Acta Medica Scandinavica. Vol. 180, fasc. 4, 1966

From the Medical Clinic (Head: E. Ask-Upmark, M.D.), University Hospital, Uppsala, Sweden

The Treatment of Restless Legs

BY

ANDERS PARROW and IVAR WERNER

By restless legs (R. L.) we mean a syndrome of ill-defined discomfort in the legs. The patients usually complain of a peculiar creeping or crawling sensa- tion, rarely painful or described as pure pain, most frequently localized in the lower legs, but sometimes in the arms. The symptoms always appear a t rest and are relieved by movement. The patient feels an irresistible need to move his legs, and as the discomfort often starts a short time after the patient has gone to bed, this will prevent the patient from falling asleep. The syndrome was described early but did not attract much attention until the last decades, after the works by Ekbom in 1945 (6).

The etiology of the syndrome is still unknown (1 0). A correlation between R. L. and sideropenia has been shown (1, 7, 13), but sideropenia with or without anemia occurs only in a minori- ty of the patients, just as only a small number of patients with sideropenia complain of R.L. In spite of the fact that the distress is or completely benign character, it often causes the patients Submitted for publication March 8, 1966.

serioa trouble, especially by impeding sleep.

Many forms of treatment have been tried. Eltbom (6 ) introduced therapy with vasodilators. The discovery of the relationship between K. L. and sider- openia led to the introduction of iron, which when given intravenously often has a very good effect. Nordlander (1 3) found intravenous iron to be effec- tive also in patients without sideropenia. He was also able to show the good effect of other high molecular substances, such as high molecular dextran. During the last 10 years we have used high molec- ular dextran as standard treatment. Because of the discussion in the litera- ture, we have for the last 5 years systematically followed our patients with R. L. in order to evaluate different forms of treatment, and especially the effect of dextran.

Material

Eighty-nine patients, 25 men and 64 women, have been treated. They are all the patients treated for R. L. by us during the years 1960 to 1964. The age distribution is sh0m.n in

40 1 2-GG3002. Acta Med . Scand. Vo l . 180: 4

402 ANDERS PARROW AND WAR WERNER

15-24 25-34 35-41 45-54 55-54 65-74 75-64 ogo

P El

15-24 16-24 35-44 15-54 55-64 65-71 75-64 05-94 age

Fig, 1. Age distribution.

fig. 1. The majority of the patients did not suffer from any other detectable disease, but sought medical advice for their R.L. Among the others there was a variety of diagnoses without any apparent overrepresentation of any special disease. In 8 patients the hemo- globulin value or hematocrit or serum iron value are missing. Of the remaining 81 patients 9 had sideropenic anemia (Hb less than 11.5 g yo, Hct less than 37 %) and 12 sideropenia without anemia (serum iron less than 60 ,u yo). Only 2 patients had asymmetrical R.L., 2 had prevailingly painful sensations, 3 patients had their sensations in the arms as well as in the legs, and one patient complained of sensations only from his arms. In most cases the ailment has been intensive and longstanding - for several years - but as a rule we have no

exact information about the age of onset. The majority of patients had been treated with various drugs before seen by us, and were actually in most cases referred because of resistance to therapy.

Therapy

Most patients who had earlier undergone treatment had received vasodilator drugs or sedatives, such as barbiturates, meprobamate and klopoxide (Libriumm). Untreated pa- tients were usually given vasodilator drugs, for instance inositolnicotinate, (HexanicitB), tolazolin (VasodilO, PriscolB) . Ferrigen (Astra), an iron carbohydrate complex in 2 % solution, was used for iron therapy, the dose given being 5 ml. For dextran treatment a dextran fraction with M, 153,000 (Phar- macia) in 10 % solution was used, usually 20 ml intravenously. A number of patients were also given Ph 1000 (a mixture of equal amounts of the sulphonates of enantaldehyde and furalhyde) (Pharmacia) in tablets of 100 mg 3 times daily.

