Postgraduate Medical Journal (1986) 62, 329-333 Postgrad Med J: first published as 10.1136/pgmj.62.727.329 on 1 May 1986. Downloaded from

Review Article

The

W.R.G. Gibb and A.J. Lees National Hospitalsfor Nervous Diseases, Maida Vale, London W9 ITL, UK.

The first description of the restless legs syndrome diseases, diabetes, cold exposure or those taking (RLS) is attributed to Thomas Willis in the 'London drugs (Ekbom, 1945, 1950, 1960). A Practice of Physick' of 1685 (Ekbom, 1960). Here he diabetic patient whose symptoms vanished on the side wrote 'wherefore to some, when being a bed they of a recent leg amputation was presented as evidence betake themselves to sleep, presently in the arms and for a peripheral origin (Ekbom, 1961) and Bornstein leggs, leapings and contractions of their tendons, and (1961) speculated about abnormal connections with so great a restlessness and tossings of their members the reticular system. ensue, that the diseased are no more able to sleep than In recent years neuroleptic-induced akathisia has if they were in a place ofthe greatest torture'. In 1861 been compared with idiopathic RLS. Akathisia was Whittmaack used the term anxietas tibiarum to des- originally described in its uncommon idiopathic form cribe nocturnal discomfort of the legs, which he by Haskovec (1901) and later in relation to Parkin- considered was a common symptom of hysteria son syndromes (Sicard, 1923) and drugs such as (Ekbom, 1945). The same phenomenon was called (Sigwald et al., 1947) and the phenoth- 'impatience musculaire' in the French literature iazines (Steck, 1954). It is characterized by a state of (Ekbom, 1944; Bonduelle, 1952) and the leg jitters by mental and motor restlessness which is accompanied copyright. Allison (1943). by an irresistible compulsion to physically move Ekbom's earliest descriptions of the RLS distingui- about. Restlessness of the legs is common and similar shed a common form which he called 'asthenia crurum to that occurring in idiopathic RLS, but inner restless- paraesthetica' from a painful variant 'asthenia crurum ness of the mind and body is peculiar to akathisia. dolorosa' (Ekbom, 1946). He identified the first of Confusion between these two conditions explains why these in 34 cases. Paraesthesia with deep calf and shin promethazine and have been con-

discomfort started only when the legs were at rest and sidered both cause and ineffective remedy of RLS. http://pmj.bmj.com/ necessitated that they were moved to provide relief. He postulated that pregnancy was an aetiological factor and in some patients he diagnosed prostatitis, testos- Epidemiology terone deficiency and the burning feet syndrome due to malnutrition. Ask-Upmark noted the disorder as a Aches, pains and restless sensations in the legs and late effect of gastrectomy (Ask-Upmark & Meurling, body are at some time an almost universal experience. 1955) and on the basis of anecdotal evidence of RLS may form an extreme example ofthese affections, postural dependence of symptoms, suggested the or could be a different entity. In either case, studies on September 29, 2021 by guest. Protected cause was vascular congestion ofthe (Ask- should define the clinical criteria for diagnosis. Sug- Upmark, 1959). Some authors doubted the existence gested criteria are presented in Table I. As a result of ofa distinct syndrome; Purdon-Martin (1946) believed failure to apply definitions, comparable studies of the the symptoms were due to acroparaesthesia and same phenomenon are not reported. Masland (1947) that they were a manifestation of Surveys of 500 and 320 people identified 5% myokymia. (Ekbom, 1960) and 2.5% (Strang, 1967), respectively, By 1960 Ekbom had studied 175 people whom he with symptoms ofrestless legs. It was reported at ages had identified with restlessness of the legs. He found from 7-82 years and in children considered to be in that 5% of normal psychiatrically stable individuals the guise of growing pains (Allison, 1943). In a recent were disturbed by restless sensations, but also believed survey of surgical out-patients personally questioned it was symptomatic of anaemia, certain infectious by the investigators, 8/54 (15%) complained of un- pleasant sensations in the legs associated with an Correspondence: W.R.G. Gibb, M.B., M.R.C.P. inability to keep them still (Braude & Barnes, 1982). Accepted: 2 October 1985 Such a high prevalence is doubted by the authors of a © The Fellowship of Postgraduate Medicine, 1986 330 W.R.G. GIBB & A.J. LEES Postgrad Med J: first published as 10.1136/pgmj.62.727.329 on 1 May 1986. Downloaded from

