Is Restless Legs Syndrome an Inflammatory Disease? Leonard Weinstock, MD Associate Professor of Clinical Medicine Washington University School of Medicine

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Is Restless Legs Syndromean Inflammatory
Disease?Leonard Weinstock, MDAssociate
Professor of Clinical MedicineWashington
University School of Medicine

• President, Specialists in Gastroenterology

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Disclosures

• Speakers Bureau
• Salix, Entera Health, Actavis, Romark
• Consultant
• Actavis
• Off label use of medicine educational
  information, not promotional

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RLS clinical importancePathophysiologyRole
of SIBORifaximin studiesInflammation
endorphin defSequential rifaximin LDN study

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RLS Clinical Aspects

• Four basic criteria 1
• Compelling urge to move, often w/
  discomfort
• Occurrence w/ rest
• Worsening at bedtime
• Alleviated by movement
• Exclusion of RLS-like conditions

1. Allen et al. Sleep Med.
20034101-19.
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RLS Classifications

• Idiopathic
• Familial (known genomic markers)
• Secondary RLS

1. Allen et al. Sleep Med. 20034101-19.
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RLS Clinical Aspects

• Occurs in 7-10 1/2 receive meds 1
• Poor sleep (50) 2 and QOL 3
• HBP, CV disease, and stroke 4
• 90 have PLMD
• Severity IRLS scale 0-40 (10 questions),
  global response, actigraphy

1. Allen et al. Sleep Med. 20034101-19. 2.
Garcia-Borreguero. Eur J Neurol 20061315-20. 3.
Abets et al. Value Heath 20058157-67. 4.
Walters et al. Sleep 200932589-97.
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RLS Pathophysiology

• CNS iron deficiency 5
• Altered dopaminergic system 6
• Peripheral neuropathy 6
• SIBO 7
• Inflammation 8
• Immune disorder 8
• Endorphin deficiency 9

5. Allen. Arch Intern Med. 20051651286-1292. 6.
Trenkwalder. Clin Neurophysiol.
20041151978-1988. 7. Weinstock. Dig Dis Sci.
2008531252-1256 8. Weinstock. Sleep Med Rev
201216341-354. 9. Walters. J Neurol Sci
200927962-65.
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Iron in RLS

• Low CNS iron found in 1o and 2o RLS 1
• Decreases D2 receptor Fx and s in substantia
  nigra
• Autopsy study increase in hepcidin 2
• Mice - circadian rhythm in CNS Fe
• Clue to night time RLS symptoms 3

1. Unger. J Appl Physiol. 2009106187-193. 2.
   Clardy. J Neuro Sci 2006.
   3. Earley. Neurology. 2000541698-1700.

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How good is current Rx?

• IV iron complete with iron def in 68
• Dopaminergics Pramipexole -3.1
  IRLS (global response 50)
• Neuropathic agents Pregabalin -6.1
  IRLS (global response 61) (vs 33 for
  plb)
• Narcotics Oycodone-naloxone (Targin) -16.5 vs.
  plc -9.4

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Case 1 - 2005

• 65 y.o. WM with 14 yr post infectious IBS
  followed by RLS
• Rifaximin 550 mg TID 3 wks
• Dramatic improvement in RLS
• No change in periodic limb movement disorder

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Case 2 - 55 y.o. WF

• Pi-IBS 22 yrs
• Fibromyalgia - 21 yrs
• RLS - 13 yrs
• IC - 10 yrs
• Abnormal LBT

• RLS, IBS, FM 90 better
• after 2 weeks rifaximin Rx
• Excellent health since 2006
• with erythro and later LDN

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RLS Theory 2005-2011 SIBO link via
SIBO-inflammation
SIBO
RLS
IBS
Pi-IBS

Cytokines
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Hepcidin Fepeptide regulator
Liver

• Hepcidin1 leads to
• Decreased intestinal iron absorption
• Serum iron sequestration by macrophages
• Role of choroid plexus
• hepcidin 2 in RLS?

