Some interesting reading here, and not just for parents (or grand-parents).
I did not have time to format the tables as well as I would have liked to, but you are still able to follow them with a little more attention.
From Current Opinion in Pulmonary Medicine
Restless Legs Syndrome and Periodic Limb Movements Disorder in the Pediatric Population
Umakanth Khatwa; Sanjeev V. Kothare
Posted: 11/03/2010; Curr Opin Pulm Med. 2010;16(6):559-567. © 2010 Lippincott Williams & Wilkins
Abstract and Introduction
Abstract
Purpose of review Restless legs syndrome (RLS) and periodic limb movements of sleep (PLMS) are common neurological disorders in childhood which are usually underdiagnosed. As many pediatricians and pediatric pulmonologists with interest in sleep medicine will be encountering children with RLS and PLMS in their practice, we feel a comprehensive review of these disorders from a pediatric perspective would be very important in understanding basic pathophysiology, clinical features in early diagnosis, and effective management.
Recent findings There has recently been increased awareness about these disorders in children, and the American Academy of Sleep Medicine has recently published pediatric specific diagnostic criteria. There have also been exciting discoveries into the basic pathophysiology of these conditions which have helped to better understand these disorders. Genetics plays a very important role in their development, and current management strategies have been very successful in treatment of these conditions.
Summary RLS occurs in 1 out of 120 school-age children. In many children, diagnosis is not even suspected as these children present with atypical symptoms and associated comorbid conditions. In this review, we will discuss RLS and PLMS in the pediatric population and briefly review their pathophysiology, clinical presentation, risk factors, neurobehavioral consequences, and newer diagnostic criteria along with recent advances in their management.
Introduction
Although restless legs syndrome and periodic limb movement disorder symptoms overlap, we have described them separately so that we can better characterize each entity and help differentiate one from another.
Restless Legs Syndrome
Restless legs syndrome (RLS) is a primary central nervous system (CNS) sensori-motor network disorder. The diagnostic criteria include an urge to move the extremities associated with unpleasant sensations, symptoms that are worst at rest, relieved by movement, and most severe at night.[1,2] Some patients present predominantly with unpleasant sensations (paresthesias), whereas others manifest with a significant urge to move their legs, and children may appear 'fidgety'. As RLS symptoms occur during bedtime they are most likely to interfere with sleep onset. These symptoms may be confused with bedtime resistance and limit setting-type behaviors. RLS along with periodic limb movements of sleep (PLMS) together can impact total sleep duration and quality, leading to impaired cognition, daytime functioning, mood and overall quality of life.[3–6]
Periodic Limb Movement
Periodic limb movements (PLMs) were first reported by Symonds[7] and initially thought to be nocturnal myoclonic epilepsy. PLMS is characterized by brief, repetitive, and highly stereotypical jerky limb movements occurring during sleep. These are more commonly seen in the legs, feet, and toes than in the upper extremities.[8,9] The typical movement involves extension of the big toe and dorsiflexion of the ankle. They are sometimes, but not necessarily, associated with an electroencephalographic arousal or an awakening resulting in sleep fragmentation.
Patients are usually unaware of their own symptoms and often reported by their bed partner or parent. Nocturnal periodic limb movements without any associated consequence of sleep fragmentation are called PLMS. Periodic limb movements occurring while awake are called periodic limb movement of wakefulness (PLMW). If PLMS is associated with symptoms of sleep disturbances and/or daytime functioning then it is called periodic limb movement disorder (PLMD). Whereas PLMS is merely a polysomnography (PSG) finding, PLMD is a clinical syndrome.
Not all patients with PLMS manifest with PLMD. Up to 80% of patients with RLS have PLMS;[10] however, most patients with isolated PLMS may not experience RLS. PLMS is considered as a supportive diagnostic criterion for RLS in adults and an essential criterion for RLS in children.[1]
History
The term 'restless legs' was coined by Karl-Axel Ekbom.[11,12] In 1944, he reported eight patients with restless legs and later published his doctoral thesis on this entity.[12] There were no detailed pediatric studies reported until the mid-1990s. The consensus criteria for the diagnosis of RLS in children and adolescents were published at a workshop at the National Institute of Health (NIH) in 2003.[1] These new pediatric RLS criteria were subsequently included in the International Classification of Sleep Disorders (ICSD) Diagnostic Manual (2nd edition).[9]
Prevalence
The prevalence of RLS and PLMS is described below.
