Restless Leg Syndrome

ACCREDITATION The Yale School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. TARGET AUDIENCE Attending physicians, house staff/fellows, medical students, nurses, physician assistants. NEEDS ASSESSMENT Sleep physicians need to understand how to appropriately diagnose and manage patients with restless legs syndrome (RLS). RLS treatment may involve the use of intravenous iron therapy and monitoring for treatment side effects including augmentation. LEARNING OBJECTIVES At the conclusion of this talk, individuals will learn to: 1. Review the assessment of patients for RLS. 2. Discuss treatment strategies for patients with RLS. 3. Understand the importance of assessing patients with RLS for suicidal ideation. DESIGNATION STATEMENT The Yale School of Medicine designates this live activity for 1 AMA PRA Category 1 Credit(s)TM. Physicians should only claim the credit commensurate with the extent of their participation in the activity.

s syndrome), emphasizing the frequency of the disorder and its distressing symptoms. The syndrome is characterized by a creeping, crawling sensation in the lower legs, usually at night. It is accompanied by an irresistible urge to move the legs, and this movement eventually relieves the symptoms. It is found in 5% of the general population, with a higher incidence in pregnant women and people with anemia, but no vascular, neurological or other abnormalities are found on examination. Patients are treated empirically with vasodilators or intravenous iron. The etiology is unknown. TN 1944 the Swedish neurologist Ekbom1 described an old but almost completely neglected syndrome which he called "the restless leg syndrome". This syndrome is characterized by an unpleasant crawling or creeping sensation in the legs, occurring usually at night or during periods of rest, and relieved by movement of the affected limbs. This paper calls attention to this common disorder which is still generally unrecognized in daily xipedical practice. Because of its frequency and the discomfort it causes, and because many patients will not complain about it unless specifically asked, this problem demands greater recognition by general practitioners and specialists alike. HISTORY Ekbom's paper in 1944 was thought to be the first description of this syndrome in the literature, but since that time he and others have found descriptions dating back to Thomas Willis,6 who in 1685 wrote: "Wherefore to some, when being a Bed they betake themselves to From  sleep, Presently in the Arms and Leggs, Leapings and Contractions of the Tendons, And so great a Restlessness and Tossing of their Members ensue, that the diseased are no more able to sleep, Than if they were in a place of the greatest Torture." Wittmaack in 1861 described a similar complaint which he called "Anxietas Tibiarum". Beard in 1880 felt that this was a symptom of spinal irritation, and Oppenheim in 1923 felt that it was due to hysteria. A number of further reports published before Ekbom's description have been found, but he was the first to describe the signs and symptoms carefully and note the high incidence of the disorder. Since Ekbom's original papers, there have been a number of publications with various views on this syndrome,710 but little new has been added except for Norlander's relationship of restless leg syndrome to anemia7' 8 and Gorman, Dyck and Pearson's9 theory as to a psychogenic basis for it.

CLINICAL FEATURES
Patients variously describe the sensation in their legs as "creeping", "crawling", "numbness", "tingling", "tickling", "ants under the skin", "a jittery feeling", and with other figurative words. The area involved is usually from the knees to the ankles, but the thighs, feet and even the hands may be involved. The symptoms are bi¬ lateral, but about one-half have a dominant side and occasionally this changes from one leg to the other.
The sensation is felt to be deep "in the bones", not superficially. Although most find it difficult to explain the feeling, or often use such terms as "diabolical" and "internal itch", they all agree that it is unlike the sensation of their legs "going to sleep". The feeling may be agonizing, causing patients to lose many hours of sleep each night, and may occur nightly for many years. Gorman, Dyck and Pearson9 had six patients with a history of longer than 20 years.
