Review of periodic limb movement and restless leg syndromeR Natarajan
Department of Pulmonary and Critical Care Medicine, and Sleep Medicine, University of Massachusetts, Worcester, USA
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.65284
Source of Support: None, Conflict of Interest: None
Periodic limb movement (PLM) and Restless leg syndrome (RLS) are types of sleep disorders that are not very well recognized in clinical practice. While RLS is a clinical diagnosis, the diagnosis of PLM is made by polysomnography. They share the same pathophysiology and often respond to the same treatment. To date all the epidemiological studies have reported the prevalence between 2% and 15%. It has recently become known that mild obstructive sleep apnea and upper airway resistance syndrome (UARS) can masquerade as PLM syndrome. New discoveries have been made with regard to genetics and PLM and RLS. Detailed review on this subject should improve the awareness of these disorders, both among general physicians and specialists. Extensive review of journals in the past 20 years was made using Medline search.
Keywords: Periodic limb movement, PLM, restless leg syndrome, RLS
Periodic Limb Movements (PLMs) and Restless Leg Syndrome (RLS) are among the most common disorders seen in sleep clinics. The prevalence of these disorders is higher than that of epilepsy. They cause tremendous distress and affect the quality of life of those afflicted. Generally speaking, these disorders are not well understood in terms of the pathophysiology and symptomatology. Ironically, RLS can be described as the most common condition one has never heard of. A comprehensive discussion of the epidemiology, pathophysiology, symptomatology and treatment as attempted in this article should improve the awareness of these entities among general practitioners and Sleep specialists and help them manage these cases more effectively. A thorough Medline search was made from the past 20 years using the titles PLM and RLS.
Periodic limb movements are a type of motor disorder that occurs typically in sleep. They are described as parasomnias. They are characterized by repetitive movements of the legs that result in poor quality of sleep and insomnia. Periodic Limb Movements most commonly involve the lower limbs and in severe cases may resemble the Babinski reflex  (extension of the big toe and fanning of the other toes). Movements are typically bilateral but are not necessarily symmetrical or occur simultaneously. They may predominate in one leg or alternate between legs.  Periodic Limb Movements involving the upper extremities often manifest as repetitive flexion at the elbow. They can occur either during sleep or during wakefulness. When occurring during relaxed wakefulness [periodic leg movements of wakefulness (PLMW)], they appear as jerk-like movements with an appearance and distribution similar to PLMs affecting the lower limbs, but with greater intensity and speed.  In this article further discussion of PLMs refer only to those affecting the lower limbs and occurring in sleep.
The universally accepted criteria for diagnosis of PLMs are as follows:
There should be at least four leg movements in a 90-s period. Contractions should be more than 0.5-s and less than 5-s.  When they are recorded from both anterior tibialis muscles, they should be separated by an interval of at least 5-s for them to be counted as two separate movements. They can either be associated with EEG arousals or in severe cases even overt arousals. The PLM Index (PLMI) is calculated by dividing the total number of PLMs by sleep time in hours. Periodic Limb Movements Index of more than 5 and less than 25 is considered mild; PLMI of >25 and <50 is considered moderate and >50 is severe. The diagnosis of PLM disorder can be made when patients present with insomnia, tiredness and daytime sleepiness in the presence of a high PLMI. Sometimes spouses can complain that their partners kick their legs during sleep. Patient may report sleep onset problems or frequent arousals because of these movements. In contrast, those who are unaware of these movements may simply complain of un-refreshing sleep, 'leg tiredness' on awakening in the morning. The diagnosis of idiopathic PLM disorder is made when no other psychiatric, medical or sleep disorders can be found to account for the symptoms, and patients are not on medications that can result in PLMs. There are two types of PLMs. Type I (spontaneous) has peak frequency between midnight and 3 a.m. followed by decrease in late morning hours. Type II, which is associated with Sleep-related Breathing Disorders (SRBD), REM Behavioral Disorder (RBD) and narcolepsy has a more even distribution throughout the night.
With the improvements in polysomnographic technology and respiratory monitoring, it has been recognized recently that PLMS may occur in the setting of Upper Airways Resistance Syndrome (UARS), and appear to be caused by it.  It is also clear now that in some cases a diagnosis of PLMS is made when actually the underlying problem is either UARS or a mild obstructive sleep apnea. In these cases, Continuous Positive Airway P ressure treatment results in a significant improvement in the PLMS.  Interestingly, severe Obstructive Sleep Apnea (OSA) can mask underlying PLMS and they merely become more noticeable during CPAP treatment.  Adding to the confusion is the observation that CPAP in and of itself can cause PLMs. ,,
PLMS are rare in children and are more common with advancing age. They can be found in >34% of patients over 60 years of age. They are common in a variety of sleep disorders including SRBD (20-30%), Restless Leg Syndrome (RLS) (80-90%), RBD (70%) and narcolepsy (45-60%) and have been reported in 1-15% of patients with insomnia. The actual prevalence of this disorder in the general population is not known, as this requires polysomnography for the diagnosis. While 80-90% of patients with RLS have PLMS, only 30% of PLM patients have RLS.