Restless Legs Syndrome
Population-based studies in adults using the four main diagnostic criteria for RLS found a prevalence of 5–10% in the US and Western Europe.[5,13–16] It is usually more common in women. However, preliminary studies have found a much lower prevalence of RLS in certain Asian countries such as Singapore[17] and India.[18,19] Studies have reported that, in adults with RLS, 25% of them had onset of their symptoms between 10 and 20 years of age and 18% of them had onset before 10 years of age.[10,20] A study from the Mayo clinic pediatric sleep disorders clinic reported a pediatric RLS prevalence of 5.9%.[21]
Different studies have reported a prevalence of RLS in children of between 1 and 6% using various RLS definitions.[22,23] In a 2007 landmark study (Pediatric 'REST' study) employing a telephonic survey of over 10 000 families, about 1.9% of 8–11-year-olds and 2% of 12–17-year-olds met the criteria for diagnosis of RLS using 2003 National Institute of Health Pediatric RLS consensus criteria.[24] About 0.5–1% of these children reported severe RLS symptoms (moderate-to-severe symptoms ≥2 days per week). This study indicates that about one million school-age children in the US are likely to be affected by RLS. RLS symptoms are thus common in children and adolescents, occurring more commonly than epilepsy or diabetes!
Periodic Limb Movements of Sleep
The prevalence of PLMS is about 4–11% in the general population and increases with age, reaching 25–58% in the elderly.[22] No sex difference has been described. Picchietti and Walters[23] were the first to report that PLMS were seen in children and adolescents. Various pediatric studies have revealed a 5–25% prevalence rate of PLMS (>5 per hour) in children referred for sleep studies.[25–28] Some studies have reported that PLMS appear to be more common in Caucasians than African–American children.[29]
Pathophysiology
The specific pathophysiology of idiopathic RLS[30••] as well as PLMS is not well understood. As they may share common pathogenesis, prevailing causative hypotheses are considered together in this section.
Neurotransmitters Theory
Dopaminergic medications have been shown to dramatically alleviate symptoms of RLS, whereas dopaminergic antagonists aggravate RLS, suggesting dopaminergic dysfunction in patients with RLS. The possible mechanisms include dysfunction in dopaminergic neurotransmission and/or a potential neuro-anatomical alteration in the dopaminergic neurons. In addition, alteration and redistribution in binding of the endogenous opioid system[31] and altered central processing of pain in patients with RLS have also been reported.[32]
Neuroanatomy
Restless legs syndrome may be the consequence of sensori-motor dysfunction. Several studies recently have reported that the principal dopaminergic pathology in human RLS may be in a diencephalon–spinal pathway originating from A11 dopaminergic neurons.[33–35]
Iron Deficiency Theory
Iron has been implicated in the pathophysiology of RLS and PLMS. Brain MRI studies and transcranial ultrasound using special techniques have detected low brain iron, particularly in the subtantia nigra.[36–39] Other imaging studies of the brain have also revealed changes in brain iron metabolism in patients with RLS, along with reduced ferritin levels in cerebrospinal fluid (CSF) and abnormalities in the circadian pattern of dopamine metabolites in CSF.[40,41] The 'iron–dopamine model' suggests that iron deficiency in the brain causes an abnormality in the dopaminergic system leading to manifestation of RLS. The mechanism proposed is related to the fact that iron is a co-factor for tyrosine hydroxylase, an important enzyme in the synthesis of dopamine. Various hypotheses indicating abnormalities in the pathway of iron metabolism, storage and transfer of iron into the central nervous system, and abnormalities in the ferritin subunits, hepcidin and transferrin receptor expression have been proposed.[42–45]
There are a number of studies documenting low iron (serum ferritin <50 ng/ml) in both the adult and pediatric population with symptoms of RLS as well as PLMS.[21,46] Whereas hemoglobin synthesis is affected and anemia usually develops when ferritin level falls below 10–12 ng/ml, patients with RLS or PLMS are usually not anemic at presentation. Serum ferritin below 50 ng/ml is considered an indication for using supplemental iron treatment in symptomatic patients.
