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1 How to Treat PULL-OUT SECTION Complete How to Treat quizzes online to earn CPD or PDP points. INSIDE Pathophysiology Clinical features Diagnosis Management Severe or refractory cases Case study the authors Dr Omar Ahmad neurologist, Macquarie Neurology and Macquarie University, Macquarie, NSW. Restless legs syndrome Background Dr Kate Ahmad neurogenetics and neuromuscular fellow, Royal North Shore Hospital, St Leonards, NSW. RESTLESS legs syndrome (RLS) is a common sleep wake disorder and is characterised by an urge to move. The symptoms are often difficult to describe or painful and display a circadian pattern. Two forms are described (primary or secondary) based on the presence or absence of an underlying cause. The syndrome was first described by the physician Sir Thomas Willis (who, incidentally, is the eponym for the Circle of Willis ) in His eloquent observations continue to be relevant: Wherefore to some, when being abed they betake themselves to sleep, presently in the arms and legs, leapings and contractions on the tendons, and so great a restlessness and tossings of other members ensue, that the diseased are no more able to sleep, than if they were in a place of the greatest torture. The syndrome was described occasionally after this but it was not until the thesis of Karl-Axel Ekbom in 1945, that it was characterised comprehensively. 2 Up to 10% of the adult population is affected with minor RLS symptoms and 2.7% are affected more severely with symptoms at least twice a week. 3,4 It is most often diagnosed in middle to late life and the prevalence increases with age until the age of 79. In practice, it is unusual for the primary form of RLS to present late in life; elderly patients are more likely to have a secondary form. It has been reported in children with an incidence of 2% and affects women twice as often as men. 5 While most epidemiological data comes from Caucasian populations in Europe and America, RLS has also been described at a similar incidence in other racial groups. cont d next page Copyright 2013 Australian Doctor All rights reserved. No part of this publication may be reproduced, distributed, or transmitted in any form or by any means without the prior written permission of the publisher. For permission requests, howtotreat@cirrusmedia.com.au Paediatrics Earn CPD POINTS Reserve your space today Full day seminar for GPs MELBOURNE 10 AUGUST SYDNEY 24 AUGUST PERTH 31 AUGUST BRISBANE 7 SEPTEMBER ADELAIDE 7 SEPTEMBER Endorsing Partner Sponsor Supporting Sponsors 2 August 2013 Australian Doctor 23

2 Pathophysiology MANY regions and processes within the nervous system are involved in RLS. Importantly, abnormalities of brain iron metabolism, dopaminergic transmission and genetics all play a role in the pathophysiology. The genetics of RLS is not fully understood but a family history is present in at least 40% of patients. Linkage studies have identified eight loci that are associated with RLS but they are not causally related. Genome-wide association studies have found four gene variants that convey an increased risk. 6-8 One of these genes is a marker of body iron stores whereas the mechanism by which the others are associated with the pathogenesis of RLS is unknown. 6 Figure 1: Normal MRI brain (susceptibility weighted imaging) at the level of the midbrain showing iron content of deep nuclei. Image courtesy Professor John Magnussen, Macquarie Medical Imaging. Iron deficiency Iron deficiency is implicated in the pathogenesis and is supported by multiple lines of evidence. Firstly, RLS patients have significantly lower ferritin levels compared with controls. Low CSF ferritin levels are also observed in RLS patients. 9 Recent insights suggest that there is dysregulation of iron entry via the endothelial cells of the blood brain barrier. 10 These cells serve as a reservoir for brain iron and have significantly altered expression of iron management proteins. In addition, autopsy, MRI (figure 1) and sonographic studies have shown reduced iron levels within neuromelanin cells of the substantia nigra. 11 Iron also plays an important role in dopamine production through tyrosine hydroxylase and is involved in noradrenaline and serotonin transmission. Reduced dopaminergic activity Dopaminergic signalling also plays an important role as highlighted by the efficacy of dopaminergic drugs. Autopsy studies have shown reduced dopamine D2 receptor binding in the basal ganglia. Functional imaging studies have shown conflicting results, with some showing reduced dopamine D2 receptor binding in the basal ganglia while others have shown increased or unchanged binding Spinal dopaminergic pathways may also be important and several animal studies have focused on this pathway. Clinical features RLS is characterised by the urge to move the legs and its features can be conveniently remembered by the acronym URGE (Urge to move, Rest induces symptoms, Getting active brings relief, Evening and night worsens). 