Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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Periodic limb movements in sleep consist of flexion movements at the ankles, knees and hips, and sometimes the arms, recurring every 10 to 90 seconds, especially during light NREM sleep stages. Though representing an almost obligate accompaniment of restless legs syndrome and frequently associated with various neurologic and physical diseases, they are also widely prevalent among the general population. In this article, the authors examine the clinical significance of periodic limb movements in sleep and advances in understanding the pathophysiology of this phenomenon that, if accompanied by day- or nighttime consequences, is considered to be a disorder (periodic limb movement disorder). They review the treatment options now available, emphasizing that among the different therapeutic strategies, dopaminergic agents in particular have been shown effective in controlled trials. Finally, they discuss the possible role of periodic limb movements in sleep as a risk for cardiovascular consequences.
• Periodic limb movements are repetitive flexion movements of the toes, ankles, knees, and hips, sometimes the upper limbs too, lasting from 0.5 to 10 seconds that recur primarily in stage N1 and stage N2 of sleep with a periodicity ranging from 10 to 90 seconds.
• Periodic limb movements may be associated with no EEG changes or with EEG evidence of arousal or other transient activities, such as bursts of delta waves, and are preceded and associated with autonomic activation.
• Periodic limb movements in sleep tend to occur more frequently in the elderly population, and have been reported associated with several other medical conditions, but are especially frequent in restless legs syndrome.
• Periodic limb movement disorder is diagnosed when movements occur at a rate of more than 5 per hour in children or 15 per hour in adults, causing clinically significant sleep disturbance or impairment in mental, physical, social, occupational, educational, behavioral, or other important areas of functioning.
• Periodic limb movements in sleep respond to dopaminergic treatment.
The first clinical description of periodic limb movements in sleep was reported by Symonds in 1953 (181). He coined the term “nocturnal myoclonus” and described 5 patients who complained of recurrent episodes of involuntary jerking or twitching of the limbs, occurring during sleep, at the moment of falling asleep, or during relaxing wakefulness. Symonds supposed that the nocturnal myoclonus might represent an epileptic syndrome, maybe familial (181). In 1965 Lugaresi and associates first described the polysomnographic characteristics of nocturnal myoclonus in a series of patients with restless legs syndrome (117), and in 1966 they noted that nocturnal myoclonus might be present also as an isolated symptom (115), and subsequently in the 1970s and 1980s Coleman pointed out that it could be associated to a variety of clinical conditions other than restless legs syndrome (34). Moreover, because nocturnal myoclonus tends to occur periodically at 20- to 40-second intervals in sleep and is rarely myoclonic (less than 250 msec) during sleep, Coleman suggested to name it as “periodic movements in sleep” (34). Only later were the terms “periodic leg movements in sleep” and “periodic limb movements in sleep” introduced.
Two sets of scoring rules have been proposed in the last decades: the first by the International Restless Legs Syndrome Study Group (IRLSSG) and the World Association of Sleep Medicine (WASM) and the second by the American Academy of Sleep Medicine (AASM) (212; 17). The WASM rules have been updated integrating with the data obtained from studies that have better characterized the features of periodic limb movements in sleep (55).
The term “periodic limb movement disorder” is referred by the American Academy of Sleep Medicine to a specific sleep-related movement disorder characterized by: (A) polysomnography demonstrates periodic limb movements in sleep, as defined in the American Academy of Sleep Medicine Manual for the Scoring of Sleep and Associated Events (16); (B) the frequency is greater than 5 per hour in children or greater than 15 per hour in adults; (C) the periodic limb movements in sleep cause clinically significant sleep disturbance or impairment in mental, physical, social, occupational, educational, behavioral, or other important areas of functioning; and (D) the periodic limb movements in sleep and the symptoms are not better explained by another current sleep disorder, medical or neurologic disorder, or mental disorder (eg, periodic limb movements in sleep occurring with apneas or hypopneas should not be scored) (07).
Periodic limb movements in sleep are involuntary movements characterized by repetitive, very stereotyped movements mostly of the lower limbs, with extension to the big toe, often in combination with partial dorsiflexion of the ankle, flexion of the knee, and sometimes of the hip. The tibialis anterior muscles are the most frequently involved muscles (approximately 75%), followed by the gastrocnemius (approximately 60%), biceps femoris (approximately 55%), and rectus femoris (approximately 40%); antagonist muscles may be activated, axial muscles are rarely involved, and muscles of the upper limbs are also sometimes involved (58).
Moreover, periodic limb movements may also occur during relaxed wakefulness, when the patient is sitting or mostly laying, occasionally prolonging sleep latency.
Periodic limb movements in sleep are frequently observed in restless legs syndrome (prevalence 80%-90%), representing a supportive diagnostic criterion, but they may also be present in other sleep disorders such as obstructive sleep apnea syndrome, narcolepsy (prevalence 45%-65%), REM sleep behavior disorder (prevalence about 70%), and sleep-related eating disorder (50; 38; 05). Moreover, periodic limb movements in sleep may be found also in patients affected by neurologic diseases such as Parkinson disease, multisystem atrophy, dopa-responsive dystonia, multiple sclerosis, after cerebral or pontine infarction, in several medical conditions, such as spinal cord injury, depression, posttraumatic stress disorder, cardiovascular disease, and end-stage renal disease, and also in association with some medications such as antidepressants and neuroleptics (15; 98; 07; 102; 101; 65).
Periodic limb movements in sleep themselves may be considered a specific sleep disorder, periodic limb movement disorder, when accompanied by nocturnal or diurnal consequences. In fact, a clinical history of problems in sleep starting, in sleep maintenance or unrefreshing sleep is necessary for its diagnosis, in association with a periodic limb movements in sleep index greater than 5 per hour in children or greater than 15 per hour in adults, and the sleep disturbances cannot be better explained by any other cause. When only the bed partner complains about the problem or a high periodic limb movements in sleep index is not associated with clinical signs, periodic limb movements disorder cannot be diagnosed (07).
Finally, periodic limb movements in sleep may be found also in the general healthy population, mostly after the age of 40 years, with higher prevalence with increasing with age, although the prevalence in the general population has not been reliably estimated (66; 105).