Circadian Link
Restless legs syndrome is a circadian disorder in that it mainly occurs in the late evening or night and usually resolves by midnight to 2 a.m..[47–50] However, the circadian rhythmicity is lost with increasing severity and during 'augmentation', when symptoms may be present during the daytime, or throughout the 24 h in extreme cases. Iron, dopamine and dopamine metabolism also exhibit a circadian pattern, whose nadir in the late evening and early night might coincide with severity of RLS symptoms.[51]
Genetics
The pediatric 'REST' study reported that, in more than 70%, at least one biological parent, and, in 16%, both parents were affected, indicating a strong genetic component.[24] Familial aggregation of RLS has been well reported.[52] The postulated mode of inheritance is autosomal dominant,[53,54] but is likely more complex. Genome-wide association studies have identified variants within the intronic or intergenetic regions of MEIS1 (2p), LBXCOR1/MAP2K5 (15q), BTBD9 (6p), neuronal nitric oxide synthase (NOS1) (12q) and protein tyrosine phosphatase receptor type delta (9p) genes.[55] BTBD9 accounts for 50% of the genetic abnormality in RLS and PLMS.[56] Overall, disturbances in iron metabolism, the central dopaminergic system, and genetics seem to be the primary factors in the pathophysiology of RLS.
Risk Factors
The risk factors for RLS and PLMS have been shown in Table 1.[57,58] These conditions can potentially worsen the underlying RLS and PLMS and hence need to be taken into consideration.
Table 1. Risk factors for RLS and PLMS
Risk factors for RLS Risk factors for PLMS
1. Sleep deprivation 1. Obstructive sleep apnea
2. Caffeine and nicotine intake 2. Autism and ADHD
3. Pregnancy 3. Narcolepsy
4. Peripheral neuropathy and myelopathy 4. REM behavior disorder
5. Thyroid dysfunction and diabetes mellitus 5. William syndrome and Tourette syndrome
6. End-stage renal disease 6. Medications: SSRIs, lithium, tricyclic antidepressants
7. Medications: SSRIs, lithium, tricyclic antidepressants
PLMS, periodic limb movements of sleep; REM, rapid eye movement sleep; RLS, restless legs syndrome; SSRI, selective serotonin reuptake inhibitor. Reproduced with permission from.[56,57]
Clinical Presentation
The clinical presentations of RLS and PLMS are described separately.
Restless Legs Syndrome
The common symptoms of RLS can be broadly categorized into sensory, motor, sleep-related and daytime symptoms.[57] As the diagnosis of RLS is mostly clinical, it is challenging to diagnose it in children who present with atypical symptoms and are unable to describe them. Establishing a good rapport with the child will greatly enhance chances of accurately assessing sensory symptoms, while other symptoms can be given by the parents. It is very important to avoid leading questions and facilitate expression of the sensation in the child's own words. Sensory symptoms are difficult to explain by children and simple description such as a funny feeling, pain, hurting, tickling, bugs, spiders, ants, goose bumps in the legs can be accepted.[57,58]
Most children will not describe an 'urge to move' per se, but parents may report frequent stretching, kicking, pacing and running around and/or requests for leg massage. These symptoms may be perceived by parents as bedtime resistance behaviors. They may also have difficulty falling asleep; these children avoid being in bed and lying still as these symptoms may worsen by inactivity. Sometimes children may draw pins, needles, tiny sand particles, bugs, or a saw over their legs when asked to depict their symptoms. It is very important to assess the severity of RLS by determining the frequency, duration, and intensity of symptoms, along with the impact on daytime functioning, mood, school performances and learning.