15 The clinical features are similar for both primary and secondary forms of RLS. The motor symptoms are preceded by an uncomfortable sensation in the legs that is poorly localised and poorly described. It can be characterised as creeping, pulling, crawling or pain. This symptom is relieved by movement and brought on by rest. The symptoms peak at night and are often worst between midnight and 2am. Patients not uncommonly need to climb out of bed to relieve their symptoms. With increasing disease severity, the circadian pattern becomes less pronounced and symptoms become noticeable earlier in the evening or throughout the day. This daytime encroachment of symptoms is often first noted in situations where prolonged sitting is required (eg, in the cinema, day trips, or on public transport). Sleep disruption is an associated feature of RLS and significantly impacts quality of life and general health. Impaired sleep may be due to a combination of an initial difficulty in falling asleep and the frequent need to relieve symptoms with activity, which then necessitates leaving the bed. Physical examination is usually With increasing disease severity, the circadian pattern becomes less pronounced and symptoms become noticeable earlier in the evening or throughout the day. normal unless a secondary cause is responsible. Periodic limb movements of sleep About 85% of RLS sufferers also have periodic limb movements in sleep. These are brief stereotyped jerking movement of the lower limbs that occur in sleep. They can cause arousal from sleep and are an additional cause of insomnia and daytime drowsiness in RLS. Periodic limb movements in sleep have separate diagnostic criteria and can be diagnosed on polysomnography (figure 2). However, this condition is not specific to RLS and can be seen in degenerative neurological conditions and with ageing. Figure 2: Polysomnography findings in periodic limb movements in sleep, a condition associated with, but diagnostically distinct from RLS. Boxed areas show periodic muscle discharges from left leg tibialis anterior. Image courtesy Dr Jonathan Williamson, Macquarie Respiratory and Sleep. Diagnosis THE diagnosis of RLS rests on meeting the essential and supportive criteria developed by the International RLS Study Group (IRLSSG), as illustrated in the box on the next page. 16 These criteria were developed in 1995 and revised in 2002 and The specificity of having the first four essential features is 84% for a diagnosis of RLS. 17 Although they are not part of the most recent criteria, associated features further improve the diagnostic accuracy. There is no biological marker specific for RLS and often the most useful test is the response to dopaminergic therapy. The use of a levodopa challenge is one approach and involves using a single dose of 100/25mg at the usual onset time. Another approach is to start a low-dose dopamine agonist and assess treatment response in a week. Adverse effects are unlikely and a lack of clear response may warrant further investigation for mimics or specialist referral. Of note, the circadian pattern of RLS is the most useful at differentiating it from other mimics. Primary vs secondary RLS Primary RLS is typically associated with an earlier onset and young onset (<30 years) when compared with secondary forms. It is associated with a positive family history in 60-90% of cases and is very slowly progressive over many years. 18 The three classical causes of secondary RLS are iron deficiency, pregnancy and renal failure. RLS is also commonly described in a variety of neurological and autoimmune conditions (table 1). Iron deficiency and/or anaemia are highly associated and feature in the pathophysiology of the disorder. 19 Pregnancy can be associated with severe RLS symptoms, which tend to be worse in the third trimester. 20 The association may relate to the induction of relative iron deficiency during pregnancy, or be due to hormonal influences. RLS is frequently seen in patients with end-stage renal failure and occurs in 21% of dialysis patients. 21, 22 Interestingly, in this clinical setting it is associated with increased mortality but is not clearly related to iron levels or anaemia. It may be that it relates to associated neuropathy, which is found in a high proportion of patients with end-stage renal failure. Neuropathy as the aetiological culprit may also be true for the connective tissue disease and coeliac associations Conditions associated with RLS Several recent trials have reported an increased prevalence of RLS in patients with Parkinson s disease, 24 Australian Doctor 2 August