According to the American Academy of Sleep Medicine, diagnostic criteria for periodic limb movements in sleep are: on a polysomnogram, a series of at least 4 consecutive limb movements during sleep lasting 0.5 to 10 seconds, occurring within 5 to 90 seconds of each other, and with an amplitude of at least 8 µV higher than the resting electromyogram amplitude (16). Both lower limbs should be recorded because the leg movements may affect both limbs but not always simultaneously, and leg movements on 2 different legs separated by less than 5 seconds between movement onset are counted as a single leg movement. Movements of the upper limbs should be monitored if clinically indicated. It is mandatory to discriminate periodic limb movements in sleep from other movements in sleep, such as a simple change in body position, stretching of a limb or a muscle cramp, or movements associated with respiratory events, hypnagogic foot tremor, or alternating leg muscle activation during sleep (07).
The International and European Restless Legs Syndrome Study Groups (IRLSSG and EURLSSG) and World Association of Sleep Medicine (WASM) have revised and updated the current standards for recording and scoring leg movements in polysomnographic recordings (55). Also, some nomenclature changes have been proposed:
• Leg movement activity (LMA) now refers to all tibialis anterior muscle activity events of 1 leg that has an onset threshold of greater than or equal to 8 μV above resting baseline and an offset threshold of less than 2 μV above resting baseline, which stays below this offset threshold for 0.5 seconds.
• Leg movements (LM) are all leg movement activity that have a minimum duration of 0.5 seconds and a median EMG amplitude greater than or equal to 2 μV above resting baseline.
• Candidate leg movements (CLM), in turn, are leg movements that have a maximum duration of 10 seconds and, thus, become candidates to be evaluated for periodic limb movements. Two to 4 monolateral candidate leg movements (mCLM) from the 2 legs overlapping each other within 0.5 seconds windows are combined as 1 bilateral candidate leg movement (bCLM) if their combined total duration is below 15 seconds.
According to the new criteria, periodic leg movements series are now defined by runs of at least 4 consecutive candidate leg movements with an intermovement interval (IMI) greater than or equal to 10 seconds and less than or equal to 90 seconds without any candidate leg movements preceded by an interval less than 10 seconds interrupting the series of periodic leg movements. The rate of periodic leg movements may now first be determined for all candidate leg movements, not excluding any related to respiration and, subsequently, the rate of periodic leg movements should also be calculated without considering the respiratory-related events. Moreover, intervening leg movements (iLM) are nonperiodic leg movements, which occur between 2 periodic leg movements, distorting their periodicity and ending a series of periodic leg movements (89).
Hundreds of periodic limb movements in sleep may be present during a single night of polysomnographic recording. The number of periodic limb movements in sleep may vary considerably in an individual patient from night to night, but when groups of patients are looked at collectively, little night-to-night variation for the group as a whole takes place. In a single patient, the number of periodic limb movements in sleep remains the same from night to night and seems to represent an individual trait (185).
Periodic limb movements in sleep are often associated with a generalized oscillatory EEG pattern, the cyclic alternating pattern, and with autonomic sympathetic activation. The cause-effect relationships between periodic limb movements in sleep and cyclic alternating pattern are not yet clear because the pattern of presentation is not stereotyped but it may vary, indicating that the mechanism underlying the association between periodic limb movements in sleep, arousal, and autonomic activation is very complex. The most frequent pattern is represented by increased transient slow EEG activity, followed by a small, albeit significant increase in heart rate, and then by the occurrence of the periodic limb movements in sleep event, which in turns heralds or coincides with an increase in fast EEG activities and a further increase in heart rate (64). About 60% of periodic limb movements in sleep are associated with arousals, 4% show slow wave activity, and 36% do not seem to show evident EEG changes with visual analysis (168). When periodic limb movements in sleep are accompanied by theta activity or alpha EEG activity, heart rate is even faster (169; 199). Rises in blood pressure have also been found to accompany periodic limb movements (141; 170; 28; 171), regardless of apnea-hypopnea index as shown in one study (113), although they are more pronounced when periodic limb movements are associated with restless legs syndrome (142). Moreover, periodic limb movements in sleep have been associated with changes in cerebral hemodynamics, such as increases in cerebral blood flow and cerebral oxygen metabolism in the frontal regions, indicating hyperarousal during sleep in restless legs syndrome patients with periodic limb movements in sleep (24; 210).
Periodic limb movements in sleep with arousals are prevalent in stage N1 and stage N2, whereas periodic limb movements in sleep without arousals are prevalent in slow wave sleep. Periodic limb movements in sleep display a pattern of progressive decline throughout the night following the exponential decline in slow wave activity (168).
Although each periodic limb movement in sleep may be associated with a cortical and/or autonomic arousal or less frequently with an awakening, the patient is typically unaware of the phenomenon, particularly if most of the periodic limb movements in sleep are not associated with arousals, and often the bed partner is the one who complains about the sleep disorder whereas patients are more likely to report insomnia (187), disrupted sleep with frequent awakenings, mild or excessive daytime sleepiness (85), or fatigue. Anyway, whether periodic limb movements in sleep play a role in sleep disruption is controversial. A selective pharmacological approach using pramipexole, which suppresses periodic limb movements in sleep without affecting arousals, or clonazepam, which does the opposite, may disconnect periodic limb movements in sleep from arousal events, suggesting an indirect and complex interrelationship (119). This concept is supported by the correlation of the arousal sleep disturbance with the thalamic glutamate and glutamine changes detected by magnetic resonance spectroscopy and the lack of correlation with the amount of periodic limb movements in sleep of restless legs syndrome patients (04).
Periodic limb movements in sleep occur in both children and adults, with onset also in infancy, but they tend to occur more frequently in the elderly. The natural history of periodic limb movements in sleep has not been described in detail because they are typically asymptomatic. When periodic limb movements in sleep are associated with arousals and the periodic limb movements in sleep index is higher than 15 per hour in adults or higher than 5 per hours in children, they may cause sleep disruption, resulting in impaired diurnal performances. Some studies showed that periodic limb movements in sleep are associated with increased mortality in patients with systolic heart failure and in patients with end-stage renal disease with sleep disorders (15; 209), and a study has shown that an increased periodic limb movement index is associated with an increased risk of all-cause mortality, independently from sleep efficiency and of sleep latency (31).
