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President, Specialists in Gastroenterology

Is Restless Legs Syndrome an Inflammatory Disease? Leonard Weinstock, MD Associate Professor of Clinical Medicine Washington University School of Medicine. President, Specialists in Gastroenterology. Disclosures. Speakers Bureau Salix, Entera Health, Actavis , Romark Consultant

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President, Specialists in Gastroenterology

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  1. Is Restless Legs Syndromean Inflammatory Disease?Leonard Weinstock, MDAssociate Professor of Clinical MedicineWashington University School of Medicine President, Specialists in Gastroenterology

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

  3. RLS clinical importancePathophysiologyRole of SIBORifaximin studiesInflammation & endorphin defSequential rifaximin & LDN study

  4. RLS: Clinical Aspects 1. Allen et al. Sleep Med. 2003;4:101-19. 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

  5. RLS Classifications 1. Allen et al. Sleep Med. 2003;4:101-19. Idiopathic Familial (known genomic markers) Secondary RLS

  6. RLS: Clinical Aspects 1. Allen et al. Sleep Med. 2003;4:101-19. 2. Garcia-Borreguero. Eur J Neurol 2006;13:15-20. 3. Abets et al. Value Heath 2005;8:157-67. 4. Walters et al. Sleep 2009;32:589-97. 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

  7. RLS: Pathophysiology 5. Allen. Arch Intern Med. 2005;165:1286-1292. 6. Trenkwalder. Clin Neurophysiol. 2004;115:1978-1988. 7. Weinstock. Dig Dis Sci. 2008;53:1252-1256 8. Weinstock. Sleep Med Rev 2012;16:341-354. 9. Walters. J Neurol Sci 2009;279:62-65. CNS iron deficiency 5 Altered dopaminergic system 6 Peripheral neuropathy 6 SIBO 7 Inflammation 8 Immune disorder 8 Endorphin deficiency 9

  8. Iron in RLS Low CNS iron found in 1o and 2oRLS 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 • Unger. J Appl Physiol. 2009;106:187-193. 2. Clardy. J Neuro Sci 2006.; 3. Earley. Neurology. 2000;54:1698-1700.

  9. 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

  10. Case 1 - 2005 • 65 y.o. WM with 14 yrpost infectious IBS followed by RLS • Rifaximin 550 mg TID 3 wks • Dramatic improvement in RLS • No change in periodic limb movement disorder

  11. 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

  12. RLS Theory: 2005-2011 SIBO link via SIBO-inflammation SIBO RLS IBS Pi-IBS Cytokines

  13. Hepcidin: Fe++peptide 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. 2005;352:1011-23. 2. Marques. Endocrinology. 2009;150:2822-8.

  14. 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. 2000;47:804-11. 2. Riordan. Scand J Gastroenterol. 1996;31:977-84. 3. Anderson. Curr Opin Gastroenterol. 2009;25:129-35.4. Marques.Endocrinology. 2009:150:2822-8.

  15. Prevalence of SIBO in 1o RLS • RLS > controls * *P<0.001 vs. controls Weinstock LB, Walters. 2011

  16. Rifaximin Treatment for RLS Weinstock. Poster presented at: 3rd International World Sleep Congress; November 7-11, 2009; Sao Paulo, Brazil.

  17. Rifaximin Treatment for RLS Weinstock et al. Dig Dis Sci. 2008;53:1252-1256.

  18. Rifaximin Open-label Study Rifaximin 1200 mg/d for 10 d then rifaximin 400 mg every other day for 20 d -10 RLS for global responders (9/14) N=14 Day

  19. RLS-SIBO Rifaximin DB Study • Idiopathic RLS pts screened using LBT • Inclusion for Rx: abnl LBT, IRLS ≥ 15, ferritin ≥20 • Pts randomized 2:1 • Rifaximin 1650 mg/d or placebo for 10 days • IRLS scale and GI sx: days 0, 11, 18, 25

  20. 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 *P=0.03 vs. baseline. †P=0.007 vs. baseline.‡One patient was excluded because of initiation of benzodiazepine therapy during the study period. IRLS = international restless legs syndrome.

  21. RLS: Pathophysiology 5. Allen. Arch Intern Med. 2005;165:1286-1292. 6. Trenkwalder. Clin Neurophysiol. 2004;115:1978-1988. 7. Weinstock. Dig Dis Sci. 2008;53:1252-1256 8. Weinstock. Sleep Med Rev 2012;16:341-354. 9. Walters. J Neurol Sci 2009;279:62-65. CNS iron deficiency 5 Altered dopaminergic system 6 Peripheral neuropathy 6 SIBO 7 Inflammation 8 Immune disorder 8 Endorphin deficiency 9

  22. Neurological (15) Gastrointestinal (5) Rheumatologic (5) Metabolic (6) Pulmonary (5) Other (4)

  23. Diseases in yellow –LDN Research Fund • Red - elsewhere

  24. Since 2012 review – HIV and Post-polio syndrome

  25. Inflammation and RLS: evidence • ESRD-RLS: assoc with inc. CRP, IL-6, ferritin, natriuretic peptide, 8-OHdG (8-hydroxy-2'-deoxyguanosine), 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

  26. 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 2009;279:62-65.; 2. Sun. J Neurol Sci. 2011.; 3. von Spiczak. Brain. 2005.

  27. 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

  28. 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

  29. Rifaximin-LDN Sequential Rx Responders = 65%

  30. LDN Dose Evaluation Responders = 78% vs. 47% No difference in AE

  31. LDN Rx where original LBT normal by 2009 standards Responders = 57%

  32. 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)

  33. RLS Theory: SIBO Iron defic. Cytokines Endorphin deficiency D2 dysfx Others inc. peripheral neuropathy RLS

  34. 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

  35. Back up slides

  36. 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 2009;132:2403-12

  37. 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.

  38. GI disorders and RLS • Gastric resection • Chronic liver disease • Celiac disease • Crohn’s disease • SIBO Weinstock and Walters. Sleep Med Rev. 2012.

  39. 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. 2008;1:45-9.

  40. 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.

  41. Crohn’s 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.

  42. 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.

  43. RLS and IBS • 59 RLS pts interviewed • 23/59 (38.9%) had IBS 1 vs. 394/5009 (7.8%) of gen pop 2 (p<0.001 by Z-comparison) Walters and Weinstock. ANA. Abstract 2010. Hungin et al. Aliment PharmacolTher. 2005;21:1365-75.

  44. 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

  45. Patient Demographics 1 placebo pt eliminated from therapeutic follow up analysis – added benzodiazepine on own * P=0.004

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