Restless leg syndrome is a clinical diagnosis unlike PLMS. The first description of RLS is attributed to Thomas Willis in 1685. Ekbom coined the term restless legs. In 1945, he gave a full description of the syndrome based on a large series of patients. This condition is sometimes referred to as Ekbom's syndrome.
The most recent diagnostic criteria for RLS developed by National Institute of Health with members of IRSSLG (International Restless Leg Syndrome Study Group) require four essential criteria for the diagnosis of RLS: 
There are two types of RLS:
Ekbom estimated the prevalence of RLS to be 5% in the general population. Subsequent surveys have estimated the prevalence to be 1-29%.  The RLS epidemiology, symptoms and treatment (REST) trial is the largest survey till date to study the prevalence of RLS.
There are significant geographical variations in the prevalence of RLS. The factors that may be responsible for these variations are not well understood. Most prevalence studies have been conducted on Caucasian populations. Prevalence estimates in East Asians include 0.1% in a Singaporean survey  and 12% in a Korean survey.  Recently Rangarajan et al. found a prevalence of 2% from the door-to-door survey in Bangalore, India. 
Factors that affect the prevalence of RLS
Many epidemiological studies have shown a female preponderance.  This could well be a result of reporting bias. An increasing prevalence of RLS with age has been found in a few population-based studies.  Phillips et al. found a 3% prevalence of RLS symptoms in persons less than 30 years of age, about 10% in persons 30-79 years of age and 19% in persons 80 years of age and older. The IRLSSG has also defined criteria for diagnosis of RLS in children. The prevalence of RLS in children is not known, as there have not been any population-based studies. It is very likely that there are quite a few children and adolescents affected by this disease as some adults recall onset of symptoms in childhood.
Racial differences in RLS have not been completely understood.  The prevalence of RLS in some ethnic groups may have been underestimated because of their underrepresentation in RLS specialty clinics. This could also be true with regard to prevalence studies in countries such as India where access to specialty clinics may indeed be a problem.
Restless leg syndrome and associated conditions
The term secondary RLS is used whenever this condition is found in association with another medical condition. The most frequently found associations are renal failure, iron deficiency and pregnancy. RLS in association with hemodialysis population is estimated to be around 20% and the disease is usually more severe than primary RLS. In this population the presence of RLS is also a predictor of mortality.  Lower levels of ferritin have been noted in patients with RLS in comparison with controls.  RLS can be associated with pregnancy typically after 20th week and the incidence is estimated to be around 20%. Ekbom made the first observation that there is a high prevalence of RLS in pregnancy. Subsequently Manconi et al. by applying IRLSSG criteria in 200 consecutively enrolled pregnant women found the incidence to be 27% for those with twice weekly and 12% for those with thrice-weekly symptoms respectively.  The prevalence of both RLS and PLMs in post menopausal patients has not been systematically studied as yet. However, it is believed that there is simply a worsening of an unrecognized RLS/PLM disorder in post-menopausal patients. The pathophysiology may be related to down regulation of dopamine receptors and disinhibition of Catecholamine-O-methyl transferase (COMT) by a falling estrogen level associated with menopause. 
Restless Leg Syndrome has been found in association with myelopathy, diabetes mellitus, neuropathy and Parkinson's disease. There are anecdotal reports of RLS in patients with spinal lesions. Hogl et al. demonstrated the incidence of transient RLS following spinal anesthesia in a prospective manner.  Skomro et al. found twice the prevalence of RLS in patients with type II diabetes mellitus in comparison with controls.  Merlino in a large case-control study found a significantly high prevalence of RLS among diabetics independent of polyneuropathy.  Gomez-Esteban et al recently found a higher prevalence rate of RLS in patients with Parkinson's disease. In a study of 114 patients, 25 out of 114 patients had RLS (21.9%).  Dopamine antagonists (antipsychotics and anti-emetics) have been shown to cause motor restlessness (akathisia) and increased PLMS and RLS.  Although antidepressant medications, especially SSRIs and TCA have been anecdotally reported to cause or exacerbate RLS, a review of 200 patients presenting to the sleep clinic found no incontrovertible association between RLS and antidepressant medication.  There is a higher prevalence of periodic leg movement disorder and RLS among children with Attention Deficit Hyperactivity Disorder (ADHD) compared with controls. A small uncontrolled trial of dopaminergic treatment in children with RLS and ADHD demonstrated significant improvement in both conditions, suggesting an etiological link. , An association between lack of physical activity and RLS has been shown. A single, small, randomized trial of prescribed exercise for RLS demonstrated significant improvement in RLS severity.  The salutary effects of both acute and chronic exercise on PLM and sleep quality have been well studied by Andrea M Esteves et al. 
