Neurological Sciences

, Volume 35, Issue 2, pp 199–204

Postural control in restless legs syndrome with medication intervention using pramipexole

Authors

    • Forensic PsychiatryNational Institute for Health and Welfare
  • Hannu Lauerma
    • Forensic PsychiatryNational Institute for Health and Welfare
    • Mental Hospital for Prisoners
  • Seppo Kähkönen
    • BioMag LaboratoryHelsinki University Central Hospital
  • Heikki Aalto
    • Department of Otorhinolaryngology & Head and Neck, Surgery, University of HelsinkiHelsinki University Central Hospital
  • Katinka Tuisku
    • Department of PsychiatryHelsinki University Central Hospital
    • Finnish Institute of Occupational Health
  • Matti Holi
    • Department of PsychiatryHelsinki University Central Hospital
  • Ilmari Pyykkö
    • Department of OtorhinolaryngologyTampere University Hospital
  • Ilpo Rimpiläinen
    • Department of Clinical NeurophysiologyHelsinki University Central Hospital
    • Institute of Biomedical EngineeringTampere University of Technology
Original Article

DOI: 10.1007/s10072-013-1478-6

Cite this article as:
Ahlgrén-Rimpiläinen, A., Lauerma, H., Kähkönen, S. et al. Neurol Sci (2014) 35: 199. doi:10.1007/s10072-013-1478-6

Abstract

Central dopamine regulation is involved in postural control and in the pathophysiology of restless legs syndrome (RLS) and Parkinson’s disease (PD). Postural control abnormalities have been detected in PD, but there are no earlier studies with regard to RLS and postural control. Computerized force platform posturography was applied to measure the shift and the velocity (CPFV) of center point of forces (CPF) with eyes open (EO) and eyes closed (EC) in controls (n = 12) and prior and after a single day intervention with pramipexole in RLS subjects (n = 12). CPFV (EO) was significantly lower in the RLS group (p < 0.05) than in controls. After pramipexole intake, the difference disappeared and the subjective symptom severity diminished. Pramipexole did not significantly influence CPFV (EC) or CPF shift direction. Subjects with RLS used extensively visual mechanisms to control vestibule-spinal reflexes to improve or compensate the postural stability. Further research is needed to clarify altered feedback in the central nervous system and involvement of dopamine and vision in the postural control in RLS.

Keywords

Restless legs syndromePostural controlVision

Background and purpose

Central dopamine regulation plays an important role in postural control and in the pathophysiology of RLS and Parkinson’s disease (PD). Altered brain iron metabolism, hypodopaminergia in the receptor level, and dysfunction of spinal dopamine regulation in the central nervous system (CNS) are suggested to lie behind the RLS symptoms [14].

Dopaminergic treatment increases the postural sway, especially in the mediolateral direction in persons with PD, which may be in connection with risk of falling through stiffness relieving effect of these agents. In healthy individuals, the sway in anterior–posterior direction can be better managed [5]. Alterations of postural reflexes have been demonstrated, especially in the advanced stages of PD [6]. Even though dopaminergic treatment is effective against major symptoms of PD, it has failed to improve balance impairment in PD. Early automatic postural reflexes are only partially corrected by dopaminergic treatment, and later occurring voluntary postural corrections are not improved at all. In other parkinsonian syndromes, such as neuroleptic-induced parkinsonism, posturally destabilizing reflexes are considered normal. Thus, also other mechanisms than dopaminergic motor control systems must be involved in the altered responses observed in PD [6, 7].

We could not find earlier investigations of postural control in RLS, even though RLS is a common sensory-motor disorder and share etiological factors referring to central hypodopaminergia with PD [4]. Typical RLS symptoms are unpleasant sensations in the legs, often also in the arms and an urge to move one’s legs. The symptoms worsen at night and at rest, are relieved at least partially by moving the legs or by walking and respond well to dopaminergic treatment [8, 9]. Dopamine agonist pramipexole is well tolerated and has a high selectivity for dopamine-2- and dopamine-3-receptors. A single oral dose of 0.125–0.750 mg in the evening is often sufficient to alleviate the motor and sensory symptoms in the legs [10, 11].

Persons with PD have demonstrated a greater sway and higher visual dependence in maintaining the postural balance compared to healthy controls [57]. Subjects with schizophrenia on anti-dopaminergic treatment demonstrated less sway in nonvisual condition than controls [12], which may refer to role of dopamine regarding the observed changes. In addition, some genetic mutations and gait analysis tests [13, 14] refer to disturbed dopaminergic control of supraspinal structures impacting the spinal control of gait and postural control in the central nervous system in RLS.

Based on these facts, we found it reasonable to investigate postural control in RLS with an intervention with a dopaminergic agent using computerized force platform posturography (CFPP) [15, 16].

