Restless Legs Syndrome

Etiology

There are two types of restless legs syndrome, primary restless legs syndrome and secondary restless legs syndrome.[1] Commonly, RLS is a primary central nervous system (CNS) disorder. This idiopathic disease may be familial in 25-75% of patients. In familial cases, RLS is observed to have autosomal dominant or recessive patterns. Patients with a familial type of RLS tend to present earlier (< 45 years) with slower disease progression. In some familial cases, a progressively decreasing age of onset in successive generations has been described ie, genetic anticipation. Psychiatric factors, stress, and fatigue may also exacerbate symptoms of RLS.

Secondary restless legs syndrome can occur secondary to some disorders including: [2][3]

• Iron deficiency
• End-stage renal disease
• Diabetes mellitus
• Rheumatic disease
• Venous insufficiency
• Peripheral neuropathy
• Folate or magnesium deficiency
• Amyloidosis
• Lumbosacral radiculopathy
• Fibromyalgia
• Celiac disease
• Medications have been known to cause or exacerbate the symptoms of restless legs syndrome. They include antidopaminergic medications (e.g., neuroleptics), diphenhydramine, tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), alcohol, caffeine, lithium, and beta-blockers.

Restless leg syndrome affects close to 1/3rd of pregnant patients, but luckily the symptoms subside in a few weeks after delivery. However, in a long-term, follow-up study, patients who developed RLS during pregnancy demonstrated a 4-fold increased risk of having chronic RLS as opposed to women with no RLS during pregnancy.[4]

RLS has been observed in 25-50% of patients with end-stage renal disease; the symptoms in these patients are typically worse during hemodialysis. One study observed that anxiety, hyperphosphatemia, and coping mechanisms for stress were independently related to RLS in uremic patients undergoing hemodialysis.RLS may resolve after kidney transplantation.[5]

Epidemiology

Between 5% to 15% of the population may have restless legs syndrome. Familial restless legs syndrome tends to occur at ages younger than 45 years. Age can be from childhood to older than 90 years.  Women are affected more than men. African Americans are less frequently affected as compared to whites, it stands true for patients on hemodialysis.[6] Eleven percent to 29% of pregnant women are affected. It is threefold more common in pregnant women than in nonpregnant women and has a higher prevalence in the third trimester.[7][8] As many as 25% to 50% of patients with end-stage renal disease have restless legs syndrome with symptoms, particularly during hemodialysis.[9][10]

Pathophysiology

The pathogenesis of restless legs syndrome is not completely known.[5][11][12] In idiopathic restless legs syndrome, a dysfunction of the dopaminergic system and iron stores in specific regions in the brain diminish. There may be an autosomal dominant inheritance; there have been reports of several large kindreds with different susceptibility loci with restless legs syndrome. This suggests a genetic basis for the disease.[13][14]

Calcium/phosphate imbalance, anemia, functional iron deficiency, and subclinical peripheral nerve abnormalities may be involved in the pathophysiology of uremic restless legs syndrome.

Vitamin D deficiency and calcium metabolism, pre-eclampsia, a strong family history, low serum iron, ferritin level, and high estrogen levels may also play a role in pregnancy. 

Polymorphisms in genes including BTBD9 and MEIS1 are associated with restless legs syndrome.

Human neuropathologic and imaging studies have shown decreased iron in different brain regions including substantia nigra and thalamus. These areas also demonstrate a state of relative dopamine excess.[8][15][1]

Restless leg syndrome is extremely common during pregnancy, especially during the third trimester.

History and Physical

Patients describe sensations such as crawling, creeping, pulling, itching, drawing, or stretching, all localized to deep structures rather than the skin. Pain and tingling paresthesia of the type that occurs in painful peripheral neuropathy is usually absent, and there is no sensitivity to the touching of the skin. Symptoms can range from some patients experiencing very mild problems to others having major disruption of sleep and impairments in quality of life.

Symptoms typically worsen towards the end of the day and are maximal at night, when they appear within 15 to 30 minutes of reclining in bed. In severe cases, symptoms may occur earlier in the day while the patient is seated, thereby interfering with attending meetings, sitting in a movie theater, and similar activities. In milder cases, patients will fidget, move in bed, and kick or massage their legs for relief. Occasionally, the arms may be affected. Patients with more severe symptoms feel forced to get out of bed and pace the floor to relieve symptoms. 

Periodic leg movements of sleep are characterized by involuntary, forceful dorsiflexion of the foot lasting 0.5 to five seconds and occurring every 20 to 40 seconds throughout sleep. There may be limb twitching during sleep. These occur in 80% of patients with restless legs syndrome.

The physical examination is usually normal in patients with restless legs syndrome. It is performed to identify secondary causes. 

Essential diagnostic criteria (all must be met):[16]

• An uncontrollable urge to move the lower extremities and unpleasant and uncomfortable sensations may accompany it.
• The urge to move the extremities is less during the day but gets progressively worse in the evenings and at night. The symptoms also appear at rest or during periods of sleep and inactivity.
• The urge to move the lower extremities may partially or completely be relieved by ambulation or stretching the legs. As long as the activity is continued, the symptoms are mild or absent.
• The urge to move the lower extremities ae worse during the evenings and make it impossible to sleep. Thus, the patient is often fatigued during the day.
• The presence of these symptoms must not be attributed to other behavior conditions, such as tardive dyskinesia, leg cramps, muscle spasms, or discomfort from the position.

The leg movements are usually involuntary and may involve sudden dorsiflexion motions that may last 1-5 seconds and recur every 30-40 seconds throughout sleep. Positive family history is common in children.

The physical exam is usually normal. However, the patient must be examined to rule out a neurological disorder, radiculopathy, or Parkinson's disease.