Periodic Limb Movement Disorder
Periodic limb movement disorder in children may present with nonspecific clinical symptoms such as restless sleep, 'growing pains', frequent awakening at night and daytime hyperactivity. Up to 80% of patients with RLS also have PLMS. Once asleep, parents may report that these children are very restless, tend to kick, twitch and jerk during sleep and have a tendency to fall off their bed. As a consequence of sleep fragmentation and sleep deprivation, they may present with excessive daytime sleepiness, fatigue, the feeling of nonrestorative sleep, and difficulty waking up in the morning. Poor attention span, learning difficulties, mood changes, anxiety, depression and irritability may also be seen. In addition some children may develop aggressive behavior, hyperactivity and impulsivity and are misdiagnosed as having attention deficit hyperactivity (ADHD).
'Growing pain' may be described as recurrent discomfort in the legs at bedtime which may lead to sleep disturbances. RLS and PLMS are frequently misdiagnosed as growing pain.[46] Although it is a common complaint in children with RLS, it is a nonspecific symptom and does not necessarily suggest RLS. In the pediatric 'REST' study, a history of 'growing pain' was reported in 77–85% of children meeting diagnostic criteria for RLS, but was also found in 64% of children without RLS.[24]
Comorbid Conditions
These include ADHD, depression, anxiety and chronic renal failure.[59–61] Of all these, ADHD has been best characterized. About 25% of adults, as well as school-age children, with RLS meet the criteria for ADHD, whereas 12–35% of children with ADHD met the criteria for RLS.[59,62] Children with ADHD are more likely to have iron deficiency,[63–66] and treatment with supplemental iron has been reported to help reduce their PLMD symptoms, improve sleep quality and subsequently decrease ADHD symptoms.[65]
History and Physical Examination
Although diagnosis of RLS is based entirely on clinical history, diagnosis of PLMS requires documenting PLMS by overnight PSG. Hening coined the acronym 'URGE' to help remember the key features of RLS, which are listed below.[30••,67,68]
1. U = Urge to move legs, usually associated with unpleasant sensation
2. R = Rest induces symptoms
3. G = Getting active (physically and mentally) brings relief
4. E = Evening and night make symptoms worse
In most cases, the clinical examination is normal, except when associated with comorbidities. Various diagnostic criteria that would aid in making a diagnosis of RLS (333.94) in adults and children are listed below.[9]
Diagnosis in adult patients (age >12 years):
1. The patient reports an urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs.
2. The urge to move or the unpleasant sensations begin or worsen during periods of rest or inactivity, such as lying or sitting.
3. The urge to move or the unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues.
4. The urge to move or the unpleasant sensations are worse, or only occur, in the evening or night.
5. The condition is not better explained by another current sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder.
Diagnosis in pediatric patients (age 2–12 years) (1 alone or 2 and 3 satisfy the criteria):
1. The child meets all four essential adult criteria for RLS listed below and relates description in his or her own words that is consistent with leg discomfort (the child may use terms such as 'leg pain', 'hurts', 'tickle', 'spider', 'boo-boos' 'want to run' to describe symptoms. Use of age-appropriate descriptors is encouraged).
1. An urge to move the legs.
2. The urge to move begins or worsens when sitting or lying down.
3. The urge to move is partially or totally relieved by movement.
4. The urge to move is worse in the evening or night than during the day or only occurs in the evening or during the night.
2. The child meets all four essential adult criteria for RLS listed above and does not relate description in his or her own words that is consistent with leg discomfort.
3. Two of three following supportive criteria are met.
1. Sleep disturbance for age.
2. A biological parent or sibling has definite RLS.
3. The child has a polysomnographically documented periodic limb movement syndrome index of greater than 5 per hour of sleep.
In addition these children should be screened for any associated comorbid medical conditions and associated sleep disorders such as obstructive sleep apnea syndrome (OSAS),[69] narcolepsy[70] and rapid eye movement sleep (REM) behavior disorder.[71]
Daytime symptoms related to the report of sleep disturbance should be assessed in every patient. A detailed medication history is also important. Family history of RLS in a first-degree relative is very common and should be inquired about in every patient. A thorough clinical examination (of the upper airway to evaluate risk for OSAS, pallor for anemia, knee and ankle joints examination for arthritis, skin examination for dermatitis, leg muscles for cramps, and a thorough neurological examination to evaluate a peripheral neuropathy and polyradiculopathy) is also very important.
