Restless legs syndrome and periodic limb movements

The history, clinical aspects, and treatment of restless legs syndrome (RLS), a heterogeneous distressing sensorimotor disorder, and periodic limb movements (PLMs) that are the typical motor accompaniment of the syndrome, are described. A positive family history, a positive response to dopaminergic treatment, and the presence of PLM while awake or asleep are supportive criteria for the diagnosis of the disorder. RLS and PLM occur more frequently at the beginning of night and exponentially decline across sleep cycles, suggesting circadian influences. Altered circadian rhythmicity in dopamine metabolism and enhanced circadian variations in dopaminergic functions have been reported in the disorder. Dysfunction or atrophy of A11 cells from the diencephalic-spinal dopamine A11 system has been suggested to explain the efficacy of dopaminergic drugs in relieving RLS symptoms and the circadian rhythmicity of RLS. Studies support the hypothesis that the A11 dopaminergic neurons and spinal pathways may be more involved in the pathophysiology of RLS than the nigrostriatal system. Neurophysiological evidence indicates that the involuntary movements in RLS may be of spinal or propriospinal origin. Despite these findings, however, the pathogenic mechanisms underlying the peculiar sensory and motor manifestations of RLS remain unexplained. Among the current treatment options offered for the treatment of RLS, dopaminergic agents have provided the best evidence for efficacy in symptom relief.     

The acute effect of a low dosage of pramipexole on severe idiopathic restless legs syndrome: an open-label trial

BACKGROUND: Pramipexole is a D3 dopaminergic agonist that has shown a major effect on both sensory and motor manifestations of restless legs syndrome (RLS) in long-term trials. No data regarding the acute effect of low doses of pramipexole have been reported. OBJECTIVE: To evaluate the acute effect of a low dosage of pramipexole (0.125 mg) on sensory symptoms and motor signs of RLS and on the macro- and microstructure of sleep. METHODS: We initially recruited 13 patients affected by severe idiopathic RLS and included 10 of them in our study. For 2 consecutive nights the selected patients were evaluated. Pramipexole 0.125 mg was administered before the second night at 9:00 p.m. A visual analog scale was used to assess the sensory symptoms of RLS. The motor manifestations of RLS and the architecture of sleep were analyzed by polysomnography. RESULTS: After the acute administration of pramipexole, we observed a significant improvement of the sensory symptoms and motor signs of RLS. Several sleep macrostructure and microstructure parameters improved as well. CONCLUSIONS: Our results suggest that low doses of pramipexole are effective in reducing sensory symptoms and motor signs of RLS, even after the first administration.     

Apomorphine in idiopathic restless legs syndrome: an exploratory study

BACKGROUND: Dopaminergic and opioidergic drugs have been found to be effective in patients with restless legs syndrome (RLS). OBJECTIVES: To test the effect of apomorphine--a combined opioidergic and dopaminergic agonist--and subsequent selective antagonism by naloxone and metoclopramide on subjective and objective symptoms in patients with idiopathic RLS. METHODS: Nine patients with RLS were pretreated with oral domperidone for three days. A modified suggested immobilisation test (SIT) was carried out between 8 pm and 1 am under the following conditions of intravenous drug administration: baseline-apomorphine-apomorphine plus naloxone-apomorphine plus metoclopramide. Outcome variables were a visual analogue scale (VAS) of subjective RLS symptoms and EMG documented periodic leg movements while awake (PLMW). RESULTS: Compared with baseline, apomorphine resulted in a rapid and significant improvement in subjective RLS symptoms as measured by VAS (54.5% improvement; p = 0.011), and an almost immediate cessation of PLMW, measured by PLMW index (98.0% improvement; p = 0.012). Neither additional naloxone nor metoclopramide blocked this effect significantly. While given apomorphine with metoclopramide, there was a trend to reappearance of PLMW. CONCLUSIONS: Apomorphine may be an effective treatment for idiopathic RLS. Its effectiveness may reflect both to its dopaminergic and its opioidergic activity, and is not diminished significantly by blocking only one of these pathways. The trend to a worsening of the PLMW index with metoclopramide hints at a primarily dopaminergic effect of apomorphine in idiopathic RLS.     

