Keywords

Asystole, Laryngoscopy, Neurosurgery.

Introduction

Definition

Restless legs syndrome (RLS) is a type of movement disorders that is often associated with a sleep complaint and generally involving the limbs. Persons who suffer from RLS may report unpleasant ill-defined sensations, such as strong not painful urge to move the legs, crawling, creeping, pulling, itching, drawing, or stretching, forceful bothering inner pressure in legs, uncomfortable treading of legs when they lie down for sleep. These intolerable sensations are relieved by movement of the legs or by walking. The feeling usually is bilateral and the arms are rarely involved. Recently, Lang et al. reported Restless Genitalia syndrome (Lang et al. JAMA neural Oct 6 2014).

RLS may lead to significant physical and emotional disability.

Signs and Symptoms

Unfortunately, RLS usually is missed during primary exams [3, 7]. Lots of patients are not diagnosed until many years after onset of signs and symptom. RLS commonly starts at middle age or older, although it may begins at any age, even as early as infancy.

DSM-5 has cleared specific criteria for RLS

1. An urge to move the legs usually accompanied by or in response to uncomfortable and unpleasant sensations in the legs, characterized by all of the following:
   1. The urge to move the legs begins or worsens during periods of restoring activity.
   2. The urge to move the legs is partially or totally relieved by movement.
   3. The urge to move the legs is worse in the evening or at night than during the day, or occurs only in the evening or at night.
2. The symptoms in Criterion A occur at least three times per week and have persisted for at least 3 months.
3. The symptoms in Criterion A are accompanied by significant distress or impairment in social, occupational, educational, academic, behavioral, or other important areas of functioning.
4. The symptoms in Criterion A are not attributable to another mental disorder or medical condition (e.g., arthritis, leg edema, peripheral ischemia, leg cramps) and are not better explained by a behavioral condition (e.g., positional discomfort, habitual foot tapping).
5. The symptoms are not attributable to the physiological effects of a drug of abuse or medication (e.g., akathisia).

The symptoms of RLS usually are worsen during inactivity and often interfere with sleep, leading to chronic sleep deprivation and stress [8].

Approximately 85% of RLS patients suffer from abnormal periodic limb movements during sleep, that usually involving the legs (periodic leg movements of sleep [PLMS]) [2]. PLMS is characterized by involuntary, forceful dorsiflexion of the foot lasting almost 0.5-5 seconds and occurring every 20-40 seconds throughout sleep.

Other features commonly associated with RLS but not required for diagnosis include the following:

• Sleep disturbances.
• Daytime fatigue.
• Involuntary, repetitive, periodic, jerking limb movements:Either during sleep or while awake and at rest.

The International RLS Study Group (IRLSSG) updated its diagnostic criteria in 2012. The current IRLSSG criteria are nearly identical to the DSM-5 criteria listed above.

Etiology

RLS may be either primary or secondary. In most instances, RLS is a primary, idiopathic central nervous system (CNS) disorder. Such idiopathic disease can be familial in 25-75% of cases. In these familial cases, RLS appears to follow a pattern of autosomal dominant or recessive inheritance. Various chromosomes have been implicated so far, like 12q, 14q, 9p, 20p, 4q, and 17p.

Patients with familial RLS tend to have an earlier age of onset (< 45 years) and slower disease progression. In some families, a progressive decrease in age of onset with successive generations (i.e. genetic anticipation) has been described. Psychiatric factors, stress, and fatigue can exacerbate symptoms of RLS.

Secondary RLS can develop as a result of certain conditions or factors. The most important and common causes of secondary RLS are iron deficiency and peripheral neuropathy [6, 7]. due to the prevalence of these conditions in the general population, their association with RLS must be keep in mind.

Pregnancy is another important causative factor for RLS, which is estimated to affect 25-40% of pregnant women. The syndrome usually subsides within a few weeks after delivery. A long-term follow-up study reviled that women who develop RLS during pregnancy have a 4 time increased risk of developing chronic primary RLS compared with women without similar history [16].

RLS also occurs in as many as 25-50% of patients who have endstage renal disease; these patients find their symptoms to be particularly bothersome during hemodialysis.

Takaki et.al found that hyperphosphatemia, anxiety, and a high degree of emotion-oriented coping with stress were independently related to the presence of RLS in patients with uremia who were undergoing hemodialysis [9]. RLS may improve after kidney transplantation.

Medication’s side effect is another cause for secondary RLS. The following medications have been known to cause or exacerbate the symptoms of RLS:

• Anti-dopaminergic medications (eg, neuroleptics)
• Diphenhydramine
• Tricyclic antidepressants (TCAs)
• Selective serotonin reuptake inhibitors (SSRIs)
• Serotonin-norepinepherine reuptake inhibitors (SNRIs)
• Alcohol
• Caffeine
• Lithium
• Beta-blockers

Some other uncommon causes of RLS include the following:

• Folate or Magnesium deficiency
• Amyloidosis
• Diabetes Mellitus
• Lumbosacral Radiculopathy
• Lyme disease
• Monoclonal gammopathy of undetermined significance
• Rheumatoid arthritis
• Sjögren syndrome
• Uremia

Epidemiology

Estimated prevalence of RLS affects in the United States is almost 5-15%. Although the exact international prevalence of the disease is uncertain, limited studies have indicated that 2-15% of the world’s population may experience symptoms of RLS [6].