Periodic limb movements in sleep and cardiovascular disease. Based on the fact that almost each single periodic limb movement in sleep may be accompanied by an autonomic activation with sympathetic hyperactivity, with a raise in heart rate and in blood pressure, in the last years periodic limb movements in sleep have been hypothesized to have a possible role as a cardio- and cerebro-vascular risk factor (193; 67; 203). Moreover, in patients with restless legs syndrome/periodic limb movement disorder, a compromised cardiovagal control with greater peripheral vascular resistance has been demonstrated (18).
Current evidence suggests that periodic limb movements in sleep may be a prognostic factor for incident cardiovascular events and mortality (99), and periodic limb movements in sleep index has also been found to predict incident myocardial infarction (200). Several studies have shown that periodic limb movements in sleep may be associated with increases in blood pressure, although there is no clear evidence of association also with diurnal hypertension (142; 58; 35). In 1 study involving 1740 subjects, hypertension was modestly associated with periodic limb movements in sleep index and periodic limb movements in sleep-arousal index, and both hypertension and systolic blood pressure were significantly associated with the frequency of periodic limb movements in sleep in African Americans and Chinese Americans (102). Another cross-sectional study involving 314 children showed that children with periodic limb movements were at significantly higher risk for nocturnal systolic and diastolic hypertension. However, children with periodic limb movements were few in number (n=17), and mean nocturnal blood pressure did not differ between children with and without periodic limb movements, and the trend for higher daytime blood pressure in children with periodic limb movements in sleep was not significant (198).
In an elderly male cohort involving 2911 subjects, patients with higher periodic limb movements in sleep index and higher periodic limb movements in sleep-arousal index had an increased risk of all-cause cardiovascular disease after adjustment for conventional cardiovascular risk factors. After stratification, risk of incident all-cause cardiovascular disease among the high-periodic limb movements in sleep index and high-periodic limb movements in sleep-arousal index groups was significantly elevated only for men without prevalent hypertension (100). This is in line with the increased cardiovascular and cerebrovascular risk in patients with chronic kidney disease and higher periodic limb movements in sleep index (150; 112). Interestingly, levels of lipoprotein-associated phospholipase A2 (Lp-PLA2), a novel marker of vulnerable plaque (prone to rupture plaque), were significantly increased in patients with elevated periodic limb movements in sleep index showing a linear correlation (14). Large arterial stiffness, which is considered an independent risk factor for cardiovascular disease, was found increased in patients with significant periodic limb movements in sleep when compared to controls and comparable to those with moderate/severe obstructive sleep apnea (42). The obstructive sleep apnea/periodic limb movements in sleep group had the highest large arterial stiffness index, implying a possible additive effect of obstructive sleep apnea and periodic limb movements in sleep on arterial stiffness and, thus, cardiovascular disease risk. A study comparing obstructive sleep apnea patients with clinically significant and nonsignificant periodic limb movements showed that periodic limb movements in sleep are associated with a rise in systolic blood pressure regardless of apnea-hypopnea index (113). Periodic limb movements in sleep have also been associated with an increased prevalence of atrial fibrillation in patients with mild sleep-disordered breathing (204).
Korkmaz and colleagues described low plasma levels of apelin, an antioxidant and antiinflammatory molecule secreted by adipose tissue with a protective effect on cardiac and neuronal tissue, in restless legs syndrome patients, especially those with a periodic limb movements in sleep index above 15 (103). The authors speculated that decreased apelin levels may explain the increased risk for vascular diseases in those patients.
A review and metaanalysis of the association of periodic limb movements in sleep and cardiovascular disease showed significantly higher comorbidity rates of coronary artery disease and cardiovascular disease, but not acute myocardial infarction in the periodic limb movements in sleep group compared to controls (93).
Although several studies suggest that periodic limb movements in sleep are involved in increasing cardiovascular risk, there is no conclusive evidence of causality, and further studies are needed to better determine cardiovascular risk in periodic limb movements (121; 132; 35; 30; 124).
Finally, in a follow-up study, periodic limb movements in sleep have been associated with severe congestive heart failure (52% vs. 11% in control subjects) (82).
Periodic limb movements in sleep and mortality in end-stage renal disease. Restless legs syndrome and periodic limb movement disorder are frequent in chronic kidney disease, with a prevalence of 40% to 70% in patients on hemodialysis (65). Approximately 50% of patients with end-stage renal disease presented with excessive daytime sleepiness that seems to be related both to uremia and to sleep fragmentation associated with periodic limb movements in sleep (81). The close relationship between restless legs syndrome/periodic limb movements in sleep and renal disease have been also demonstrated by remission of refractory restless legs syndrome/periodic limb movements in sleep after dual kidney transplantation (02).
Evidence is mounting that periodic limb movements in sleep may be a marker for mortality in end-stage renal disease. Benz and colleagues found that a periodic limb movements in sleep index of more than 20/hour was associated with 50% of 20-months survival rate compared to 90% in patients with periodic limb movements in sleep index lower than 20/hour; similarly, Jung and colleagues found that periodic limb movements in sleep were an independent predictor of mortality in uremic patients undergoing hemodialysis (15; 96). A high periodic limb movements in sleep index was found to be an independent predictor of higher cardiovascular and cerebrovascular risk score in patients with end-stage kidney disease (112). Moreover, left ventricular internal diameter in diastole and left ventricular mass were reported to be significantly increased in uremic restless legs syndrome patients with periodic limb movements in sleep compared with patients without (73).
Periodic limb movements in sleep and psychiatric disorders. An association of periodic limb movements in sleep with posttraumatic stress disorder, nightmare disorder, depression, chronic widespread musculoskeletal pain, and attention deficit hyperactivity disorder has been reported (37; 173; 101; 126). A high association of anxiety and depression with restless legs syndrome and with periodic limb movement disorder has also been reported (10).
Typical case report. A 52-year-old man was referred to the sleep outpatient service for disturbed and unsatisfactory nocturnal sleep with consequent diurnal fatigue and hypersomnolence (Epworth sleepiness scale: 17). During the collection of the clinical history, his wife reported that in the last 3 years he had presented continuous sudden movements of the legs during sleep. He was totally unaware of these movements. There were no associated medical problems and no history of restless legs syndrome. He underwent a nocturnal polysomnography that showed a mild positional obstructive sleep apnea syndrome (AHI 11) and a periodic limb movements in sleep index of 43/hour of sleep. Therapy with gradually increasing doses of pramipexole until the dosage of 2.1 mg in a single evening dose was set, with benefit since the first days; moreover, positional treatment for obstructive sleep apnea syndrome was recommended. Repeated polysomnography revealed a periodic limb movements in sleep index lower than 10 per hour.