Methods

Twelve individuals with RLS (11 females and 1 male, mean age 50.7, SD = 12.5, range 26–62) were recruited for this study through advertisements in a health magazine. They fulfilled the ICD-10 diagnosis and the essential criteria for RLS [1] criteria with chronic (lasting over 1 year), frequent (in over 50 % of the nights), and subjectively distressing symptoms of RLS. Twelve healthy controls (11 females and 1 male; mean age 49.4, SD = 5.5, range 38–57) were recruited among the employees of University of Helsinki Psychiatric Hospital and Vantaa Prison. Exclusion criteria included current RLS symptoms relieving medication used during the past 2 weeks, long-term use of any central nervous system (CNS) affecting drugs, major somatic or neurologic illnesses, serious head trauma or injuries of the extremities, vertigo, orthostatic syndromes, secondary causes for RLS, identified periodic limb movement disorder, and any lifetime Axis I psychiatric disorders diagnosed based on structured clinical interview (SCID) [17].

Blood tests for renal and hepatic function, blood glucose, ferritin, B-12 vitamin, and blood cell account and plasma level of hemoglobin were checked to rule out any secondary causes for RLS. Concomitant neurological disturbances were excluded by a clinical neurological examination.

A self-created visual analogue scale (VAS) [8] was completed (from 0 up to 100 %) by eleven out of twelve RLS subjects: maximum symptom severity during the past 2 weeks (VAS max) and subjective average symptom severity during the past 24 h, prior to the intake of pramipexole (VAS 1) and after intake of pramipexole (VAS 2). Symptoms of akathisia were evaluated with the help of Barnes Akathisia Rating Scale (BAS) [18] (Table 1). Right-handedness of all participants was determined with the help of the Edinburgh Handedness Inventory [19]. Informed consent was obtained from all the participants and the study was approved by the Ethics Committee of Helsinki University Central Hospital, attributable to ethical standards stipulated in the 1965 Declaration of Helsinki.
Table 1

Subjective symptom severity (mean values ± SD) gathered in a visual analogue scale (VAS, scale 0–100 %) and assessed symptoms of akathisia (Barnes akathisia rating scale, global scores) in subjects with RLS

Evaluated symptoms in RLS

n

Mean values/change (%)

Standard deviation (SD)

VAS max

11

56.82

16.77

VAS 1

11

67.27

19.25

VAS 2

11

20.45

19.24

BAS 1

12

1.00

1.04

BAS 2

12

0.33

0.65

VAS1–VAS2 and BAS1–BAS2

 

Decrease~60 %

 

VAS max maximum symptom severity during the past 2 weeks, non-medicated; VAS 1 symptom severity during the past 24 h non-medicated; VAS 2 symptom severity during the past 24 h after intake of medication; BAS 1 scores of akathisia non-medicated; BAS 2 scores of akathisia after intake of medication

A custom made computerized force platform that processes the platform signal to a digital form was used to evaluate the postural control. The force distribution applied by a standing subject to the platform surface through one’s feet can be measured. The center point of the forces (CPF) is like a single point on the platform, where all the forces are focused concentrated at the same moment. The movement of the CPF reflects the position and movement of the center of body mass (i.e., the visible body sway). The length and the direction of the trace of the CPF were measured. The average position shift is used to quantify the effect of eye closure and calculated separately in lateral (rightward–leftward) and anterior–posterior (AP) directions. The average sway velocity (CPFV) is calculated by dividing the CPF path length by the duration of the test. CPFV characterizes the postural stability: the higher the CPFV, the more unstable is the postural stance [20].

The platform was placed in a peaceful investigation room. The subjects stood with their shoes on, arms crossed over the chest, heels distanced about 2 cm from each other, and feet abut at 30° angle mimicking a pendulum position for body sway. The subjects were asked to look at a piece of paper placed at the height of their eyes at a distance of 1 m on a wall and stand still on the platform during the measurement, first with eyes open for 30 s. After a 15 s adaptation time with the eyes closed, the postural sway eyes closed was recorded for 30 s. Each measurement lasted 75 s.

The first posturographic measurements in subjects with RLS were performed without medication, and the second one after intake of medication at 16–18 pm within a 3-day interval in between. The dosage was 0.88 mg twice a day (8.00 am and 2.00 pm). The measurements in controls were performed once and without medication. The effect of visual orientation was determined with Romberg’s quotient (RQ = CPFV in eyes closed condition divided by CPFV in eyes open condition) [21]. In general, RQ indicates a better postural stability with eyes open than eyes closed. During eyes closed condition, RQ seems to show greater interindividual variability resulting in wider range of mean CPFV values [22].

