Secondary periodic limb movement disorder and restless legs syndrome

Sleep Medicine

SLEEP MEDICINE

Reviews, Vol. 3, No. 2, pp 147-158, 1999

pziz

REVIEW ARTICLE

Secondary periodic limb movement and restless legs syndrome R. M . Rijsman

disorder

and A. W . de Weerd

Centre for Sleep and Wake Disorders, MCH, 2501 CK The Hague, The Netherlands

Westeinde Hospital,

Postbox 432,

Periodic limb movement disorder (PLMD) and restless legs syndrome (RLS) are zuell-known entities from a clinical and polysomnograpkic point of view. PLMD and RLS are seen mostly as primary or hereditary diseases, but may occur in conjunction to other diseases suck as uremia, polyneuropatky, Parkinson’s disease, and deficiencies of iron and magnesium. This review zuill discuss the prevalence, etiology and patkopkysiology of secondary PLMD and RLS. Key words: periodic limb movement disorder (PLMD), restless legs syndrome (RLS), uremia, Parkinson’s disease, iron-deficiency, ferritin-deficiency, polyneuropathy, magnesium

Periodic limb movements in sleep (PLMS) are often associated with the restless syndrome (RLS) and are an important and characteristic polysomnographic finding

legs [l].

The PLMS-syndrome, or periodic limb movement disorder (PLMD) can be diagnosed without accompanying RLS. PLMD is a distinct entity. Because PLMD and RLS are overlapping disorders, it is not possible to discuss one without mentioning the other. In 1953, Sir Charles Symonds introduced the term nocturnal myoclonus (NM) to refer to involuntary clonic movements of the lower extremities during sleep. He classified these cases as “epilepsy variants” [2]. Four out of his five patients also appeared to suffer from familial RLS. Oswald [3] questioned NM and whether its features

were identical

to physiological

“sleep

starts”.

One of Oswald’s

cases probably

also had RLS. A correlation between NM and RLS was suggested. Lugaresi et al. [4] confirmed this correlation in a polysomnographic study of insomnia patients. Coleman introduced the term periodic movements in sleep (PMS) and described it as an entity on its own. He defined the characteristics of the periodic movements as duration, periodicity and arousal phenomena induced by these movements [5]. For the purpose of this review we have used the description given by Piillmacher and Schulz [6]: Periodic limb movement disorder (PLMD) is a condition characterized by periodic episodes of repetitive and highly stereotyped limb movements that occur

Correspondence to be addressed to: R. M. Rijsman, Centre for Sleep and Wake Disorders, MCH, Westeinde Hospital, Postbox 432, 2501 CK The Hague, The Netherlands. Tel: +31 70 3302004. Fax: + 31 70 3882636. E-mail: [email protected] 1087-0792/99/020147+12$12.00/0