The cause of periodic limb movements is unknown, although genetics and drugs may play a role. Furthermore, the site of the generator of periodic limb movements in sleep remains also unknown, and the results of neurophysiological studies are conflicting. Clinical characteristics of periodic limb movements in sleep, which almost never involve the muscle above the neck, their association to sleep, and the resemblance to the Babinski reflex suggest that they occur as a sleep-related failure of motor inhibition, presumably occurring at the level of the brainstem; the disinhibition by the brainstem structures activates a secondary motor center in the lumbosacral spinal cord resulting in periodic limb movements, maybe in subjects with a genetic predisposition.
Possible genetic role. Some genome-wide association studies have revealed that periodic limb movements in sleep are associated with genetic variants or single nucleotide polymorphisms on different genes (131). Stefansson and colleagues found an association between an intronic variant of BTBD9 and restless legs syndrome with periodic limb movements in sleep and with periodic limb movements in sleep without restless legs syndrome, but it was not present when restless legs syndrome was not associated with periodic limb movements in sleep, indicating a greater genetic association with periodic limb movements in sleep rather than with restless legs syndrome (180). Moreover, in the same study, homozygosis for the A allele of the marker rs3923809 of the BTBD9 gene was associated with the lowest levels of serum ferritin and the highest periodic limb movements in sleep index, suggesting an involvement of the iron metabolism in the periodic limb movement pathophysiology. Haba-Rubio and associates found a strong association between the marker rs3923809 of the BTBD9 gene and the periodic limb movements in sleep index, mostly when homozygosis (79). These authors also found a significant association for dichotomized periodic limb movements in sleep (PLMS index < 15/h vs. PLMS Index ≥ 15) for rs3104788 (TOX3) and for rs2300478 (MEIS1). All these findings suggest that a genetic basis underlies periodic limb movements in sleep.
Possible role of medications intake. Periodic limb movements are associated with the intake of some drugs and medications, in particular antidepressant, antipsychotics, and dopamine-receptor antagonists (Table 1).
Name of drug
Serotonin reuptake inhibitor antidepressants
Possible role of the pyramidal tracts and cerebral cortex. As dorsiflexion of the large toe resembling the Babinski sign is a component of periodic limb movements in sleep, it has been suggested that periodic limb movements in sleep occur as a result of sleep-related failure of the pyramidal tracts to inhibit spinal cord reflexes or of higher cortical centers to properly convey their inhibitory message through the pyramidal tracts to the spinal cord (176). Neurophysiological studies have shown a suprasegmental disinhibition of brainstem and spinal reflexes in patients affected by restless legs syndrome/periodic limb movement disorder (48; 11). Additional evidence supporting suprasegmental disinhibition as a cause of periodic limb movements includes the following: (1) the observation that periodic limb movements in sleep can be seen unilaterally after cerebral or pontine infarction (98; 106); (2) the finding of periodic limb movements in patients with myelopathy due to spinal cord injury, multiple sclerosis, resected schwannoma, or syringomyelia, and periodic limb movements remit along with the remission of motor weakness (206; 40; 107; 134; 60; 151) and after complete transection of the spinal cord in experimental animals (49); and (3) the observation that periodic limb movements in sleep can occur with epidural and spinal anesthesia and that they disappear as the anesthesia wears off (196). If suprasegmental disinhibition does occur, it is likely that it originates subcortically and not in the cerebral cortex. The observations that periodic limb movements in sleep almost never involve the face, suggests that the generator of periodic limb movements in sleep is below the level of the facial nucleus in the brainstem. In addition, no electrically generated cortical potential has been found to precede the periodic limb movements in sleep when the EEG signal prior to the periodic limb movements in sleep is back-averaged (182).
Electrophysiological studies in patients with periodic limb movements in sleep and restless legs syndrome have shown simultaneous sequential activation of muscle groups both distal and proximal to the lumbosacral spinal cord (183), suggesting that the final generator for periodic limb movements in sleep is located in the lumbosacral cord and is activated by a disinhibition phenomenon (183). Provini and colleagues hypothesized that an abnormal hyperexcitability along the entire spinal cord might be the primary cause of periodic limb movements in sleep, triggered by supraspinal sleep-related factors not yet identified (152).
Possible role of the reticular system and subcortical structures. The possible existence of a brainstem generator for periodic limb movements in sleep was proposed by Lugaresi and colleagues in 1972 (116).
Involvement of the brainstem in the pathogenesis of periodic limb movements in sleep is also suggested by the observation that multiple sclerosis patients with periodic limb movements in sleep had larger lesion loads in this area (51). Functional MRI studies have provided strong evidence that the red nucleus and brainstem areas close to the reticular formation are involved in the generation of periodic limb movements in patients with restless legs syndrome (23).
The periodic limb movements in sleep may also resemble the flexor withdrawal reflex, which is modulated by the dorsal reticulospinal tract, and it has also been implicated in the pathogenesis of restless legs syndrome (206). Increased excitability of the flexor reflexes, especially during sleep, has been reported in restless legs syndrome associated with renal failure (01).
Periodic limb movements in sleep are characterized by a periodic pattern of motor phenomena sometimes associated with EEG changes and arousals. The brainstem reticular formation may be the originator of these periodic arousals because the reticular activating system is a well-known mediator of cortical arousal. The periodicity of the periodic limb movements in sleep recalls the physiological cyclic alternating pattern of NREM sleep. Periodic limb movements in sleep are most often associated with the arousal phase (phase A) of the cyclic alternating pattern, as opposed to the return to baseline low-amplitude EEG activity (phase B) (130; 139). The fact that A phase phenomena such as K-alpha complexes recur periodically, even after periodic limb movements have been suppressed by dopaminergic therapy, suggests that arousals are more likely to cause the periodic limb movements, rather than vice versa or, alternatively, that the arousals and periodic limb movements are independent manifestations that tend to synchronize (128; 139; 52; 61). This view is also supported by the fact that periodic limb movements are heralded by heart rate changes and a significant activation of delta EEG in NREM sleep (06). Conversely, a study has declared that periodic limb movements are followed by increases in EEG activity, blood pressure, and heart rate during sleep (172).
