanied by continuous or
  semicontinuous sinuous, quivering, writhing, or
  wriggling contractions of the toe flexors and
  extensors, abductors, and adductors.
• Movements often disappear in sleep.

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Laboratory Evaluation of RLS

• Polysomnography is not indicated in evaluation of
  RLS!
• Serum ferritin, iron, B12, folate
• Screen for uremia
• Screening for diabetes
• other tests for potential secondary causes if
  suspected

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Incidence PLMs

• 30 of people over the age of 50. 50 of people
  over the age of 60.

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Clinical Features of PLMs

• PLMS is a polysomnographic diagnosis.
• Four Movements in a row of 0.5-5 seconds that
  are 5-90 seconds apart.
• 25 of amplitude of EMG calibration signal.
• 5/hr or more with arousals to be clinically
  significant.
• May have arm and leg movements but hardly ever
  arms alone.

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PLMs increased in

• RLS
• Older age gt 60
• Narcolepsy
• Sleep apnea

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LOC ROC C3-A2 O1-A2 Chin EMG EKG LAT-RAT
EMG Intercostal EMG Airflow
Significant only when accompanied by EEG arousal
Chin EMG may decrease prior to jerk
Jerks may last from .5 to 5 seconds
Single PLMS jerk
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RLS Vs PLMS

• RLS is a symptom
• RLS is diagnosed in the physicians office
• 80 of people who have RLS will have PLMs

• PLMs are an electromyographic finding
• PLMs are diagnosed in the sleep laboratory
• 30 of individuals who have PLMs have RLS
  symptoms

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Clinical Importance of PLMs in Relation to RLS

• PLMs are neither necessary nor sufficient to
  make the diagnosis of RLS
• Asymptomatic PLMs do not require treatment

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Pathogenesis

• RLS is a neurologic movement disorder
• Location of the lesion is not known. However,
  PET studies suggest that a mild striatal
  presynaptic dopaminergic dysfunction may be
  involved in the pathogenesis of RLS.
• Only assessed nigrostriatal system
• All imaging studies have been conducted in
  daytime when RLS symptoms are minimal

Eisensehr et al. Neurology. 2001571307-1309. Mic
haud et al. J Neurol. 2002249164-170. Ruottinen
et al. Neurology. 200054502-504. Turjanski et
al. Neurology. 199952932-937. Tribl et al. Nucl
Med Commun. 20042555-60.
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RLS/PLMS may involve the peripheral nervous system

• Patients with clinical evidence of peripheral
  neuropathy as a cause of RLS have same RLS/PLMS
  pattern as those with idiopathic RLS.
• Nerve biopsies in idiopathic RLS may disclose
  evidence of subclinical peripheral neuropathy.
• Peripheral leg sensations due to nerve damage
  could convey the message to the CNS to generate
  PLMS.

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Nonpharmacologic Treatment

• Listen, support, and validate
• Reconsider medications known to exacerbate RLS
  (Lithium, SSRIs, tricyclics, antihistamines)
• Not helpful sclerotherapy, electrical
  stimulation
• Possibly beneficial in some patients hot baths,
  delayed sleep time/rise time, exercise, avoid
  alcohol, caffeine, chocolate, and nicotine.

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Pharmacologic Treatment

• Dopaminergic medications
• Benzodiazepines
• Opioids
• Anticonvulsants
• Others

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Treatment Considerations

• Age of patient
• Combination strategies
• Distribution/frequency/severity of symptoms
• No drug has FDA approval for use in RLS until
  2005 with ropinirole.
• Treatment is symptomatic, not curative
• In general, smaller doses are used than in other
  conditions

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Iron Therapy

• Replace iron in patients with serum ferritin
  levels below 45 mcg/L

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Dopaminergic Medications

• Carbidopa-levodopa (Sinemet Ò)
• 25-100 CR-100/400 CR qhs
• Bromocriptine (Parlodel Ò)
• 5-15 mg
• Pergolide (Permax Ò)
• 0.05 qhs, increasing by 0.05 q 3 days
• Pramipexole (Mirapex Ò)
• 0.125-1.0 mg qAM, after dinner, and qhs.
• Ropinirole (Requip Ò)

Double blind studies have shown these to be
effective in PLMS and RLS.
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Disadvantages of Da Agonists

• With Sinemet, watch for rebound of symptoms and
  nausea. Extra doses of carbidopa may need to be
  given.
• Pergolide and bromocriptine are rarely used.
• Mental confusion and chorea more common in
  patients with Parkinsons. This is rare in RLS.
• May cause drowsiness.
• Hypotension.