During the day the patient may not have any complaints, or only a mild discomfort, but at night the crawling feeling may be extremely upsetting. This may occur with periods of rest as well; some patients have symptoms when sitting for a long time in a chair, on long ear drives, or in the movies. Some patients state that only dull movies precipitate the onset. Most patients, however, develop their greatest discomfort, and sometimes their only discomfort, after retiring at night. All patients agree that the symptoms are always unpleasant, and that they find it almost impossible to keep their legs still when they occur. Restlessly moving their legs about may be enough to give relief, but often the patient has to walk around, sometimes for an hour or more.
Gorman, Dyck and Pearson9 described one pa¬ tient who had massaged his legs, kicked them in the air, pedalled with his legs elevated, and would "do anything that would exhaust them".
One of Ekbom's patients would do the Charleston dance before she was able to get to sleep. Once asleep, the patient may be awakened again by the crawling, creeping sensation and have to walk around some more. The spouse often notes that the patient's legs also move restlessly when she/he is asleep. In severe cases the patient may be up repeatedly during the night, or not able to get to sleep until the early morning.
On examination, no physical or neurological abnormalities are found to explain the leg com¬ plaints. The only common clinical situations seen with the restless leg syndrome are anemia and pregnancy.

Incidence
Ekbom15 has stressed the frequency of this syndrome in the general population, although most have mild symptoms which do not require treatment. In 500 otherwise healthy subjects he found a 5% incidence of symptoms suggestive of the restless leg syndrome. The age of onset ranges from 10 to 82 years in cases seeking medi¬ cal aid.
In pregnancy, the incidence is reported as 11%; it occurs usually in the last trimester and disappears with delivery.
An incidence of 24% has been found by some authors in anemia of various types. Most of the cases reported are of patients with irondeficiency anemia, but it has also been seen in anemia due to other causes. The symptoms usu¬ ally leave when therapy is instituted for the anemia.
Severe symptoms are less common, of course, but Ekbom5 reported 175 patients classified as severe cases up to 1960, 72 men and 103 women.

Etiology
There is no known cause for the restless leg syndrome and it is not related to any one disease. Similar symptoms are associated with barbiturate withdrawal, poliomyelitis and other infectious diseases, avitaminosis, diabetes, lengthy exposure to cold, and reactions to drugs.promethazine. prochlorperazine, diphenhydramine hydrochlor¬ ide (Benadryl), cyanoacetic acid hydrazide, and DDT. Why the sensation arises, or in what structures, is unknown.
Ekbom mentions two monozygotic twins and their mother with the same symptoms; about one-third of the patients have relatives with similar symptoms, suggesting a familial inci¬ dence.
Norlander,7'8 in describing patients with anemia and the restless leg syndrome, describes many with the symptoms of both starting simul¬ taneously. Recurrence of the anemia was com¬ monly though not necessarily accompanied by the restless leg syndrome, and vice versa.
Gormon, Dyck and Pearson9 found a high incidence of previous symptoms considered to be due to anxiety states, depression, or both. Thirteen of their patients were depressed, one had a hysterical reaction and one was schizo¬ phrenic. Four related their symptoms to emo¬ tional upset. Seventeen were given the Minne¬ sota Multiphasic Personality Inventory Tests, and 11 had abnormal profiles. These workers concluded that the restless leg syndrome is most commonly associated with anxiety and depres¬ sion, but Ekbom states flatly that "the patho¬ genesis is unknown but the ailment is not psycho¬ genic". Ekbom and many other authors have plainly stated that most of their patients were emotionally stable, with no indication of a func¬ tional basis for their symptoms.
There may be many causes for the restless leg syndrome, but no clinical differences were seen in those who responded better to one form of therapy than to another.