Proton magnetic resonance spectroscopy at 4 Tesla disclosed that GABA levels in the thalamus were positively correlated with both periodic limb movement in sleep indices and restless legs syndrome severity, whereas GABA levels in the cerebellum were negatively correlated, suggesting that known cerebellar-thalamic interactions may modulate the intensity of periodic limb movements in sleep (202).
Possible role of the peripheral nervous system. Although periodic limb movements in sleep are centrally generated, the stimulus to the central nervous system generator might be influenced by peripheral inputs. The frequency of periodic limb movements in sleep can be entrained by peripheral (peroneal) nerve electrical stimulation. Patients who have both restless legs syndrome and periodic limb movements in sleep sometimes have evidence of peripheral neuropathy, and the abnormal sensory input from the damaged peripheral nerves could favor the brain or spinal cord to generate periodic limb movements in sleep (160; 94).
Possible role of the sympathetic and adrenergic systems. Sympathetic overactivity leading to vasoconstriction has been postulated to play a role in the genesis of periodic limb movements in sleep (76). Patients with periodic limb movements in sleep may have cold feet and reduced peripheral pulses, suggesting vasoconstriction, and both the vasoconstriction and the periodic limb movements were reduced by the alpha-1 postsynaptic adrenergic receptor blocker phenoxybenzamine in a "chemical sympathectomy" (195). The adrenergic hypothesis for the generation of periodic limb movements in sleep is further supported by the observation that tricyclic antidepressants, which are presynaptic nerve terminal reuptake blockers of norepinephrine, can increase periodic limb movements in sleep. However, the inhibitory presynaptic alpha-2 adrenergic receptor may be less critical to the generation of periodic limb movements in sleep; in fact, clonidine, which activates this receptor and inhibits norepinephrine release, improved restless legs syndrome, but not periodic limb movements in sleep (189). Heart rate variability study showed a significant predominance of basal sympathetic activity during NREM sleep in a periodic limb movements in sleep group of 58 subjects respective to control subjects (13). A study assessing cardiac autonomic function during sleep in patients with obstructive sleep apnea and periodic limb movements during sleep compared with patients affected by only obstructive sleep apnea or periodic limb movements in sleep and controls showed that apnea hypopnea index and periodic limb movement index synergically increase sympathetic activity in patients with obstructive sleep apnea (111).
Possible role of the dopaminergic and opiate systems. L-dopa, dopamine agonists, and opioids seem to suppress periodic limb movements in sleep, the dopamine agonists acting at low doses and just after the first administration (120; 118); thus, it has been postulated that an underactivity of the endogenous dopaminergic or opiate systems might play a role in the pathogenesis of periodic limb movements in sleep. Positron emission tomography and SPECT scans have shown both mild presynaptic nigrostriatal and postsynaptic striatal dopaminergic hypofunction in patients with periodic limb movements in sleep or restless legs syndrome (177; Turjanski et al 1999; 156), whereas another study did not (184). Happe and colleagues showed that reduced striatal [(123)I]beta-CIT binding correlated with the number of periodic limb movements in sleep in Parkinson disease patients (83). Moreover, patients with parkinsonism not receiving dopaminergic treatment had significantly higher rates of periodic limb movements in sleep than patients under treatment (19). Lesioning of the dopaminergic diencephalospinal neurons in the rat at the level of the hypothalamic A11 nuclei, a diencephalospinal dopaminergic system that may have an important role in mediating the state-specific sensorimotor activity that is relevant to periodic limb movements and restless legs syndrome (157), led to increased standing, as would be expected in restless legs syndrome in humans (137). Accordingly, in A11-lesioned rats, the number of periodic limb movements during the dark period was increased (114).
Further, it has been observed that the opiate receptor blocker, naloxone, led the reappearance of periodic limb movements when awake in opioid-treated patients with restless legs syndrome (87). Opiate receptor blockers reverse the effect of the opioids, but dopamine receptor blockers may reverse the effect of both the opioids and L-dopa, suggesting that the opioids mediate their effect by modulating the dopaminergic system.
Possible role of iron and magnesium. Iron is a cofactor for tyrosine hydroxylase, the rate-limiting enzyme in the formation of dopamine. In the Wisconsin Sleep Cohort, a periodic limb movements in sleep index of 15 or greater was associated with low (≤ 50 ng/ml) serum ferritin levels, after controlling for cofactors, suggesting a role for low iron stores in the pathogenesis of periodic limb movements in sleep (110). In children, the presence of periodic limb movements in sleep was frequently associated with low serum iron and a tendency toward low serum ferritin levels (174). Moreover, in children iron therapy led to a significant improvement in periodic limb movements in sleep index, also causing the resolution of a significant proportion of NREM sleep parasomnia, that seem to be correlated with periodic limb movements in sleep (78). Interestingly, the intronic variant of the BTBD9 gene, associated with restless legs syndrome and periodic limb movements in sleep, affects ferritin level and iron storage (180). A review regarding the association between sleep and iron deficiency highlighted that current evidence of association between iron deficiency and periodic limb movements is limited, but findings suggest to continue investigating this association (109).
Magnesium supplementation is often thought to be effective for restless legs syndrome and periodic limb movements, but one review showed that it is not clear whether magnesium supplementation really helps relieve restless legs syndrome or periodic limb movements (125).