3 though this co-pathology is perhaps less pronounced than would be expected, given there is dopaminergic dysfunction in both conditions. 27,28 Conversely, the evidence for a link with multiple sclerosis is mounting. This relationship has been explored recently in a metaanalysis of 24 studies showing fourfold-increased odds for RLS in MS patients. 29 There are several possible explanations for this, with corticospinal tract pathology seemingly most likely to cause RLS symptoms. A similar explanation may account for other associations with spinal cord disease and spinocerebellar ataxia. A review of the patient s medications is always warranted as drugs are another association that should not be overlooked. The most common offenders are antidepressants and metoclopramide. Drugs may also exacerbate primary RLS, and should be reviewed whenever a patient s symptoms become more severe. Screening for secondary causes If RLS is suspected, a basic screen for secondary causes should be performed. This would include iron studies, vitamin B12 and renal function. Selected patients may warrant further investigation with an autoimmune panel (ANA, RF, ENA, SS-A/SS-B), coeliac serology and nerve-conduction studies. Polysomnography is not necessary for making a diagnosis of RLS and is used mainly for treatment-resistant cases and for judging treatment response in clinical trials. Restless legs syndrome diagnostic criteria from the international RLS Study Group (2011) Essential An urge to move legs usually but not always accompanied by or felt to be caused by uncomfortable sensations in the legs The urge to move the legs and any accompanying unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting The urge to move the legs and any accompanying unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, as long as that activity continues The urge to move the legs and any accompanying unpleasant sensations during rest or inactivity only occur or are worse in the evening or night than during the day The occurrence of the above features are not solely accounted for as symptoms primary to another medical or a behavioural condition (eg, myalgia, venous stasis, leg oedema, arthritis, leg cramps, positional discomfort, habitual foot tapping) Associated features Dopaminergic responsiveness Presence of periodic limb movements in sleep or in wakefulness Positive family history Usually progressive clinical course Normal neurological examination in the idiopathic form Sleep disturbance Table 1: Secondary causes of RLS Patient Prevalence in patient population General population 7% Pregnancy 13.5% Iron deficiency anaemia 31% Renal failure 21% Polyneuropathies 20% Parkinson s disease 20% Rheumatoid arthritis/systemic 25% sclerosis Coeliac disease 31% Multiple sclerosis 29% Spinocerebellar ataxia (SCA3) 45% Medications such as SSRIs, - TCAs, lithium, anticonvulsants, metoclopramide, antipsychotics Condition Nocturnal leg cramps Radiculopathy Painful neuropathy Akathisia Vascular/neurogenic claudication Table 2: Mimics Distinguishing features Calves only, painful. Urge to move legs is confined to stretching out the cramp. More sudden in onset and brief duration One-sided, positional not just with rest, radiation from back Can be nocturnal, sensory symptoms or numbness. Neurological signs include loss of vibration and ankle jerks Motor restlessness. Related to neuroleptic exposure, absence of pain, affects whole body and present throughout day Opposite pattern, worse with walking/ standing. Nil circadian pattern Venous insufficiency Evidence of venous hypertension discolouration, varicose veins, oedema. Present throughout day and preference for leg elevation Pressure-related symptoms Others: Inflammatory arthritis, erythromelalgia, complex regional pain syndrome Short duration, relief with change in position. Affects arms as well as legs. Often unilateral. Normal phenomenon Difficult to confuse with RLS. Continuous in nature Differential diagnoses Differential diagnoses, or mimics, of RLS are relatively easy to differentiate as they tend to lack the cardinal RLS features of worsening at night and relief with movement. The most common mimics are painful neuropathy, leg cramps, akathisia, and pressure-related sensory symptoms (table 2). Painful neuropathies are the most difficult to exclude as symptoms often overlap with RLS. In addition, early neuropathies may not initially result in abnormal investigations. Some chronic pain syndromes can present in the legs and lower back without a clear structural basis. These are often associated with psychological features and are typically not responsive to dopaminergic therapy. Management MILD symptoms of RLS (IRLS score <10) can be managed with simple measures such as increased activity in the evening or a trial of magnesium supplements (powdered or tablet form at night). Good sleep hygiene should be encouraged, as should the avoidance of stimulants at night. Treatment with an oral iron replacement can be useful if the ferritin is less than 50μg/L. 30,31 While IV iron therapy is an option, the risk of iron overload and anaphylaxis needs to be taken into account. Treatment in the setting of normal levels is not proven to be of benefit. Choice of pharmacotherapy The common drugs used for the treatment of RLS are listed in table 3. The usual approach is to treat with the lowest possible dose and to use one agent at a time. In primary RLS, dopaminergic agents are considered first line followed by anticonvulsants. Opioids are used in more severe cases