Which Came First? Restless Legs Syndrome or Insomnia?

THE CASE: A 60-year-old woman complains that she has had "no energy" for the past 6 months. She adds that she has difficulty in falling asleep at night because her "legs don't want to go to sleep." She wants to know how she can get a better night's sleep and inquires about new insomnia medications she has seen advertised on television.

How should this patient's nighttime symptoms and lack of energy be evaluated and treated?

Although this patient complains of insomnia and fatigue, the fact that she mentions nightly discomfort in her legs is a clear indication that the real problem may not be insomnia but restless legs syndrome (RLS). Insomnia medications--even the newer ones--are not indicated for patients with this condition.

RLS was first identified by Swedish neurologist Karl Ekbom in 1945 and was initially known as Ekbom's syndrome.¹ He defined the condition as an urge to move associated with dysesthesia at rest. Patients may use the terms "creepy-crawly," "jittery," or "shock-like" to describe the sensation. The symptoms are worse at night and remit for a short time when the patient gets up and walks around for a few minutes.

The estimated prevalence of RLS is 15%. However, this percentage varies with age: RLS affects 10% of persons aged 18 to 29 years and 27% of persons older than 65 years. The condition is 3 to 5 times more common in those with an affected first-degree relative and affects more women than men.²

The mechanism of RLS has become more clearly defined in recent years. A correlation with anemia was first identified in women with RLS who were menstruating or pregnant and in patients with end-stage renal disease. As far back as 1953, parenteral iron was found to relieve RLS symptoms.³

A number of studies since then have evaluated laboratory iron values and iron metabolism in patients with RLS. More recently, studies have focused on CNS iron values. One study found that patients with RLS had lower cerebrospinal fluid ferritin levels and higher transferrin levels than controls, which suggests CNS iron deficiency.⁴ This occurred despite normal peripheral iron levels. Other studies of patients with RLS have evaluated MRI scans of the brain for regional iron content and have shown decreased iron stores in the substantia nigra.⁵

It now seems likely that RLS is an abnormality of the regulation of transferrin receptors in the substantia nigra. This presumption has been confirmed by autopsy evaluation.² The fact that iron is a cofactor in dopamine(Drug information on dopamine) synthesis may explain the effectiveness of dopaminergic agents in treating RLS.

The 4 criteria for the diagnosis of RLS are listed in the Table.⁶

Other features have been identified, although they are not part of the diagnostic criteria. Patients may report that alcohol, caffeine(Drug information on caffeine), and tobacco exacerbate their symptoms. Many patients complain of sleep disruption and subsequent sleepiness. About half of patients get 4 hours or less of sleep each night, and only 10% get as much as 7 hours.⁷ This significantly affects quality of life. In addition, dysesthesia may cause discomfort in social situations or at work.

History. A thorough history taking is essential. Many elderly patients consider RLS symptoms a "normal" part of aging. Patients who are vegetarians and those who donate blood repeatedly are prone to anemia and thus susceptible to RLS.^8,9 Inquire about any blood loss via the GI tract.

Physical examination. Patients with RLS generally have normal physical examination results. Neurologic and vascular examinations are recommended.

Differential diagnosis. RLS symptoms may overlap with those of periodic limb movements of sleep (PLMS). Patients with PLMS (also known as nocturnal myoclonus) experience involuntary, repetitive jerking movements. PLMS is diagnosed primarily by polysomnography. This condition may be secondary to obstructive sleep apnea, narcolepsy, or another neurologic disorder; it generally resolves with treatment of the primary illness. However, many patients with PLMS also have daytime symptoms that resemble those of RLS.

The differential diagnosis of RLS includes hypothyroidism, leukemia, vitamin B₁₂ deficiency, folic acid(Drug information on folic acid) deficiency, electrolyte abnormalities, and diabetes. High-risk patients include those whose diets are poor, pregnant women, and patients with end-stage renal disease. Also at risk are patients taking such medications as tricyclic antidepressants, selective serotonin reuptake inhibitors, lithium(Drug information on lithium), and dopamine antagonists.