Periodic limb movements in sleep are common in the healthy population, increasing with advancing age, but the prevalence of periodic limb movements in sleep in the general population has not been reliably estimated yet. Some studies reported prevalence rates between 3.9% and 11% in the general population and 1 study published in 2016 showed a very high prevalence of 28.6% (90; 165; 79). Ferri and colleagues showed that in restless legs syndrome the periodic limb movements in sleep index changes with advancing age, reaching a plateau at 15 to 25 years of age, remains stable up to 65 years, and then it shows a new increase (59). Also, the periodicity index shows striking age-related changes with a progressive increase up to 35 years of age, followed by a relative stability up to about 85 years. In addition, racial differences have been documented with African Americans that have generally lower prevalence of periodic limb movements in sleep (165). Periodic limb movements in sleep have also been reported in childhood (192; 37; 39), with considerable individual night-to-night random variability (145). There is a closely similar prevalence of parental restless legs syndrome and pediatric periodic limb movement disorder, suggesting that periodic limb movements in sleep may be a marker or endophenotype for the restless legs syndrome genotype (145). In children, periodic limb movements may represent an early manifestation of restless legs syndrome that will develop later in life (146). However, there is now strong evidence that true periodic limb movements in sleep and periodic limb movement disorder are rare in children in whom the mechanisms of periodicity described above might be weak, and even in children with restless legs syndrome, they start to show up during adolescence and not earlier (54; 39). Ferri and colleagues evaluated the leg movement activity during sleep in 61 normal school-age children and adolescents, 46 children with restless legs syndrome, and 44 children with narcolepsy type 1 (54). They found that the periodic limb movements in sleep index tended to decrease from school-age children to adolescents in normal controls and in narcoleptic subjects, whereas in subjects with restless legs syndrome it tended to increase. They also found that a periodic limb movements in sleep index cutoff of 2/hour best differentiated restless legs syndrome from controls in school-age children (accuracy 70.0%) and in adolescents (accuracy 70.8%) (54).
Among the sleep disorders, periodic limb movements in sleep are increased in restless legs syndrome, narcolepsy (38; 75; 147), unexplained insomnia (57), sleep apnea, Cheyne-Stokes respiration (123), and REM sleep behavior disorder (122). Eighty percent or more of all restless legs syndrome patients have periodic limb movements in sleep, and periodic limb movements in sleep may be inherited in an autosomal dominant fashion as a component of restless legs syndrome (191; 90; 158). Unilateral periodic limb movements in sleep may be associated with ipsilateral restless legs syndrome, with little response to dopaminergic drugs (186). Periodic limb movements in sleep associated with restless legs syndrome show age-related changes in numbers during sleep and in periodicity index (59) and correlate to the syndrome severity (91).
In children affected by chronic static pediatric acute-onset neuropsychiatric syndrome, in which sleep disruption is a major component, an elevated periodic limb movements in sleep index (higher than 5 per hour) with periodic limb movements in sleep also during REM sleep has been found (161). Polysomnographic studies documented that periodic limb movements in sleep occur more commonly in children with attention deficit hyperactivity disorder than in normal controls (159) but only when they are affected by obstructive sleep apnea syndrome. Furthermore, the limb movements in sleep of these patients showed low periodicity and were not considerably modified by L-dopa treatment (53).
DelRosso and colleagues identified in children with elevated periodic limb movements index (PLMI) a high prevalence of chronic kidney disease, chronic heart disease, use of antidepressants, antipsychotics, stimulants, and, unlike the adult population, epilepsy (39).
Periodic limb movements in sleep have also been described in association with neurologic disorders such as multiple system atrophy, dopa-responsive dystonia, Parkinson disease (36), Huntington disease, corticobasal degeneration, spinocerebellar ataxia type 2, Lewy body dementia, Tourette syndrome, Rett syndrome, stiff-person syndrome, Isaacs syndrome, motor neuron disease, post-polio syndrome, hyperekplexia (startle disease), diffuse subcortical band heterotopia, refractory enuresis, various myelopathies, stroke, and peripheral neuropathy (160; 206; 94; 197; 33; 188; 26; 143). Further associations are reported with myotonic dystrophy type 1 (208) but not with myotonic dystrophy type 2 (154), Charcot-Marie-Tooth disease type 1 (20), cognitive decline (108), dementia, and refractory epileptic encephalopathies (27).
Moreover, periodic limb movements in sleep have been associated with chronic obstructive pulmonary disorder, anemia, childhood leukemia, childhood beta-thalassemia or congenital dyserythropoietic anemia type 1, systolic heart failure, renal dysfunction, fibrositis, juvenile fibromyalgia, hypnic headache, male erectile dysfunction, normal variant short stature children, children with sickle cell disease, prematurity, normal multiple pregnancy, and abrupt discontinuation of heavy marijuana use (133; 95; 29; 21; 25; 32).
No means of prevention are known.
Risk factors include advancing age, restless legs syndrome, renal dysfunction, anemia, iron deficiency, and other sleep disorders (eg, narcolepsy and sleep apnea). Periodic limb movements in sleep have been attributed to pharmacologic and toxic effects, such as those associated with tricyclic antidepressants, neuroleptics, and alcohol. Also, SSRI antidepressants and lithium may precipitate periodic limb movements (07).
Periodic limb movements in sleep must be distinguished from other involuntary movements that occur during sleep or at the transition from sleep to wakefulness or from wakefulness to sleep. These include sleep starts, hypnic jerks, alternating leg muscle activation during sleep and arousals, phasic REM twitches, sleep-related epilepsy, REM sleep behavior disorder, night terrors, nocturnal paroxysmal dystonia, and excessive fragmentary myoclonus. Finally, a study reported periodic limb movements in sleep mimicking REM sleep behavior disorder in a case series (69). The clinical history or a polysomnographic study with accompanying videotape, or both, help to make these distinctions.
Particular attention should be paid to frank sleep apnea or with more subtle forms of sleep-disordered breathing (ie, upper airway resistance syndrome). In fact, the increase in periodic limb movements in sleep in moderate to severe obstructive sleep apnea syndrome has been related to the "unmasking" of an underlying periodic limb movement disorder by the respiratory effort-related arousals (12). The 2016 World Association of Sleep Medicine standards recommend that, in a clinical context, for patients with significant obstructive sleep-related breathing disorders, extreme caution should be exercised in interpreting the periodic limb movements in sleep index when it includes respiratory-related leg movements (63).
Periodic limb movements in sleep may be suggested by a history of nighttime kicking during sleep, most often reported only by the bed-partner, but clinical data are only predictive of the presence of periodic limb movement disorder, and for the correct diagnosis polysomnography is required (88).
Polysomnography has to include EMG recording of the bilateral anterior tibialis muscles, EEG electrodes attached to the scalp to assess the relationship of the periodic limb movements in sleep with the various sleep stages and to help with the identification of accompanying awakenings or arousals. Respiratory function should also be monitored to distinguish true periodic limb movements in sleep from periodic movements associated with arousals or periodic apnea (pseudo-periodic limb movements) (07; 55). Other than the classical periodic limb movements in sleep index, new parameters such as periodicity index and the distribution of inter-movement intervals have been introduced to better describe the time structure of leg movement activity during sleep (52; 56; 62; 175) because this parameter seems to be more stable than the periodic limb movements in sleep index (56; 63). An automatic leg movement count and periodic leg movement analysis have been validated (179).
