Compromised Dynamic Cerebral Autoregulation in Patients with Restless Legs Syndrome

Figures & data

Table 1 Clinical Characteristics and Phase Difference in Mild, Moderate, Severe, Very Severe RLS Patients and Controls

	Controls (n = 30)	Mild RLS (n = 30)	Moderate RLS (n = 30)	Severe RLS (n = 30)	Very Severe RLS (n = 30)	χ^2/F	P
Male, n (%)	12 (40.0)	12 (40.0)	13 (43.3)	10 (33.3)	10 (33.3)	1.019	0.907
Age (years)						8.124	0.775
< 35	3 (10.0)	1 (3.3)	3 (10.0)	1 (3.3)	3 (10.0)
35 <= Age < 45	4 (13.3)	4 (13.3)	4 (13.3)	7 (23.3)	3 (10.0)
45 <= Age < 55	15 (50.0)	10 (33.3)	10 (33.3)	10 (33.3)	12 (40.0)
≥ 55	8 (26.7)	15 (50.0)	13 (43.3)	12 (40.0)	12 (40.0)
BMI (kg/m^2)						14.449	0.071
< 18.5	2 (6.67)	2 (6.67)	1 (3.33)	0 (0.0)	0 (0.0)
18.5 <= BMI < 24	13 (43.3)	13 (43.3)	24 (80.0)	17 (56.7)	17 (56.7)
≥ 24	15 (50.0)	15 (50.0)	5 (16.7)	13 (43.3)	13 (43.3)
MAP (mmHg)	85.03 ± 14.90	84.00 ± 9.42	89.10 ± 9.70	88.23 ± 7.44	87.17 ± 8.38	1.300	0.273
Heart rate (beats/min)	74.5 ± 8.1	73.6 ± 7.5	74.7 ± 9.9	75.7 ± 6.6	72.6 ± 7.3	0.640	0.635
IRLS	—	6.73 ± 2.45	15.96 ± 2.81	26.30 ± 2.73	33.73 ±2.53	—	—
Hypertension, n (%)	5 (16.7)	4 (13.3)	4 (13.3)	5 (16.7)	6 (20.0)	0.694	0.952
Hyperlipidemia, n (%)	4 (13.3)	4 (13.3)	5 (16.7)	4 (13.3)	3 (10.0)	0.577	0.966
Smoking, n (%)	3 (10.0)	2 (6.67)	4 (13.3)	5 (16.7)	3 (10.0)	1.725	0.786
Iron (µmol/L)	20.10 ± 4.83	18.72 ± 4.78	19.14 ± 4.04	16.38 ±7.53	17.97 ± 8.33	1.544	0.193
Ferritin (µg/L)	130.25 ± 52.62	128.65 ± 57.45	116.56 ± 77.99	109.43 ± 38.52	109.52 ± 73.59	0.801	0.526
Phase difference (degree)	52.37 ± 9.39^a	50.58 ± 10.00^a	39.34 ± 10.11^b	39.54 ± 7.20^b	37.48 ± 7.82^b	18.353	< 0.001*
End-tidal CO2 (mmHg)	35.65 ± 4.74	35.84 ± 4.20	35.00 ± 4.61	35.81 ± 4.61	35.64 ± 5.70	0.364	0.834

Notes: *P value < 0.05 (statistically different in one-way analysis of variance and the chi-square test). Similar superscript letters indicate no significant difference, while different superscript letters indicate significant difference in Bonferroni’s post-hoc test.

Abbreviations: RLS, restless legs syndrome; BMI, body mass index; MAP, mean arterial pressure; IRLS, International restless legs syndrome severity scale.

Table 2 Polysomnography Parameters in Mild, Moderate, Severe, Very Severe RLS Patients and Controls

	Controls (n = 30)	Mild RLS (n = 30)	Moderate RLS (n = 30)	Severe RLS (n = 30)	Very Severe RLS (n = 30)	F	P
Total sleep time (min)	400.40 ± 34.72^a	377.99 ± 89.39^ab	386.96 ± 114.52^ab	337.80 ± 70.04^b	330.27 ± 90.18^b	4.069	0.004*
Sleep onset latency (min)	15.53 ± 3.03^c	15.53 ± 3.33^c	17.11 ± 4.10^c	22.41 ± 9.14^b	27.89 ± 10.85^a	18.240	< 0.001*
Sleep efficiency (%)	86.50 ± 8.72^a	73.46 ± 15.66^b	71.06 ± 13.37^b	63.34 ± 11.44^bc	58.13 ± 14.19^c	19.977	< 0.001*
Stage N1 (%)	4.42 ± 1.24^c	19.06 ± 6.68^b	24.47 ± 9.04^b	24.47 ± 8.69 ^b	31.43 ± 11.77^a	45.086	< 0.001*
Stage N2 (%)	50.47 ± 6.97	51.29 ± 10.06	50.82 ± 7.22	51.93 ± 10.53	48.63 ±12.70	0.490	0.743
Stage N3 (%)	21.20 ± 5.02^c	11.92 ± 7.46^c	6.68 ± 4.82^c	6.02 ± 3.92 ^b	3.43 ± 3.12^a	57.748	< 0.001*
REM sleep (%)	23.90 ± 8.59^b	17.38 ± 7.49^b	16.82 ± 7.78^b	16.81 ± 9.77^b	16.52 ± 10.02^a	3.861	0.005*
Arousal index (events/h)	6.00 ± 3.58^c	16.01 ± 4.86^b	22.56 ± 11.65^ab	19.92 ± 8.47^a	25.10 ± 7.71^a	27.559	< 0.001*
AHI (events/h)	2.12 ± 1.61	2.31 ± 0.99	2.56 ± 1.37	2.30 ± 1.39	2.22 ± 1.23	0.437	0.781
PLMI (events/h)	0.89 ± 0.77^d	16.89 ± 6.40^bc	18.93 ± 5.86^c	35.70 ± 2.83^b	79.73 ± 25.08^a	75.534	< 0.001*

Notes: *P value < 0.05 (statistically different in one-way analysis of variance). Similar superscript letters indicate no significant difference, while different superscript letters indicate significant difference in Bonferroni’s post-hoc test.