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Benzodiazepines

• Clonazepam (Klonipin Ò)
• 0.5-4.0
• Triazolam (Halcion Ò)
• Lorazepam ( Ativan Ò)
• Temazepam (RestorilÒ)
• 15-30 mg
• Diazepam (Valium Ò)
• 5-10 mg

Disadvantages tolerance, somnolence, confusion,
worsened snoring/SDB Double blind studies have
shown these to be effective in reducing
PLMS. Controls the PLMS associated arousals and
not as much the PLMs itself.
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Opioids

• Oxycodone (Percocet Ò, Percodan Ò)
• Propoxyphene (Darvon Ò)
• 130-520 mg/day
• Codeine
• 15-240 mg/day
• Methadone (Dolophine Ò)
• 5-30 mg/day
• Hydrocodone
• Tramadol hydrochloride (Ultram Ò)

Disadvantages tolerance, constipation,
addiction Double blind studies have shown these
to be effective in reducing PLMS and
RLS. Controls the PLMS associated arousals and
not as much the PLMs itself.
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Anticonvulsants

• Gabapentin (Neurontin Ò)
• 100-2700mg/day
• Carbamazepine (Tegretol Ò)

Disadvantages daytime sedation Double blind
studies have shown these to be effective in
reducing RLS but not PLMS.
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Others

• clonidine
• baclofen
• vitamin B 12
• vitamin E
• Magnesium
• ? IV lidocaine
• ? Mexilitine

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Pramipexole Effects on IRLS
Becker, PM. Neurology. 1998
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Ropirinole Three 12-Week, Double-Blind,
Placebo-Controlled Trials
Objective Compare efficacy and tolerability of
Requip vs placebo in the treatment of signs and
symptoms of moderate-to-severe primary RLS
TREAT, Therapy With Ropinirole Efficacy and
Tolerability in RLS
1. Data on file, GlaxoSmithKline (TREAT RLS US).
2. Trenkwalder et al. J Neurol Neurosurg
Psychiatry. 20047592-97. 3. Walters et al. Mov
Disord. 2004191414-1423.

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Combined Demographic Characteristics TREAT RLS
US, TREAT RLS 1, and TREAT RLS 2
Requip Placebo Total n464
n467 n931 AgeMean (range) 53.5 (18-79) 54.5
(19-79) 54.0 (18-79) Sex n ()Male 191 (41)
170 (36) 361 (39)Female 273 (59) 297
(64) 570 (61) IRLS total score 23.2 23.6 23.4
at baseline (mean) Duration of disease
18.9 18.9 18.9 (mean years) Age at onset
34.7
35.5 35.1 disease
(mean years)
n457 (data not available for all subjects).
n456 (data not available for all
subjects). n913 (data not available for all
subjects). Data on file, GlaxoSmithKline (TREAT
RLS US, TREAT RLS 1, and TREAT RLS 2).
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Study DesignTREAT RLS US, TREAT RLS 1, and TREAT
RLS2
Randomization
Requip (0.254 mg/day)
Requip or matched placebo tablets taken once
daily 1-3 hours before bedtime.
Dosage titrated to effect during weeks 17
(TREAT RLS 1-2) or weeks 1-10 (TREAT RLS US) and
no further dosage changes permitted.
Placebo
Washout phase
Double-blind treatment phase
Follow-up phase
Day 7 Screening visit
Day 0 Baseline visit
Week 12
7 3 days after cessation of study medication
Assessment visits Day 2, Wk 1, 2, 3, 4, 5, 6, 7,
8, 12
Data on file, GlaxoSmithKline (TREAT RLS US).
Trenkwalder et al. J Neurol Neurosurg
Psychiatry. 20047592-97. Walters et al. Mov
Disord. 2004191414-1423.
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Ropirinole Improved RLS Symptoms TREAT RLS US
Mean IRLS Rating Scale Total Score at Each Visit
25
Week 12 LOCF Plt0.0001
20
15
IRLS Rating Scale Total Score (mean)
Placebo (n193)
10
5
Requip (n187)
0
Baseline
Day 3
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Week 8
Week 10
Week 12
Time Point (OC)
A decrease in score denotes improvement.
Data on file, GlaxoSmithKline (TREAT RLS US).
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Statistical Significance With ropirinole on
IRLS Rating Scale Score at Week 12
TREAT RLS 11,2
TREAT RLS 21,3
TREAT RLS US1
n186
n190
n144
n135
n128
n131
Adjusted Mean ChangeFrom Baseline (LOCF)



