restless leg syndrome treatment

restless leg syndrome treatment

How and/or why did the patient develop restless legs syndrome?

Familial studies have suggested that early onset primary RLS might follow an autosomal dominant pattern. Linkage analyses have discovered some common loci for RLS, but no causally related sequence variant or protein have been found.

In RLS, there are some iron and dopamine abnormalities in the brain. Iron-deficient patients are more likely to develop RLS than are controls. RLS patients have been found to have a lower brain iron concentration in the substantia nigra and the red nucleus, as quantified by MRI, compared to controls. Reduced ferritin was also found in the cerebrospinal fluid of the RLS patients. Dopamine and iron levels fall at night, indicating a circadian pattern.

Since iron is a cofactor for an enzyme involved in dopamine synthesis, the brain iron deficiency in RLS patients is likely to produce dopaminergic dysfunction. The evidence for the involvement of dopamine in the physiopathology of RLS comes from several observations:

• The dopaminergic system is involved in movement control.
• Dopamine levels are lower at night and have a wider diurnal variation compared to normal subjects without restless leg syndrome.
• Dopamine agonists relieve RLS symptoms.
• Dopamine antagonists exacerbate RLS symptoms.
• Animal iron deficiency studies show a decrease in dopamine transporter functioning on the cell surface.
• Autopsy studies in the brain of RLS patients have found a decrease in Dopamine-2 receptors that correlates directly to RLS severity.

These findings support the notions that alteration of the dopaminergic system in the brain can contribute to the symptoms of RLS and that iron and dopamine have a strong connection.

Some medications can worsen RLS. Selective serotonin reuptake inhibitors increase serotonin transmission, which lead to inhibition of the function of dopaminergic neurons; neuroleptics are dopamine-blocking agents; and lithium has been shown to decrease dopamine release.

Which individuals are at greatest risk of developing restless legs syndrome?

RLS is more common in women and older individuals than in men and younger people. More than 40 percent of RLS cases are hereditary.

Secondary RLS is most commonly found in patients with iron deficiency. RLS has been described in patients who were iron-deficient as a result of malignancy, partial gastrectomy, or blood donation. RLS patients also have decreased ferritin levels compared to controls, even when they have the same hemoglobin levels as controls. Patients with serum ferritin less than 50µg/L experience more severe RLS. Iron therapy has a beneficial impact on RLS symptoms.

RLS has been found in about 26 percent of pregnant women when stringent criteria from the International Restless Legs Syndrome Study Group were applied, and RLS symptoms increase from preconception to the third trimester. Pregnant women are two to three times more likely to develop RLS than are non-pregnant women. When compared to a pregnant control group, pregnant women with RLS have lower ferritin and folate levels. RLS remits post-partum in most women but might be persistent in some, which suggests that pregnancy is a risk factor for developing RLS.

RLS is common in patients with end-stage renal disease. RLS can occur before or after installation of dialysis treatment, whether hemodialysis or peritoneal dialysis. In those patients, an association was found between RLS and anemia with a positive response to epoetin alpha. RLS can improve or even resolve after successful renal transplantation.

RLS can occur in patients with neuropathy or radiculopathy, especially in patients with type 2 diabetes who also have myelopathies. Small-fiber sensory neuropathy is commonly associated with RLS.

RLS is also associated with rheumatoid arthritis; it can affect up to 25 percent of rheumatoid arthritis patients, especially women. RLS may be linked to the presence of neuropathy in this patient population, as the likelihood of developing RLS seems to correlate with the severity of the rheumatoid arthritis.

RLS is also associated with fibromyalgia and Sjogren syndrome. Whether RLS is associated with Parkinson’s disease is subject to debate since some authors have not found a higher prevalence of RLS among Parkinson’s patients, while others have found a high prevalence of Parkinson’s disease in RLS patients.

Medications and substances that can worsen or trigger RLS include the selective serotonin reuptake inhibitors, venlafaxine, mirtazapine, mianserin, bupropion, the tricyclic antidepressants, antipsychotics, antihistamines, lithium, dopamine antagonists, and even caffeine.

Secondary RLS most often remits once the associated disease process has been successfully treated.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

The patient should be screened for iron deficiency; a ferritin level <75µg/L is a good indicator of low iron stores and warrants iron supplementation. The blood work should also include renal function and a screen for diabetes with HgA1C, B12, and folate deficiency.

What imaging studies will be helpful in making or excluding the diagnosis of restless legs syndrome?

Spinal MRI might be helpful if spinal cord disease is suspected as a secondary cause of RLS.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of restless legs syndrome?

Pulmonary diagnostic studies are not indicated.

What diagnostic procedures will be helpful in making or excluding the diagnosis of restless legs syndrome?

If the diagnosis of RLS is uncertain, a full polysomnography might be useful to evaluate for the presence of increased numbers of periodic leg movements during sleep, which would be a supportive criteria. The number of periodic leg movements usually correlates with RLS severity. Nerve conduction studies may be indicated if there is doubt about the presence of a neuropathy.