0 1999 W.B. Saunders Company

Ltd

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during sleep and in wakefulness (particularly during rest). The movements usually occur in the legs and consist of extension of the big toe in combination with partial flexion of the ankle, knee, and sometimes hip. This movement may be said to resemble the triple-reflex. Periodic movements may also occur in the upper limbs. In this case, the arm repetitively flexes at the elbow. These movements can be unilateral or bilateral, they are not usually symmetrical or simultaneous and sometimes they alternate from one extremity to the other [7]. Periodic limb movements are predominately present during light sleep [non-rapid eye movement (NREM) phase 1 and 21, decrease during deep sleep (NREM stage 3 and 4) and are only sporadically present or completely disappear during rapid eye movement (REM) sleep. The prevalence of PLMD becomes higher with increasing age [S]. The diagnosis of PLMD first requires identification of PLM. A leg movement is classified as PLM if it is part of a periodic sequence of leg movements (LMs). The criteria for detecting a PLM have been thoroughly described by the ASDA Task Force Atlas i.e., four or more consecutive LM with a duration of 0.5-5.0 s, with an EMG amplitude of 25% or more of the calibration movement, and a minimum interval of 5 s and a maximum of 90 s between two consecutive LMs. Furthermore, the association between forms of PLM i.e. with or without arousal (A), is noted. The number of PLM (+A) per hour of total sleep time (PLM index) is essential for diagnosis as are assessments of the severity of the PLMD. These requirements make a polysomnographic evaluation obligatory. According to the ASDA criteria, a diagnosis of idiopathic PLMD can be made if the patient complains of insomnia or excessive daytime sleepiness (EDS), and shows no evidence of any medical or psychiatric disorder that could account for the primary complaint and also has a PLM index of more than 5. Classification of severity is made according to the PLM ( + A) index (Mild: PLM index = 5-25 PLM/h.; Moderate: PLM index = 25-50 PLM/h; Severe: PLM index >50 or PLM + A index >25) [l]. There may be a history of frequent nocturnal awakenings, not feeling refreshed after sleep or chronic insomnia [9]. Patients who are unaware of sleep interruptions may complain of EDS. It is possible that the patient’s symptoms are a reflection of the frequency of movements (and associated awakenings, arousal and inhibition of slow wave sleep) [IO]. Other studies, however, do not confirm this correlation between the number of PLM and sleep quality or EDS [ll]. In formulating the between PLM, sleep starts and other motor differential diagnosis, a distinction phenomena should be made. Examples of the latter are nocturnal cramps in the calves, nocturnal epileptic seizures and myoclonic epilepsy, REM sleep disorders with phasic REM twitches or REM sleep behavior disorder. Leg movements seen in association with sleep apnea may resemble periodic limb movements, but disappear on treatment of the primary condition. However, sleep apnea syndrome (SAS) and PLMD can co-exist and this combination may lead to a therapeutic paradox as the treatment of one disturbance may lead to aggravation of the other

W I. Myoclonic motor phenomena occurring during wakefulness should be distinguished from PLMD. These occur in Lance-Adams syndrome, Alzheimer’s disease, CreutzfeltJacob disease and several other neurological conditions. Thomas Willis first described RLS in the 17th century [13]. In 1995, an international study group formulated the criteria for the diagnosis RLS [14]. The four criteria essential to establish the diagnosis are:

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(1) desire to move the limbs usually associated with paresthesias/dysthesias; (2) motor restlessness, i.e. patients feel compelled to move and use different motor strategies to relieve unpleasant sensations associated with their restless legs; (3) symptoms are worse or present exclusively during rest (i.e. lying, sitting); (4) symptoms are worse in the evening or during the night. The additional five criteria of the RLS study group are not always found in RLS but are frequently present. These criteria are: (1) sleep disturbances and their consequences: e.g. difficulty in initiating and/ or maintaining sleep, daytime fatigue or exhaustion and sometimes excessive daytime somnolence [14, 151; (2) involuntary limb movements such as PLM during sleep and/or wakefulness; (3) a normal neurological examination in the primary form of RLS; (4) a quite typical clinical course; RLS may begin at any age, it is generally a chronic condition but remissions and/ or exacerbation’s (e.g. during pregnancy or caused by caffeine) may occur; (5) there is often a positive family history, the disease being inherited in an autosomal dominant mode. In most patients PLMD and RLS are seen as idiopathic disorders. However, both entities are also associated with other diseases. This review will discuss the prevalence, symptomatology and the current hypotheses on secondary forms as seen in patients with uremia, Parkinson’s disease, polyneuropathy, iron deficiency and magnesium deficiency.

