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Pathophysiology of Restless Legs Syndrome and Periodic Limb Movements in Sleep

Pathophysiology of Restless Legs Syndrome and Periodic Limb Movements in Sleep. Arthur S. Walters, M.D. Professor of Neurology Associate Director Sleep Medicine Vanderbilt University School of Medicine Nashville, Tennessee. Disclosures for last year.

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Pathophysiology of Restless Legs Syndrome and Periodic Limb Movements in Sleep

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  1. Pathophysiology of Restless Legs Syndrome and Periodic Limb Movements in Sleep • Arthur S. Walters, M.D. • Professor of Neurology • Associate Director Sleep Medicine • Vanderbilt University School of Medicine • Nashville, Tennessee

  2. Disclosures for last year Consultant to UCB Pharma on adult and pediatric RLS.

  3. The International Restless Legs Syndrome Study Group (IRLSSG) Consists of over 130 physicians and scientists from 17 countries dedicated to research on Restless Legs/Periodic Limb Movements in Sleep. Developed a consensus definition of RLS published originally in 1995 and updated for better clarity and republished in 2003. Same definition also was accepted by International Classification of Sleep Disorders Version 2.

  4. Obligate Clinical Features RLS An urge to move the legs usually accompanied or caused by uncomfortable and unpleasant sensations in the legs. The urge to move or unpleasant sensations begin or worsen 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.

  5. Supportive Clinical Features of RLS Positive Family History of RLS. Improvement with dopaminergic therapy. Periodic Limb Movements In Sleep (PLMS). At least 4 movements in a row – at least 8 mcv high, 0.5-10 seconds in duration and 5-90 seconds apart. Periodic Limb Movements in Wakefulness (PLMs).

  6. --- PLMS

  7. Associated Features of RLS Sleep Disturbance. Neurological Examination – Normal in idiopathic or familial cases. Evidence of Peripheral Neuropathy or Radiculopathy in “secondary cases”. Serum ferritin < 50 mcg/L. Clinical course— Most patients middle to older age, but may be seen in children. Usually progressive but static course may be seen. Remissions of a month or more may be seen in 15% of cases.

  8. Therapy of RLS • First line– Dopaminergic Agents • L-Dopa, ropinirole, pramipexole • Second line – • Opioids • Anticonvulsants – gabapentin, pregabilin • Benzodiazepines – clonazepam, diazepam • Iron Therapy

  9. Pathogenetic Mechanisms and Hypotheses

  10. Summary of talk Therapy has led to pathogenetic hypotheses- Iron, Dopaminergicagonists,Opioids We will also review Genetics Immunologic Hypothesis

  11. Summary of talk Circadian Control of RLS/PLMS Brief Summary of Neurophysiology of RLS/PLMS Relationship of RLS/PLMS to Cardiovascular Disease

  12. Iron pathogenesis and RLS • Some RLS patients present with iron deficiency. Their serum and CSF ferritin levels are low (Earley et al, 2000). • With MRI, Allen et al. (2001) revealed that RLS patient’s iron level is low at the Substantia Nigra (SN) area and the MRI iron values of this area correlate with RLS severity. • Conner, et al. (2003) found SN dopaminergic cells intracellular Fe level is low in both primary and secondary RLS patients with post-mortem autopsy.

  13. Dopaminergic system pathogenesis in RLS A-11 dopaminergicdiencephalo spinal lesions lead to a restless rat. DA agonist treatment with pramipexole improves restlessness (Ondo et al MovDisord 2000). In human RLS in basal ganlia circuit there is down regulation of D2 receptors and up regulation of Tyrosine Hydroxylase, the rate limiting step for dopamine synthesis (Connor et al Brain 2009)

  14. Dopaminergic system pathogenesis in RLS • L-DOPA treatment of RLS pushes symptoms to an earlier time of day (Augmentation). • When augmentation occurs the Dim Light Melatonin onset (DLMO) occurs earlier (Garcia-Borreguero et al. 2004) • This supports a role for the circadian pacemaker in the production of RLS symptoms and supports a role for dopaminergic deficit in the triggering of the onset and timing of the onset of RLS symptoms.