and after other approaches have failed. Combination therapy is required in up to 20% of cases. Longer-acting agents are in theory better at achieving a good response and less likely to be associated with rebound of symptoms in the middle of the night. Timing of treatment should be directed towards the evening about two hours before symptom onset. The decision to begin pharmacotherapy should be based on symptom severity. This can be gauged by applying the IRLS rating scale (see Online resources, page 30). This is used primarily in a research setting, however it is still relatively simple and its components are a useful guide for initiating treatment. Dopamine agonists Dopamine agonists, the first-line agents for primary RLS, have had their efficacy confirmed in 18 randomised controlled trials. The proportion of responders (>50% reduction in IRLS score) is in the order of 61% with a number needed to treat of Dopamine agonist therapy is also shown to improve sleep quality parameters and periodic limb movements in sleep. Studies comparing the various dopamine agonists are lacking. Dopamine agonists have been studied in patients with moderate to severe RLS symptoms. Ergotderived dopamine agonists, despite having good evidence (eg, cabergoline and pergolide) are no longer used for prolonged periods because of the risk of fibrotic complications. The three non-ergot dopamine agonists used are pramipexole, ropinirole and rotigotine. There is no known cross-tolerance among agents, and lack of response to one may not influence response to another agent. Pramipexole Pramipexole can be started at a dose of mg two hours before symptom onset. Doses up to 0.75mg a day can be used cont d next page Dopaminergic agents Table 3: Drug therapies Half-life Initial dose (hours) Maximum Levodopa /12.5mg 400/100mg Pramipexole mg 1.5mg Pramipexole extended mg 2.25mg release Ropinirole 6 0.5mg 4mg Rotigotine 5 constant 2mg/24 hrs 4g/24 hrs Anticonvulsants Gabapentin mg 1200mg Gabapentin enacarbil* 6 600mg 2700mg Pregabalin 10 25mg 300mg Opioids Oxycodone 6.5 5mg 25mg Tramadol mg 150mg Others Clonazepam mg 2mg Clonidine mg 0.4mg *not currently marketed in Australia 2 August 2013 Australian Doctor 25

4 from previous page although some patients may require even higher doses. Splitting the dose by using a small dose early in the evening and a higher dose before bed is a good approach for patients with more prolonged symptoms. An extended release formulation is approved for Parkinson s disease (Sifrol ER) and has anecdotal evidence as a therapeutic option for RLS (although it has not been formally studied in this condition). Features and treatment of augmentation Features Increasing symptom severity without known trigger Earlier onset of symptoms Shorter latency to symptoms when at rest Extension of symptoms to other body parts Decreased duration of medication benefit Paradoxical response to medication Treatment Lowest possible dose of dopaminergic agent for as long as possible Exclude or treat iron deficiency Increase daytime activity (eg, encourage walking) Split dose of dopaminergic medication or add additional dose Switch to another dopamine agonist nil cross-tolerance Switch to anticonvulsant or opioid Combination therapy Drug holidays Ropinirole Ropinirole can be started at a dose of 0.5mg a day. It can be gradually increased as required and the usual maintenance dose is in the order of 2mg daily. Doses up to 4mg daily can be used. The extended-release formulation of ropinirole is not available in Australia. Rotigotine Rotigotine is available as a transdermal patch for once-daily dosing. It is available in doses from 2-8mg every 24 hours. It is particularly useful for moderate to severe RLS with daytime symptoms. Skin reactions occur in 17% of patients. It has recently been approved for Parkinson s disease in Australia and its cost is the main drawback for use in RLS. Levodopa Levodopa has the longest history of use in RLS. It has a short halflife (1-2 hours) and can therefore be associated with rebound symptoms later in the night. It also has a high rate of augmentation over time (60% see below) and is generally avoided in patients with moderate to severe symptoms. 33 Levodopa may have a role in patients with very mild or occasional symptoms and can be used intermittently rather than regularly in this setting. A dose of 50/12.5mg- 100/25mg of regular-release preparation is used initially. Because of its rapid action, levodopa can be used as a diagnostic test and a partial or complete response to a single dose is suggestive. If levodopa therapy is to be used in more severe disease, longeracting preparations are preferred to avoid rebound symptoms and often in combination with a short-acting formulation (eg, Sinemet CR 100/25mg + Sinemet 100/25mg). Levodopa in combination with a catechol O-methyl transferase (COMT) inhibitor (Stalevo) is another option for increasing half-life. Dopamine agonist side effects Dopamine agonists are associated with unique side effects that have come to light in more recent times