Although the prevalence of RLS is increased with age, it has a variable range of onset age, even can occur in children. 33-40% of Patients with severe RLS had their first symptom before the age of 20 years, although the precise diagnosis of RLS was made much later [17]. RLS usually progresses slowly to daily symptoms and severe disruption of sleep after age 50. Individuals with familial RLS tend to have onset of symptoms before age 45 years. [17].

Women are affected more commonly than men, in a ratio of almost 2:1. The increased risk of RLS in women is thought to be related to parity; nulliparous women have the same risk of developing RLS as men age-matched [17].

RLS affects African Americans less commonly than white individuals; this applies even to secondary RLS caused by hemodialysis [18].

Pathophysiology

The pathogenesis of RLS is not clear [2, 9-11]. Nowadays, Genetic sources are the most accepted mechanism about RLS, which lead to some abnormalities in the central subcortical dopamine pathways and impaired iron homeostasis [12, 13].

Results of single-photon emission computed tomography (SPECT) have shown a deficiency of dopamine D2 receptors in the brain. Iron homeostasis abnormalities have been implicated through cerebrospinal fluid (CSF) iron profile measures [14].

In addition, different researches have shown an increased severity of RLS with decreasing availability of serotonin transporter in the brainstem, which supports the hypothesis that increasing serotonin transmission in the brain may exacerbate RLS [14].

Diagnosis

Any person who suspected for RLS should be tested for iron deficiency [3, 4]. A complete iron panel should be checked, including:

• Iron levels
• Ferritin
• Transferrin saturation
• Total iron binding capacity

At least a Ferritin serum level has to be controlled if we could not check complete Iron profile, but due to falsely elevated level of ferritin in Acute Inflammatory states, complete Iron profile check is strongly recommended.

Other laboratory and para-clinically tests should be ordered If another sources for RLS are suspected according to the patient’s finding in history and general or neurologic examination, or poor response to RLS treatment. The commonest of these tests are:

• A complete blood count (CBC)
• Measurement of levels of the following:
  
  1. Blood urea nitrogen (BUN)
  2. Creatinine
  3. Fasting blood glucose
  4. Magnesium
  5. Thyroid-stimulating hormone (TSH)
  6. Vitamin B-12
  7. Folate
• Needle electromyography and nerve conduction studies: (Should be done if polyneuropathy or radiculopathy is suspected on clinical grounds, even if the results of the neurologic examination are apparently normal) [5, 24].
• Polysomnography: (can be done to quantify PLMS or to recognize sleep architecture, especially in children and in patients who continue to have significant sleep disturbances despite relief of RLS symptoms with treatment.)

Management

RLS could be treated and controlled by medications and/or nonpharmacological methods. Complete treatment is possible for secondary PLS, but there is no cure for primary type disease and Drugs with non-drug therapies are mainly symptomatic [8].

Pharmacologic therapy

Medications used in the treatment of RLS include the following:

• Dopaminergic agents like Promipexole, Ropinirole, and Rotigotine [25-28].
• Benzodiazepines
• Opioids
• L-Dopa
• Anticonvulsants like Gabapentine [29].
• Presynaptic alpha2-adrenergic agonists [30].
• Iron salt [31].
• Glucocorticosteroids [33].

Non-pharmacologic treatment consists of [34]

• Sleep hygiene measures
• Avoidance of caffeine, alcohol, and nicotine in patients with mild RLS who are sensitive to these substances
• Discontinuation, when possible, of medications that cause or exacerbate RLS, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinepherine reuptake inhibitors (SNRIs), diphenhydramine, and dopamine antagonists
• Exercise (Physical modalities before bedtime, such as a hot or cold bath, whirlpool bath, limb massage, and vibratory or electrical stimulation of the feet and toes).

Education of patients with RLS and their families should focus on providing a better understanding of the disease and on emphasizing the importance of compliance for alleviating the symptoms [19-21].

Silber MH, Ehrenberg BL, Allen RP, et al. have arranged a useful algorithm for the management of restless legs syndrome[38].

Prognosis

In about two thirds of RLS patients, the symptoms progress over time. The severity of symptoms in patients with RLS ranges from mild to intolerable. In addition to being experienced in the legs, sensations also may occur in the arms or elsewhere. RLS symptoms are generally worse in the evening and night and less severe in the morning.

Whereas RLS may present early in adult life with mild symptoms, by age around 50 it usually progresses to severe symptoms; daily disruption of sleep leading to decreased daytime alertness. RLS has been associated with reduced quality of life in cross-sectional analysis [17, 19].

Patients with RLS and periodic leg movements of sleep (PLMS) may be at increased risk for hypertension. PLMS is associated with an autonomic surge and an increase in blood pressure [20].

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 [20].

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Essential Update

The US Food and Drug Administration (FDA) have cleared a device for improving sleep in patients with primary RLS. It has given commercial clearance to the first device (Relaxis) for improvement of sleep quality in patients with primary RLS. The device, a vibrating pad, delivers vibratory counter-stimulation to the patient’s legs as an individual lies in bed. Approval was based on 2 randomized studies that showed greater improvements in sleep quality with the device than with a placebo pad [37].