Is RLS a genetically transmitted disease?
An inherited susceptibility to RLS has long been known, as there is a higher proportion of RLS patients with an affected first-degree relative. Walters et al. found that patients with symptoms before the age of 20 had a positive family history (81%) as compared with only 58% with later onset symptoms.  It has been suggested that early onset of RLS could be transmitted as an autosomal dominant trait  . Stefansson et al. reported an association between a sequence variant in chromosomes 6P and periodic leg movements in sleep in a distinct Icelandic and American cohorts of subjects with RLS and their families.  Winkleman et al. showed an association between RLS and the same sequence variant, as well as two additional single nucleotide polymorphisms (SNPs) in German and Canadian cohorts with RLS. ,
Pathophysiological aspects of RLS
The basic pathophysiologic mechanisms of RLS remain elusive. Pharmacological, physiological, pathological and newer imaging studies have implicated dopaminergic systems, brain iron metabolism and the endogenous opioid system. The nigrostriatal dopaminergic system has been implicated in the pathogenesis of RLS and PLMs. The role of iron in RLS has been supported by demonstrated therapeutic benefit of iron in both RLS and PLMs. MRI and autopsy studies have shown lower iron levels in substantia nigra of RLS patients. Other studies have even found lower CSF ferritin levels with normal serum iron stores in RLS patients. The inability to store iron in the brain is more profound in early onset RLS than in patients with late-onset RLS.
Akpinar in 1982 accidentally came across the beneficial effects of levodopa on RLS.  Since then levodopa and other dopaminergic agents have been used effectively in the treatment of RLS and PLM. This has led to the conclusion that dopaminergic systems must play some role in the pathophysiology of RLS. It has also been observed that co-administration of domperidone (a peripheral dopamine antagonist) does not decrease the efficacy of pergolide (a dopamine agonist) in treating RLS, which lends support to the hypothesis that central rather peripheral dopaminergic systems are responsible for RLS. It has been hypothesized that there is a dysfunction in the central processing of sensory stimuli. There is a defective D2 binding in the medial thalamus and anterior cingulate gyrus that are involved in central sensory processing. The dienecephalo-spinal dopaminergic tract has received much attention as the potential anatomic site of dopaminergic dysfunction in RLS. The system projects to the limbic system, sensory cortex and spinal cord. The proximity to the circadian control centers in the hypothalamus may offer some explanation for the circadian pattern of symptoms observed in RLS. 
Iron deficiency has long being associated with RLS, and iron therapy has been found to be effective and curative in some cases. Earley et al. demonstrated markedly reduced cerebrospinal fluid ferritin levels and elevated transferrin levels in RLS patients compared with controls, even though there was no difference in serum ferritin levels.  It is possible that even in the absence of total body iron deficiency, defective iron metabolism in the brain could be responsible for RLS. A large study using MRI found decreased regional brain iron concentration in early onset RLS patients relative to controls.  Based on the fact that transferrin receptor quantity is decreased (the opposite of what is seen in iron deficiency state) and iron regulatory protein1 (IRP1) is deficient, it is been hypothesized that a primary protein dysfunction in the brain iron regulation system is responsible for RLS. 
Multiple potential biochemical links exist between dopaminergic system and brain iron metabolism. Iron is a cofactor for tyrosine hydroxylase, the rate-limiting enzyme in synthesis of dopamine.  The dopamine transporter (DAT) is also impaired during iron deficiency. 
Significant improvement of RLS symptoms has been demonstrated with oral opioids. A negative correlation with RLS severity and 11C-diprenorphine uptake in the caudate nuclei, medial thalami and anterior cingulate gyri has been found by some investigators.  The pathophysiological significance of this finding is not clear.