Changes of cortical excitability after dopaminergic treatment in restless legs syndrome

ObjectiveDopaminergic pathways are most likely involved in the pathophysiology of restless legs syndrome (RLS). In previous investigations, an alteration of cortical excitability was suggested to be related to a dopaminergic dysfunction in RLS. The purpose of our study was to compare practice-dependent plasticity in RLS patients before and after a month of dopaminergic treatment.MethodsSingle-pulse transcranial magnetic stimulation (TMS) was used to define motor evoked potential (MEP) amplitude, motor threshold, and silent period (SP) as well. Subjects performed three exercise blocks (bimanual motor task). MEP amplitude, registered immediately after each exercise block and after a rest period, was compared to baseline. The time course of intra-cortical inhibition was tested using paired-pulse TMS at short inter-stimulus intervals. For the single-pulse TMS procedures, we enrolled 12 patients affected by primary RLS and 12 normal subjects. For the paired-pulse TMS procedures, only six patients underwent the examination. RLS patients underwent the examination in both pre- and post-dopaminergic treatment conditions.ResultsIn RLS patients MEP amplitude increased after the rest period only in the post-treatment condition, showing a delayed facilitation. After exercise, MEP amplitude increased, but not enough to be significant, showing a positive trend but not a clear-cut post-exercise facilitation. In the pre-treatment condition instead, MEP amplitude did not change either after rest period or after exercise.RLS patients showed a marked increase of the central motor inhibition, assessed by using paired-pulse TMS at short inter-stimulus intervals after pramipexole treatment. On the contrary, the duration of the SP did not change compared to the pre-treatment condition.ConclusionsIn RLS patients after dopaminergic treatment, the main finding was the changing of MEP amplitude after rest following a motor task. Since dopaminergic treatment can reverse delayed facilitation in RLS, we hypothesized that cortical plasticity related to dopaminergic systems may play a crucial role in RLS pathophysiology.     

Abnormal motor behavior during sleep

Abnormal motor behaviors during sleep can be classified into four categories, ranging from myoclonic jerks to complex and integrated motor behaviors There have been recent developments in several of these conditions, in particular restless legs syndrome (RLS) and rapid-eye-movement sleep behavior disorder (RBD). RLS is one of the major causes of insomnia. Familial aggregation of RLS has been demonstrated by several groups, and molecular genetics studies have suggested the presence of susceptibility genes on chromosomes 12q and 14q. Pharmacologic and brain imaging studies suggest the involvement of dopaminergic mechanisms in RLS, but recent work has focused on brain iron metabolism. Studies indicate that RBD patients may eventually develop Parkinson's disease (PD). Conversely, RBD has been found in patients already diagnosed with PD. Single-photon emission computed tomography and positron emission tomography studies have shown a decrease in binding to presynaptic dopamine transporter in both idiopathic RBD and PD. Patients with RBD (associated or unassociated with PD) also have neuropsychological deficits. RBD may therefore represent the prodrome of a neurodegenerative disease leading to multiple system atrophy and Lewy body dementia. Understanding the underlying pathophysiology of abnormal sleep motor behaviors may prove useful in the management of insomnia.     

Impairment of sensory-motor integration in patients affected by RLS

Much evidence suggests that restless legs syndrome (RLS) is a disorder characterized by an unsuppressed response to sensory urges due to abnormalities in inhibitory pathways that specifically link sensory input and motor output. Therefore, in the present study, we tested sensory-motor integration in patients with RLS, measured by short latency afferent inhibition (SAI) and long latency afferent inhibition (LAI). SAI and LAI were determined using transcranial magnetic stimulation before and after 1month of dopaminergic treatment in RLS patients. Ten naïve patients with idiopathic RLS and ten healthy age-matched controls were recruited. Patients with secondary causes for RLS (e.g. renal failure, anaemia, low iron and ferritin) were excluded, as well as those with other sleep disorders. Untreated RLS patients demonstrated deficient SAI in the human motor cortex, which proved revertible toward normal values after dopaminergic treatment. We demonstrated an alteration of sensory-motor integration, which is normalized by dopaminergic treatment, in patients affected by RLS. It is likely that the reduction of SAI might contribute significantly to the release of the involuntary movements and might account for the sensory urge typical of this condition.     

