Embed Size (px)
Citation preview
Actn ledica Scnndinnvica. Vol. CXLV, fasc. VI, 1953.
From the Medical Clinic of the University of Upsala, Sweden (Chief: Professor E. Ask- Upmark, M. D.)
Therapy in Restless Legs. BY
NILS BRAGE NORDLANDER.
(Submitted for publication January 7, 1953.)
In 1945 Ekboni (2) described a syndrome which he called restless legs. Although existing in a more or less severe form in about 5 per cent of a normal population, this syndrome is seldom treated in the medical literature. The reason for this may be that the disease is not a deadly one; most patients never visit a doctor for it, and if they visit a doctor for another reason, they do not mention their restless legs until directly asked about it.
The syndrome is a sort of paresthesia, a crawling sensation felt deeply in the legs, ))in the very bone marrow)), sometimes amounting to real pain. The troubles are as a rule bilateral, but sometimes unilateral, and start when the patient has gone to rest, in a few cases during the day, but generally not until she has gone to bed in order to sleep. The paresthesia then begins to torment the patient and forces her to move her legs about in the bed or to get up for hours of restless walk in the room. Moving decreases the uneasy feeling. Some patients t ry to diminish the crawling by washing their legs in cold water, others try hot water or massage. Drugs may ameliorate the condition, for example salicylates or barbiturates in some cases, but vasodihting drugs such as Priscol or Dory1 have hitherto been the treatment of choice for these patients and they help in about 213 of the cases (2, 3, 4). The paresthesia is often accompanied by cold feet and a feeling of weak- ness in the legs, but if a sympathectomy is performed and the leg gets warm, the paresthesia does not disappear. The syndrome is more common in women and a few conditions are known to provoke it: p regnane (in about 11 per cent), polio- myelitis, certain drugs as benadryl, malononitrile and DDT, vitamin-deficiency (described from Japanese prison-camps), prolonged exposure to cold (workers in freezing-rooms). More than one third of these patients have relatives suffering from the same disease (2).
In 1951 I observed three cases of anemia from different causes (bleeding gastric ulcer, chronic nephritis, leukemia) where the syndrome restless legs developed in
4 54 NIL8 BRAG& NORDLANDER.
parallel with the anemia and disappeared when the anemia was cured by blood transfusions. In the patient with chronic nephritis this parallelism was repeated several times. In cases of sideropenia without anemia where restless legs occurred, they have been cured by iron therapy per 0s (3). Since then I have tried intravenous iron therapy with aIntrafen (identical with d’errivenin)} and containing a 2 per cent colloidal solution of saccharated oxide of iron) in patients with restless legs. As the result of one or two injections the paresthesia as a rule disappeared after a day and remained absent for a long time. Thus 10 patients with iron-deficiency- anemia were entirely cured of their restless legs for months. Some of them are still free from symptoms; in others relapses have occurred, but they were relieved by another injection of Intrafer.
In two cases the anemia was treated by iron per 0s and even then the restless- ness of the legs disappeared, but 1-2 months of treatment were required to achieve a complete cure.
Now Intrafer was tried in cases with restless legs without anemia and with nor- mal serum iron. The effect was just as quick and complete as in the anemic pa- tients, in spite of the fact that they had more than 100 7 yo of iron in their serum. It is possible, however, that there can exist an iron deficiency in the tissues in spite of normal serum iron. In such cases the iron-binding capacity of the serum proteins is considered to be increased to more than 400 mgyo (7, 6) . In two of my successfully treated patients however the iron-binding capacity was normal. In the light of these experiences it is difficult to explain the favorable effect of in- travenous iron treatment on the theory that restless legs might, in common with choilonychia rhagads, glossitis or Plummer-Vinson-dysphagia, be a sign of iron deficiency.
In view of the fact that Intrafer is a colloidal iron solution, the effect of other colloidal solutions must be of interest. In order to investigate this I gave an in- travenous injection of 20 ml of a 10 per cent Dextran solution, containing poly- saccharides in colloidal solution, to a patient who had been suffering from restless legs every night since two years back. From that very evening, for 4 months he has been perfectly relieved from his symptoms and has enjoyed an undisturbed night’s sleep. Quite recently he has had some mild paresthesia again, but so far he considers it unnecessary to have any treatment for it. In another patient, however, Dextran was useless, whereas Intrafer entirely removed the symptoms.
It is well known that heparin interferes with the colloidal structure of at least the lipids in the blood and makes turbid serum clear. Heparin was therefore tried in one of the most resistant cases of restless legs I ever saw. It was a woman of 30, who had undergone several therapeutic measures - Priscol, Dory1 and even unilateral sympathectomy - without any effect whatsoever, and who was relieved for only one day by Intrafer or Dextran. After intravenous injection of heparin she was free from symptoms during three days, and this sequence was repeated a couple of times. In other cases heparin has had very little therapeutic effect.