-

Results

The results are shown in table I. Fifty- five out of 64 patients (86 %) became completely symptom-free after treat- ment with intravenous dextran. Some patients recovered completely already after 1 injection of 20m1, some patients not before 3-4 injections were given. The duration of the remission varied between some weeks and more than two years. Four patients improved but were not completely free from symptoms, and five patients did not improve at all, in spite of repeated injections (maxi- mum 4). Among these patients there was a man with discomfort solely in the arms (he was later completely cured by librium and Valium).

RESTLESS LEGS 403

TABLE I. Results of treatment

Effect of therapy

- Therapy No of pat. + ( + )

Dextran 14 s 50 9

Intravenous iron 9 s 21 ?

Vasodilator drugs 17

Ph 1,000 19

12 43

7 13

0

1

1 3

1 2

3

10

1 4

1 6

I4

8

+ = symptom-free. (+) = improved but not symptom-free. - = no effect.

Twenty out of 30 patients treated with intravenous iron were completely free from symptoms (67 %). The ordinary dose has been 5 ml intravenously after an initial test dose of 2 ml. The effect was usually encountered after 2-3 injections (the test dose included). As a rule the sideropenic patients, when symp- tom-free by intravenous iron injections, continued with peroral iron prepara- tions. As for the dextran-treated patients, the duration of remission varied between some weeks and more than 2 years. Three patients improved but were not completely symptom-free, and in 7 patients there was no effect a t all. All of these last 10 patients were non- sideropenic. All the sideropenic pa- tients treated with iron intravenously became completely symptom-free, but only one half of the non-sideropenic patients, 11 /23, became symptom-free on intravenous iron injections.

All the sideropenic patients treated with dextran (1 1 patients) became completely free from symptoms.

The treatment with vasodilating drugs was much less effective. None of the patients became completely symptom- free, three improved, and in 14 there was no demonstrable effect.

Ph 1,000 had also only a moderate effect. One patient became free from symptoms, 10 improved, and in 8 pa- tients there was no effect a t all.

Complications

During all the time that we have used high molecular dextran (about 10 years with over 600 injections in 250 patients), I / . the following complications have occurred.

1. A 5 1 -year-old man, suffering from bronchial asthma, developed urticaria the day after the second injection. However, some days before he had also started sulphonamide therapy.

2. A 50-year-old man experienced a short-lasting nausea, when about 14 ml of dextran had been injected.

3. An 85-year-old woman, who ex- perienced nausea during the injection.

404 ANDERS PARROW AND IVAR WERNER

4. A 62-year-old woman, who after the second injection of dextran ex- perienced a sensation of weakness lasting about 15 minuts, after which she completely recovered. After the third in- jection a few days later she experienced the same sensations but this time more accentuated. She was dizzy and had difficulty in standing. After one hour’s rest she recovered completely.

5 . A 39-year-old woman, who 6 months earlier had been given dextran intravenously with excellent effect. Dur- ing injection on account of a relapse, she showed blood pressure fall and circulatory arrest. She recovered spon- taneously after about 30 seconds. Four days later she was in perfect health.

Discussion

The etiology of R. L. has been very much discussed during the last years but must still be considered unknown (2, 3, 4, 5 , 7, 8, 10, 14). It is not our intention to give a complete review of the problem in this article. However, considering our own experience, we want to stress some points.

Sideropenia is common among pa- tients suffering from R. L. Among our 81 patients there was evidence of sideropenia in 21 cases, which is in good agreement with the frequency given by Ekbom, 13/34 (7), 16/48 (8), 19/77 (9). It also corresponds well with the frequency of sideropenia in com- parable patient materials. It might possibly be presumed that the real percentage of sideropenia is still higher,

as we nowadays know that neither Hb nor Hct nor serum iron values give a reliable interpretation of the occurrence of sideropenia (1 8).