Adjusted treatment difference -3.7 95 CI
-5.4, -2.0 Plt0.0001. Adjusted treatment
difference -3.0 95 CI -5.0, -1.0
P0.0036. Adjusted treatment difference -2.5
95 CI -4.6, -0.4 P0.0197.
1. Data on file, GlaxoSmithKline (TREAT RLS US,
TREAT RLS 1, and TREAT RLS 2). 2. Trenkwalder et
al. J Neurol Neurosurg Psychiatry.
20047592-97. 3. Walters et al. Mov Disord.
2004191414-1423.
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Ropirinol Increased Proportion of Patients With
CGI-I Score at Week 12 (LOCF)TREAT RLS US,
TREAT RLS 1, and TREAT RLS 2
100
Requip (n464)

80
Placebo (n464)

73

60
60
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Percentage of Patients
53
40
41
40
20
n187
n193
n146
n137
n131
n134
0
TREAT RLS US1
TREAT RLS 11,2
TREAT RLS 21,3
Adjusted odds ratio 2.1 95 CI 1.4, 3.3
P0.0006. Adjusted odds ratio 1.7 95 CI
1.0, 2.7 P0.0416. Adjusted odds ratio 2.3
95 CI 1.4, 3.8 P0.001.
1. Data on file, GlaxoSmithKline (TREAT RLS
US). 2. Trenkwalder et al. J Neurol Neurosurg
Psychiatry. 20047592-97. 3. Walters et al. Mov
Disord. 2004191414-1423.
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Study Design RESET PLM

• Study design, inclusion criteria, and exclusion
  criteria same as TREAT 1 and 2 studies except

• Patients also required to have PLMI 5 PLM/hr of
  sleep

RESET, Ropinirole Efficacy and Safety in the
Treatment of PLM PLMI, periodic leg movement
index, number of periodic leg movements/hr

• Allen et al. Sleep. 200427907-914.

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Efficacy EndpointRESET PLM

• Mean change from baseline to week 12 (LOCF) in
  periodic leg movements with arousal per hour
  (PLMA/hr)

Allen et al. Sleep. 200427907-914.
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Moderate-to-Severe Primary RLS With PLMS
Reduction in Mean PLMA/hour at Week 12RESET PLM
Ropirinole (n32)
22
Percentage Reduction in Mean PLMA/hour
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Placebo (n33)
Plt0.0096
PLMA/hourperiodic leg movements with
arousal/hour (PLMA index). Allen et al. Sleep.
200427907-914.
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Complication of Therapy

• Augmentation?The earlier onset of symptoms in the
  evening (or afternoon), increase in symptoms, and
  spread of symptoms to involve other extremities
• Rebound?A worsening of symptoms in the early
  morning hours associated with use of
  dopaminergic agents in RLS

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Conclusions

• RLS and PLMS is common, treatable, and
  underdiagnosed.
• The pathophysiology of RLS and PLMS is unknown.
• With RLS, the diagnosis is made by history.
• With PLMS, the diagnosis is made by ANPSG.
• Treatment is mainly pharmacologic

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Thank You