The statistical analysis for CPFV, CPF shift, and the changes from eyes opened conditions to eyes closed conditions in controls and in nontreated and treated conditions of participants with RLS were performed with the help of PASW (version 18) using nonparametric tests, Mann–Whitney test for independent samples between the groups, and Wilcoxon test for related samples within the groups. With the help of the Spearman’s test with Bonferroni-correction, the intercorrelations between RQ, CPFV eyes open and closed and BAS, VAS, and maximum symptom severity were analyzed, before and after medication intervention in RLS. The level of significance was set p < 0.05.

Results

Each study participant completed the study protocol. The mean values and standard deviations (+SD) of CPFV(cm/s) and changes of the velocity between condition eyes closed and eyes open and the position (CPF) shifts (cm) in anterior–posterior and lateral directions are presented in Fig. 1 and in Table 2. Figure 2 and Table 3 present an example of the sway in a subject with RLS prior to and after intake of pramipexole and in a healthy control person.
https://static-content.springer.com/image/art%3A10.1007%2Fs10072-013-1478-6/MediaObjects/10072_2013_1478_Fig1_HTML.gif
Fig. 1

Mean values of CPFV (sway velocity cm/s) in participants with RLS (RLS, RLSp) and in controls (CTRL) eyes open and eyes closed and the change in CPFV and in average position shifts (cm) in anterior–posterior (+A/−P) and lateral (+rightward/−leftward) directions from eyes open to eyes closed conditions. Significant differences (p < 0.05) were obtained in the following measures: (1)* CPFV eyes open was significantly slower in nontreated RLS subjects than in controls. (2)* RQ was higher in nontreated RLS subjects than in controls. (3) CPFV eyes closed compared to eyes open was significantly higher within ** nontreated, *** treated, and **** control group, reflecting normative change between visual and nonvisual conditions. RQ Romberg’s quotient, SD standard deviation; RLS nontreated (the first bar + SD on the top of the bar); RLSp treated with pramipexole (the second bar + SD on the top of the bar); CTRL control (the third bar + SD on the top of the bar)

Table 2

Mean values of the CPF shift (cm) in anterior–posterior and lateral directions in conditions eyes open and eyes closed in non-medicated (RLS 1) and medicated (RLS 2) subjects with RLS and in controls (CTR)

Group

AP max eyes open

AP max eyes closed

AP ave eyes open

AP ave eyes closed

Lat max eyes open

Lat max eyes closed

Lat ave eyes open

Lat ave eyes closed

RLS1(n = 12)

Mean

0.23

0.37

−1.16

0.66 *

−0.11

0.44

1.79

−0.06 **

SD

0.57

1.10

1.42

0.77

0.54

0.97

0.55

0.36

RLS2(n = 12)

Mean

0.26

0.38

−1.01

0.47 ***

−0.40

0.01

1.93

−0.03 ****

SD

0.60

1.07

1.16

0.81

0.49

1.03

0.83

0.45

CTR(n = 12)

Mean

0.01

–0.22

−0.07

0.17

−0.35

−0.15

1.58

−0.09 *****

SD

0.88

1.33

1.65

0.65

0.70

0.87

0.51

0.38

AP +anterior, −posterior direction; Lat lateral direction (+rightward, −leftward); max maximum; ave average; n number of subjects, SD standard deviation

Significant differences (p < 0.05, Wilcoxon) between conditions eyes open and eyes closed were obtained: (1) within nontreated RLS group in AP average (*Z = −2.51) and lateral average (**Z = −3.06) position shift, (2) within treated RLS group in AP average (***Z = −2.59) and lateral average (****Z = −3.56) position shifts, (3) within controls in lateral average (*****Z = −3.06) position shift

https://static-content.springer.com/image/art%3A10.1007%2Fs10072-013-1478-6/MediaObjects/10072_2013_1478_Fig2_HTML.gif
Fig. 2

Presents examples of CPF shift in subjects with RLS without medication (A), with medication (B), and in a control (C). The firstupper line shows forward–backward leaning (upward–downward, respectively; AP anterior–posterior) and the second line below shows leaning to the right and left (upward–downward, respectively; L lateral). The first 30 s were recorded eyes open and the last 30 s eyes closed. There was an adaptation time of 15 s between the visual and nonvisual conditions

Table 3

Measures reflecting posturographies of the subjects A, B and C related to Fig. 2

Eyes

Open

Closed

Open

Closed

Open

Closed

Measure

CPFV

CPFV

CPF/AP

CPF/AP

CPF/L

CPF/L

Subject A

0.563

2.069

–1.072

0.478

1.711

–0.477

Subject B

0.616

2.093

0.243

1.258

1.974

–0.589

Subject C

1.440

3.581

–0.814

1.462

1.534

–1.158

CPF center point of pressure (cm), CPFV center point of force velocity (cm/s)

Without medication

CPFV in eyes open condition was significantly (U = 27.0, p = 0.008) lower in the RLS group (0.68 + 0.12) than in controls (0.99 + 0.34), whereas CPFV eyes closed did not differ significantly between the groups. RQ (Fig. 1) was significantly higher (U = 28, p = 0.01) in RLS (2.42 + 0.71) than in controls (1.69 + 0.45).