Laboratory Testing
Due to the association of RLS/PLMS with iron deficiency, a complete blood count, serum ferritin and transferrin saturation should be measured. A serum ferritin below 50 ng/ml indicates need for treatment with supplemental iron. In patients who are thought to have secondary RLS, screening for renal disease, thyroid dysfunction, vitamin B12 and folic acid deficiency (peripheral neuropathy) should be considered.[33]
Polysomnography
Although PSG helps to evaluate for PLMS, this is usually not necessary to make a diagnosis of RLS; however, documentation of PLMS of more than 5 per hour on PSG is important as a supportive criteria for diagnosis of RLS in children. New approaches to define RLS-specific PLM patterns have been described.[72] PLMW are now increasingly being taken into account and are being considered as an indicator of RLS..[73] PLMS are commonly seen in stage N2 sleep and decrease in stage N3 sleep and are usually reduced or absent in REM. Figure 1 demonstrates the polysomnographic features of PLMS. The diagnostic criteria for PLMS (327.51) are listed below.[9]
Figure 1. (NOT SHOWN)
This 2 min epoch of the sleep study demonstrates periodic limb movement during stage N3 sleep
There are seven periodic leg movements noted in 2 min.
1. Polysomnography demonstrates repetitive, highly stereotyped, limb movements that are
1. 0.5–5 s in duration.
2. Of amplitude greater than or equal to 25% of toe dorsiflexion during calibration.
3. In a sequence of four or more movements.
4. Separated by an interval of more than 5 s (from limb-movement onset) and less than 90 s (typically there is an interval of 20–40 s).
2. The periodic limb movements (PLMs) index exceeds 5 per hour in children and 15 per hour in most adult cases. Of note, the PLMs index must be interpreted in the context of a patient's sleep-related complaint. In adults, normative values higher than the previously accepted value of 5 per hour have been found in studies that did not exclude respiratory event-related arousals (using sensitive respiratory monitoring) and other causes for PLMs. New data suggest a partial overlap of PLM index values between symptomatic and asymptomatic individuals, emphasizing the importance of clinical context over an absolute cutoff value.
3. There is clinical sleep disturbance or a complaint of daytime fatigue. Of note, if PLMS are present without clinical sleep disturbance, the PLMS can be noted as a polysomnographic finding, but criteria are not met for a diagnosis of periodic limb movement disorder PLMD.
4. The PLMS are not better explained by another current sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder (e.g. PLMS at the termination of cyclically occurring apneas should not be counted as true PLMS or PLMD).
Periodic limb movements of sleep may be associated with cortical or subcortical (autonomic) arousals. PLMS is considered significant when the PLM index (PLMs/hour during sleep) is at least 15 per hour in adults and at least 5 per hour in children.[74] PLMS is not diagnosed if the leg movements are associated with an obstructive event. Like adults, children also show considerable individual night-to-night variability of PLMS, and PSG may not always reflect the true severity of this condition.[75]
Differential Diagnosis
Table 2 [60,76] lists various differential diagnoses for RLS as well as for PLMS. Sometimes the differentiation may be difficult and may warrant further testing.