  15. Dopaminergic system pathogenesis in RLS • L-DOPA • Suppresses Prolactin • Increases Growth Hormone However, in RLS patients this response occurs more at night when RLS symptoms are expected to be maximum (Garcia-Borreguero et al 2004). This suggests that a circadian dip in dopamine levels at night triggers the symptoms of RLS.

  16. RLS Genetics

  17. RLS Genetics Linkage studies have yielded 5 chromosomes but no genes Allelic Association studies have yielded 4 variants of common genes that account for over 50% of all RLS ( Simultaneous publication by group of David Rye, NEJM and group of JulianeWinkelmann Nat Genet 2007)

  18. Genetics of RLS/PLMS The gene found in common by both JulianeWinkelmann and David Rye on chromosome 6 is the BTBD9 gene which stands for Broad complex- tramtrack-bric-a-brac - domain 9. May have something to do with iron metabolism since there was a drop is serum ferritin of 13% for each copy of the variant of the gene.

  19. Genetics of RLS/PLMS The Meis 1 gene (one of the 6 genes associated with RLS) may also have something to do with general iron metabolism ( Silver et al SLEEP 2010)

  20. Genetics of RLS/PLMS Another two genes that convey genetic risk for RLS were recently discovered– Protein tyrosine phosphatase receptor type delta gene (PTPRD) and the Nitric Oxide Synthase gene (NOS). ADHD is more common in RLS/PLMS and vice versa. These genes also convey genetic risk for ADHD

  21. The Immunologic Hypothesis About 15% of RLS patients undergo remissions of a month or more that are independent of therapy. This is reminiscent of Multiple Sclerosis, an immunologically mediated Neurological Disease also characterized by exacerbations and remissions.

  22. The immunologic hypothesis RLS is more common in Rheumatoid Arthritis (up to 1/3) but not osteoarthritis (4%) (Auger et al 2005; Salih et al 1994). RLS is more common in Multiple Sclerosis (up to 1/3). (Auger et al 2005; Manconi et al 2007). Multiple Sclerosis and Rheumatoid Arthritis but not osteoarthritis are thought to have an immunologic diathesis.

  23. RLS and the immunologic hypothesis Hornyak M et al. Neurology 2008; 70: 1620-2. Double blind crossover study. 10 RLS patients either hydrocortisone 40 mg iv or saline placebo. Statistically significant Improvement in sensory leg discomfort (p = 0.032).

  24. The immunologic hypothesis Gamignani et al MovDisord 2006 RLS in 29 of 97 consecutive patients with polyneuropathy More often sensory neuropathy of small fiber type (15 of 29 vs. 16 of 68;P 0.009). In the RLS group, dysimmune neuropathies, significantly more frequent (11 of 29 vs. 10 of 68; P = 0.016).

  25. Weinstock and Walters Background: Irritable Bowel Syndrome (IBS) is frequently associated with Small Intestinal Bacterial Overgrowth (SIBO). Small Intestinal Bacterial Overgrowth can be detected by a positive Lactulose Breath Test (LBT).

  26. Weinstock and Walters RLS Group - 33 General Population Controls -25 2nd control group were GI disease was excluded - 30 27% RLS patients had Irritable Bowel Syndrome (IBS) as opposed to 4% in the general population controls (p=.0326)

  27. Weinstock and Walters A positive LBT was found in 67% of RLS patients as opposed to 28% of General Population controls (p =.0074) and10 % of Completely Healthy controls This indicates that a full 57% of positive LBTs and therefore Small Intestinal Bacterial Overgrowth can be attributed to RLS

  28. Prevalence of SIBO in RLS • RLS > controls with 2003 and 2009 criteria * *P<0.001 vs. controls for both criteria (30/39 patients screened randomized for treatment)

  29. The immunologic Hypothesis SIBO ---cytokines and/or translocation of lipopolysaccharides ---- increased Hepcidin--- abnormal central processing of iron. Alternatively SIBO may induce a direct auto-immune attack on the brain and/or peripheral nervous system in RLS.