It is fundamental to collect data about comorbidities, drugs and medications, alcohol abuse, as well as about sleep habits and sleep hygiene. Blood tests are required in order to identify any other disorders that might be cofactor in developing periodic limb movements such as iron deficiency and impaired renal function.
Alternative methods to polysomnography, such as actigraphy and portable movement sensor detectors, have been proposed, particularly for community studies and ambulatory patients due to the higher cost of polysomnography. The actigraphy technique in particular has been shown as a practical and reliable tool and has been validated against electromyography of the anterior tibial muscle with polysomnography (167; 08), but this may not apply in children (127; 09). Contactless monitoring of body movements by a 3-dimensional time-of-flight camera mounted above the bed has also been proposed for the detection of periodic limb movements in sleep (72).
In 2012 the American Academy of Sleep Medicine published guidelines about the treatment of restless legs syndrome and periodic limb movements, concluding that there is no sufficient evidence to recommend treatment of periodic limb movement disorder alone (09), so clinical judgement must be used in the pharmacological management of the disorder. However, there are some data about therapy of restless legs syndrome supporting some medical intervention also in periodic limb movement disorder, such as levodopa, pramipexole, ropinirole, rotigotine, gabapentin, and pregabalin (09).
It should be noted that several medications have also been reported to worsen periodic limb movements (Table 1); therefore, a thorough drug review must be undertaken and the possibly offending medications should be withdrawn prior to starting any treatment option.
Dopaminergic therapy. There are no studies of dopaminergic therapy on periodic limb movement disorder, and results of its effects arise from many studies evaluating this therapy on restless legs syndrome. A decrease in periodic limb movements in sleep index has been demonstrated after treatment with levodopa and with dopamine receptor agonists, including pramipexole, ropinirole, and rotigotine.
In 1986 Montplaisir and colleagues evaluated the effects of treatment with levodopa on 7 patients affected by restless legs syndrome and periodic movements in sleep, and found a significant reduction of periodic leg movements during sleep in the first third of the night and a rebound in the last third, according to the short duration of action of levodopa (129). Conversely, the positive effect of a single-dose of levodopa-carbidopa-entacapone, which has a long-lasting action, lasted throughout the night (149). In a Cochrane metaanalysis including double-blind, randomized controlled trials investigating levodopa treatment in patients with restless legs syndrome, Scholz and colleagues found that levodopa improved the periodic limb movements in sleep index by -26.28/hour in subjects affected by restless legs syndrome and periodic limb movements in sleep compared to placebo, and they concluded that levodopa is efficacious for the short-term treatment of restless legs syndrome, although attention should be paid to augmentation (163).
A Cochrane meta-analysis showed the superiority of dopamine agonists over placebo in randomized controlled trials for up to 7 months. The mean reduction of periodic limb movements in sleep was −22.4/hour, lower than in placebo (95% CI −27.8 to −16.9). Among the different drugs, larger effects were seen in cabergoline, pergolide, pramipexole, and rotigotine trials and lower effects in the sumanirole and ropinirole trials. One trial investigated the periodic limb movements index when treated with pramipexole in comparison to levodopa, which were found to have a similar effect (164).
In a double-blind, randomized study of 7.5 mg of bromocriptine at bedtime versus placebo in patients with restless legs syndrome, Walters and colleagues found a significant decrease in number of periodic limb movements in sleep per hour of sleep (190). The dopamine agonist pramipexole (0.125 to 2.5 mg daily) has been used with excellent effectiveness in the treatment of both restless legs syndrome and periodic limb movements in sleep. It was effective at low doses and within the first night of administration (120). A study provided class III evidence that for patients with periodic leg movements and restless legs syndrome pramipexole as compared to an estimated equivalent dose of bromocriptine results in greater improvement after 1 night of treatment, suggesting that D3 receptor preferential agonists are preferable to the D2 preferential agonists (121). Other dopamine agonists found to be successful in reducing periodic limb movements and restless legs syndrome are ropinirole (0.5 to 12 mg daily) (03) and rotigotine transdermal patch (1 to 3 mg per 24 hours) (135; 70). Also, apomorphine completely abolished periodic limb movements 30 minutes after subcutaneous administration (138).
Benzodiazepines. There are few and contrasting results about the utility of benzodiazepines in the treatment of periodic limb movements in sleep. In fact, triazolam at the dosage of 0.125 to 0.25 mg was shown to be useful in increasing total sleep time and improving sleep efficiency in a group of elderly subjects with fragmented sleep secondary to periodic limb movements in sleep, although the total number of leg movements was not reduced (22). Clonazepam (0.5 to 2 mg per night) has been shown to improve subjective complaints and to decrease the total number of leg movements in subjects with periodic limb movements in sleep and insomnia and hypersomnia (136). Peled and Lavie studied the effect of clonazepam (0.5-2 mg per night) in a group of 20 patients suffering from periodic limb movements in sleep, and they found a significant decrease in the number of leg movements and a significant improvement in sleep parameters and in subjective complaints, indicating that it is an effective treatment for periodic limb movements in sleep (140). Seletu and colleagues studied the acute effects of 1 mg clonazepam on idiopathic periodic limb movements in sleep, and they found that clonazepam improved subjective sleep quality, objective sleep efficiency, but failed to reduce the periodic limb movements in sleep index, concluding that it is useful for insomnia rather than periodic limb movements in sleep (166). Accordingly, Manconi and associates showed that clonazepam is not effective in decreasing the periodic limb movements in sleep index (119). Moreover, clonazepam was not more effective than cognitive-behavioral therapy in patients with periodic limb movement disorder (46).
Opioids. Among the opioids, only oxycodone 5 mg at an average of 10 to 15 mg per night in divided dosages decreased the number of periodic limb movements in sleep, decreased arousals, and improved sleep efficiency (194).
Baclofen. In a double-blind study, dosages of 20 to 40 mg of baclofen decreased the amplitude and the intermovement interval of periodic limb movements in sleep, but not the total number, which in turn was increased. The effect on sleep was dose-related (77).