Table 2. Differential diagnosis of RLS and PLMS
Differential diagnosis of RLS................Differential diagnosis of PLMS
1. Growing pain...............................1. Hypnic jerks (sleep starts)
2. Nocturnal cramps (charley horse)........2. Normal phasic REM activity
3. Peripheral neuropathy.....................3. Limb movements due to arousals
4. Chronic arthritis...........................4. OSAS
5. Dermatitis..................................5. Nocturnal seizure disorder
6. Akathasia......................................................................
OSAS, obstructive sleep apnea syndrome; PLMS, periodic limb movements of sleep; RLS, restless legs syndrome. Reproduced with permission from.[60,93]
Consequences of Restless Legs Syndrome and Periodic Limb Movements of Sleep
Restless legs syndrome and PLMS can potentially lead to cardiovascular and neurocognitive consequences in adults and children[77,78] due to sleep fragmentation. Studies have reported that there is a nocturnal surge in autonomic activity (autonomic arousals) with accompanying nocturnal elevations in blood pressure in adults[79,80] as well as children[81•] with PLMS. They can also present with impaired cognitive abilities, attention, memory, and emotional regulation in children,[82–84] hyperactivity, and may be misdiagnosed as ADHD. Depression and anxiety are also common in RLS and PLMD and occur more frequently than in the general population.[60,85–87] Studies have reported increased frequency of parasomnias related to sleep fragmentation in children with RLS and PLMD, with resolution of these parasomnias after treatment of RLS and PLMD.[88]
Management
The clinical decision to treat RLS depends on the severity of symptoms, sleep disturbances and consequences for daytime functioning. Similarly, the threshold to treat PLMS depends on the overall severity of PLMS (PLM index), associated sleep disturbances (PLM arousal index) and daytime functioning. A recent population survey revealed that only 6.2% of children and 6.4% of adolescents with definitive RLS received ongoing prescription medication.[24]
Treatment Options
The various treatment options for RLS and PLMS are described below. It is important to note that various combinations of these measures may be required to successfully treat these conditions.
Good Sleep Hygiene
Although there is no evidence to suggest that good sleep hygiene is beneficial to patients with RLS, it is well known that sleep deprivation aggravates RLS. Hence adequate sleep duration, regular bed timings and routine principles of good sleep hygiene are important in their management.[58,89] Diet containing caffeine should be avoided in the late afternoon. Daily exercises in the daytime (avoid vigorous exercise and mind-stimulating activities around bedtime) can improve sleep quality and help reduce RLS symptoms. In certain milder cases, biofeedback and relaxation techniques may be helpful.[57] However, if symptoms are more severe some form of pharmacological intervention may be required.
Iron Supplementation
Treatment with iron supplementation is indicated if serum ferritin is below 50 ng/ml. The usual recommended dose is 3–6 mg/kg/day of elemental iron for 3 months, with repeat serum ferritin levels to assess response and avoid iron overload.[90] Iron supplementation is repeated for an additional 3 months if ferritin level continues to be below 50 ng/ml. If ferritin levels are very low or levels fail to improve after treatment with iron, these children may require referral to hematology for evaluation of their iron deficiency (e.g. occult blood loss, malabsorption). There are some data in adults showing that intravenous iron therapy is effective in treatment of severe iron deficiency or with iron malabsorption.[91] However, no such data exist in children.
Pharmacological Treatment
Treatment with pharmacological agents may be indicated in children with moderate-to-severe RLS symptoms and PLMD who did not respond to the above measures. Currently there is no Food and Drug Administration (FDA) approval for the use of pharmacological agents in children and all medications are used 'off-label'. A few case series have reported success in the cautious use of certain pharmacological agents in pediatric RLS and PLMD.[76,88,93,94]
Medication should be combined with nonpharmacological measures noted above to achieve optimum results. It is prudent to start them at the lowest possible doses and slowly titrate upwards with close monitoring for adverse effects. Most of the children who need medications need to be referred to a sleep specialist. Table 3 lists the various medications that can be used in treatment of RLS and PLMS in children.[57,92]
Table 3. Commonly used medications for treatment of RLS and PLMS in children
Drug.... Mechanism of action.. Dosage.... Adverse effects ....... Safety profile
Clonidine.. Central α-2 adrenergic receptor agonist ... 0.05–0.3 mg... Hypotension, bradycardia, dry mouth Rebound night terror, REM suppression
---------------------------------------------------------------------------------------------------------------------------------------------
