1. Restless Leg Syndrome Nin Bajaj Consultant Neurologist

2. Historical Context ‘Instructions for curing the Watching evil “in London practice of Physick” published in 1685: ‘…..Wherefore to some, when being in 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 the members ensure, that the diseased are no more able to sleep, than if they were in the place of the greatest torture!…..’

3. Glaxo denies pushing 'lifestyle' treatments · 'Restless leg syndrome can ruin people's lives' · British drug firms' figures outstrip expectations Fiona Walsh Friday April 28, 2006 Guardian GlaxoSmithKline, Europe's biggest drugs manufacturer, yesterday defended itself against accusations that it is turning healthy people into patients by "disease mongering" and pushing "lifestyle" treatments for little-known ailments. Studies published in a respected medical journal, the Public Library of Science Medicine, this month accused the big pharmaceutical companies of "medicalising" problems such as high cholesterol and sexual dysfunction. The authors of the report highlighted the "restless legs" syndrome, described by GSK as "common yet unrecognised" when it launched its Ropinirole treatment last year. David Stout, head of GSK's pharmaceutical operations, yesterday denied the accusations, saying: "You need to talk to the patients. Things like restless leg syndrome can ruin people's lives. It is easy to trivialise things when you don't have them. If people did not want the treatments, they would not seek them."

4. Sleep Disturbance Nine out of 10 people with RLS either cannot get to or stay asleep, or their sleep is disturbed during the night [Hening et al, 2004a], and people with moderate to severe RLS average less than five hours sleep per night [Allen et al, 2003].

5. Description of Sensation Like an electric current The heeby-jeebies Crazy legs Like Coca-Cola bubbling through my veins The gotta-moves Aching in my bones Pulling Elvis Legs

6. Description of Sensation Tearing Throbbing Creepy Crawly Pain Like a tooth ache in the legs Growing pains Itching bones Like maggots crawling through my veins

7. Supportive Features 1.Dopaminergic responsiveness 2.Periodic limb movements during sleep (PLMS) (in individuals under 50 years of age). Periodic limb movements are clonic type movements (or uncontrollable 'jerks') - usually of the lower extremities. 3.Family history- 60% of patients with RLS especially early onset

8. Associated Features 1.Usually progressive, most patients middle to older age. May occur de novo during or be exacerbated by pregnancy. 2.Neurological examination usually normal but can be an associated neuropathy/radiculopathy 3.Sleep disturbance that can be associated

9. Prevalence 5-10% of the population experiencing symptoms at some time in their lives [reviewed in detail in Allen & Earley, 2001]. In the recent RLS Epidemiology, Symptoms and Treatment (REST) Primary Care Study, 3.4% of the sample of 23,052 patients reported RLS symptoms twice a week which were judged to have a moderate or severe impact on their quality of life [Hening et al, 2004a].

10. Familial History 24% of young onset RLS patients (< age 45) have a first degree relative with RLS Up to 60% may have a family history

11. Genetics Desautels et al. genome-wide scan in a large French-Canadian family significant linkage chromosome 12q for RLS with a significant LOD score of 3.59 (RLS 1) autosomal recessive

12. Genetics Desautels et al. 2005 another study which supported the previously reported chromosome 12q linkage results 276 individuals from 19 families

13. Genetics Bonati et al. (2003) reported (RLS 2) locus on chromosome 14q13-21 region in a 30-member, three-generation Italian family affected by RLS and PLMS autosomal dominant inheritance pattern

14. Genetics Chen et al. (2004) 15 large and extended multiplex pedigrees consisting of 453 subjects, 134 were affected with restless legs syndrome novel significant RLS susceptibility locus on 9p24-p22 with a multipoint nonparametric linkage (NPL) score of 3.22 (RLS 3).

15. Neurochemical Basis Iron, dopamine, opiates

16. Iron hypothesis conditions that cause secondary RLS – iron deficiency anaemia, pregnancy and end stage renal failure – are all linked to iron deficiency [Philipps 2004 Neurology 62:S9-S16] Serum iron levels exhibits circadian variation with up to a 50% drop in iron concentration at night Iron is needed for the conversion of tyrosine to dopa by tyrosine hydroxylase, so a lack of iron could affect dopaminergic function MRI studies have shown depleted iron levels in the substantia nigra of RLS patients [Allen et al, 2001], and

17. Iron hypothesis autopsy studies have confirmed depleted iron and altered iron protein levels [Connor et al, 2003] iron-deprived rats, reduced central iron concentrations have resulted in striatal changes, including D2R and dopamine transporter levels, and increased extracellular dopamine – a pattern of dopamine abnormalities similar to RLS patients [Allen and Earley, 2001]

18. Iron hypothesis Intravenous iron supplementation has been shown to have beneficial effects on RLS symptoms [Allen and Earley, 2001], but the same has not been shown for oral iron treatment [Davis et al, 2000] In the absence of a peripheral iron deficiency, the GI tract may not be able to absorb sufficient iron to affect central stores in the brain.