Recent reports claim successful treatment in some cases of restless legs by ascorbic acid per 0s (9) and by nRigidyb - one of the new drugs used against Parkinson’s disease (6). Leg pains in adolescents, often called ))growing painso,
THERAPY IN RESTLESS LEQB. 455
have been successfully treated with several remedies. These pains are certainly due to different causes - not seldom to rheumatic fever - but may in some cases be restless legs.
Discussion.
It is an observed fact that a series of medicamenb have proved to be effective against restless legs. This can partly be due to the fact that there are great spontane- ous variations in the symptoms. One of my patients had really tormenting paresthesia in the spring and summer but was relatively free during the winter. There are also other forms of variations and in such a disease the effect of a treatment is difficult to judge. Suggestive treatment can sometimes have good effect (6). The intravenous injection of Intrafer, however, is followed by quick and convincing relief in nearly every case and I think this effect must be a real one.
It is impossible to say in which way the treatment works as long as the patho- genesis of the disease is unknown. In the first place the syndrome must be dis- tinguished from other paresthesias. Restless legs manifest themselves only during rest and disappear during exercise. In contrast with this, intermittent claudica- tion starts and increases during physical movement, and rheumatic pains and paresthesia in arthrosis deformans get worse during exercise. The syndrome rest- less legs should for the present be confined to the legs, but it must be admitted that similar symptoms can be observed from the arms and possibly from other parts of the body; here, however, the limits are hard t o determine.
The only common conditions known to be sometimes associated with restless legs are pregnancy and anemia, but this association ie not the rule. Only about 11 per cent of pregnant women display this syndrome, and most anemic patients whom I have interrogated, deny such troubles. Restless legs are sometimes met with after ventricular resection for gastric ulcer, but here again not regularly (1).
The paresthesia cannot be deliberately provoked. In some anemic patients with restless legs where the two symptoms have been cured simultaneously, the anemia later on returns without restless legs. In other cases the two conditions fluctuate in parallel.
The pathogenesis of the syndrome still remains obscure, but it is possible that the fate of the colloids in the organism can throw'some light upon it. It is well known that Intrafer - and other colloids too - become attached to the reticulo- endothelial cells and are stored there for several weeks. If the therapeutic effect depends upon a blocking of the reticulo-endothelial system, that could explain the long standing improvement after one or two injections. Investigations are going on in order to test this possibility.
Further remarks about the patients. No. 1. Later on the patient had another melena with anemia but without r. 1.
2. The anemia returned several times, always accompanied by r. I., and on each
6. The thrombopenia was improved by X-ray therapy. Later on she got anemic occasion both were effectively cured by blood transfusions.
again but felt no r. 1. 31--530613. Acta med. Scandinau. Vol . CXLV.
Table 1. Therapeutic effect in 30 patients with restless legs (r. 1 . ) . +++ = symptoms completely absent for several months after 1-3 injections ++ = * u a n * n a more prolonged t,reatment
ymptoms absent for a few days after the treatment + - ?atient no.
1. b m
2. MK
3. MK
4. MK
5. MK
6. MK
7. M P
8. MP
9. MK
LO. MK
11. M P
12. M P
13. M P
14. MP
15. MK
16. M P
17. M P
18. M P
19. MP
20. M P
21. MP
22. M P
23. KK
24. M P
25. MP
26. MP
27. M P
28. MP
1477151
216/61
2315151
2319/51
2747151
474152
2099152
3247152
2342152
2626152
7978152
6982151
6852151
792152
760152
526152
3718152
1107152
2742152
57/52
1648j52
4928152
551/44
152
47/52
3272152
4268152
4822152
4937152
4946162
39. M P
30. M P
- - I - Sex
JV
W
W
M
W
W
w M
M
M
W
M
M
W
W
M
W
W
W
M
W
W
M
W
W
W
M
M
-
M
W
- - = Age rears
42
39
59
75
46
82
68
28
19
73
55
23
37
54
48
42
44
43
41
75
62
54
41
71
24
55
47
42
-
60
31
MK = Medical Clinic
z [gt %
49
55
49
67
52
61
79
74
36
51
73
52
58
44
58
57
52
58
68
72
73
-
- - -
70
79
89
-
72
82
= ierum. ,any Y - - - - 57
25
20
72
123
22
25
28
36
42
44
65
66
-
-
-
-
107
117
136
139
142 - - -
- 157
Duration of r. 1.
several months
n
n
3 months
L a
iany year1
2 years
1 year
3 months
L n
iany year;
3 months
L months
1 year
3 n
1 montha
1 year
several months
j months
several months 10 years
17 a
4 n
20 n
3 mont.hs
1 year
iany year
3 years
2 b
4 a
rherapj - Blood- transf.