Stomach
LPS
Hepcidin
IL-6
Fe2
Duodenum
Decreased Fe2
Decreased Fe2 absorption
Increased Fe2
Macrophage
1. Weiss. New Engl J Med. 20053521011-23.
2. Marques. Endocrinology.
20091502822-8.
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Theory SIBO inflammation hepcidin

• TNF-a increases gut permeability
• Translocation lipopolysaccharides
• LPS increases hepcidin
• IL - 6 increases hepcidin
• Hepcidin reduces Fe transport/absorb
• Inflam mice new choroid plexus
  hepcidin production less iron in brain

1. Spiller. Gut. 200047804-11. 2. Riordan.
Scand J Gastroenterol. 199631977-84. 3.
Anderson. Curr Opin Gastroenterol.
200925129-35. 4. Marques. Endocrinology.
20091502822-8.

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Prevalence of SIBO in 1o RLS

• RLS gt controls

Plt0.001 vs. controls
Weinstock LB, Walters. 2011
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Rifaximin Treatment for RLS
Study Design Treatments Results
Open-label Idiopathic RLS pts (N21) Rifaximin 30 days 71 pts had LBT 14/21 were RLS global-responders IRLS scale 66 improvement in 9/14 In 5 non-responders 2 better with rifaximin combined with metronidazole

Weinstock. Poster presented at 3rd
International World Sleep Congress November
7-11, 2009 Sao Paulo, Brazil.
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Rifaximin Treatment for RLS
Study Design Treatments Results
Open-label IBS pts with SIBO and idiopathic RLS (N13) Rifaximin 1200 mg/day 10 days then promotility 2 mo probiotic and zinc 1 mo 77 had 80 improvement in global RLS symptoms (F/U mean 60 d) 6/13 pts had 100 relief

Weinstock et al. Dig Dis Sci.
2008531252-1256.
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Rifaximin Open-label Study
N14

• Rifaximin 1200 mg/d for 10 d
• then rifaximin 400 mg every other day
  for 20 d
• -10 RLS for global responders (9/14)

Day

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RLS-SIBO Rifaximin DB Study

• Idiopathic RLS pts screened using LBT
• Inclusion for Rx abnl LBT, IRLS 15, ferritin
  20
• Pts randomized 21
• Rifaximin 1650 mg/d or placebo for 10 days
• IRLS scale and GI sx days 0, 11, 18, 25

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Double Blind study

• Rifaximin significantly reduced IRLS score vs.
  baseline on d-11 and d-18
• Effect lost by d-25
• No change with placebo

Treatment
Day

• P0.03 vs. baseline. P0.007 vs. baseline. One
  patient was excluded because of initiation of
  benzodiazepine therapy during the study period.
  IRLS international restless legs syndrome.

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RLS Pathophysiology

• CNS iron deficiency 5
• Altered dopaminergic system 6
• Peripheral neuropathy 6
• SIBO 7
• Inflammation 8
• Immune disorder 8
• Endorphin deficiency 9

5. Allen. Arch Intern Med. 20051651286-1292. 6.
Trenkwalder. Clin Neurophysiol.
20041151978-1988. 7. Weinstock. Dig Dis Sci.
2008531252-1256 8. Weinstock. Sleep Med Rev
201216341-354. 9. Walters. J Neurol Sci
200927962-65.
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Highly Associated Diseases/ Conditions with RLS Iron Deficiency SIBO Inflammatory and/or Immunological Disorders
Total disorders (40) 25 15 33
Neurological (15) Gastrointestinal
(5) Rheumatologic (5) Metabolic (6) Pulmonary
(5) Other (4)
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Neurologic conditions associated with RLS Iron deficiency SIBO Inflammatory and/or immunological alterations
Charcot-Marie- Tooth NS NS Yes
Polyneuropathy NS NS Yes
Amyloidosis NS Yes Yes
Parkinson's dis. No Yes Yes
Multiple sclerosis Yes NS Yes
Essential tremor NS NS NS
Myelopathy No NS Yes
Narcolepsy NS NS Yes

• Diseases in yellow LDN Research Fund
• Red - elsewhere

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Neurologic conditions associated with RLS (cont.) Iron deficiency SIBO Inflammatory and/or immunological alterations
Migraine Yes NS Yes
ADHD Yes NS Yes
Tourette's synd. Yes NS Yes
Huntington's dis. Yes NS Yes
Chiaris malformation NS NS NS
Friedreich's ataxia Yes NS NS
Narcolepsy NS NS Yes
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GI conditions associated with RLS Iron deficiency SIBO Inflammatory and/or immunological alterations

Gastric resection Yes Yes NS
Chronic liver disease Yes Yes Yes
IBS No Yes Yes
Celiac disease Yes Yes Yes
Crohns disease Yes Yes Yes
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Rheumatologic conditions associated with RLS Iron deficiency SIBO Inflammatory and/or immunological alterations