and these need to be discussed with patients before starting therapy. The common side effects include nausea, headache, dizziness and oedema. Attacks of sudden onset of sleep and excessive daytime sleepiness are associated with dopamine agonist therapy in Parkinson s disease. Its prevalence in RLS is slightly higher than controls and patients need to be cautioned about driving and operating heavy machinery in the early stages of treatment. Doses used in RLS are lower than Attacks of sudden onset of sleep and excessive daytime sleepiness are associated with dopamine agonist therapy... patients need to be cautioned about driving and operating heavy machinery. Table 4: Incidence of augmentation Dopaminergic agonist % of cases with augmentation Levodopa 27-82% Pramipexole % Ropinirole 7% Rotigotine 9.7% Tramadol reports in Parkinson s and with night-time dosing this complication is less commonly encountered. Impulse-control disorders Impulse-control disorders have been well reported and characterised in Parkinson s and were thought to be rare in RLS. Recent data have reported rates of 7-17%, similar to rates in Parkinson s disease. 34 Impulse-control disorders are a complex of disinhibitory psychomotor behaviours and include excess gambling, hypersexuality, excess shopping and dopamine addiction. These can be devastating for patients and cause financial ruin. Screening for these disorders should be routine during follow-up. Impulse-control disorders are reversible upon cessation of dopamine agonist therapy or lowering of dose. The common occurrence of impulse-control disorders in the RLS-treated population may be an argument against their current use as first-line agents. Levodopa therapy does not seem to carry this risk. Augmentation Augmentation is a significant complication of dopaminergic therapy for RLS. It is an intensification of RLS symptoms above baseline associated with prolonged dopaminergic stimulation. Some factors favour the development of augmentation. These include high medication doses, use of short half-life medications, longer duration of therapy and positive family history of RLS. It is therefore most commonly seen with levodopa therapy (table 4) and can be seen within 2-4 months. Dopamine agonists are also associated with augmentation at lower rates. The presentation is that of quite severe RLS symptoms and may involve more pain and paraesthesia. Diagnosis. Clues to the development of augmentation include earlier onset of symptoms in the evening, a shorter latency during inactivity and extension of symptoms to other body parts (see box above right). In its most severe form, it may resemble akathisia, with a feeling of inner restlessness and inability to sit or stand still. The circadian pattern may also be lost and walking may not relieve symptoms. It is likely related to overstimulation of dopamine receptors with subsequent decreased receptor sensitivity. Management. The major goal is prevention and using the lowest effective dose of dopaminergic medication is recommended. Severity of symptoms should also be taken into account and mild augmentation may not require change in medication. Exacerbating factors should be addressed; in particular iron deficiency (ferritin <50μg/L) should be sought and treated. With moderate symptoms, dopaminergic medication can be split into two with an earlier dose given in the afternoon. Alternatively, a changeover to a longer-acting formulation can be trialled. Another strategy is to change to a different dopamine agonist, as there is no cross-tolerance. With severe symptoms, it may be necessary to stop dopaminergic therapy altogether while overlapping therapy with a different class of agent. Another approach that can be used is rotation of dopaminergic therapy at three-monthly intervals. Anticonvulsants The most widely used anticonvulsants in RLS are gabapentin and pregabalin. Gabapentin enacarbil, a prodrug of gabapentin, has also been well studied in RLS. It has the advantage of more prolonged action compared with gabapentin, but it is not currently available in Australia. Anticonvulsants are effective agents for moderate to severe symptoms and are not reported to produce augmentation as a side effect. Their efficacy has been confirmed in seven trials with a responder rate of 61% (>50% reduction in IRLS score) and a number needed to treat of They have also been shown to improve sleep parameters. They are a good choice in patients with secondary forms of RLS such as coexisting neuropathy or in haemodialysis patients. Anticonvulsants are also a good choice in patients with prominent pain. Often they are used in combination with other RLS agents to treat severe symptoms. Their side-effect profile is also favourable although elderly patients may develop dizziness, somnolence and oedema. Although they have not been directly compared with dopaminergic agents, they are seen as being less effective for the primary form of RLS. Valproate, carbamazepine and topiramate have also been evaluated in RLS with mixed results. These drugs side-effect profile is less favourable, which also limits their widespread use. Gabapentin is initiated as a night-time dose of mg and increased as required. Doses up to 1200mg at night can be used. A regular daytime dose is often given when symptoms progress. Pregabalin is utilised in a similar fashion and is started at 25-50mg at night. cont d page Australian Doctor 2 August