Phenoxybenzamine and clonidine (adrenergic agents). The postsynaptic alpha-1 adrenergic receptor blocker phenoxybenzamine (10 to 20 mg) reduced periodic limb movements in sleep in a nonblinded study. In a double-blind study, clonidine, which impairs norepinephrine release by activating inhibitory presynaptic alpha-2 adrenergic receptors in the brainstem, improved the symptoms of restless legs, but did not decrease periodic limb movements in sleep (189).
Anticonvulsants. To our knowledge no studies investigating directly the effect of carbamazepine on periodic limb movements in sleep have been performed, and data derive from studies in subjects with restless legs syndrome. One study conducted by Zucconi and colleagues showed that carbamazepine does not modify the pattern of the “nocturnal myoclonus” (211).
Staedt and colleagues reported a reduction of periodic limb movements in sleep in 2 patients treated with lamotrigine (178). Based on these findings, Youssef and associates conducted a pilot study of lamotrigine in patients with restless legs syndrome, and they found a trend toward improvement on objective measures of periodic limb movements in sleep, but these results were inconsistent (207). In an open-label study valproate at the dosage of 125 to 600 mg daily was administered to patients affected by periodic limb movement disorder and was shown to have long-term beneficial effect in reducing the periodic limb movements in sleep index and in improving the sleep efficiency (47). Gabapentin at the dosage of 300 mg daily was as successful as ropirinole in the treatment of periodic limb movements in sleep in subjects with restless legs syndrome (84). Also, gabapentin enacarbil at the dosage of 1200 mg once daily significantly reduced periodic limb movements in sleep associated with arousal per hour of sleep compared with placebo (201). A double-blind, placebo-controlled study provides class II evidence that pregabalin (mean effective dose 322.50 mg/day) is effective for the treatment of restless legs syndrome and periodic limb movements in sleep in placebo-unresponsive patients (71).
Other. Hornyak and associates showed that in patients with insomnia related to periodic limb movements in sleep, oral magnesium therapy at the dosage of 12.4 mmol in the evening for 4 to 6 weeks decreased periodic limb movements in sleep with or without arousal, indicating that magnesium supplementation may be a useful alternative therapy (92).
Another alternative treatment might be estrogen replacement therapy in postmenopausal women, although research findings are controversial. In fact, Polo-Kantola and colleagues observed that short-term estrogen treatment did not alter the incidence of or intensity of periodic limb movements in sleep (148) whereas Hachul and associates described a case report of a symptomatic postmenopausal patient with high periodic limb movements in sleep index who experienced a significant decrease of periodic limb movements in sleep after transdermal estradiol therapy (80).
A positive response to melatonin has been postulated to be due to circadian or chronobiotic effects (104).
Bupropion, unlike many other antidepressants, is not associated with higher periodic limb movements in sleep, but on the contrary, patients in therapy with bupropion had periodic limb movements in sleep index lower than patients taking venlafaxine or SSRI and also with respect to control subjects (205). These findings may be useful for clinicians during the selection of an antidepressant, especially for patients with severe sleep complaints due to periodic limb movements in sleep.
In children with periodic limb movements in sleep associated with low serum iron and low serum ferritin, iron sulfate therapy gave clinical improvement (174), and a sustained improvement in periodic limb movements in sleep index and maintenance of adequate ferritin levels 2 years after iron therapy initiation in a pediatric restless legs syndrome/periodic limb movement disorder cohort with a long-term follow-up has been described (44). An open-label study demonstrated that intravenous ferric carboxymaltose in pregnant women with restless legs syndrome and iron deficiency or anemia decreased periodic limb movements in sleep index (162).
Nonpharmacologic treatment. Nonpharmacologic treatment has been tried. De Mello and colleagues recruited 12 voluntary males with complete spinal cord injury between T7 and T12 who participated in a physical training program for 44 days and submitted them to polysomnographic recordings before and after physical exercise (41). Results showed a statistically significant reduction of periodic limb movements in sleep recorded after the exercises, suggesting that regular and systematized physical activity promotes the reduction of periodic limb movement activity in subjects with spinal cord injury.
Periodic limb movements in children. The management of restless legs syndrome and periodic limb movement disorder in children involves both nonpharmacologic and pharmacologic approaches. Although there is emerging literature supporting medical therapy in children with restless legs syndrome/periodic limb movement disorder, the overall experiences with these medications remain limited, and currently there is no approved medication for this age group. Most children and adolescents with restless legs syndrome/periodic limb movement disorder have low iron storage; therefore, iron therapy should be considered as the first line of treatment in children when ferritin is less than 50 ug/l (144; 43). There is increasing evidence on the effectiveness of dopaminergic medications in children that may be considered a second-line treatment but the data are quite limited and their use is limited due to the side effects. Other medications such as α2δ-1 ligands, benzodiazepines, and clonidine are frequently used but have not been adequately investigated in children (155; 43). In a review about pharmacological therapies in children with restless legs syndrome/periodic limb movement disorder, Dye and colleagues concluded that choosing the correct pharmacological treatment for children is challenging, and physicians first of all should be cautious in making the correct diagnosis (43).
Periodic limb movements in sleep occur frequently in restless legs syndrome, and the leg discomfort and motor restlessness of restless legs syndrome frequently are exacerbated by pregnancy. Periodic limb movements may themselves occur more frequently in multiple pregnancies (133). Patients with restless legs also show more periodic limb movements before and after delivery, particularly during sleep stage 1 and wakefulness; periodic limb movements decreased postpartum in subjects with restless legs syndrome (45).
Periodic limb movements in sleep and periodic limb movements in wakefulness can be observed in epidural and spinal anesthesia, and the involuntary movements disappear as the anesthesia wears off (196).
Patrizia Congiu MD PhD
Dr. Congiu of University of Cagliari, Italy, has no relevant financial relationships to disclose.See Profile
Monica Puligheddu MD PhD
Dr. Puligheddu of University of Cagliari, Italy, received consulting fees from Jazz and Livanova for speaking engagements.See Profile
Raffaele Ferri MD
Dr. Ferri of Oasi Research Institute IRCCS in Troina, Italy, has no relevant financial relationships to disclose.See Profile
Antonio Culebras MD FAAN FAHA FAASM
Dr. Culebras of SUNY Upstate Medical University at Syracuse received an honorarium from Jazz Pharmaceuticals for a speaking engagement.See Profile
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Jan. 18, 2022
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