Rheumatoid arthritis Yes Yes Yes
Fibromyalgia Yes Yes Yes
Scleroderma No Yes Yes
Sjögrens synd. Yes NS Yes
Bruxism NS NS NS
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Metabolic diseases associated with RLS Iron deficiency SIBO Inflammatory and/or immunological alterations

Renal disease Yes Yes Yes
Diabetes Yes Yes Yes
Pregnancy Yes NS Yes
Obesity Yes Yes Yes
Hypothyroidism Yes Yes Yes
Hyperparathyroidism Yes NS Yes
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Pulmonary conditions associated with RLS Iron deficiency SIBO Inflammatory and/or immunological alterations

Sleep apnea No NS Yes
Sarcoidosis Yes NS Yes
COPD Yes NS Yes
Pulmonary Hypertension NS NS Yes
Lung transplantation Yes NS Yes
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Other conditions associated with RLS Iron deficiency SIBO Inflammatory and/or immunological alterations

Anemia Yes NS No
Age Yes Yes Yes
Depression Yes NS Yes
Erectile dysfunction NS NS NS

Since 2012 review HIV and Post-polio syndrome
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Inflammation and RLS evidence

• ESRD-RLS assoc with inc. CRP, IL-6, ferritin,
  natriuretic peptide, 8-OHdG (8-hydroxy-2'-deoxygua
  nosine), and decr. transferrin sat (8-OHdG level
  independent risk factor for high IRLS score) 1
• HIV-RLS IL1B and IL17A pro-inflm. genes 2
• Mixed-RLS with PLMD CRP increases with PLM
  severity (OR 8) (not IL-6 or TNF) 3
• (timing of IL-6 and TNF draws were not
  ideal)

• 1. Higuchi. Sleep Med. 2015. 2. Hennessy. Biol
  Res Nurs. 2014. Trotti. Brain Behav Immun. 2012

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Endorphin Deficiency and RLS

• Autopsy study - 37.5 reduction in beta-endorphin
  and met-enkephelin in thalamus vs. controls
• Cell culture - application of enkephelin
  protected substantia nigra DA cells from
  apoptosis d/t Fe def
• Implication in RLS pts with iron def, endorphin
  Rx may improve dopamine dysfunction
• PET scan study in RLS pts found negative
  correlations between endorphin binding in various
  parts of the brain and RLS severity
• Less endorphin binding --- greater severity of
  RLS

• 1. Walters. J Neurol Sci 200927962-65. 2. Sun.
  J Neurol Sci. 2011. 3. von Spiczak. Brain. 2005.

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Case 3

• 60 y.o. WF with 3 yr Hx RLS, constipation and
  halitosis
• LBT methane excretor
• Rifaximin 550 mg TID 14 d
• LDN 2.5 qHS long-term
• Remission 6 yrs

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Latest RLS Study Sequential Rx

• Chart review (1/06 - 12/14)
• Rif-LDN Rx N 52 40 pt 1 OV after Rx
• Rifaximin 1650 mg/day/2 weeks immediately
  followed by LDN
• 38/40 had chronic GI symptoms
• LBT positive in 37 by pre-2009 standards,
  7 reread as normal and 3 ND
• 4 men 36 women

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Rifaximin-LDN Sequential Rx
  Markedly better Moderately better Slightly better No change
Pts (N 40) 21 5 3 11
Responders 65
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LDN Dose Evaluation
N 40  Markedly Better Moderately better Slightly better No change
2.5 mg (N 23) 15 3 0 5
4.55.0 mg (N 17) 6 2 3 6
Responders 78 vs. 47 No difference in AE
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LDN Rx where original LBT normal by 2009
standards
  Markedly Better Moderately better Slightly better No change
N 7 2 2 - 3
Responders 57
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RLS LDN Rx

• 23 responders without AE LDN
  for x 107 wks (now up to 7 yrs)
• AE led to cessation of LDN in 6/40 (15)
• 3/6 AE were in responder group (LDN for
  6, 8 and 28 wks)

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RLS Theory
SIBO
Iron defic.
Cytokines

Endorphin deficiency
D2 dysfx
Others inc. peripheral neuropathy
RLS
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Summary