5 Severe or refractory RLS Opioids THE opioids have traditionally played an important role in the management of RLS. They have been less well studied in comparison with dopamine agonists or anticonvulsants. Despite this, they can be highly effective even at low doses. The two agents most commonly used are oxycodone and tramadol. The single oxycodone trial showed a 52% improvement in RLS symptoms along with improvement in periodic limb movements in sleep. 35 These agents should be used with caution, given the risk for abuse and addiction. However, in severe cases there is often little choice but to recommend these agents. The main side effects are constipation, respiratory depression and dependence. Respiratory depression requires special mention, as there is a higher prevalence of sleep apnoea in RLS patients. These agents are often used in combination with dopaminergic agents to control symptoms completely. Augmentation has been reported with tramadol and it is not yet clear whether this extends to other opioids. Oxycodone is started at a dose of 5mg at night and used at mean doses of 15mg daily. The extended release formulation is typically used. Tramadol is started at 50mg and is available in a sustained-release formulation. Other drugs Clonazepam This agent has been studied in two small trials with mixed results. 36,37 It is less effective than other therapies and is used primarily for insomnia associated with RLS. Clonazepam has a long half-life and may cause daytime somnolence. It is also prone to cause respiratory depression and dependence. Despite these drawbacks, it is useful in combination with other therapies to improve sleep. Clonazepam is started at doses of 0.25mg at night and can be used at doses up to 2mg. Clonidine Clonidine is associated with significant side effects and has a minor role in RLS therapeutics. It has shown benefit in two trials and is used at doses of 0.05mg a day up to a maximum of 0.4mg a day. 38,39 The main side effects are sedation, dry mouth and hypotension. When to refer It is not unreasonable for GPs to initiate therapy for mild to moderate RLS. Referral may be sought after an adequate trial of one or two agents, when symptoms become more severe or if there is a lack of response. The development of augmentation is another indication for referral. Referral should also be considered in secondary forms of RLS to assist with management. All general neurologists are capable of managing RLS, although more advanced aspects of therapy may require input from a movement disorder specialist. Research and other measures Pneumatic compression devices have shown promise in a single controlled trial and are still investigational. 40 Little data is available on other nonpharmacological therapies, as these studies use very small numbers. Recommended approach A PRACTICAL approach is to use dopaminergic agents as first-line therapy for primary RLS in the younger population. With RLS that starts later in life, is secondary in nature or has prominent pain, anticonvulsants often make the best first-line therapy (figure 3). In those with addictive personality traits, dopamine agonists are best avoided as first-line agents. In general, opioids should be avoided initially and only used in combination with other agents for moderate to severe disease. Anecdotally, while clonazepam can be useful as an adjunct to therapy it does not provide complete control of symptoms when used as monotherapy. Special populations Certain situations require an alteration of approach and this is especially true of pregnancy. Pregnancy In pregnancy, RLS is severe in 40% of cases and treatment cannot always be avoided. Iron replacement should be used first line, followed by opioids, as there are fewer safety concerns with these agents. Dopaminergic agents such as pramipexole can also be used in severe cases, as there is reasonable evidence of safety from other populations; however, they are considered as a last resort. End-stage renal failure In patients with end-stage renal failure or on dialysis, gabapentin is used first line and requires dose adjustment. In this setting, iron infusion may also be successful. Clonidine is an alternative option that may be considered. RLS will often subside following renal transplantation. Parkinson s disease In patients with Parkinson s, the Mild symptoms Sleep hygiene Exercise Iron replacement if ferritin low Low-dose levodopa prn Restless legs syndrome Primary RLS Moderate to severe symptoms Pramipexole Ropinirole Gabapentin or pregabalin Long-acting dopamine agonist Dopamine agonist and opioid/clonazepam Dopamine agonist and gabapentin In those with addictive personality traits, dopamine