Augmentation of restless legs syndrome with long-term tramadol treatment.

Restless legs syndrome (RLS) augmentation, defined as a kind of suppression of the circadian rhythm of the disease in which sensory and motor symptoms appear earlier during the day (and over previously unaffected body parts), with a progressive phase advance until, backwards, the symptoms may cover the entire day, has been described only after treatment with dopaminergic drugs. We report clinical and polysomnographic accounts of a patient developing RLS augmentation after long-term treatment with tramadol, an opioid agonist with selectivity for mu-receptor and added norepinephrine and serotonin reuptake inhibition properties. Polysomnographic measures showed an improvement of RLS and a disappearance of diurnal sensory and motor RLS symptoms after tramadol was stopped. Our case confirms a recent retrospective report of augmentation of RLS after treatment with tramadol, and begs the question whether augmentation is truly restricted to dopaminergic drugs.     

Endocrine rhythms in patients with restless legs syndrome

There is increased evidence that the dopaminergic system plays a major role in the pathophysiology of the restless legs syndrome (RLS). Dopamine is the major inhibitory factor of prolactin release and also influences growth hormone (hGH) secretion.The aim of this study was to measure the endocrine activity of RLS patients, to compare it with that of normal subjects and to detect possibly altered patterns of hormonal secretion in RLS patients. Prolactin, hGH and cortisol plasma levels were measured every 20 min for 24 hours in 10 male never-medicated RLS patients (aged 56 ± 6 years) who have had mild to moderate symptoms for 15 ± 10 years and in 8 age-matched male controls (aged 57 ± 5 years). The blood samples taken during the night were paralleled by polysomnographic recordings including the assessment of periodic leg movements (PLM). Plasma levels as well as frequency and amplitude of the pulses of prolactin, hGH and cortisol were not different between RLS patients and controls. Both groups showed the same rhythms during the night- and daytime for all hormones. Cross correlations resulted in high correlation coefficients for each hormone at lag 0 (0.964, 0.943 and 0.971 for mean locations of cortisol, hGH and prolactin, respectively). Concerning sleep parameters, there were no significant differences between the two groups apart from a higher PLMS arousal index in RLS patients (25.9 ± 17.1) compared with the controls (12.0 ± 9.2; p < 0.05). It is suggested that a possible dysfunction of the dopaminergic system in RLS does not affect the release of prolactin and hGH from the pituitary gland. Received: 2 October 2000, Received in revised form: 2 March 2001, Accepted: 30 May 2001     

Cırcadian changes in cortical excitability in restless legs syndrome

Various investigations have revealed a widespread and somewhat controversial pattern of cerebral, cerebellar and brainstem involvement in the pathophysiology of restless legs syndrome (RLS). However, several studies which investigated functional or structural aspects indicated cortical involvement in RLS. In this study, we aimed to analyze circadian changes of cortical excitability in idiopathic RLS patients by means of transcranial magnetic stimulation (TMS). Eleven idiopathic RLS patients and eight healthy age and sex matched subjects were investigated using single-pulse TMS and motor nerve conduction studies during early afternoon when there were no symptoms and late at night (22:00-23:00) when the symptoms reappeared. Central motor conduction time, latencies and amplitudes of scalp and cervical motor evoked potentials, resting and active motor thresholds, and cortical silent period were measured. Measured parameters were similar between RLS patients and healthy subjects during the daytime. At night, cortical silent periods tended to shorten, and motor thresholds tended to decrease in the RLS group, whereas in controls they tended to increase. At night, active motor-threshold measurements were significantly lower in the RLS group (28.5 ± 6.2% vs 40.4 ± 8.4%, p=0.006). Therefore, we propose that in patients with RLS, conduction along the motor corticospinal axons is normal, with the possible loss of subcortical inhibition at nighttime.     