Table I Diagnostic criteria In Parkinson syndrome Ekbom found that 3 of 28 patients had restless legs and Strang found a 7% 1. Discomfort ofboth legs ofa peculiar restless quality. incidence among 600 patients, but presumably none 2. Aching and tension in calfmuscles. were drug-induced (Strang, 1967). According to 3. A desire to shift the legs because ofthe uncomfortable Strang (1967) and Sicard (1923) untreated Parkinson's restless sensation. Other features: disease can be associated with both idiopathic restless movement oflegs provides partial or complete relieffor a legs syndrome and akathisia, although their prevalen- variable period; ces are unknown. reliefby walking is most effective; symptoms are worse in the evenings; occurs in discrete episodes lasting days, weeks or months. Pathogenesis Exclusion criteria: other neurological symptoms or the presence of A peripheral aetiology has often been considered neurological signs; likely. This assumption is based on the peripheral local causes in the legs: nature of the complaints and the absence of a closely antagonist or depleting drugs; associated neurological disorder or indication of a Parkinsons syndromes. central neurochemical abnormality. However, struc- tural abnormalities in peripheral nerve or muscle have questionnaire based survey of 452 patients of whom not been found to support this concept. The adverse less than 20 complained ofrestless legs (Feest & Read, effects ofanaemia or local ischaemia and the beneficial 1982). When these 20 were interviewed their symptoms effects of movement, vasodilatation and fever were considered non-specific. There is probably no (Ekbom, 1960) once supported the belief that the major sex difference (Morgan, 1967; Sandyk, 1983), disorder was provoked by an excessive accumulation the recent incorporation of twice as many women as of metabolites. men in a study of carbamazepine, may reflect the In a number of patients with leg discomfort and method of selection of patients. This study was based restlessness, nocturnal myoclonic jerks of the limbs in general practice (Telstad et al., 1984). Early studies occur excessively frequently during sleep or relaxation noted that 1/3 to 1/2 of patients reported affected (Frankel et al., 1974; Callaghan, 1966; Thanh et al., copyright. relatives (Ekbom, 1945; Morgan, 1967) and there are 1975). Long recognized as a benign phenomenon examples of familial occurrence (Bornstein, 1961; Oswald (1959) noted nocturnal myoclonic jerks were Boghen et al., 1975; Boghen & Peyronnard, 1976). often linked to an stimulus, suggesting that It is recognized that healthy individuals can be afferent impulses from the legs influenced a susceptible affected, but there have been many suggestions of reticular activating system. During relaxation and the possible causes. These include pica (Ekbom, 1966), onset of sleep an imbalance between inhibitory and late pregnancy, folate-deficiency in pregnancy (Botez excitatory mechanisms in the reticular system allows it & Lambert, 1977), anaemia, blood loss to become susceptible to afferent sensory input. This http://pmj.bmj.com/ (Morgan, 1967), chronic bronchitis, cancer (Ekbom, input precipitates a discharge ofmotor neurones down 1960), neuropathies (Harriman et al., 1979; Gorman et reticulospinal paths. al., 1965, Heinze et al., 1967), venous insufficiency, The recently discovered diencephalo-spinal Parkinson's disease (Morgan, 1967), barbiturate with- dopaminergic system could conceivably be involved in drawal (Gorman et al., 1965), caffeine (Ekbom, 1966), the pathogenesis of restless legs, in neuroleptic-in- a-blockers (Morgan 1975), (Harriman duced akathisia or in the pathology of Parkinson's et al., and depression 1979), (Morgan, 1967; disease (Lindvall et al., 1983b). It is feasible that there on September 29, 2021 by guest. Protected Gorman et al., 1965). Morgan considered many is an abnormal modulation of sensory information in patients had symptoms considered to be of psy- the dorsal horn involving dopaminergic, noradrener- chosomatic origin such as tension , dyspep- gic or serotinergic neurones. The possibility of altera- sia or proctalgia fugax (Morgan, 1975). Ekbom found tions in muscle tone or abnormal activity at muscle an incidence of 11% in late pregnancy, 24% in iron stretch receptors also remains. deficiency anaemia (Ekbom, 1960) and 12.6% after Akathisia, in contrast, is usually considered to be of gastrectomy (Ekbom, 1966). The aetiological role of central origin because of its association with known neuropathies has not been clarified although it is neurochemical alterations in Parkinson syndrome, described in uraemia (Callaghan, 1966; Thomas et al., neuroleptic therapy and its strong subjective compon- 1971), in alcoholic and diabetic patients (Gorman et ent. Here the most plausible theory implicates the al., 1965) and in painful amyloid neuropathy (Heinze meso-cortical dopamine system (Marsden & Jenner, et al., 1967). Recently, one renal unit has stated that as 1980; an hypothesis involving the cortex being par- many as 15-20% of their patients on dialysis have ticularly desirable in view ofthe accompanying mental appropriate symptoms (Read et al., 1981). agitation. THE RESTLESS LEGS SYNDROME 331 Postgrad Med J: first published as 10.1136/pgmj.62.727.329 on 1 May 1986. Downloaded from