Clonazepam... GABA-A receptor agonist... 0.01 mg/kg... Daytime sedation, cognitive difficulties, antegrade amnesia... Respiratory depression, tolerance, worsening of OSA, abuse
-------------------------------------------------------------------------------------------------------------------------------
Levodopa/carbidopa... Metabolic precursor of dopamine... 25/100mg tab (1/2 to 3 tab per day).... Hallucination, confusion, orthostatic hypotension.... Augmentation
----------------------------------------------------------------------------------------------------------------------------------
Pramipexole.... Nonergot dopamine receptor agonist... 0.125–0.75 mg... Headaches, hypotension, insomnia, daytime somnolence... Impulse control behavior, gambling, augmentation
-------------------------------------------------------------------------------------------------------------------------------------
Ropinirole.. Nonergot dopamine receptor agonist... 0.5–4 mg... Headaches, hypotension, insomnia, daytime somnolence.... Impulse control behavior, gambling, augmentation
--------------------------------------------------------------------------------------------------------------------------------------
Gabapentin... May potentiate neuronal GABA synthesis... 100–500 mg... Drowsiness, irritability, worsening behaviors... Blurred vision, tremors, weight gain, sleepiness
--------------------------------------------------------------------------------------------------------------------------------------------------
OSA, obstructive sleep apnea; PLMS, periodic limb movements of sleep; REM, rapid eye movement; RLS, restless legs syndrome. Original, but data obtained from reference.[56,92]
Of all these medications, treatment response to dopaminergic agents is so dramatic that, in certain patients, these agents are used as a 'therapeutic test' to confirm the diagnosis of RLS.[95] Dopaminergic medications are considered the first line of treatment for RLS.[96] The common adverse effects of these medications are also listed in Table 3. Other important adverse effects reported with these agents include augmentation,[97] characterized by the paradoxical worsening of RLS symptoms after starting dopaminergic medication; as the dose is increased, the symptoms of RLS worsen and start appearing earlier than the anticipated time of onset, sometimes occurring in the daytime and at times also appearing in the upper extremities.
Augmentation is often seen with associated iron deficiency. Augmentation occurs very frequently with levodopa (up to 70–80%) but can also occur with other dopamine agonists such as pramipexole and ropirinole (up to 15–40%).[76,98] The management of augmentation consists of reducing and maintaining low doses of dopaminergic agents along with iron supplements. Switching to an alternate medication, for example nondopaminergics or opiates, may also be considered, especially when one experiences augmentation with more than one dopaminergic agent.
Prognosis
There are no data on long-term consequences and outcomes of RLS and PLMD in children. A pattern of slow progression has been reported in children, as about 40% of adults with RLS report a history of onset in childhood.[46]
Conclusion
1. RLS and PLMD are common in children and may present with sleep disturbances, and daytime symptoms mimicking ADHD.
2. Diagnosis of RLS and PLMD require specific diagnostic criteria published by the American Academy of Sleep Medicine. Symptoms in children are atypical and family history is very important.
3. RLS is a clinical diagnosis. Consider a sleep study for evaluation of associated PLMS due to the strong association of RLS with PLMS. PLMW may be an indicator of RLS and should be scored during PSG if diagnosis of RLS is suspected. However, PLMD requires PSG for a diagnosis.
4. Screening for risk factors and associated co-morbid conditions such as ADHD is important.
5. All children with RLS and PLMD should be screened for iron deficiency and treated if serum ferritin is below 50 ng/ml.
6. Dopaminergic medication should be considered in symptomatic children with normal iron levels or who fail iron treatment.
The direction for future research should focus on genotype/phenotype correlation and its link between overlapping comorbid conditions including ADHD. Studies to identify biomarkers as a screening tool for RLS and PLMS may be useful particularly in children, as they may present with atypical symptoms and as early diagnosis and treatment would be likely to promote improved neurocognitive development and overall academic performance. Clinical trials of effective medications in children to identify their long-term safety profile and efficacy are needed.
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•• This is an excellent review of pathophysiology, clinical presentation and management of restless legs syndrome. The authors review the diagnostic criteria and discuss recent developments in pathophysiology of RLS.
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Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 624–625).
Curr Opin Pulm Med. 2010;16(6):559-567. © 2010 Lippincott Williams & Wilkins
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