Uremia Chronic renal dialysis, despite its successful record in prolonging life, often fails to eliminate the pervasive feelings of fatigue and tiredness [16] and the disturbed sleep patterns reported by 50-80% of end-stage renal failure (ESRF) patients [17,18]. Cardiac and pulmonary disease, anemia and depression are all causative factors, but sleep disorders probably also play an important role in causing these symptoms. RLS and PLMD are the most common sleep disorders found in ESRF patients receiving dialysis and they cause great distress. RLS is estimated to be present in between 17 and 57% of cases [18-231. The wide variance in prevalence of RLS can be ascribed to the various definition criteria in usage. If the minimal criteria of the international RLS working group are applied, the prevalence is estimated at between 22 and 30% [22, 231. The prevalence of periodic movements with or without RLS is estimated at between 20 and 45% [17, 241. These estimates are based on the results of questionnaires. As previously mentioned, the diagnosis of PLMD can only be made on the basis of a polysomnography. For this reason, PLMD as an entity could very well be an underestimated sleep problem in a population known to suffer from severe insomnia. It seems that the severity of RLS and PLMD in ESRF patients is greater than in the idiopathic RLS and PLMD patient groups. Severity expressed by the frequency of motor symptoms during the day and frequency of PLMS during the night, has been found to be higher in uremic RLS with PLMD patients than it is in similar patients with disease of an idiopathic origin [25, 261. The number of periodic leg movements

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occurring during wakefulness is significantly higher in uremic RLS patients. The presence of uremia appears to be a pre-condition for developing motor symptoms, although no direct relationship between uremia and PLM has been found. Subjective sleep quality also seems to be worse in the uremic variant compared with idiopathic RLS [27]. Sleep disordered breathing such as the SAS is also a commonly found sleep disorder amongst ESRF patients. However, Wadhwa et al., [28] found that it was PLMD and not apnea which predicted the ESRF patients opinion on their quality of sleep. On the other hand, no association between PLMD and subjective sleep quality was reported in other studies using self-assessment reports [17] or polysomnography [29, 301. In the study by Benz et al. [31], the severity of PLMD appeared to be an even better predictor of mortality in ESRF than serum albumin, urea reduction ratio, or co-morbid medical disease! The pathophysiology of RLS and PLMD is still unresolved. Several conditions related to uremia and dialysis may play a role. Callaghan [32] suggested that RLS in uremic patients is a condition, which could result from abnormal peripheral nerve function. Nielsen [33], however, reported a similar occurrence of RLS in uremic patients both with and without neuropathy and he suggested different mechanisms for RLS and distal paresthesias. Anemia, or some closely related factor, might be implicated in the pathogenesis of RLS in dialysis patients. Roger and colleagues found a significant association between RLS and anemia in a population of 55 uremic patients [34]. Correction of anemia with epoetin alfa significantly improved the RLS symptoms. However, Collado-Seidel et al., failed to find any correlation between serum hemoglobin level and the presence of definite RLS in their group of hemodialysis patients. The correlation between iron deficiency and RLS, as shown in idiopathic RLS patients in other studies [35], was not found in uremic RLS patients in this study. Intact parathyroid hormone (iPTH) levels were significantly lower in uremic patients with RLS compared with those without RLS, but calcium and phosphate concentrations did not differ [23]. These authors concluded that the same unidentified factor may possibly be responsible for both secondary RLS and lower iPTH levels in uremic patients. In contrast to this reciprocal relationship in RLS, PLMD and iPTH seem to be positively correlated. Stepanski et al. [30] found a significantly higher serum iPTH during continuous ambulant peritoneal dialysis in patients with PLMD (PLM index>25/ h./n =3) when compared to those without PLMD (n =4). Kidney transplantation can lead to a decrease of RLS complaints [36]. Trenkwalder [37] found that reduction of RLS symptoms is directly proportional to the functioning of the transplanted kidney. The quality of life of ESRF patients is already impaired by the primary disorder (renal failure) and its therapy (dialysis). Their quality of life can probably be improved by adequate therapy for their sleep/wake disorder [25]. Therefore, the recognition and diagnosis of RLS and PLMD and the delivery of effective therapy is important for these chronically ill patients. Drugs that have been found to be effective in secondary RLS and PLMD in uremic patients are the same as used in idiopathic forms of these disorders. These are dopamine-precursors such as L-dopa/carbidopa or L-dopa/ benserazide and [25,3840] benzodiazepines such as clonazepam [21,41] and possibly dopa-agonists like pergolide. Unfortunately, most studies on therapy in uremic patients

Secondary PLMD have been small with a short follow-up crossover or double-blind in design.

