This is a Neurological movement disorder characterized by a distressing need or urge to move the legs or arms (akathisia) usually accompanied by an uncomfortable deep-seated sensation in the legs that is brought on by rest; sitting or lying down, relieved by moving or walking, and worse at night or in the evening.
It may be accompanied by involuntary limb movements while the patient is asleep and can lead to significant physical and emotional disability. Also called Wittmaack-Ekbom syndrome
It was first described by Sir Thomas Willis in 1672 (the founder of clinical neuroscience) who also described of the Circle of Willis.
It affect about 2-15% of the world’s population and Caucasians are more prone to this syndrome than African. Can occur at any age and worsens as the patient gets older, Affects women more than men, with a female:male ratio of 2:1.
Mechanism of the disease (Pathophysiology)
Several mechanisms have been implicated;
1) Genetic/run in families; implicated chromosomes are; 12q, 14q, 9p, 20p, 4q, and 17p in autosomal dominant and recessive pattern
2) Low iron levels; as seen in the substantia nigra (brain) of patients with Restless leg syndrome
3) Abnormalities in the central subcortical dopamine pathways
Causes
This depends on the type; Primary or Secondary.
Primary or idiopathic central nervous system (CNS) disorder; which can be familial, following a pattern of autosomal dominant or recessive inheritance with an earlier age of onset (< 45 years) and slower disease progression. Psychiatric factors, stress, and fatigue can worsen symptoms of restless legs syndrome.
Secondary;
Iron deficiency (Particularly); blood ferritin below 50 µg/L (seen in 20% of cases)
peripheral neuropathy
Hypoglycaemia
Parkinson's Disease
Folate or magnesium deficiency
Vitamin B-12 deficiency
Diabetes mellitus
Frequent blood donation
Rheumatoid arthritis
Uremia
End-stage renal disease (seen 25-50% of patients with End stage renal disease & may improve after kidney transplantation)
Hemodialysis
Pregnancy (seen in 25-40% of pregnant women & usually subsides within a few weeks after delivery).
Drugs; Alcohol, Caffeine, Beta blockers, Diphenhydramine, Lithium, Antidopaminergic medications, Tricyclic antidepressants, Selective serotonin reuptake inhibitors (SSRIs), Serotonin-norepinepherine reuptake inhibitors (SNRIs) etc.
Signs and Symptoms
Diagnosis
This is mostly from the history.
The International Restless Legs Syndrome Study Group (IRLSSG) updated its diagnostic criteria in 2012. The current IRLSSG criteria are nearly identical to the DSM-5 criteria.
According to the IRLSSG, Restless legs syndrome (RLS) is diagnosed by ascertaining a syndrome that consists of all of the following features:
(1)An urge to move the legs usually but not always accompanied by or felt to be caused by uncomfortable and unpleasant sensations in the legs.
(2)The urge to move the legs and any accompanying unpleasant sensations begin or worsen during periods of rest or inactivity such as lying down or sitting.
(3)The urge to move the legs and any accompanying 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 the legs and any accompanying unpleasant sensations during rest or inactivity only occur or are worse in the evening or night than during the day.
(5)The occurrence of the above features are not solely accounted for as symptoms primary to another medical or a behavioral condition (e.g., myalgia, venous stasis, leg edema, arthritis, leg cramps, positional discomfort, habitual foot tapping).
Specifier for clinical significance of RLS
The symptoms of RLS cause significant distress or impairment in social, occupational, educational, or other important areas of functioning by the impact on sleep, energy/vitality, daily activities, behavior, cognition, or mood.
Specifiers for clinical course of RLSf
(A)Chronic-persistent RLS: symptoms when not treated would occur on average at least twice weekly for the past year.
(B)Intermittent RLS: symptoms when not treated would occur on average <2/week for the past year, with at least five lifetime events.
Note that ;
i) Sometimes the urge to move the legs is present without the uncomfortable sensations and sometimes the arms or other parts of the body are involved in addition to the legs.
ii) For children, the description of these symptoms should be in the child’s own words.
iii) When symptoms are very severe, relief by activity may not be noticeable but must have been previously present.
iv) When symptoms are very severe, the worsening in the evening or night may not be noticeable but must have been previously present.
v) These conditions, often referred to as “Restless Legs Syndrome mimics,” have been commonly confused with Restless Legs Syndrome, particularly in surveys because they produce symptoms that meet or at least come close to meeting criteria 1–4 above. The list here gives some examples that have been noted as particularly significant in epidemiological studies and clinical practice. However, Restless Legs Syndrome may also occur with any of these conditions, requiring a clear delineation of the Restless Legs Syndrome feelings from the other sensations.
vi) The clinical course criteria do not apply for pediatric cases or for some special cases of provoked Restless Legs Syndrome such as pregnancy or drug-induced Restless Legs Syndrome, in which the frequency may be high but limited to the duration of the provocative condition.