Restless legs syndrome improved by pramipexole: a double-blind randomized trial

BACKGROUND: Restless legs syndrome (RLS) is characterized by leg paresthesia associated with an irresistible urge to move. Currently used dopaminergic agents, such as levodopa, pergolide, and bromocriptine, offer incomplete control of sensory and motor symptoms and induce severe side effects. OBJECTIVE: To assess the safety and efficacy of pramipexole, a full D3-receptor agonist, in the treatment of RLS. METHODS: Ten RLS patients were studied before and after two 1-month treatments (placebo and pramipexole) administered in a double-blind crossover fashion. The severity of sensory and motor manifestations was assessed by 1 week of home questionnaires and 2 consecutive nights of sleep laboratory recordings. The indexes of periodic leg movement during sleep (PLMS) and during wakefulness (PLMW) were used as primary outcome variables. RESULTS: Pramipexole dramatically reduced the PLMS index to normal values (Wilcoxon, p = 0.005). The PLMW index was also significantly reduced (Wilcoxon, p = 0.007). Pramipexole also alleviated leg discomfort at bedtime and during the night as measured by the home questionnaires. CONCLUSIONS: Pramipexole is the most potent therapeutic agent ever tested for RLS. Measures of both sensory and motor functions returned to normal values after treatment. Moreover, these results further support the hypothesis that D3 receptors play a major role in the physiopathology of this condition.     

Dopamine agonists restore cortical plasticity in patients with idiopathic restless legs syndrome

In the present work, we aimed at assessing whether patients with idiopathic restless legs syndrome (RLS) showed alterations of sensory‐motor plasticity, an indirect probe for motor learning, within the motor cortex (M1). Previous findings suggest that learning in human M1 occurs through LTP‐like mechanisms. To test our hypothesis, we employed the paired associative stimulation (PAS) protocol by transcranial magnetic stimulation (TMS), which is able to induce LTP‐like effects in the motor cortex of normal subjects. Twelve patients with idiopathic RLS and 10 age‐ and sex‐matched control subjects were recruited. PAS protocol consisted of 0.05 Hz electrical median nerve stimulation (90 stimuli), paired with 0.05 Hz TMS (90 stimuli) over the hot spot for stimulating the abductor pollicis brevis (APB) muscle given 25 milliseconds after the onset of the electrical stimulus. Corticospinal excitability recorded in APB muscle, as indexed by MEP obtained after single stimulus, was tested before and up to 30 minutes after PAS protocol. Eight of 12 patients were studied before and after 4 weeks of dopaminergic treatment. PAS protocol increased significantly corticospinal excitability as long as 30 minutes in healthy subjects. On the contrary, PAS protocol did not change the amplitude of MEPs in patients with idiopathic RLS without treatment. PAS associative plasticity was restored after 4 weeks of dopaminergic treatment. Our data demonstrated that associative sensory‐motor plasticity, an indirect probe for motor learning, is impaired in idiopathic RLS patients but may be reverted to normal after dopaminergic treatment. © 2008 Movement Disorder Society     

Circadian effects of dopaminergic treatment in restless legs syndrome

BACKGROUND AND PURPOSE: Although an essential diagnostic feature of restless legs syndrome (RLS) is the presence of circadian symptom variations, with an increase in the evening or at night, the mechanisms underlying this time-bound variation remain unknown. Since dopaminergic mechanisms seem to play a central role in the pathophysiology of RLS, it is likely that circadian variations in the dopaminergic system or factors affecting it cause the nightly increase. The reverse is also possible; dopaminergic medication might affect melatonin function, a key element of the circadian system. The present study investigated the effects of dopaminergic medication on melatonin secretion in RLS. PATIENTS AND METHODS: Eight previously untreated patients diagnosed with idiopathic RLS underwent a three-week, open-labeled treatment with 400 mg L-DOPA (+100 mg CarbiDOPA). Dim Light Melatonin Onset (DLMO), a marker of circadian phase, was determined before and after treatment. RESULTS: Compared to baseline, earlier DLMO was found in L-DOPA treated patients (21:00+/-1:20 vs. 18:50+/-0:55; P < 0.05). Anticipation of DLMO was more marked in the subgroup of patients showing augmentation. A positive correlation was observed between change of DLMO, sleep latency and time of onset of symptoms following treatment with L-DOPA. CONCLUSIONS: Our results suggest that L-DOPA may exert chronobiotic effects in RLS.     