  30. RLS and the immunologic hypothesis We did a survey of the 40 conditions frequently associated with RLS.(Secondary forms of RLS) 30of the 40 associated with inflammationor immunedysfunction. Other Than Multiple Sclerosis and Rheumatoid Arthritis other examples include Narcolepsy and Celiac Disease.

  31. Secondary RLS: 43 disorders/risk factors • 21 can have peripheral iron deficiency • 34 can have systemic inflammation or immune disorders 1 • 17 can have small intestinal bacterial overgrowth (SIBO) 2,3 Bacterial Overgrowth Iron deficiency Inflammatory and/or immune 1. Weinstock et al. Inflamm Bowel Dis. 2009 (in Press).. 2. Weinstock et al. Dig Dis Sci. 2008;53:1252-1256. 3. Weinstock et al. Dig Dis Sci. 2009 (in Press).

  32. Dopaminergic and opiate system pathogenesis in RLS The effect of the dopaminergic agents and the opioids is probably specific to the dopaminergic and opiate receptors since blockade of the effects of these drugs in RLS treated patients brings back the symptoms of RLS.

  33. Opioids may act through the Dopaminergic System The effect of the opioids is probably mediated through the dopaminergic system since opiate receptor blockers only reverse the therapeutic effects of the opioids in RLS treated patients, but dopaminergic receptor blockers reverse the therapeutic effect of either the opioids or dopaminergic agents in RLS treated patients. (Akpinar, et al.1987; Montplaisir, et al. 1990) Naloxone Pimozide V V V V Opioids >>>> Dopamine>>>> RLS

  34. Opiate Receptor Pet Scanning and RLS • Abnormalities in Post-synaptic Receptor Binding in Medial Pain Pathways (von Spiczak et. al. 2005). • Degree of binding correlated negatively with severity of RLS This further implicates the endogenous opiate system in the pathogenesis of RLS and suggests that RLS symptoms trigger the release of endogenous opiates in the medial pain system.

  35. Opioid Hypothesis for RLS Walters AS, Ondo WG, Zhu W, Le W. Journal of the Neurological Sciences 279: 62-65; 2009. . Post-mortem study of 5 RLS patients and 6 controls. In thalamus Beta endorphin reduced by 37.5% (p= .006, effect size 2.16). In thalamus Met enkephalin reduced by 26.4% (p =.028, effect size 1.58).

  36. Possible in vitro model of RLS(Sun et al. APSS 2003—Winner of honorable mention Young Investigator Award) • Iron deficiency causes cell death in the substantia nigra in rats • The dying cells in the substantia nigra are primarily dopaminergic although glial cells are affected as well. • Opioids protect against the dopaminergic cell death under conditions of iron deprivation.

  37. Summary of animal model of RLS • Low Fe High opioids and Low Fe V V V V V V DA Cell Death Less DA Cell Death

  38. Building up a colony at UAB Genotypes identified by PCR. Mating heterozygous mu-Opioid receptor knockout mice to obtain homozygous mutant mice. Mu-Opioid Receptor Knockout Mice Genotyping +/- +/- +/+ +/- 230 bp PGK Mutant Allele Primer 1 Primer 2 230 bp WT Allele Primer 2

  39. Results to date of Mu opiate receptor deficient mouse # 1 Animals are more hyperactive during the sleepperiod as is characteristic of RLS (in mice this is during the day). Mice are more sensitive to pain as has been previously described in human RLS by StiasnyKolster et al 2004

  40. Results to date of Mu opiate receptor deficient mouse #2 Serum iron is low compared to control mice. Next Step is to sacrifice brains to see if there is brain iron deficiency, downregulation of D2 receptors and upregulation of Tyrosine Hydroxylaseas in human RLS.

  41. New Project CSF study of RLS patients and controls to look for alterations in Beta endorphin Met enkephalin Leuenkephalin

  42. Early issue on definition of RLS Are RLS patients worse at night only because they are lying down or are the symptoms under circadian control?

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