agonists are best avoided as first-line agents. Figure 3: Management guideline. Augmentation Secondary RLS Moderate to severe symptoms Gabapentin or pregabalin Gabapentin and pramipexole Gabapentin and opioid Other anticonvulsants Clonidine Split dosing of dopamine agonist Change to longer-acting dopamine agonist Change to another dopamine agonist Change to gabapentin or opioid Dopamine agonist rotation evening dose of levodopa may be increased. Rotigotine and extended release pramipexole may also be considered. Neuropathy First-line agents for patients with neuropathy are gabapentin or pregabalin. Difficult-to-treat cases may require the addition of an opioid or a dopamine agonist. Other anticonvulsants such as valproate and carbamazepine are also effective alternative treatment options. Summary of treatment Mild RLS Exercise, magnesium. Low-dose levodopa as prn therapy Treat iron deficiency Moderate RLS Pramipexole or ropinirole initially Gabapentin in certain populations With increasing duration of symptoms Split dose of dopamine agonist or extra dose earlier in evening Change to extended release formulation With increasing intensity of symptoms Add gabapentin at night Add tramadol/oxycodone Change dopamine agonist Severe RLS Dopamine agonist plus opioid or clonazepam Gabapentin/pregabalin plus opioid Dopamine agonist washout and replacement with another class Clonidine Drug holidays Rotation of dopamine agonist every three months cont d next page 2 August 2013 Australian Doctor 29

6 Case study ALBERT is an 87-year-old man who presented with persistent restless legs. He has had this problem for the past 30 years and had sought medical advice from GPs and neurologists on numerous occasions. He complains of legs that recurrently involuntarily twitch or jerk suddenly when he is trying to get to sleep, and occasionally is woken up by these movements, although he does have a disjointed sleep broken by nocturia. He blames the restless legs on his past history of polio as a child, which had affected his right leg. However, he still has full use of his legs and mobilises without aid or assistance. In the past he has trialled various medications including pramipexole, levodopa and carbidopa, clonazepam and carbamazepine. He also frequently requests temazepam to help him overcome the restless legs and get to sleep. He is currently on pramipexole 0.75mg daily and attributes his constipation to this. As a result, he is taking increasing doses of Coloxyl, Movicol and Senakot to manage this. Conclusion RLS is a very common sleep wake disorder with a complex pathophysiology. The recent insights into iron metabolism and deficiency within the nervous system are a key to understanding its pathogenesis and its likely secondary effects on other neurotransmitters. Because of treatment resistance, he proceeded to have sleep studies, which confirmed the presence of periodic limb movements in sleep and myoclonus. The pramipexole was tapered over a week and at the same time he was started on gabapentin at 200mg each night. This was increased to a maintenance dose of 400mg a night. At this dose, his limb movements subsided and he was far less troubled by limb jerking. He did not tolerate a low dose of clonazepam (0.25mg) in combination with this. Polio and in particular post-polio syndrome is a rarely described secondary cause of RLS. 41 It frequently begins when other symptoms of post-polio syndrome begin and is often associated with new muscle pain. Sleep studies in these patients demonstrate a variety of movements including periodic limb movements in sleep, myoclonus and more ballistic movements. Interruption of spinal cord pathways from past polio is a likely mechanism for RLS in this disorder. Treatment is usually the same, however the nocturnal movements are more likely to respond to anticonvulsants and benzodiazepines. It is important to recognise that there are primary and secondary forms of RLS and that management will vary according to this. The diagnosis is relatively simple and almost entirely clinically based. An important clue to this is the response to dopaminergic medication. Several treatment-related issues can complicate long-term management. The most important are those associated with dopaminergic therapy and include impulse-control disorders and augmentation. The former has emerged as a significant risk in the RLS population and requires careful discussion with patients before initiation of therapy. Despite this, dopamine agonists remain first-line agents in most cases. With increasing disease severity, more complicated regimes are employed and combination therapy is often required. Online resources International Restless Legs Syndrome Study Group Includes rating scale (IRLS) irlssg.org References Available from Further reading Walters AS, et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Medicine 2003; 4: Aurora R, et al. The treatment of restless legs syndrome and periodic limb movement disorder in adults an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses. Sleep 2012; 