I>
n
>) + op.
Blood transf. e pr 01
n
ntrafer
a
0
a
n
n
n
n
n
n
I)
Y
D
n
>)
1)
n
n
b)
0
kxtrar [ntrafex Ieparir Iextrax
[ntrafel Dextrar Aeparir
- ++t ++t ++t +++ ++t
++t ++ ++ ++t
++t ++t +++ ++t ++ ++t ++t ++t ++t
++t ++ ++t ++t ++-t
++t ++t ++t ++
++-t
++-t
(+) ( + I +
- -
-
>* 1 year
2-3 months
3 a
> 15 months
> 4
>10 a
> 1 year
> 6 months
> 2 0
> 2 * 10 *
> i 3 months
> 3 a
2 a
> 7
4 a
> 2 a
>10 n
> 4 months
>10 a
3 n
> 1 year
> 6 months
; 10 n
> 4 a
2 n
3 n
6~
> 4
3 days
MP = Medical Policlinic (outpatient department)
Remarks. Ot,her disease
Bleeding gastr. ulc.
Nephrit. chron.
Myeloic leukemia. Mom
Ca. ventr. After op. Hb
Ca. recti. 80 y % iron
Thrombocytopenia,
Plummer-Vinson-
77
after op.
melaena
dysphagia -
Anemia causa incert.
Melaena
Melaena. Relapse of
Malnutrition
Malnutrition
Plummer-Vinson-
Achylia gastrica
Achylia. Iron-binding capac. 466 y %
Anemia caus. inc. After treat. Hb 81
Nephrit. chron. levis
Complete heart block
Resect. ventr. B I1
Polyarthr. chron.
Resect. ventr. 1944 Iron bind. cap. 367
Resect. ventr. 1944 a. m. B I1
Arthrosis deform. gcnu
Anemie gravidar. mens.
Relapse, treats herself
Alcoholism
anemia and r. 1.
dysphagia
1941
111-VII
with lemon
Relapse, improved again with Intrafer
Slight relepse, no traat- ment needed
Iron binding capacity 221 s’o
KK = Surgical Clinic 1 1nt)rafer was given in doses of 6-10 ml, corresponding to 100-200 mg iron with interval of 2 - 4 days.
a > = more than, because the time stated is the present time of observation after the treatment; the In a few cases the doses were repeated every day until satisfactory results were attained.
patients are as yet free from symptoms.
THERAPY IN RESTLESS LEOS. 457
12 and 13. The patients were anemic and had entirely lost their appetite. It is difficult to say which was the cause and which was the effect. No. 13 lived ex- clusively on bread and butter. When the anemia was cured by Intrafer, their appetite returned.
14. The patient had several relapses in connection with infections or stress and every time Intrafer proved very effective.
16.. Anemia with achylia and.bleeding hemorrhoids. Relapse of anemia and r. 1. as well as general pruritus: under treatment now.
21. Relapse after 3 months, again successfully treated with Intrafer. For the present free from symptoms.
25. R. 1. started with the pregnancy; after treatment the restlessness was absent during the remainder of the pregnancy.
30. Had earlier tried every sort of therapy: Doryl, Priscol, unilateral sympath- ectomy. As a rule she is better in the winter, regardless of therapy, and for the moment she is in no need of treatment.
Summary. The syndrome mestless l egs is discussed and the therapeutic effect of different
remedies in 30 patients described. In most cases one or two intravenous injections. of saccharated oxide of iron proved very effective, regardless of whether or not the patient had anemia or sideropenia. In a few cases injections of a colloidal polysaccharide-solution (Dextran) or heparin gave better results. The theory is put forward that these remedies work by blocking the reticulo-endothelial system.
Liter8tUl'e.
1. Ask-Upmark, E. & Meurling, 8.: Personal communication. - 2. Ekbom, K. A.: Acta Med. Scand. 1945: Suppl. 158. - 3. Ekbom, K. A.: Acta Med. Scand. 1960: 246: 64. - 4. Ekbom, I(. A.: Sv. Liikartidn. 1951: 862. - 5. Hagberg, B.: Acta Ped. 1951: 40: 519. - 6. Jacobsen, E.: Ugeskr. f. leg. 1952: 973. - 7. Laurell, C. B.: Acta Physiol. Scand. 1947: 14: suppl. 46. - 8. Olhagee, B.: Personal communication. - 9. Wersiill, J.: Sv. Liikartidn. 1952: 2032.
(I am indebted to Dr. B. Hagberg for performing the determinations of iron-binding capacity of the serum in some patients.)