Abbreviations: RLS, restless legs syndrome; REM, rapid eye movement; Stage N1, stage 1 non-REM; Stage N2, stage 2 non-REM; Stage N3, stage 3 non-REM; AHI, apnea-hypopnea index; PLMI, periodic limb movement index.

Figure 1 The autoregulatory parameter and statistical distributions in each group. Statistical distributions of average phase difference (A) and its transfer function (B) in each group. Similar lowercase letters indicate no significant difference, while different lowercase letters indicate significant difference (P < 0.001) (One-way analysis of variance and Bonferroni’s post-hoc test). The dashed frame represents a specific frequency domain (0.06–0.12Hz).

Table 3 The IRLS, Phase Difference and Polysomnography Parameters in RLS Patients with Ferritin <45 µg/L and Ferritin ≥45 µg/L

	Ferritin < 45 µg/L (n=25)	Ferritin ≥ 45 µg/L (n=95)	χ^2/t	P
Male, n (%)	10 (40.0)	35 (36.8)	0.084	0.772
Age (years)	42.8 ± 8.7	53.9 ± 8.0	−6.095	< 0.001*
IRLS, n (%)			14.198	0.003*
1–10	4 (16.0)	56 (44.8)
11–20	8 (32.0)	22 (17.6)
21–30	3 (12.0)	28 (22.4)
31–40	10 (40.0)	19 (15.2)
Total sleep time (min)	364.92 ± 122.11	356.50 ± 86.50	0.395	0.694
Sleep onset latency (min)	22.14 ± 9.41	20.37 ± 8.80	0.885	0.378
Sleep efficiency (%)	69.70 ±15.59	66.19 ± 14.69	1.049	0.296
Stage N1 (%)	25.50 ± 10.11	24.49 ±10.17	0.358	0.721
Stage N2 (%)	50.70 ±7.06	50.66 ±10.98	0.019	0.985
Stage N3 (%)	6.82 ± 5.14	7.07 ± 6.12	− 0.118	0.851
REM sleep (%)	16.46 ± 6.27	16.70 ± 9.30	− 0.274	0.784
Arousal index (events/h)	24.89 ±12.76	19.85 ± 7.56	2.530	0.013*
PLMI (events/h)	41.99 ± 24.07	36.71 ± 29.69	0.820	0.414
Phase difference (degree)	41.07 ± 9.13	41.91 ± 10.49	− 0.364	0.717

Notes: *P value < 0.05 (statistically different in one-way analysis of variance and the chi-square test).

Abbreviations: RLS, restless legs syndrome; IRLS, International restless legs syndrome severity scale; REM, rapid eye movement; Stage N1, stage 1 non-REM; Stage N2, stage 2 non-REM; Stage N3, stage 3 non-REM; PLMI, periodic limb movement index.

Figure 2 Relations between phase difference and IRSL (A), arousal index (B), and PMLI (C) in patients with RLS (Spearman correlation test).

Table 4 Univariable and Multivariable Analysis for the Phase Difference

Factors	Phase Difference, Degree
	Univariable Analysis		Multivariable Analysis
	β	P	β	P
Gender	0.086	0.349
Age	− 0.046	0.576
BMI	0.011	0.894
MAP	− 0.119	0.195
Heart Rate	0.013	0.886
Hypertension	0.033	0.721
Hyperlipidemia	0.103	0.263
Smoking	− 0.096	0.297
End-tidal CO2	0.036	0.390
IRLS	− 0.359	< 0.001^ab	− 0.193	0.140
Iron (µmol/L)	− 0.032	0.730
Ferritin (µg/L)	0.118	0.198
Total Sleep Time (min)	0.160	0.081^a	0.064	0.5443
Sleep onset latency (min)	− 0.336	< 0.001^ab	− 0.164	0.129
Sleep Efficiency (%)	0.172	0.061^a	0.014	0.896
Stage N1 (%)	− 0.183	0.046^ab	− 0.002	0.983
Stage N2 (%)	0.029	0.756
Stage N3 (%)	0.292	0.001^ab	0.142	0.164
REM Sleep(%)	0.027	0.769
Arousal Index (events/h)	− 0.218	0.017^ab	− 0.091	0.324
AHI (events/h)	0.070	0.444
PLMI (events/h)	− 0.240	0.008^ab	0.021	0.854

Notes: ^aNominally significant values (P < 0.1) included in the multivariable model; ^bP value < 0.05 (statistically different).

Abbreviations: BMI, body mass index; MAP, mean arterial pressure. IRLS, International restless legs syndrome severity scale; REM, rapid eye movement; Stage N1, stage 1 non-REM; Stage N2, stage 2 non-REM; Stage N3, stage 3 non-REM; AHI, apnea-hypopnea index; PLMI, periodic limb movement index.

Figure 3 The autoregulatory parameter and statistical distributions in RLS patients before and after treatment. Statistical distributions of phase difference (A) and its transfer function (B) in RLS patients before and after treatment (Wilcoxon signed-rank test).