Neurologic and vascular causes sometimes produce symptoms similar to those of RLS; however, in many instances, serious underlying conditions may be ruled out. For example, the symptoms of amyotro-phic lateral sclerosis, such as muscle twitches, occur throughout the day and are not relieved by movement. Symptoms of claudication from vascular disease worsen with activity and are relieved by rest, which is the opposite of the pattern seen in RLS.

Leg cramps are very common and may be confused with RLS. However, leg cramps occur mainly during the day, may be unilateral, and are sometimes associated with such factors as muscle overuse and electrolyte imbalance.

Laboratory testing. Routine testing includescomplete blood cell count; serum chemistry; and thyroid, methylmalonic acid, homocysteine, and iron studies (ferritin, total iron-binding capacity, and percent saturation).

Initial measures. Counsel patients to avoid alcohol(Drug information on alcohol), caffeine, and nicotine(Drug information on nicotine) at night. Initial treatment consists of correction of any abnormality found on basic testing, such as replacement of vitamin B₁₂ or administration of thyroid hormone. If testing reveals iron deficiency, the decision to start iron therapy is straightforward. However, many patients have normal results on iron studies. Some reports suggest that RLS symptoms may be exacerbated in patients with serum ferritin levels below 50 ng/mL^10,11 and that iron repletion is likely to relieve symptoms. Treatment consists of ferrous sulfate(Drug information on ferrous sulfate), 325 mg, taken twice daily, along with vitamin C, 100 to 200 mg. The supplements are taken on an empty stomach to increase absorption. Relief of symptoms may not be felt for weeks or months, until iron stores have been replenished.

Pharmacotherapy. If the patient does not have an iron deficiency, other pharmacologic agents may be considered.

Dopaminergic agents. The first dopaminergic medication studied was levodopa(Drug information on levodopa)/carbidopa. It is effective and relatively safe. Rare side effects include nausea, vomiting, tachycardia, hallucinations, and hypotension. Pergolide and cabergoline(Drug information on cabergoline) are effective but are associated with an increased prevalence of these side effects compared with levodopa/carbidopa.

The use of dopaminergic agents in the treatment of RLS is considered off label, although many of these medications have been used for years and have been studied in a number of trials. Newer agents, such as ropinirole and pramipexole(Drug information on pramipexole), have been the focus of RLS research in recent years. Ropinirole(Drug information on ropinirole) is the first and only FDA- approved medication specifically for RLS. In recent studies, it was not associated with any serious adverse effects.^12,13 Less serious effects associated with ropinirole include nausea, drowsiness, vomiting, and dizziness. It is important to start this medication at low doses and titrate over the course of weeks to months until the effective dose is reached. The recommended starting dosage is 0.25 mg/d, which is increased gradually over the course of 7 weeks to the desired effect or 5 mg/d, whichever comes first.

Dopaminergic agents have been associated with the phenomenon of augmentation. Patients with this side effect notice that their symptoms occur earlier in the day. In addition, the medication may not work as well as it once had. Generally, augmentation takes months to a year or more to develop. When it occurs, a switch to a different dopaminergic agent is recommended. After 1 to 2 years, or if augmentation symptoms develop with the second agent, many patients may subsequently return to their initial medication.

Anticonvulsants. Carbamazepine was the first of this class of agents to be studied for RLS, but it proved ineffective. More recently, gabapentin(Drug information on gabapentin) has been found effective and is associated with few adverse events.¹⁴ No studies have directly compared dopaminergic agonists and gabapentin. Anticonvulsants may be useful for patients who cannot tolerate dopaminergic agents.

Opioids and benzodiazepines. These medications show modest benefit but are considered third- or fourth-line treatments. They have generally fallen out of favor for the initial treatment of RLS be- cause of the advent of newer, safer medications.

The patient's laboratory test results were within the normal range. Ropinirole was begun and was titrated to the effective dose. Within 2 weeks, the patient reported dramatic improvement, with better sleep, fewer awakenings, and more energy.