Differential Diagnosis
Other conditions that present like Restless Leg syndrome include;
Akathisia
Neuropathy
Nocturnal leg cramps
Painful legs and moving toes
Vascular disease
Radiculopathy
Investigations
A complete iron panel; iron levels, ferritin, transferrin saturation, and total iron binding capacity.
Complete blood count (CBC)
Blood urea nitrogen (BUN)
Also check for the following;
Creatinine
Fasting blood glucose
Magnesium
Thyroid-stimulating hormone (TSH)
Vitamin B-12 & Folate
Needle electromyography (EMG) and nerve conduction studies should be considered if polyneuropathy or radiculopathy is suspected on clinical grounds, even if the results of the neurologic examination are apparently normal.
Treatment
Medical
For primary Restless Leg Syndrome, drug therapy is only for symptomatic relieve; curative treatment is possible only for secondary Restless Leg Syndrome.
A Task Force of the International Restless Legs Syndrome Study Group (IRLSSG) developed evidence-based guidelines for long-term pharmacologic treatment of RLS which are as follow;
· Pregabalin - Effective for up to 1 year in treating RLS (evidence level, A).
· Pramipexole, ropinirole, and rotigotine - Effective for up to 6 months in treating Restless Leg Syndrome (evidence level, A)
· Gabapentin enacarbil (1 year), pramipexole (1 year), ropinirole (1 year), levodopa (2 years), and rotigotine (5 years) - Probably effective in treating Restless Leg Syndrome for durations ranging from 1 to 5 years (evidence level, B)
· Pergolide and cabergoline - Because of associated safety concerns, not to be used in treating Restless Leg Syndrome unless the benefits clearly outweigh the risks
The IRLSSG Task Force recommends either a dopamine-receptor agonist or an alpha2-delta calcium-channel ligand as first-line treatment therapy for RLS in most patients, with the choice of medication depending on symptom severity, cognitive status, history, and comorbid conditions.
All patients with low iron levels (ferritin < 50 ng/mL) should receive supplemental iron therapy. In iron deficiency, 325 mg of ferrous sulfate may be given with 250 mg of vitamin C. Absorption is increased by taking this on an empty stomach and waiting 60 minutes before eating. Parenteral iron may also have a role in the treatment of RLS secondary to iron deficiency anemia.
Children with low serum ferritin (< 50 ng/mL) should be treated with supplemental iron therapy. Dopaminergic therapy was found to be effective in small series in children with RLS.
Non-Medical Therapy;
Non-pharmacologic management and sleep hygiene measures are the treatments of choice in children. A regular sleep/wake schedule and the elimination of stimulating activity and caffeine before bedtime are important measures.
Prognosis
Over time, the symptoms worsen in about 2/3rd of this patients, ranging from mild to intolerable. In addition to being experienced in the legs, sensations also may occur in the arms or elsewhere.
By the age of 50 symptoms usually progresses to severe, daily disruption of sleep leading to decreased daytime alertness. RLS has been associated with reduced quality of life in cross-sectional analysis.
Patients with RLS and periodic leg movements of sleep (PLMS) may be at increased risk for hypertension because PLMS is associated with an autonomic surge and an increase in blood pressure.
Patients may also be more prone to headaches (migraine and tension-type). The headaches are probably secondary to disturbances in sleep associated with RLS and PLMS.
Learning and memory difficulties have also been associated with RLS, presumably secondary to disrupted nocturnal sleep.
REFERENCES
Abetz L, Allen R, Follet A, et al. Evaluating the quality of life of patients with restless legs syndrome. Clin Ther. Jun 2004;26(6):925-35.
Berger K, Luedemann J, Trenkwalder C, et al. Sex and the risk of restless legs syndrome in the general population. Arch Intern Med. Jan 26 2004;164(2):196-202.
Cesnik E, Casetta I, Turri M, Govoni V, Granieri E, Strambi LF, et al. Transient RLS during pregnancy is a risk factor for the chronic idiopathic form. Neurology. Dec 2010;75(23):2117-20
Ekbom K, Ulfberg J. Restless legs syndrome. J Intern Med. Nov 2009;266(5):419-31.