As mentioned earlier in the article except for some differences in the timing of the medication there is a lot of similarity between treatment of RLS and PLM. Treatment of PLMs based on polysomnographic studies should be strongly discouraged. Some patients with both OSA and PLM do well just with the treatment of OSA with CPAP. Only if symptoms persist such as persistent leg movements as noticed by spouse or persistent residual daytime sleepiness is treatment justified. Patients who present with RLS should, in addition to a thorough physical examination, also get a complete blood count and an iron level. Low iron level may reflect an underlying bleeding condition such as colon cancer. Suffice it to say that before starting the treatment with iron, patient may need further investigations such as colonoscopy to determine this possibility. It is generally recommended that ferritin level less than 50 mcg/l should be taken as a cut-off number for treatment with oral iron. The dose of iron will depend on the blood level. The normal dosage is usually 50-65 mg of elemental iron 2 or 3 times a day. Even though the absorption of iron is better on an empty stomach it is generally recommended that patients take their pills with food to prevent gastric side effects, which might lower the compliance with these medications. Vitamin C may enhance iron absorption. Once iron treatment has been started, ferritin levels should be repeated every 2 to 3 months. The goal is a ferritin level of at least 60 mcg/l.
Caffeine, alcohol, nicotine and medications that aggravate RLS should be avoided. Physical and mental activity may help ameliorate symptoms in mild cases.
The most commonly used dopaminergic agents are levodopa, dopamine agonist such as ropinirole, pramipexole and in some countries the ergot-derivative pergolide. The efficacy of dopaminergic agents has been shown to be 90% in randomized placebo-controlled trials. , They are generally effective in not only relieving symptoms but also actually decreasing the number of movements at night. Levodopa/carbidopa generally works better for intermittent symptoms and as prophylaxis prior to car rides and plane trips. For daily symptoms, either ropinirole or pramipexole can be used. , These are longer acting in comparison with levodopa. They should be administered at least 2 hr prior to the onset of symptoms. For RLS symptoms that occur mostly in the early part of the night, taking these medications with dinner maybe helpful. In cases of PLMs, they should be given an hour prior to going to sleep. Both pramipexole and ropinirole can be started at 0.25 mg and increased as tolerated. The maximum dose of these medications his generally 3 mg. In patients who are intolerant to dopaminergic medications, the ergot-derivative pergolide can be used. The starting dose is a 0.025 mg and increased up to 0.5 mg.
A major problem with pergolide is fibrosis of cardiac valves pericardium mediastinum and retroperitoneal space.  Common side effects of levodopa are nausea, insomnia, nasal stuffiness and fluid retention. Augmentation is the most common side effect with long-term use of levodopa in RLS.  After initial improvement, should symptoms worsen, consideration should be given to the possibility of augmentation. Patients generally complain that symptoms start earlier than usual and may also be troubled by these symptoms in the early morning hours. Augmentation has also been reported with other dopaminergic agents and the incidence with these agents is probably around 20%. When physicians recognize this phenomenon they should explain to the patient that these medications are responsible for these symptoms and that they should be withheld rather than increased. Physicians should also explain that stopping the medications usually result in rebound symptoms and that they can be managed effectively with benzodiazepine receptor agonists.
Opiates can be used in severe cases, especially in those with neuropathy with accompanying painful dysesthesiae. The risk of addiction in long-term treatment with opioids is low  Rarely augmentation has been noted with tramadol. Antiepileptic agents such as gabapentin and lamotrigine have been effectively used as second line agents in the treatment of RLS. Efficacy of these agents has been shown in many double-blind cross-over trials. ,, Common side effects are sleepiness, dizziness and fluid retention. A single does of 1500 mg of gabapentin at bedtime may suffice in most cases. Lamotrigine at a dose of 200 mg at bedtime has shown promise in some cases of RLS and PLM. Two small open label trials have reported improvement in symptomatology with lamotrigine.  Benzodiazepines-like medications such as zolpidem, zaleplon have been used in the treatment of these conditions, especially when patients are unable to take dopaminergic agents because of side effects including augmentation. Clonazepam at a dose of 0.5 mg going up to 3 mg has been used. None of these agents have been shown to decrease PLMs in polysomnographic studies. Nonetheless, they result in subjective improvement in the quality of sleep.
Symptoms of RLS are quite common. The prevalence of RLS, severe enough to cause impairment in Quality of Life (QOL) and warrant medical treatment is probably around 2-3%. This makes clinically significant RLS 2 to 6 times as common as epilepsy in developed countries (estimated prevalence of epilepsy 0.5-1%). Not in keeping with this fact is that publications and reports on epilepsy have outnumbered those on RLS and PLM. Restless leg syndrome and periodic leg movement syndrome can cause significant impairment of sleep and compromise QOL. Prompt recognition and management will result in significant improvement in symptoms and improve patient's QOL and efficiency at work.