Cabergoline reverses cortical hyperexcitability in patients with restless legs syndrome

OBJECTIVE: To reverse the profile of abnormal intracortical excitability in patients with restless legs syndrome (RLS) by administering the dopaminergic agonist cabergoline. METHODS: The effects of this drug on motor cortex excitability were examined with a range of transcranial magnetic stimulation (TMS) protocols before and after administration of cabergoline over a period of 4 weeks in 14 patients with RLS and in 15 healthy volunteers. Measures of cortical excitability included central motor conduction time; resting and active motor threshold to TMS; duration of the cortical silent period; short latency intracortical inhibition (SICI) and intracortical facilitation using a paired-pulse TMS technique. RESULTS: Short latency intracortical inhibition was significantly reduced in RLS patients compared with the controls and this abnormal profile was reversed by treatment with cabergoline; the other TMS parameters did not differ significantly from the controls and remained unaffected after treatment with cabergoline. Cabergoline had no effect on cortical excitability of the normal subjects. CONCLUSIONS: As dopaminergic drugs are known to increase SICI, our findings suggest that RLS may be caused by a central nervous system dopaminergic dysfunction. This study demonstrates that the cortical hyperexcitability of RLS is reversed by cabergoline, and provides physiological evidence that this dopamine agonist may be a potentially efficacious option for the treatment of RLS.     

Restless legs syndrome in a patient with multifocal motor neuropathy

Restless legs syndrome (RLS) has been frequently reported in association with peripheral neuropathy, and it is especially frequent in some forms of polyneuropathy with preferential involvement of small sensory fibers. Here, we describe a patient with multifocal motor neuropathy, who developed RLS during the course of the disease. Our findings support the notion that RLS may develop in the context of immune-mediated neuropathies and it should be specifically investigated even in those patients with preferentially or exclusive motor involvement.     

The Involvement of Dopaminergic and Opioidergic Neuronal Systems in the Control of the Early Rise in LH Secretionin Bull Calves

There is an early rise in secretion of luteinizing hormone (LH) in bull calves between 6 and 20 weeks of age. This study was designed to examine the involvement of opioidergic and dopaminergic neuronal systems in the control of this early rise in gonadotrophin secretion.     

When restless legs syndrome turns malignant

Usually symptoms of restless legs syndrome (RLS) respond well to treatment with dopaminergic drugs, opiates, or anticonvulsant medications. Yet sometimes symptoms can be severe and become refractory, even to high-dose combination therapy. Here we present two cases of familial RLS with rigorous and unusual motor and sensory symptoms in the form of episodes of myoclonic hyperkinesias and painful sensations in addition to more characteristic features of RLS. Stepwise reduction of all RLS—and antidepressant medication down to opiate monotherapy—and subsequent opiate rotation led to an improvement of symptoms. Yet in both cases, reintroduction of low-dose dopaminergic drugs was necessary to achieve satisfactory treatment effect. We have termed this form of RLS refractory to multiple combinations of all classes of commonly used drugs malignant RLS. Therapeutically simplification and reduction of the drug scheme and opiate rotation should be considered in malignant RLS.     