19. Dopamine and RLS chance finding that low doses of l-dopa provided almost complete relief from RLS [Akpinar, 1982]. dysfunction of the central dopaminergic system due to cellular loss in the mesocorticolimbic dopamine systems have been implicated

20. Dopamine and RLS positron emission tomographic (PET) and single photon emission computed tomographic (SPECT) studies in RLS patients have found small decreases in dopaminergic measures in the striatum, compared with controls [Allen and Earley, 2001

21. Dopamine and RLS Binding studies showed a decrease for dopamine D2 receptor in the striatum methodology issues make it difficult to be sure that observed differences were not due to sleep loss, age differences between patients and controls, or to changes in extracellular dopamine [Allen and Earley, 2001].

22. Dopamine and RLS RLS may originate from disinhibition of the spinal reflexes as a result of abnormalities of the dopaminergic and dopamine-linked systems final common pathway may be influenced by supraspinal opioid and monoamine pathways

23. Opiates/Dopamine and RLS RLS patients have been shown to have disturbed supraspinal pain modulation involving the basal ganglia and/or the descending dopaminergic pathways [Stiasny- Kolster et al, 2004] Endogenous opioids may play a secondary role possibly via their effects on the dopaminergic system High doses of opiates can relieve RLS symptoms, and their beneficial effects can be blocked by the dopamine antagonist, pimozide [Montplaisir et al, 1991].

24. Secondary RLS One in five pregnant women get RLS [Hening et al, 1999], usually during the later stages of pregnancy or after childbirth [Allen and Earley, 2001]. ?associated with reduced serum ferritin/folate Self resolving on parturition

25. Secondary RLS Iron deficiency anaemia Diabetes mellitus End stage renal disease (ESRD) (particularly patients receiving haemodialysis or peritoneal dialysis Vitamin B12 /Folate deficiency Parkinson's disease

26. Secondary RLS Peripheral neuropathy Fibromyalgia Rheumatoid arthritis Spinocerebellar ataxia Charcot-Marie-Tooth disease (type 2)

27. Differential Diagnosis Nocturnal leg cramps Peripheral neuropathy (not usually associated with motor restlessness or helped by movement) Vascular disease (such as varicose veins or deep vein thrombosis)

28. Differential Diagnosis Painful legs and moving toes Intermittent claudication Neuroleptic induced akathisia Attention Deficit Hyperactivity Disorder in children "growing pains" Anxiety or generalised anxiety disorder

29. Making the Diagnosis Clinical symptoms Normal neurological and vascular exam Exclude secondary causes with blood tests Full blood count Iron studies Serum ferritin Serum Vitamin B12 /Folate Thyroid function tests Urea & Electrolytes Serum glucose

30. Making the Diagnosis Sometimes polysomnography to exclude PLM, Nocturnal awakenings, Sleep architecture related problems

31. Treatment- conservative Mild RLS may not require medical treatment reassurance should be offered and lifestyle changes may be useful (e.g. stopping smoking, relaxation, better sleep hygiene)

32. Treatment- conservative Some drugs may worsen RLS e.g. antidepressants, calcium blocker drugs (used to treat high blood pressure), anti-nausea medications except domperidone, high intake of caffeine and some anti-allergy medications.

33. Treatment- sleep hygiene Walking and stretching Hot or cold bath Relaxation exercises (biofeedback or yoga) Having an engaging discussion or activity during sitting to distract mind Massaging affected limbs

34. Treatment- sleep hygiene Quiet, comfortable and cool sleeping environment Regular hour for going to bed at night Waking at the same time in morning Avoiding tea/coffee before bed Avoiding water tablets before bedtime Some people find sleeping late and rising late may be beneficial

35. Drug trials- Levodopa A review of 18 studies of levodopa in RLS, including eight double blind trials, showed that treatment consistently reduced RLS and PLMS But levels of daytime augmentation up to 82% (Allen and Earley 1996) and early morning rebound of 20-35%, especially at high doses [Standards of Practice Committee of the American Academy of Sleep Medicine, 1999].

