Neurology -- Correspondence for Manconi et al., 63 (6) 1065-1069

Correspondence published:

Restless legs syndrome and pregnancy: Kari A. Casas, J. Rodman Seely (10 November 2004)

Reply to Casas et al: Mauro Manconi, Enrico Granieri, Luigi Ferini-Strambi (10 November 2004)

Restless legs syndrome and pregnancy 10 November 2004

Kari A. Casas,
University of Oklahoma Health Sciences Center
940 NE 13th Street, Rm. 2B2418, Oklahoma City, OK 73104,
J. Rodman Seely
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Re: Restless legs syndrome and pregnancy

kari-casas{at}ouhsc.edu Kari A. Casas, et al.

Manconi et al [1] observe that restless legs syndrome (RLS) appears or worsens during months six through eight of pregnancy, followed by remission of symptoms during the ninth months or with delivery. The authors consider mechanical strain by the growing fetus on nerve roots in the pelvis, iron deficiency anemia (IDA), and hormonal changes of pregnancy as possible causes of RLS.
We submit that all of these factors may be related to RLS within a hypothesis of voiding dysfunction. The pontine micturition center coordinates activity of sympathetic, parasympathetic, and somatic nerves at the thoracolumbar and sacral levels. Sympathetic firing maintains urinary continence via excitatory input to the bladder neck and urethra, and voiding triggers a switch from sympathetic to parasympathetic discharge. Stress to nerves in the pelvic region, particularly mechanosensitive bladder afferents, may lead to sympathetic overactivity and resulting feelings of urgency or restlessness.
In addition to pregnancy, RLS is likewise associated with other conditions of altered voiding frequency, such as chronic nonspecific prostatitis and uremia. [2,3] Children with dysfunctional voiding often deny the urge to urinate while displaying very characteristic tightening and posturing of the lower extremities to maintain continence. Imbalance of bladder sensation and voiding control may be compounded by IDA, which is hypothesized to chronically elevate sympathetic activity. [4]
While fetal size was not a significant risk factor, women in the total RLS group were older and more likely to weigh over 79 kg, suggesting that adiposity (especially if central) and age-related wear are also involved. We have seen the same trend in a three-generation family with RLS. Four individuals in this family met International RLS Study Group criteria for RLS diagnosis. The proband reported onset of symptoms in her thirties, following a weight gain of ten pounds. Her sister was obese and had severe symptoms with earlier onset. The proband reported that urination decreased her symptoms from hours of insomnia to immediate control.
When RLS symptoms occurred, she voided once or twice, even in the absence of urge, and experienced complete relief of symptoms. Finally, we are struck by the authors� finding of seemingly paradoxical improvement of symptoms around the time of lightening, or engagement of the fetal head in the base of the pelvis. This might be explained by rise of maternal dopamine level in preparation for delivery, as modulation of sympathetic activity has been demonstrated by dopaminergic input. [5]
References
1. Manconi M, Govoni V, De Vito A, et al. Restless legs syndrome and pregnancy. Neurology 2004;63:1065-1069.
2. Lewis F. The role of the saphenous nerve in insomnia: a proposed etiology of restless legs syndrome. Med Hypotheses 1991;34:331-333.
3. Kavanagh D, Siddiqui S, Geddes CC. Restless legs syndrome in patients on dialysis. Am J Kidney Dis 2004;43:763-771.
4. Turner LR, Premo DA, Gibbs BJ, et al. Adaptations to iron deficiency: cardiac functional responsiveness to norepinephrine, arterial remodeling, and the effect of beta-blockade on cardiac hypertrophy. BMC Physiol 2002;2:1.
5. Mannelli M, Ianni L, Lazzeri C, et al. In Vivo Evidence That Endogenous Dopamine Modulates Sympathetic Activity in Man. Hypertension 1999;34:398-402.

Reply to Casas et al 10 November 2004

Mauro Manconi,
Center of Sleep Medicine, Vita-Salute University
Centro di Medicina del Sonno, San Raffaele-Turro, Via Stamira d'Ancona 20, 20127 Milano,
Enrico Granieri, Luigi Ferini-Strambi
Send Correspondence to journal:
Re: Reply to Casas et al

manconi.mauro{at}hsr.it Mauro Manconi, et al.

Casas et al note similarities between the pregnancy related restless legs syndrome (RLS) and bladder voiding dysfunction. The first similarity concerns the clinical aspect of restlessness (the main feature of RLS) that usually accompanies the urge to urinate. The leg movement represents the solution for the RLS symptoms or the bladder voiding.
These findings could suggest a link between the afferent mechanisms inducing whether the urge to urinate (bladder wall stress) or the urge to move, and between the efferent mechanisms to control both phenomena. In pregnant women, RLS and the urge to urinate appear during the third trimester of pregnancy and recover around the delivery, suggesting that the fetus volume could stress the pelvic nerves and induce both symptoms. [1] We note a finding not previously noted--that most of our RLS women reported that symptoms disappeared not the same day of delivery, but around 7-15 days before it. The change in fetus position in preparation for the delivery could reduce the pelvic nerve stress and therefore the symptoms.
The second similarity concerns a possible implication of the iron deficiency in the genesis of RLS and in the sympathetic hyperactivity with a consequent voiding dysfunction. [2] In our study, the oral iron supplement did not prevent RLS. Furthermore, the RLS resolved before delivery, the voiding dysfunction resolved usually just around the delivery while the pregnancy-related iron deficiency recovered only few months after the delivery. [3]
The sympathetic hyperactivity (also evident in RLS patients) is not the only consequence of an iron deficiency, but also of the most accepted theory in the RLS pathogenesis--dopaminergic hypoactivity. [4] Iron is the coenzyme of tyrosine hydroxylase which represents the limitant enzyme of the dopamin anabolism. [5] Iron deficiency, sympathetic hyperactivity and dopamine hypoactivity are interrelated and each may represent a risk factor for RLS and voiding dysfunctions.
Casas et al also reported two cases of RLS in the same family. In the first case, RLS was induced by weight gain and in the second case, RLS symptoms were relieved by voiding. In our study the mother's weight was a risk factor for RLS. We speculated that estrogens (particularly increased in the third trimester) can induce weight gain and, for their antidopaminergic effects, RLS symptoms. [1]
Regarding the second case, no patients reported this relationship between voiding and symptom relief. This finding should be more extensively evaluated. All of these hypotheses should be further investigated in order to clarify RLS pathogenesis to improve its treatment.
References
1. Manconi M, Govoni V, De Vito A, et al. Restless legs syndrome and pregnancy. Neurology 2004;63:1065-1069.
2. Turner LR, Premo DA, Gibbs BJ, et al. Adaptations to iron deficiency: cardiac functional responsiveness to norepinephrine, arterial remodeling, and the effect of beta-blockade on cardiac hypertrophy. BMC Physiol 2002;2:1.
3. Puolakka J, J�nne O, Pakarinen A, et al. Acta Obstet Gynecol Scand 1980;95(Suppl):43-51.
4. Mannelli M, Ianni L, Lazzeri C, et al. In Vivo Evidence That Endogenous Dopamine Modulates Sympathetic Activity in Man. Hypertension 1999;34:398-402.
5. Allen RP, Earley CJ. Restless legs syndrome: a review of clinical and pathophysiologic features. J Clin Neurophysiol 2001;18(2):128-147.