Altered eyeblink reflex conditioning in restless legs syndrome patients

BackgroundRestless legs syndrome (RLS) is characterized by abnormal leg sensations and an uncontrollable urge to move the lower extremities during rest periods. Evidence suggests that reflex tasks that involve sensory–motor integration may be altered in RLS patients. This led us to determine if RLS patients show alterations in a sensory–motor reflex conditioning task called differential eyeblink conditioning.MethodsRLS subjects were washed out of treatment medication for 7 days prior to testing. Subjects (20 RLS and 19 Control) received 120 discrimination conditioning trials consisting of 60 CS+ trials (i.e., an auditory stimulus paired with the airpuff-US separated by a silent 900 ms trace interval) and 60 CS? trials (i.e., a different auditory stimulus that was NOT paired with the US).ResultsControl subjects showed normal differential responding to the CS+ and CS?, but the RLS patients showed little or no differential responding. A post-test questionnaire provides evidence that symptomatic interference was not responsible for the eyeblink conditioning deficits in the RLS subjects, and further suggests that neurophysiological factors were responsible for these deficits.ConclusionsTogether these results suggest that deficits in eyeblink conditioning are related to the pathophysiology of RLS. The eyeblink conditioning test may also be useful for supporting a clinical diagnosis or treatment strategy for RLS.     

Functional neuroimaging studies in restless legs syndrome

Functional neuroimaging studies may contribute to elucidate pathophysiological mechanisms of the restless legs syndrome (RLS) which still remain unclear. Studies in patients with RLS have been performed using functional magnetic resonance imaging (fMRI), single photon emission computed tomography (SPECT) and, more recently, positron emission tomography (PET). SPECT and PET studies revealed some controversial results of the pre- and postsynaptic dopaminergic neurotransmission system and cerebral metabolism in RLS probably reflecting a dysfunction of the central dopaminergic system. However, it still has to be determined whether these alterations affect the nigrostriatal and/or other central dopaminergic systems like the diencephalospinal or mesolimbic pathway and whether they are the primary mechanisms or only secondary phenomena within the manifestation of RLS symptoms. A subtle receptor dysfunction or a synaptic dopaminergic deficit may play a major role. fMRI investigations of RLS patients revealed an activation in the red nuclei and brainstem close to the reticular formation during the symptomatic period, suggesting that subcortical cerebral generators are involved in the pathogenesis of RLS. However, both techniques are not yet clinically relevant methods to differentiate RLS from other movement disorders during sleep. Further investigations, especially at night when RLS symptoms are most pronounced, will lead to a better understanding of the mechanisms underlying RLS.     

Restless legs syndrome and periodic leg movements in sleep: the primary role of dopaminergic mechanism

We report here the possible effect of opiates on a patient exhibiting particularly severe restless legs syndrome (RLS) and periodic leg movements in sleep (PLMS). This patient was investigated in the sleep laboratory under three conditions, namely, unmedicated (baseline), medicated with codeine sulfate, and medicated with both codeine sulfate and pimozide. Codeine sulfate dramatically improved abnormal motor behavior in this patient. The addition of pimozide reversed the beneficial effect of codeine during the Forced Immobilization Test but not in spontaneous RLS or PLMS at night. These results are discussed in view of the possible involvement of the dopaminergic mechanism in RLS/PLMS syndrome.     

Functional brain imaging in combined motor and sleep disorders

The pathophysiology of sleep-related motor diseases and sleep dysfunction in movement disorders is widely unknown as yet. Functional brain imaging, in particular radioisotope and magnetic resonance techniques, are powerful tools to investigate possible pathomechanisms of combined sleep and motor dysregulation. In patients with Restless legs syndrome (RLS), only a subtle striatal dopamine deficit was found in PET and SPECT despite a good treatment effect of dopaminergic drugs. Functional MRI suggested a central generator of periodic limb movements during sleep (PLMs) in RLS. In contrast, a marked striatal dopamine depletion was demonstrated in patients with REM sleep behaviour disorder (RBD) as the base for the clinical and nosological overlap of RBD with parkinsonian disorders. PET and SPECT also suggested that sleep abnormalities in Parkinson's disease (PD), such as REM sleep diminution or increased PLMs, are indirect manifestations of the primary striatal dopamine deficiency.