Evaluation

There are no tests to diagnose restless legs syndrome except the ones to rule out secondary causes. Blood work is done to rule out other causes as well. Electromyography (EMG) and nerve conduction studies are done if one suspects radiculopathy or neuropathy. Polysomnography is often done to quantify the frequency of leg movements and characterize the pattern of sleep.

Iron studies should be done in all patients with symptoms of RLS.[17] Detailed iron studies inclusive of serum iron, transferrin saturation, ferritin, and total iron-binding capacity should be done; however, if a complete iron panel is not obtainable, then at a minimum, a ferritin level should be done.

Patients whose RLS is under control but who have a reemergence or augmentation of their symptoms should again go through an assessment of their iron status. Augmentation means the presence of one or more of the following:

• Symptoms occurring earlier in the evening

• Symptoms are more intense in the morning

• Symptoms extend to the upper parts of the body

If a secondary cause is suspected, then other laboratory tests should be carried out, such as a complete blood count (CBC) and an evaluation of levels of the following:

• Blood urea nitrogen (BUN)

• Fasting blood glucose

• Creatinine

• Magnesium

• Vitamin B-12

• Thyroid-stimulating hormone (TSH)

• Folate

In terms of the nervous system, even if the neurological examination is normal, nerve conduction studies and needle electromyography (EMG) should be considered if radiculopathy or polyneuropathy appear probable on clinical examination.

Treatment / Management

Treatment for restless legs syndrome is usually not commenced in patients with sporadic or mild symptoms.[18] A holistic management plan may involve pharmacotherapy and nonpharmacologic measures tailored to the patient’s symptoms.[18] Patients should be followed up by their primary care provider or a neurologist for the worsening of the disease.

In 2014, a device for improvement in sleep was approved by the US Food and Drug Administration (FDA) to be used commercially for patients with RLS. The device counter stimulates the patient's legs with the help of vibrations. The approval came after two randomized studies showed improvement in sleep with the device as opposed to a placebo pad.

Patients should be advised to avoid caffeine, antidepressants, antipsychotics, dopamine-blocking anti-emetics, and centrally-acting antihistamines. Short daily dialysis in renal failure patients, iron replacement, exercise, massage, and heat can all alleviate the symptoms.

Dopamine agonists, including pramipexole, ropinirole, rotigotine, and cabergoline, have reduced symptoms, improved sleep quality and quality of life. Pramipexole and ropinirole have adverse effects, including gambling addiction and extreme weight gain.

The rotigotine transdermal patch can also be used. It is well tolerated and has a relatively low risk of clinically significant augmentation of restless legs syndrome.

In a large meta-analysis involving 3286 participants, pramipexole was shown to improve the symptoms of patients with primary moderate-to-severe restless leg syndrome and maybe better than ropinirole. In a small study, rotigotine improved periodic limb movements and restless leg syndrome symptoms in the short term among end-stage renal disease (ESRD) patients. 

The use of alpha2-delta calcium-channel ligand (gabapentin or pregabalin) should be considered for the initial treatment of those patients who have severe sleep disturbance, comorbid insomnia, anxiety, pain, or a previous history of an impulse control disorder (ICD).[19][20][21](A1)

The drugs are effective anywhere from 1-5 years, but they also have adverse effects, which reduce their compliance. Today, the first-line treatment is either an alpha2 delta calcium channel ligand or a dopamine receptor agonist. Supplemental iron is recommended for all patients who have low serum ferritin levels.

Restless leg syndrome in pregnancy usually resolves after delivery.

Exercise is of benefit to many patients, but it is often not realistic in the middle of the night.

International Restless Legs Syndrome Study Group (IRLSSG) developed a guide for the long-term pharmacologic management of RLS.[22] The Task Force based the following recommendations on the results of 61 studies:(B3)

• Pregabalin - Effective for up to a year in treating RLS
• Ropinirole, pramipexole, and rotigotine - Effective for up to six months
• Gabapentin enacarbil for 1 year, levodopa for 2 years, and rotigotine for 5 years - Probably effective for durations ranging between 1 and 5 years
• Pergolide and cabergoline - Due to safety concerns, they are not being used in treating RLS

All patients with a ferritin of less than 50 ng/mL should receive the iron replacement.[18] In iron deficiency, ferrous sulfate 325 mg could be given with vitamin C 250 mg. To increase the absorption, it should be taken on an empty stomach and not eat anything for 60 minutes. Parenteral iron could also be required in the treatment of RLS because of iron deficiency.[23](A1)

In terms of nonpharmacological measures, the following should be recommended to patients:

• Sleep hygiene
• Exercise
• Hot or cold bath
• Limb massage
• Vibratory or electrical stimulation of the feet
• The elimination of caffeine before bedtime

Differential Diagnosis

Conditions to be considered while making the diagnosis of restless legs syndrome are:

• Tardive dyskinesia
• Akathisia
• Leg cramps
• Vascular disease
• Muscle spasms
• Radiculopathy

Prognosis

In about 70% of patients, the symptoms progress and become moderate to severe. In addition to the legs, some patients may start to experience the same symptoms in the arms. Overall, the symptoms are less severe in the morning and get worse during the evening and night. In some patients, the symptoms are so severe that they are disabling, interrupting sleep, and causing daytime fatigue. Studies show that restless leg patients are prone to hypertension, headaches, and sleep difficulties. The quality of life for most patients is poor.

By age 50 years, RLS usually worsens and causes daily disruption of sleep, resulting in decreased daytime alertness. RLS is associated with poor quality of life.[24][25]

Complications

Complications of the disease itself are limited to the quality of life due to disturbed sleep and fatigue. In most patients, the symptoms progress over time and cause significant quality of life issues.