The most likely cause is an abnormal accumu¬ lation of metabolites, probably in a muscle, caused by a relative decrease in blood flow when the legs are at rest. This is supported by the fact that muscle activity in the legs which increases blood flow, gives some degree of relief in all cases. Many patients also find that heat to the legs reduces the symptoms. The high incidence in pregnancy could be related to the degree of venous obstruction that is usually present, and in anemia to the relative ischemia in the deep structures of the legs. The good results with vasodilators support this hypothesis. One patient, however, gained no relief in symptoms from a sympathectomy, although the leg became warmer. However, sympathectomy produces more dilatation in the superficial vessels than in the deep vessels in the muscle. Very little experi¬ mental work has been done on this condition, and a more definitive explanation will have to await further investigation. Therapy Many forms of therapy have been used, with good results, but not all patients respond to one specific method. Often previously successful therapy in a patient may have to be changed when failure to respond occurs later.
Various vasodilating drugs have been used, sometimes with dramatic relief. Relapses occur¬ ring on medication are often successfully treated by switching to another vasodilator. Nitro¬ glycerin has been useful in patients with inter¬ mittent bouts, and relief is usually noted within a few minutes. I have been using inositol niacinate (Linodil), 1000 mg. before retiring, with good results.
Since the relationship of anemia to the restless leg syndrome was noted by Norlander,7*8 many have been treated with blood transfusions and iron therapy. The iron has been administered orally, intramuscularly and intravenously; the latter gave the best results. Some patients who developed a recurrence of anemia and the rest¬ less leg syndrome often responded to this form of therapy. The anemia and the restless leg syn¬ drome often recurred together several times in the same patient, but recurrence of the anemia without the restless leg syndrome has occurred and vice versa. Because he felt that the colloidal solution may have been the reason for the re¬ sponse to intravenous iron, Norlander tried 10% dextran, with remission of symptoms in one pa¬ tient but no success in another. He later used a higher molecular weight dextran (over 200,000) with good results. Because heparin interferes with the colloidal structures of the lipids in the blood, he used it successfully in the most severely affected patients in his series; it had no effect in other patients. Norlander described 30 patients with the restless leg syndrome associated with various other conditions, and achieved good re¬ sults with iron therapy in most cases, even in those with a normal serum iron. The response in patients with a normal serum iron was thought to be due to a high iron binding capacity, but not all the patients showed this.
Ascorbic acid, quinine, aldehydes, histaminestimulating drugs and anti-parkinson medications have been used, with variable results. Seda¬ tion is of little help and promethazine makes the symptoms worse. These patients should not be treated with narcotics because, although they get some relief, exacerbation of the symptoms occurs when the drugs are stopped, and the long-term nature of their illness in many cases makes the risk of addiction formidable.
Case Histories Case 1..A 54-year-old white man was admitted to the Victoria General Hospital in July 1966, be¬ cause of an uncomplicated, acute myocardial in¬ farction. He was questioned about his legs because he was constantly moving them.
It was learned that four years previously he began to have a "crawly" feeling in the bottom of his feet, ankles and lower legs which always occurred at night. He found that he was unable to keep his legs still when the symptoms appeared and that movement of his legs gave relief after about an hour. Usually he had to walk around the house at night before he was able to get to sleep.
He felt that concentration on the symptoms made them worse. Periodically his symptoms would be so severe that he would dread going to bed and lost many hours of sleep owing to the discomfort. His wife often complained that his leg movements oc¬ curred even after he was asleep.
While in hospital and on complete bed rest be¬ cause of the myocardial infarction, his symptoms became much worse, and the "crawly" sensation was almost always present in his legs, both day and night. He moved his legs continually to afford some degree of relief. Despite the fact that these symptoms were getting worse in bed and that be¬ cause of them he was becoming extremely anxious, he had not mentioned them to his doctor. The failure to complain about this condition is not un¬ common because patients feel it is "not a disease" and "not the kind of thing one complains about". Ekbom1 describes this reluctance to complain, and we also have been aware of it.
He was seen in consultation by a staff neurologist because of this constant movement of his legs.
On examination, no neurological, cardiovascular or other abnormalities were found in his legs to explain his symptoms. His hemoglobin level was 13 g. %.