Clinical features Treatment An unusually prominent aching discomfort is located The assorted advocated for restless legs deep in the calf and is associated with restlessness of reflect the high placebo response and spontaneous the legs and an irresistible urge to move them. Feelings remission rates. This further emphasizes the need for ofheaviness, tension, stiffness, dullness, local heat and strict diagnostic criteria, double-blind and cross over cold, mounting tension, itching, stabbing and paraes- trials. thaesias occur (Callaghan, 1966) and these occasional- The hypothesis of metabolite accumulation due to ly spread to thighs, feet and arms (Morgan, 1967). The reduced blood flow at rest was supported by the discomfort lies in muscles and occasionally bones and apparent benefit obtained from inositol niacinate, is usually bilateral. Ekbom quoted the descriptive tolazoline and nitroglycerin (Ekbom, 1960; Allison, words used by his patients; fidgets, jumps, horrors, 1943; Murray, 1967). Recently 660 patients were creeps, kicks, toothache, crawling and creeping. The entered by 147 GPs into a study whichtshowed benefit disorder is intermittent but characteristically begins from oxerutins (Pulvertaft, 1983). Out offour criteria- during relaxation in the evenings or in bed (Ask- aching or heavy legs, night cramps, restless legs at Upmark, 1955) and is often worse on lying or sitting night and paraesthesias - only two were required for (Braude & Barnes, 1982). Relief is obtained by skin entry to the study. rubbing, massage, standing, stretching, or general leg Massage, raising the legs, use of a vibrator, movements, but walking is often the only effective sedatives, narcotics, analgesics, ascorbic acid, alde- measure. Improvement often takes some minutes to hydes, dextrans, heparin, and quinine start, and full relief is often not obtained or quickly have been advocated, although Bornstein (1961) returns on stopping. It can occur each evening for considered fluctuations in symptoms occurred in- weeks or months before resolving, so that evenings are dependently of these treatnients. In those with iron disturbed and may result (Nordlander, deficiency anaemia (Ekbom, 1960) iron injections 1953). Unlike akathisia the phenomenon is more often usually provided temporary relief (Thomas et al., confined to the evening and night or appears to be 1971). The use ofiron has been extended to those who aggravated by recumbency, whereas in mild to are not anaemic (Nordlander, 1953). Oral iron therapy copyright. moderate akathisia patients often feel most at ease (Matthews, 1976) and folate supplements, particularly when lying. in pregnant patients, have been advocated (Botez & Lambert, 1977). Promethazine and phenothiazines were both noted to exacerbate symptoms (Morgan, 1967; Murray, 1967) butchlorpromazine (50-100 mg nocte) has been Restless legs syndrome is a distinct disorder which recommended (Sandyk, 1983). P-blockers have also been as cause must be distinguished from spastic paraparesis, ex- described and treatment (Strang, 1967). http://pmj.bmj.com/ trapyramidal rigidity, neuropathies or vascular or The association with prompted report of neurogenic claudication. Hudson described five cases benefit from 5-hydroxytryptophan (Menon & Kling, of a chronic neuromuscular condition, which compr- 1983), and that with Parkinson's disease from ised muscular aching and sometimes burning pain levodopa or bromocriptine (Akpinar, 1982). with fasciculations, cramps, fatigue and paraesthesia The anticonvulsant drugs phenytoin and car- (Hudson et al., 1978). It affected legs, trunk and arms bamazepine have been used. A study of 6 patients and symptoms were enhanced by physical activity and showed that 3 gained marginal improvement in relieved by rest. severity ratings and preference for carbamazepine on September 29, 2021 by guest. Protected In 1971 Spillane et al. described six patients with (Lindvall et al., 1983). Recently a double-blind study pain in the feet and legs with involuntary movements (Telstad et al., 1984) reported that placebo and of the toes. Nathan (1978) reported four more cases, carbamazepine were effective in reducing sleep distur- suggesting that major peripheral nerve or root damage bance and in having therapeutic effect. Car- was an imortant aetiological factor. It is also described bamazepine (mean dose 236 mg) was more effective after minor local trauma to the feet in the absence of than placebo. The importance ofplacebo response was features of causalgia (Schott, 1981). It had been emphasized, but criteria for entry to the study were not assumed to be a peripheral disorder, possibly due to a presented. Widespread use of carbamazepine may be spreading irritative disorder in the lower cord, but associated with cases of idiosyncratic leucopenia and evidence for a central origin has been reported exfoliative dermatitis. (Schoenen et al., 1984). The association ofinvoluntary The have been advocated ever spasms and myoclonus with Sudeck's atrophy, follow- since diazepam (Strang, 1967; Feest & Read, 1982; ing trauma, is thought to be due to a peripheral Sandyk, 1983) and chlordiazepoxide (Strang, 1967) mechanism (Marsden et al., 1984). were used. The use ofclonazepam was also prompted 332 W.R.G. GIBB & A.J. LEES Postgrad Med J: first published as 10.1136/pgmj.62.727.329 on 1 May 1986. Downloaded from by the association of RLS with myoclonus and discomfort of the legs that requires them to be moved effective relief reported in five patients (Matthews, so that relief can be obtained. It occurs during 1979). When a group of 15 renal unit patients were relaxation, particularly in the evenings or at night, given 0.5 mg at 18.00 h and 0.5 mg halfan hour before when myoclonicjerks ofthe legs and insomnia may be bed, symptoms were totally abolished in 6, although 8 experienced. A similar phenomenon accompanies the others needed larger doses (Read et al., 1981). In low syndrome of akathisia, but the two disorders are doses that are not sedative (0.5 mg in evenings), it is thought to be of different pathogenesis. There are no often very effective. proven aetiological factors and although the cause is unknown, current evidence favours a peripheral mechanism. The safest and most effective drug Conclusions therapy is a . The restless legs syndrome (RLS) consists ofa specific

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