Parkinson’s

and RLS

151

period; in general, they have not been controlled,

disease

The bad quality of sleep in patients with Parkinson’s disease (PD) is one of the major factors contributing to an unsatisfactory quality of life. Difficulties of initiating and maintaining sleep are the earliest and most frequently encountered sleep disorders in PD [42]. Nocturnal akinesia is the best known cause of sleep problems in these patients. Other known sleep disorders in PD patients are parasomnias such as REM sleep behavior disorder and hallucinations, disturbed breathing e.g. obstructive and central apneas, REM/NREM variations of nigrostriatal dopamine receptor sensitivity during sleep and also an increase in muscle activity during sleep. Whether these sleep disorders in PD patients are related to the degenerative process or to antiparkinsonian treatment is still under discussion. During NREM sleep, the so-called repetitive muscle contractions (RMC) are seen in I’D patients. They do not occur in REM sleep [43,44]. RMC during NREM sleep might be one of the factors preventing slow-wave sleep and on comparison with PLMD, appear to be part of the sleep maintenance problem in PD patients [45]. Askenasy et IZZ. [45] described RMC as the equivalent of tremor during wakefulness but the comparison to PLMD is perhaps more justified. Earlier reports suggested a connection between RLS, PLMD and PD. The following observations endorse this idea. The most effective treatment for RLS and PLMD is dopaminergic therapy. Since RLS, PLMD and PD all are highly responsive to dopaminergic drugs the assumption is made that all three disorders are secondary to central nervous system (CNS) dopamine deficiency. Whether these disorders share a common nigral or striatal localization is questionable. Autopsy studies in PLMD have not been carried out, but the SPECT study of Steadt et al. [46] showed a lower number of dopaminergic striatal D-2receptors in PLMD. On the other hand, several electrophysiological and imaging studies have indicated that involuntary periodic limb movement generators may be localized in the medullar formatio reticularis or at spinal level. Trenkwalder et al., [47] found that the recruitment pattern of muscle activity, the persistence of the periodic movements during sleep and their electrophysiological characteristics resemble propriospinal myoclonus [4749]. Dopaminergic mechanisms may be responsible for generating involuntary periodic limb movement at spinal level. This theory concerning the origin of these movements is supported by the fact that spinal dopaminergic cells (as part of the diencephalospinal dopaminergic system) have been shown to be part of the motor function process [50, 511. Other studies provide evidence that the generator of the periodic limb movements is in the medullar formatio reticularis. Using high-resolution magnetic resonance imaging, Bucher et al. 1521 showed that cerebellar and thalamic activation participates in the generation of the sensory symptoms in RLS, whereas the brain stem and red nucleus participate in the generation of periodic limb movements. Clouston et al. [53] found circumstantial electrophysiological evidence localizing the generator of periodic movements in the brain stem reticular formation and even postulated that such a brain stem myoclonus might be an early sign of Parkinsonism [53]. Linkage of RLS, PLMD and I’D is endorsed further by reports that the incidence of RLS

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[54] and PLMD 1551 may be greater in I’D patients. Finally, the typical RLS symptoms arise mostly during the “off” state of I’D patients. This period, thought to represent a dopaminergic or noradrenergic deficit, might predispose to RLS symptoms through a similar neurochemical mechanism. These observations showed that RLS symptoms seem to be more pronounced on the most akinetic or rigid side [54]. Obviously, great emphasis should be placed on distinguishing RLS and PLMD from abnormal nocturnal movements in I’D patients caused by other factors. Differential diagnostic considerations should include REM sleep behavior disorder and nocturnal dyskinesias after reduction of nocturnal dopaminergic medication.