The groups did not display any significant differences in CPF shifts in anterior–posterior or lateral directions between eyes open and closed conditions. Some significant differences were obtained in maximum and average position shifts within the groups (i.e., RLS and controls), but these results are doubtful with regard to their importance and may reflect major individual variation (Table 2). After Bonferroni-correction, there were no significant intercorrelations between CPFV and severity of symptoms, VAS, BAS, and RQ.

After medication intervention

Within the RLS group, CPFV eyes open was higher after treatment (0.73 + 0.15) than without treatment (0.68 + 0.12). CPFV did no more differ significantly from controls (eyes open 0.99 + 0.34; U = 38.5, p = 0.052 and eyes closed 1.68 + 1.11; U = 64, p = 0.67). The differences between nontreated (BAS 1, VAS 1) and treated (BAS 2, VAS 2) conditions (BAS 1-BAS2/1-0.65; p = 0.04, Z = −2.07 and VAS1-VAS2/67.3–20.5; p = 0.003, Z = −2.95) were significant meaning that subjective (VAS) and more or less objective (BAS) experienced distress caused by symptoms was relieved (Table 1). After Bonferroni-correction, there were no significant intercorrelations between CPFV, severity of symptoms, VAS, BAS, and RQ.

The RQ values between treated and nontreated conditions were not significantly different within the RLS group (Z = −1.42, p = 0.16). The RQ (U = 37, p = 0.05) of the RLS group after treatment (1.58 + 0.41) did not differ significantly from controls (1.69 + 0.45).

Discussion

The key finding of this study demonstrate that with eyes open, CPFV in nontreated condition of subjects with RLS was significantly lower than in controls (Fig. 1). This together with the high RQ indicated that subjects with RLS use extensive reliance on vision to improve their postural stability. Simultaneously, the increased control may predispose to neural fatigue of the postural system.

With eyes closed, the level of CPFV in subjects with RLS approached the level of CPFV in controls (Fig. 1). RLS participants tended to sway on average more forward, while eyes shut all study participants tended to sway on average more leftward; however, these minor findings may reflect individual variation. The average and the maximum CPF shifts did not differ significantly between the RLS and the control groups (Table 2).

These findings with regard to subjects with RLS differ interestingly from results in subjects with PD who displayed abnormalities in both postural sway area and velocity apparently dependent on the severity of the PD stage [6, 7]. However, pramipexole seemed to have a comparable enhancing effect on the postural sway in subjects with RLS as was present in the studies dealing with PD. In addition, subjects with RLS seemed to manage their postural stability better in both nontreated and treated conditions compared to respective controls, while the postural sway parameters in PD for the most subjects exceeded the values of respective controls. It can be postulated that automatic responses or later voluntary postural corrections may be less impaired in persons with RLS. A compensatory effect of the visual component on the postural stability in RLS can be discussed.

The results in this study differed from our previous research concerning medicated subjects with schizophrenia, who possessed better postural stability in the nonvisual condition compared to controls [12]. Nevertheless, dopamine involvement in the postural control abnormalities can be supported by the findings related to RLS with decreased level of dopamine [13] and with assumed impaired function of D3 receptors [15]. The compromised function in the inhibitory D3 receptor system shifts the balance toward excitation through sympathetic preganglionics. This in turn may affect the gait and the management of the upright stance and postural control, too. The lateral nuclei in diencephalon mediate the visual information to the basal nuclei that provide the primary motor control with sensory information. Thalamus may be the gating mechanism to adjust the muscle tone, particularly to set the body position [2, 3].

Limitations of this study were the small number of subjects and a lack of placebo control. All subjects wore own shoes on the platform; thus, the property of the contact surface underneath the feet could also have had a slight but not significant impact on the results, especially on the sensory-motor input [23].

Conclusions

Subjects with RLS used extensively visual mechanisms to control vestibule-spinal reflexes to improve the postural stability. Pramipexole normalized the body sway velocity in both visual and nonvisual conditions and relieved symptoms of RLS. The findings may support the dopamine-deficit theory in RLS and point to the gating mechanism of basal ganglia. The role of vision in the altered sensorimotor feedback in the CNS observed in RLS subjects should be further investigated by combining different methods such as TMS, gait analysis, and CFPP with appropriate applications.

Acknowledgments

The authors want to thank Anu Östman, M.D., for her excellent assistance and contribution to this work.

Conflict of interest

The authors of this research study attest that they have had no financial disclosures or current or past relationships with people or organizations that may have inappropriately influenced the outcome/results of this study.

Copyright information

© Springer-Verlag Italia 2013