Garcia-Borreguero D, Kohnen R, Silber MH, Winkelman JW, Earley CJ, Högl B, et al. The long-term treatment of restless legs syndrome/Willis-Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group. Sleep Med. Jul 2013;14(7):675-84
Giannaki CD, Hadjigeorgiou GM, Karatzaferi C, Maridaki MD, Koutedakis Y, Founta P, et al. A single-blind randomized controlled trial to evaluate the effect of 6 months
of progressive aerobic exercise training in patients with uraemic restless legs syndrome. Nephrol Dial Transplant. Aug 2013;
Godau, Jana; Klose, Uwe; Di Santo, Adriana; Schweitzer, Katherine; Berg, Daniela (2008). "Multiregional brain iron deficiency in restless legs syndrome". Movement Disorders 23 (8): 1184–1187.
Hening WA. Restless Legs Syndrome. Curr Treat Options Neurol. Sep 1999;1(4):309-319.
International Restless Legs Study Group. IRLSSG Diagnostic Criteria for RLS (2012). www.irlssg.org. Updated 2013. Accessed April, 2015
Kutner NG, Zhang R, Huang Y, Bliwise DL. Racial differences in restless legs symptoms and serum ferritin in an incident dialysis patient cohort. Int Urol Nephrol. Jan 2012.
"Restless legs syndrome: detection and management in primary care. National Heart, Lung, and Blood Institute Working Group on Restless Legs Syndrome". American family physician 62 (1): 108–14. 2000
Trenkwalder C, Hogl B, Winkelmann J. Recent advances in the diagnosis, genetics and treatment of restless legs syndrome. J Neurol. Apr 2009; 256(4):539-53.
It may be accompanied by involuntary limb movements while the patient is asleep and can lead to significant physical and emotional disability. Also called Wittmaack-Ekbom syndrome
It was first described by Sir Thomas Willis in 1672 (the founder of clinical neuroscience) who also described of the Circle of Willis.
 |
| Restless Leg Syndrome RLS ( Picture Credit; Orthoapnea ) |
It affect about 2-15% of the world’s population and Caucasians are more prone to this syndrome than African. Can occur at any age and worsens as the patient gets older, Affects women more than men, with a female:male ratio of 2:1.
Mechanism of the disease (Pathophysiology)
Several mechanisms have been implicated;
1) Genetic/run in families; implicated chromosomes are; 12q, 14q, 9p, 20p, 4q, and 17p in autosomal dominant and recessive pattern
2) Low iron levels; as seen in the substantia nigra (brain) of patients with Restless leg syndrome
3) Abnormalities in the central subcortical dopamine pathways
Causes
This depends on the type; Primary or Secondary.
Primary or idiopathic central nervous system (CNS) disorder; which can be familial, following a pattern of autosomal dominant or recessive inheritance with an earlier age of onset (< 45 years) and slower disease progression. Psychiatric factors, stress, and fatigue can worsen symptoms of restless legs syndrome.
Secondary;
Iron deficiency (Particularly); blood ferritin below 50 µg/L (seen in 20% of cases)
peripheral neuropathy
Hypoglycaemia
Parkinson's Disease
Folate or magnesium deficiency
Vitamin B-12 deficiency
Diabetes mellitus
Frequent blood donation
Rheumatoid arthritis
Uremia
End-stage renal disease (seen 25-50% of patients with End stage renal disease & may improve after kidney transplantation)
Hemodialysis
Pregnancy (seen in 25-40% of pregnant women & usually subsides within a few weeks after delivery).
Drugs; Alcohol, Caffeine, Beta blockers, Diphenhydramine, Lithium, Antidopaminergic medications, Tricyclic antidepressants, Selective serotonin reuptake inhibitors (SSRIs), Serotonin-norepinepherine reuptake inhibitors (SNRIs) etc.
Signs and Symptoms
- An urge to move, usually due to uncomfortable sensations that occur primarily in the legs, but occasionally in the arms or elsewhere uncomfortable.The sensations could be described as painful, antsy, electrical, creeping, itching, pins and needles, pulling, crawling, and numbness, internal itch sensation. Some people have little or no sensation, yet still have a strong urge to move. This sensation is relieved (temporary and partially) by movement mostly Walking. It is Worsened by relaxation (Sitting or lying down) and the severity depends on the duration of the rest.Symptoms worsen in the night and in the morning, though some experience it throughout the day and night; Others experience it only in the morning or only at night.
- Sleep disturbance; About 85% of this patients have periodic movements during sleep, usually involving the legs (periodic leg movements of sleep [PLMS]). PLMS are characterized by involuntary, forceful dorsiflexion of the foot lasting 0.5-5 seconds and occurring every 20-40 seconds throughout sleep, resulting in difficulty falling asleep at night.