Polyneuropathy RLS may be associated with peripheral neuropathy. In several polyneuropathies, for example uremic, amyloid and cryoglobulineamic, the co-existence of RLS has been shown. RLS can even be the initial clinical manifestation of amyloid and cryoglobulinaemic neuropathies [56, 571. The same holds true for peripheral axonal neuropathy caused by avitaminoses, carcinoma, diabetes mellitus, rheumatoid arthritis and chronic pulmonary disease; RLS may be the first positive symptom of such peripheral nerve damage [58-601. In “idiopathic” RLS and PLMD, evidence of mild neuropathy can often be found. Iannaccone et al. [61] showed the presence of subclinical neuropathy, and their morphological studies confirmed the presence of axonopathy in eight patients who had previously been defined as primary RLS. In another study, 14 out of 41 RLS patients (34%) displayed evidence of neuropathy of various types [62]. In only two of these cases were the etiology of the neuropathy identified (diabetes mellitus and alcohol abuse). Patients with idiopathic RLS had a positive family history in 92% of cases compared with 13.3% of patients with RLS possibly related to neuropathy. These authors concluded that neuropathic RLS could be an entity in itself. As both types share clinical characteristics they suggested that both be caused by common pathophysiologic mechanisms in the CNS involving similar descending dopaminergic pathways. Walters [63] mentions that the triggering of RLS and PLMD in patients with peripheral neuropathy might be explained by a disorder in sensory input into these systems. Incoming sensory stimuli may induce pathological activation of movement generators, which have a lower threshold due to the neurochemical disturbances. These generators are most probably situated in the formatio reticularis [63, 641 or in motor spinal dopaminergic cells [50]. Although a relationship between RLS, PLMD and neuropathy is possible, there are other studies that dispute these observations [65, 661. As well as polyneuropathy, radiculopathy and Lyme’s disease (Bannwarth syndrome) may be peripheral factors in RLS.

Role of iron and ferritin

deficiency

As early as 1945, Ekbom [67] reported an association between iron deficiency and RLS. RLS is more commonly found in groups who tend to develop iron deficiency e.g., pregnant women [68], the anemic [69, 701, those who have undergone partial gastrectomy [71, 721 and the elderly all have a higher occurrence of RLS.

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The first study, which related iron status to RLS and the improvement in RLS symptoms after giving iron supplements, was of an open study structure and limited to elderly people. O’Keeffe et al. [73] using the premise that serum ferritin levels are the single most important indicator of iron deficiency, showed that iron deficiency, with or without anemia [74] is an important contributor to the development of RLS in the elderly, and iron supplements can produce a significant reduction in symptoms. The ferritin levels correlated inversely to the subjective reports of severity of RLS symptoms, In a recent study of an RLS population covering the entire adult age range (29-81 years), it was shown that greater RLS severity and more periodic limb movements in sleep (PLMS) accompanied by arousal, were significantly correlated with low, but still within normal range, ferritin levels. The authors found a cut-off level of ferritin at 50 mcg/l [35]. Although not everyone with a low ferritin have severe RLS, and not all severe RLS sufferers have low ferritin, ferritin level can still be used as a target in treatment. Iron is possibly an aspect in the pathogenesis of RLS and PLMD. The iron-containing enzyme, tyrosine hydroxylase, catalyses the hydroxylation of tyrosine to dihydroxyphenyalanine (levodopa); the latter is carboxylated to form dopamine. Iron is therefore a rate-limiting step in the formation of (levo) dopa. RLS and PLMD might be induced by this type of inhibition of dopamine formation through lack of iron [75, 761. Similarly, the low serum iron often found in akathisia sufferers (a disorder presenting with phenomena resembling RLS) contributes to the hypothesis that insufficient dopamine formation might be an underlying cause of RLS [75, 77, 781. Brown’s [77] fundamental idea was that serum iron and subsequently brain iron deficit, causes D2-receptor hypo-function [79-811. The resulting reduced dopaminergic transmission could induce the symptoms of RLS.