The striking effect of iron intra- venously does not prove sideropenia to be the etiology of R. L., because relief is often seen on such small doses of iron that a fully developed sideropenia hardly can be considered improved to any note-worthy degree. Further, in our material, there are patients who in all probability were not sideropenic but nevertheless reacted immediately to iron therapy as well as certain sideropenic cases, who were quite symptom-free after dextran treatment.

In the earlier literature (cited by Ekbom (9)) R. L. was usually con- sidered to be a hysterical manifesta- tion. Gorrnan et al. (11) studied 27 patients with R. L. syndrome and found that the symptoms of R. L. were most commonly associated with anxiety or depression. In spite of the fact that we have not given our patients a thorough psychiatric examination, we, like Ek- bom, do not feel that R. L. is the result of an underlying psychic disorder.

Brennin; (3, 4, 5 ) uses the term molirnina crurwn nocfurrzu, with which he denotes R. L., nightly cramps in the legs, burning feet and other sensations. He considers them all different mani- festations of a common underlying disturbance. However, as for R. L. and night cramps it is to be noted that therapy with dextran or iron does not influence the leg cramps, while quinine or chloroquine preparations, which are very effective against cramps in the legs, have no effect on R. L. (17). For this

RESTLESS LEGS 405

and other reasons we do not consider these two disturbances to be of identical origin.

The effect of high molecular dextran is strikingly good in our patients. The mode of action is unknown. One possi- bility is that there is a direct effect of the dextran molecules on the distribution of red corpuscles and plasma in the micro- circulation. Another possibility is that the effect is due to the histamine liberating properties of the dextran fraction. The same mechanism may also be responsible for the effect of intravenously injected iron and 48/80 (cf 15).

The effect of vasodilator drugs was only moderate. Out of 17 patients none became symptom-free and only 3 im- proved. This percentage of failure may be too high, as probably many cases with moderate symptoms have tried this therapy with good results, and were thus never referred to us. Anyhow, our results with vasodilator drugs do not agree with those obtained by Ekbom and by Lindqvist (1 2).

Our experience with Ph 1,000, intro- duced by Brenning (5), was rather limited. The results do not seem very favourable, as only about 50 yo were improved and only one out of 19 com- pletely cured.

Ekbom (1 0) reported very good results on K. L. with diazepan (Valium@) and klopoxid (Librium@). Our ex- perience with these drugs are limited but the results are favourable. In some patients, however, side effects, mostly drowsiness, forced the patients to dis- continue the treatment, and in some others there was no effect a t all.

As for complications with dextran therapy, it must be considered that they were encountered in a much laryer material than that presented here. The only complications of significance were Nos. 4 and 5. During the last four years we have encountered no complications at all, which probably is due to the fact that during this time we used a slower rate of injection. If the injection of high molecular dextran is made slowly and under careful observa- tion of the patient, we consider the risk of complication very small.

Summary

Eighty-nine patients have been treated for restless legs with intravenous injec- tions of high molecular dextran in 10 yo solution, intravenous injections of iron, vasodilator drugs and a mixture of aldehyde sulphonates. Twenty-one patients had sideropenia (anemia and/or low serum iron value). Fifty-five out of 64 patients (86 yo) were symptom-free after 1-3 injections of 20 ml dextran. The effect persisted for some weeks up to more than two years.

Sideropenic patients were improved in the same percentage as nonsideropenic patients.

Twenty out of 30 patients were completely free from symptoms after intravenous injections of iron. All the sideropenic patients were symptom-free, but only one half of the non-sideropenic patients were symptom-free on iron treatment.

406 ANDERS PARROW AND IVAR WERNER

None of 17 patients were symptom-free on vasodilating drugs, but 3 had improv- ed.

One out of 19 patients treated with Ph 1,000 was symptom-free, 10 had improv- ed.

Complications of dextran therapy are rare, when appropriate technique o i injection is used.

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