- Daytime fatigue
Diagnosis
This is mostly from the history.
The International Restless Legs Syndrome Study Group (IRLSSG) updated its diagnostic criteria in 2012. The current IRLSSG criteria are nearly identical to the DSM-5 criteria.
According to the IRLSSG, Restless legs syndrome (RLS) is diagnosed by ascertaining a syndrome that consists of all of the following features:
(1)An urge to move the legs usually but not always accompanied by or felt to be caused by uncomfortable and unpleasant sensations in the legs.
(2)The urge to move the legs and any accompanying unpleasant sensations begin or worsen during periods of rest or inactivity such as lying down or sitting.
(3)The urge to move the legs and any accompanying 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 the legs and any accompanying unpleasant sensations during rest or inactivity only occur or are worse in the evening or night than during the day.
(5)The occurrence of the above features are not solely accounted for as symptoms primary to another medical or a behavioral condition (e.g., myalgia, venous stasis, leg edema, arthritis, leg cramps, positional discomfort, habitual foot tapping).
Specifier for clinical significance of RLS
The symptoms of RLS cause significant distress or impairment in social, occupational, educational, or other important areas of functioning by the impact on sleep, energy/vitality, daily activities, behavior, cognition, or mood.
Specifiers for clinical course of RLSf
(A)Chronic-persistent RLS: symptoms when not treated would occur on average at least twice weekly for the past year.
(B)Intermittent RLS: symptoms when not treated would occur on average <2/week for the past year, with at least five lifetime events.
Note that ;
i) Sometimes the urge to move the legs is present without the uncomfortable sensations and sometimes the arms or other parts of the body are involved in addition to the legs.
ii) For children, the description of these symptoms should be in the child’s own words.
iii) When symptoms are very severe, relief by activity may not be noticeable but must have been previously present.
iv) When symptoms are very severe, the worsening in the evening or night may not be noticeable but must have been previously present.
v) These conditions, often referred to as “Restless Legs Syndrome mimics,” have been commonly confused with Restless Legs Syndrome, particularly in surveys because they produce symptoms that meet or at least come close to meeting criteria 1–4 above. The list here gives some examples that have been noted as particularly significant in epidemiological studies and clinical practice. However, Restless Legs Syndrome may also occur with any of these conditions, requiring a clear delineation of the Restless Legs Syndrome feelings from the other sensations.
vi) The clinical course criteria do not apply for pediatric cases or for some special cases of provoked Restless Legs Syndrome such as pregnancy or drug-induced Restless Legs Syndrome, in which the frequency may be high but limited to the duration of the provocative condition.
Differential Diagnosis
Other conditions that present like Restless Leg syndrome include;
Akathisia
Neuropathy
Nocturnal leg cramps
Painful legs and moving toes
Vascular disease
Radiculopathy
Investigations
A complete iron panel; iron levels, ferritin, transferrin saturation, and total iron binding capacity.
Complete blood count (CBC)
Blood urea nitrogen (BUN)
Also check for the following;
Creatinine
Fasting blood glucose
Magnesium
Thyroid-stimulating hormone (TSH)
Vitamin B-12 & Folate
Needle electromyography (EMG) and nerve conduction studies should be considered if polyneuropathy or radiculopathy is suspected on clinical grounds, even if the results of the neurologic examination are apparently normal.
Treatment
Medical
For primary Restless Leg Syndrome, drug therapy is only for symptomatic relieve; curative treatment is possible only for secondary Restless Leg Syndrome.
A Task Force of the International Restless Legs Syndrome Study Group (IRLSSG) developed evidence-based guidelines for long-term pharmacologic treatment of RLS which are as follow;
· Pregabalin - Effective for up to 1 year in treating RLS (evidence level, A).
· Pramipexole, ropinirole, and rotigotine - Effective for up to 6 months in treating Restless Leg Syndrome (evidence level, A)
· Gabapentin enacarbil (1 year), pramipexole (1 year), ropinirole (1 year), levodopa (2 years), and rotigotine (5 years) - Probably effective in treating Restless Leg Syndrome for durations ranging from 1 to 5 years (evidence level, B)
· Pergolide and cabergoline - Because of associated safety concerns, not to be used in treating Restless Leg Syndrome unless the benefits clearly outweigh the risks
The IRLSSG Task Force recommends either a dopamine-receptor agonist or an alpha2-delta calcium-channel ligand as first-line treatment therapy for RLS in most patients, with the choice of medication depending on symptom severity, cognitive status, history, and comorbid conditions.