36. Drug Trials-Levodopa combination of regular and slow release levodopa prolonged the duration of response compared to conventional levodopa

37. Drug Trials-Dopamine Agonists number of dopamine agonists, with activity mainly at D2 receptors, have been used includes the ergot derivatives, pergolide, cabergoline and alpha- dihydroergocryptine (DHEC), and the non-ergot derivatives, pramipexole, ropinirole, piribedil and talipexole

38. Dopamine Agonists- Pergolide pergolide improves RLS, PLMS and sleep, both in the short and long term [Hening et al, 2004b]. nausea was reported in 41%, congestion also in 41%, and augmentation in 27% (Staisny K et al 2001) 78.6% of patients remained on long term treatment reports of serious pergolide complications, typical of ergot agents, including pleuropulmonary fibrosis or cardiac valvulopathy [Hening et al, 2004b].

39. Dopamine Agonists- Cabergoline double-blind, placebo controlled, multi-centre dose finding trial followed by an open-label extension of 47 weeks carried out on 85 patients with cabergoline (Stiasny-Kolster Neurology 2004) Severity of RLS as assessed by the RLS-6 rating scale and International RLS Study group rating scale, was markedly improved with a mean cabergoline dose of 2.2 mg/daily Augmentation occurred in 9% There were 11 withdrawals over the course of a year due to drug related side-effects including nausea and dizziness and one incident of hallucinatory psychosis.

40. Dopamine Agonists- Requip ropinirole assessed in four double blind, placebo controlled studies with a total of 818 RLS patients [Trenkwalder et al, 2004; Walters et al, 2004; Allen et al, 2004; Montplaisir, 2004] associated with significant improvements in RLS and PLMS, quality of life and sleep, which were maintained over a 36 week period. In one study, in which change in PMLS was a primary endpoint, 54% of patients achieved levels of periodic limb movements in sleep that were similar to those of people without RLS/PLMS – defined as five or fewer – by the 12th week of the study [Allen et al, 2004].

41. Dopamine Agonists- Mirapexin pramipexole in patients with moderate to severe restless legs syndrome (RLS) 12-week, double-blind, randomized, placebo-controlled trial of fixed doses of pramipexole (0.25, 0.50, and 0.75 mg/day)(N = 344) primary efficacy endpoints were patient ratings of symptom severity on the International RLS Study Group Rating Scale (IRLS) and clinician ratings of improvement on the Clinical Global Impressions- Improvement (CGI-I) scale. Secondary efficacy endpoints included quality of life (QOL) Winkelman JW et al. Neurology (2006)

42. pramipexole was superior to placebo for IRLS in a dose dependent manner pramipexole increased the percentage of patients with a CGI-I rating of "very much improved" or "much improved" at the end of the trial well tolerated: most frequent adverse events with higher occurrence in the pramipexole group were nausea (19.0% vs 4.7%) and somnolence (10.1% vs 4.7%) Dopamine Agonists- Mirapexin

43. Treatment 2 licensed drugs: ropinerole and pramipexole Start dopmaine agonist of choice

44. Treatment- Algorithm If patients are intolerant to dopamine agonists then levodopa (Sinemet or Madopar) should be given at night-time before bed 80-82% of patients taking levodopa may develop augmentation or rebound

45. Treatment If levodopa is no longer effective or if symptoms start appearing in the early morning (rebound phenomenon) or evening/daytime with spread to upper limb (augmentation), then dopamine agonists may be reintroduced cabergoline may be particularly useful as this drug works given once daily. Dopamine agonists with shorter half-life may need to be given up to 3 times a day.

46. Treatment If symptoms are resistant then carbamazepine or gabapentin may be tried inhibit the hyperactivity of the nervous system that may be related to the symptoms Gabapentin may be particularly useful for haemodialysis patients because it is dialyzable and has a long half-life, and for 'painful' RLS

47. Treatment Severe unremitting painful RLS may need to be treated by strong painkillers such as Codeine, Tramadol, Oxycodone or Propoxyphene under specialist guidance

48. Treatment Bedtime sedatives such as clonazepam or zopiclone may be useful in some cases with severe insomnia may also exert a beneficial effect by reducing nervous activity and by increasing muscle relaxation

49. Levodopa 100-600 mg/daily Bromocroptine 7.5 mg nocte Pergolide ).75 mg nocte or bd Ropinerole 0.5-4.0 mg nocte Pramipexole 1.5 mg nocte/bd Cabergoline 0.5-4mg nocte Clonzepam 0.5-2 mg nocte