The degree of impairment and the frequency of the symptoms dictate the need for therapy. In patients with intermittent symptoms, mild exercise or the elimination of caffeine may be beneficial. Other measures include hot or cold baths, leg massages, relaxation exercises, and withholding offending medications under a physician’s supervision. While mild exercise can be beneficial, strenuous exercise should be avoided since it can worsen RLS symptoms.

Intermittent symptoms can justify the use of medications before a planned prolonged period of immobility, such as that the patient is likely to experience on a plane. This strategy has been anecdotally reported to be successful.

Long-term pharmacological therapy is indicated in patients with daily or very frequent symptoms that impair their quality of life and sleep.

Four classes of medications–dopamine agonists, anti-convulsants, opioids, and iron therapy–can be used to treat RLS.

Dopamine agonists

The dopaminergic agonists, which target the D2 and D3 receptor-subtype, are the first-line treatment for RLS. They have been widely studied for the treatment of RLS and are FDA-approved for this use. Dopaminergic agents relieve RLS symptoms in up to 90 percent of patients. Pramipexole and Ropirinole are the newest non-ergotamine derivatives.

Pramipexole binds the D2-D3 receptor sub-types. The starting dose of 0.125 mg can be increased by 0.125 mg weekly to the efficacious dose of 0.25-0.70 mg. Pramipexole should be administered as a single dose one or two hours before bedtime since its half-life is eight to twelve hours. A six-month double-blind trial showed that Pramipexole is an effective and well tolerated medication that significantly decreases the symptoms of RLS, as assessed by the International RLS Study Group Rating Scale. Pramipexole also decreases the number of periodic leg movements during sleep and sleep latency. The most common side effects were mild morning nausea, headache, insomnia, somnolence, dizziness, and fatigue.

Ropinirole is another dopaminergic agonist with high affinity to the D2 and D3 receptor. The initial dose of 0.25 mg can be increased weekly by 0.25 mg to reach the efficacious dose of 0.5-4 mg/day. Ropinirole has an onset of action of approximately one hour and a half-life of six hours, so it should be given one hour before bedtime. The most common side effects are nausea, headache, fatigue, dizziness, and vomiting. Ropinirole significantly improves RLS symptoms within one week of treatment and also has a beneficial effect on sleep disturbances and quality of life. Ropinirole can also be used as needed for the treatment of mild/ and or intermittent RLS.

Anti-convulsants

Gabapentin is an analogue of the amino acid GABA. Although its mode of action is not completely understood, it may promote the release of dopamine. Gabapentin is efficacious in the treatment of RLS, especially among patients with painful symptoms, and it is also effective in primary and uremic RLS, although it is not FDA-approved for RLS.There is some clinical suggestion that Gabapentin may be useful when combined with a dopaminergic medication. The starting dose of 300 mg before bedtime should be increased by 300 mg every three days until the symptoms are controlled or a maximum dose of 1800 mg per day is reached. Side effects may include dizziness, somnolence, and peripheral edema. Gabapentin might be used as a second line therapy for patients who are not adequately controlled with dopaminergic therapy.

Opioids

Opioid therapy is not FDA-approved for RLS, but it is used as monotherapy or combination therapy with dopaminergic agents. A controlled trial showed that oxycodone at a mean daily dose of 15.9 mg is efficacious because it can decrease the number of periodic leg movements in sleep and improve sleep efficiency. Opioid therapy can be considered in patients who fail dopaminergic therapy or who present with neuropathy or painful dysthesias. Opioid use is limited by its risk for dependency and its potential to worsen sleep-disordered breathing.

Iron therapy

Iron therapy is efficacious in RLS patients with low-normal serum ferritin levels (15-75 µg/L), but efficacy can take three to six months. Iron therapy has been shown to decrease RLS symptoms significantly based on the International Restless Leg Scale scores. RLS patients should take ferrous sulfate 325 mg twice a day on an empty stomach with vitamin C 100 mg orally twice a day to increase iron absorption. Patients should be supplemented with iron until the ferritin level reaches at least 50µg/L. Ferritin levels and transferrin saturation should be followed every three months to avoid hematochomatosis. Concomitant pharmacotherapy for RLS should be considered while waiting for the ferritin level to normalize.

Benzodiazepines

The benzodiazepines bind to the alpha-subunit of the GABA-A receptor, promoting sedation. They are commonly used to treat insomnia but are not FDA-approved to treat RLS. Benzodiazepines work mainly by improving sleep.

Early case reports suggested that Clonazepam was effective for the treatment of RLS and that it could reduce periodic leg movements in sleep. However, a recent review of the literature concluded that there is no consistent evidence of clinical benefit for Clonazepam in the treatment of RLS. Clonazepam has a long half life and can cause daytime somnolence and dependence.