All patients with low iron levels (ferritin < 50 ng/mL) should receive supplemental iron therapy. In iron deficiency, 325 mg of ferrous sulfate may be given with 250 mg of vitamin C. Absorption is increased by taking this on an empty stomach and waiting 60 minutes before eating. Parenteral iron may also have a role in the treatment of RLS secondary to iron deficiency anemia.
Children with low serum ferritin (< 50 ng/mL) should be treated with supplemental iron therapy. Dopaminergic therapy was found to be effective in small series in children with RLS.
Non-Medical Therapy;
- Sleep hygiene measures should be recommended to all patients. Moreover, patients with mild RLS who are sensitive to caffeine, alcohol, nicotine, selective serotonin re-uptake inhibitors [SSRIs], diphenhydramine, or dopamine antagonists should avoid these substances.
- Exercise may be helpful for some patients; however, physical measures are only partially or temporarily helpful and should be avoided before bedtime. Some patients benefit from different physical modalities before bedtime, such as a hot or cold bath, a whirlpool bath, limb massage, or vibratory or electrical stimulation of the feet and toes.
Non-pharmacologic management and sleep hygiene measures are the treatments of choice in children. A regular sleep/wake schedule and the elimination of stimulating activity and caffeine before bedtime are important measures.
Prognosis
Over time, the symptoms worsen in about 2/3rd of this patients, ranging from mild to intolerable. In addition to being experienced in the legs, sensations also may occur in the arms or elsewhere.
By the age of 50 symptoms usually progresses to severe, daily disruption of sleep leading to decreased daytime alertness. RLS has been associated with reduced quality of life in cross-sectional analysis.
Patients with RLS and periodic leg movements of sleep (PLMS) may be at increased risk for hypertension because PLMS is associated with an autonomic surge and an increase in blood pressure.
Patients may also be more prone to headaches (migraine and tension-type). The headaches are probably secondary to disturbances in sleep associated with RLS and PLMS.
Learning and memory difficulties have also been associated with RLS, presumably secondary to disrupted nocturnal sleep.
 |
| Restless Leg Syndrome ( Picture Credit; Fooyoh ) |
REFERENCES
Abetz L, Allen R, Follet A, et al. Evaluating the quality of life of patients with restless legs syndrome. Clin Ther. Jun 2004;26(6):925-35.
Berger K, Luedemann J, Trenkwalder C, et al. Sex and the risk of restless legs syndrome in the general population. Arch Intern Med. Jan 26 2004;164(2):196-202.
Cesnik E, Casetta I, Turri M, Govoni V, Granieri E, Strambi LF, et al. Transient RLS during pregnancy is a risk factor for the chronic idiopathic form. Neurology. Dec 2010;75(23):2117-20
Ekbom K, Ulfberg J. Restless legs syndrome. J Intern Med. Nov 2009;266(5):419-31.
Garcia-Borreguero D, Kohnen R, Silber MH, Winkelman JW, Earley CJ, Högl B, et al. The long-term treatment of restless legs syndrome/Willis-Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group. Sleep Med. Jul 2013;14(7):675-84
Giannaki CD, Hadjigeorgiou GM, Karatzaferi C, Maridaki MD, Koutedakis Y, Founta P, et al. A single-blind randomized controlled trial to evaluate the effect of 6 months
of progressive aerobic exercise training in patients with uraemic restless legs syndrome. Nephrol Dial Transplant. Aug 2013;
Godau, Jana; Klose, Uwe; Di Santo, Adriana; Schweitzer, Katherine; Berg, Daniela (2008). "Multiregional brain iron deficiency in restless legs syndrome". Movement Disorders 23 (8): 1184–1187.
Hening WA. Restless Legs Syndrome. Curr Treat Options Neurol. Sep 1999;1(4):309-319.
International Restless Legs Study Group. IRLSSG Diagnostic Criteria for RLS (2012). www.irlssg.org. Updated 2013. Accessed April, 2015
Kutner NG, Zhang R, Huang Y, Bliwise DL. Racial differences in restless legs symptoms and serum ferritin in an incident dialysis patient cohort. Int Urol Nephrol. Jan 2012.
"Restless legs syndrome: detection and management in primary care. National Heart, Lung, and Blood Institute Working Group on Restless Legs Syndrome". American family physician 62 (1): 108–14. 2000
Trenkwalder C, Hogl B, Winkelmann J. Recent advances in the diagnosis, genetics and treatment of restless legs syndrome. J Neurol. Apr 2009; 256(4):539-53.
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