35: Wilt T, et al. Pharmacologic therapy for primary restless legs syndrome: a systematic review and meta-analysis. JAMA Internal Medicine 2013; 173: How to Treat Quiz Restless legs syndrome 2 August 2013 Instructions Complete this quiz online and fill in the GP evaluation form to earn 2 CPD or PDP points. We no longer accept quizzes by post or fax. The mark required to obtain points is 80%. Please note that some questions have more than one correct answer. GO ONLINE TO COMPLETE THE QUIZ 1. Which TWO statements are correct regarding epidemiology of restless legs syndrome (RLS)? a) RLS is most commonly diagnosed from midlife to later life b) RLS is rare, affecting less than 0.1% of the population c) RLS is very rare in children, affecting less than 0.02% of the paediatric population d) RLS affects women twice as often as men 2. Which TWO statements are correct regarding the epidemiology and pathophysiology of RLS? a) Excessive stimulation of the dopaminergic pathways is not implicated in the pathophysiology of RLS b) Genetics is not a factor in the pathogenesis of RLS c) Iron deficiency may be a contributing factor of RLS d) RLS may be secondary to systemic conditions such as renal failure 3. Which TWO statements are correct regarding the clinical features of RLS? a) There is an urge to move the legs that is relieved by activity b) Patients often complain of sleep disruption and insomnia impacting on quality of life and general health c) RLS is never present during the day d) RLS symptoms are typically worst in the late afternoon 4. Which TWO statements are correct regarding the diagnosis of RLS? a) Diagnosis may be made with a 100/25mg levodopa challenge b) The circadian pattern of RLS is the most useful at differentiating it from other diagnoses c) A genetic blood test confirms the diagnosis d) Polysomnography is the first-line investigation for the diagnosis of RLS 5. Which THREE of the following conditions are causes of secondary RLS? a) Coeliac disease b) Rheumatoid arthritis c) Polycythaemia d) Multiple sclerosis 6. Which THREE of the following are mimics of RLS? a) Akathisia b) Parkinson s disease c) Painful neuropathy d) Leg cramps 7. Which TWO statements are correct regarding the medications used to treat RLS? a) More than 60% of patients treated with a dopamine agonist respond with a >50% reduction in the International Restless Legs Syndrome Study Group rating scale (IRLS) score b) Ergot-derived dopamine agonists such as cabergoline are the first-line drugs of choice for RLS c) Low-dose opioids may be used with close monitoring in refractory RLS d) Levodopa is a drug of choice when the RLS is moderate to severe 8. Arthur, an 82-year-old man, presents with frequent insomnia because of an urge to move his legs that is relieved only when he moves his legs. Which TWO statements are correct? a) RLS can be clinically diagnosed with 84% specificity if Arthur has the first four essential features of the 2011 revised IRLS criteria b) Elderly patients presenting with first-onset RLS are more likely to have a secondary form c) Arthur should be screened for co-occurring multiple sclerosis d) Arthur should be referred to a sleep physician for further review 9. Which TWO statements are correct regarding investigation and diagnosis of Arthur s presentation? a) Blood tests should be ordered, including iron studies, vitamin B12, renal function, and possibly an autoimmune panel, coeliac serology and nerve conduction studies b) The presence of periodic limb movements in sleep is diagnostic of RLS c) RLS is excluded if Arthur also experiences symptoms during the day d) A review of Arthur s medications, including antidepressants, is essential 10. Which TWO statements are correct in the management of Arthur s condition? a) Arthur may be advised that dopamine agonists are hormone mimics and therefore have no significant side effects b) For mild symptoms, sleep hygiene, iron replacement and exercise may be sufficient c) Arthur should be started on a dopaminergic agent as the first-line therapy d) Augmentation may occur within 2-4 months of dopamine agonist therapy CPD QUIZ UPDATE The RACGP requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the triennium. You can complete this online along with the quiz at Because this is a requirement, we are no longer able to accept the quiz by post or fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online. how to treat Editor: Dr Steve Liang steve.liang@cirrusmedia.com.au Next week The prevalence of chronic disease and comorbidity increases significantly with age. Therapeutic guidelines give little consideration to age or comorbidity. The next How to Treat looks at the complexities of pharmacological therapy for the older patient, as this population is vulnerable to prescribing complications. The authors are Associate Professor Sarah Hilmer and Associate Professor Susan Ogle, both senior staff specialists, Royal North Shore Hospital, St Leonards, and associate professors, Sydney Medical School, University of Sydney, NSW. 30 Australian Doctor 2 August