Magnesium

deficiency

Magnesium may play an important role in the development and amelioration of RLS and PLMD. Popoviciu et al. 1821 were the first to mention magnesium deficiency as a possible cause of RLS. Patients with (intra and extracellular) low magnesium levels may develop symptoms similar to those mentioned in The International RLS Study Group report. Treatment with magnesium reduced symptoms resembling those of RLS in pregnant women [83, 841. Only one recent study has reported the therapeutic effect of magnesium on patients with “idiopathic” mild/moderate PLMD-related insomnia and RLS [85]. This open pilot-study with a follow-up time of 4-6 weeks in 10 subjects, revealed improvement of several sleep and PLMD parameters. Most of these patients had normal serum magnesium levels. The authors postulate that supplementation of magnesium results in normalization of intracellular magnesium deficiency which is probably most important for relief of PLMD. Various hypotheses on the possible role of magnesium in the pathomechanisms of RLS and PLMD have recently been described [85, 861. Partial blockade of N-methylD-asparate (NMDA)-glutamate receptors, [87] and direct action on the nervous system through calcium antagonism [88], and regulation of acetylcholine or gamma-aminobutyric acid (GABA) might play a role. But to date, none of these mechanisms has been proven to play a role in the pathophysiology of RLS or PLMD. Some caution is warranted in the interpretation of the efficiency of magnesium on RLS and PLMD.

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Concluding

remarks

PLMD and RLS can be secondary to a variety of diseases. To date, research in this field has been directed in particular towards description of the disorder and its epidemiology. Much work still remains to be done on the elucidation of these aspects. In cases of uremia for example, history and gross polysomnographic evaluation reveals a disorder resembling PLMD. However, close inspection of polysomnographies shows differences with primary PLMD in uremic patients. The prevalence of secondary PLMD and its natural course are largely unknown. The relationship between PLMD and other disorders is intriguing from a pathophysiological point of view. The overall picture that emerges from many of the studies on this aspect of PLMD points to the generation of periodic movements at the spinal level. The movements might occur due to disinhibition from spinal and medullar pathways. What exactly happens, is still a matter for speculation. Studies of secondary PLMD might provide clues, as this condition so often occurs in conjunction with other disorders about which much neuroanatomic and in particular, neurochemical data is already known. The best example of this is the concurrence of PLMD with disorders that most probably have influence on or are caused by, failure in dopaminergic transmission. Another interesting point is the similarity of the movements in PLMD to those of the triple response [89]. This observation endorses the ideas on dysfunction of the descending pathway in the CNS, but may give a pointer to a way of approaching the study of the pathophysiology of PLMD. Finally, there is the conjunction of PLMD with those disorders in which polyneuropathy is part of the disease. It would be interesting to separate patients and look for with PLMD into two groups i.e., with and without neuropathies other, more peripherally located, clues on how and where movements in PLMD are generated.

Research Agenda

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Practice Points

1. In some “risk-groups” (see practice point 2) the prevalence of PLMD and RLS is reported to be high but still these disorders are underestimated. Some riskgroups consist of chronically ill patients for whom treatment is limited to symptomatic relief and improvement of quality of life. To maximize the latter, one must be aware that PLMD and RLS might be of major importance in case of complaints about: e difficulties with sleep onset and/or maintaining sleep; l extreme fatigue or, sometimes, excessive daytime sleepiness; e symptoms

of RLS according

to the criteria of Walters et d. [63]

2. The so called risk-groups are patients with: 0 uremia 0 anemia l ferritin/iron deficiency 0 serum ferritin concentration <45 mgfl l Parkinson’s disease e polyneuropathy l radiculopathy e Bannwarth disease l hypothetically: relative deficiency of intracellular magnesium 3. A “minimal work-up” is advised in case PLMD and RLS are suspected: l questionnaire focussed on “risk-groups” l general physical examination * neurological examination l hematological: hemoglobin, hematocrit, MCV, MCH, MCHC l chemical: iron, ferritin, serum magnesium, urea, creatinine, sodium, potassium, chloride, bicarbonate, TIBC (total iron bindings capacity) * measurement of nerve conduction velocities a polysomnography: in order to diagnose PLMD and exclusion of other sleep disorders.

Acknowledgement We greatly acknowledge study (grant 97/1569).

“Nier

Stichting

Nederland”

who financially

supported

this

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*The most important references are denoted by an asterisk.

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in sleep (nocturnal

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andthe