At the same time (four years before) that the restless leg syndrome developed, he began to have two to three episodes a day of suddenly falling asleep while sitting at his desk at a local television station. These lapses lasted only two to three minutes, but occasionally he would fall out of his chair. He also would fall asleep for two or three minutes while watching television, but felt very refreshed afterwards. Because of his tendency to have a sudden sleep attack while sitting, he stated that he had a "sleep button in my buttocks". It is also interesting that different people knew him by different nicknames. He was known as "Jumping Jim" by people who had observed his restless leg movements, and as "Rip Van Winkle" by those who had noted his sleeping episodes.
About one year before his admission he began to have sudden "falling spells", usually when talking to people at work, although he does not remember any relationship to laughing, anger or anxiety. These were without warning, and he would suddenly fall to the floor. He felt that he was conscious throughout the episode and would get up as soon as he hit the floor. On one episode he sustained a laceration of his forehead which required sutures.
Although he is described as having been a nervous person all his life,, circumstances at the time of his myocardial infarction precipitated anxiety to the point where he had to be admitted to the psychiatric ward of the Victoria General Hospital. His brother died of a myocardial infarction while this patient was convalescing. His wife was recovering from a broken leg, and he was extremely worried about his son, who had left university because of a nervous breakdown. There was no history of similar symptoms in his family. CASE 2.-A 29-year-old woman, para 4, gravida 4, complained of an unpleasant tingling sensation in her legs during her last two pregnancies. She felt that she might have had similar symptoms in her first two pregnancies, but these were mild and she recalled little about them. The symptoms occurred only in the last trimester of pregnancy and disappeared with delivery.
She described these symptoms in her legs as a feeling of unpleasant tingling, as if the legs were excessively fatigued from exercise. These symptoms occurred during the evening and after going to bed and were relieved by moving her legs and feet. Usually, however, she had to walk around the house for 30 to 60 minutes before getting relief. Often her symptoms would not completely disappear, but when they were mild she was able to fall asleep. During the evenings she would develop the symptoms if she sat down to relax. She was unable to watch television and would continue housework during the whole evening in order to remain free of the symptoms.
During both these pregnancies, her hemoglobin was about 11 g. % at the onset of her symptoms.
However, oral iron, although improving her hemoglobin level, did not alter the symptomatology. She has never had similar symptoms other than in pregnancy.
These two cases are presented as typical examples of this syndrome. In Case 1 the onset of narcolepsy and the restless leg syndrome developed together, relatively late in life. These have not been reported together in the literature previously, but may be due to a coincidence in this case. Case 2 is a typical restless leg syndrome associated with pregnancy. It is interesting that this patient also had mild anemia during both pregnancies, but oral iron therapy, although improving the anemia, did not alter the symptoms. The restless leg syndrome in this case disappeared after delivery.
Often a diagnosis may be made by asking the patient about the specific symptoms. Recently I have encountered a father, son and daughter with the syndrome, the first two being physicians and the latter a nurse.

SUMMARY
The restless leg syndrome or Ekbom syndrome is characterized by a peculiar, unpleasant, crawling or creeping sensation in the lower legs occurring at rest and relieved by movement of the affected limbs.
The cause is not known, but a definite relationship between pregnancy and anemia has been found in many cases. No vascular or neurological abnormalities are found in the legs. It is suggested that the most likely cause is an abnormal accumulation of metabolites, probably in the muscles, caused by a relative decrease in blood flow in the legs at rest. The relief from vasodilators, heat and muscular movement of the limbs and the aggravation by pregnancy and anemia supports this theory.
The symptoms of the restless leg syndrome are found in 5% of the population, although in most patients they are not severe. The reported incidence in the third trimester of pregnancy is 11% and in anemia 24%. Some patients have severe discomfort, losing many hours of sleep each night, often for many years.
Various forms of therapy have been used with variable success. The best results have been with vasodilators and intravenous iron. Until more experimental work has been done in this syndrome, we will have to wait for a more acceptable explanation of the pathogenesis and a more rational form of therapy.