• RLS is a significant illness
• SIBO and inflammation may explain sig. portion of
  idiopathic RLS and 2o RLS
• Endorphin def. exacerbates CNS iron deficiency
  induced dopamine dysfunction
• Multimodality treatment is often needed in RLS
  remission is possible (generally unknown to
  occur)
• LDN can play important role in RLS Rx

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Back up slides
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Dopaminergic system pathogenesis in RLS

• Autopsy Study in Human RLS
• In human RLS in basal ganglia circuit there is
  down regulation of D2 dopamine receptors and up
  regulation of Tyrosine Hydroxylase, the rate
  limiting step for dopamine synthesis (Connor et
  al Brain 2009)

Connor JR et al. Brain 20091322403-12
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Problem with the dopamine hypothesis

• Down regulation of D2 receptors implies increased
  dopamine in RLS. This is not just a
  manifestation of dopaminergic therapy as the
  results are found in non-dopaminergic treated
  patients as well.
• Results do not explain why RLS patients respond
  to dopaminergic therapy.

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GI disorders and RLS

• Gastric resection
• Chronic liver disease
• Celiac disease
• Crohns disease
• SIBO

• Weinstock and Walters. Sleep Med Rev. 2012.

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Chronic Liver Disease and RLS

• N 141
• Prevalence (overall) 64
• Prevalence w/o other risk factor 16
• No relationship to cirrhosis or cause
• Reduced QoL mod. severity
• No CRF, neuropathy (31), Fe def, ETOH, Dopamine

Franco et al. J Cin Sleep Med. 2008145-9.
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Celiac and RLS

• N 85
• Incidence 35
• Prevalence 25 vs. 9 spouses
• 21 started before GI Sx
• Iron def. in 40 w/ active RLS
• 50 pts improved w/ GFD

Weinstock et al. Dig Dis Sci. September 2009.
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Crohns disease and RLS

• N 272
• Incidence 43
• Prevalence 30 vs. 8 spouses
• 92 started after onset of CD
• 45 stated RLS sx correlated with
  activity GI sx severity
• No correlation with iron levels

Weinstock et al. Inflammatory Bowel Dis. July
2009.
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IBS and RLS

• N 90 (20-55 y.o.)
• Prevalence 29
• Confirmed by sleep study in 24/26 pts
• Risk is higher with IBS-d

Basu et al. Am J Gastroenterol. October 2009
Abstract.
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RLS and IBS

• 59 RLS pts interviewed
• 23/59 (38.9) had IBS 1
• vs.
• 394/5009 (7.8) of gen pop 2
• (plt0.001 by Z-comparison)

1. Walters and Weinstock. ANA. Abstract 2010.
2. Hungin et al. Aliment Pharmacol Ther.
   2005211365-75.

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Conclusions from Rifaximin Studies

• SIBO is common in idiopathic RLS
• GI symptoms are common in RLS
• 10 days of rifaximin reduces RLS severity (may
  not be long enough)
• The connection between SIBO and hepcidin should
  be investigated in both 1o and 2o RLS
• Total SIBO Rx (antibiotic, diet, motility,
  probiotics, and zinc) and iron Rx if needed
  increases success in my clinical practice

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Patient Demographics
Clinical Characteristics Rifaximin(n20) Placebo(n10)
Mean age SD, y 53 10 60 14
Male Female, n 9 11 2 8
Mean IRLS score SD 26 5 23 5
Mean duration of RLS SD, y 13 11 11 14
Dopaminergic Rx SSRI use BMI gt30 Ferritin levels, ng/mL (range) 70 55 30 106 (29-395) 60 30 30 72 (25-138)
Ferritin 50 (30 each group) First degree relative Irritable bowel syndrome Chronic bloating 80 50 30 20 10 20

1 placebo pt eliminated from therapeutic follow
up analysis added benzodiazepine on own
P0.004
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Double blind study GI Evaluation
LBT-pos (N30) LBT-neg (N9)
IBS 33 33
Abd. pain 53 78
Bloating 63 67

• 33 of the LBT-pos group had no GI sx
• Rifaximin slight reduction in pain (2.8 to
  2.5) bloating (3.2 to 2.7)
• (at day 11) (scale 0-6)

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Adverse events

• RLS worsening
• Rifaximin 4/20
• 2 at end of study after good response
• 2 associated with increased fructose intake
• Placebo 2/10
• 1 marked and 1 moderate
• GI symptoms worsening
• Rifaximin 5/20
• All slight
• Placebo 2/10
• All slight