Management of restless legs syndrome in chronic liver disease: A challenge for the correct diagnosis and therapy

Table 1 Baseline general conditions of patients recruited

Characteristic	Hepatic failure, n = 211
Male/female	107/104
Age in year, mean and standard deviation	59 ± 4.7
(median range)	(36-74)
BMI, kg/m2	25.43 ± 4.1
Cause of liver disease, n	211
Previous alcohol abuse	139
Hepatic venous outflow tract obstruction	14
Cryptogenic	12
Liver primary tumor	46
Child-Pugh class; number	211
A	132
B	54
C	25

BMI: Body mass index.

Table 2 Baseline metabolic parameters of 211 patients recruited

Labs parameter (normal values)	Average of 211 patients (range)
Hemoglobin (14-16 g/dL)	11.1 (7.5-12.3)
Platelets counts (150-400 × 1000/μL)	97 (65-423)
Serum protein (g/dL)	7.6 (3.4-10.1)
Serum bilirubin (0.1-1.3 mg/dL)	1.7 (0.9-12)
Alanine aminotransferase (8-55 IU/L)	77 (24-452)
Aspartate aminotransferase (8-48 IU/L)	71 (34-715)
International normalized ratio (INR)	1.8 (1.0-4.9)
Serum creatinine (0.6-1.2 mg/dL)	1.0 (0.6-2.1)
Serum albumin (3.7-5.0 g/dL)	3.5 (1.5-5.1)
Ammonium (40-80 μg/dL)	97 (45-134)
Folate (3.89-26.0 ng/mL)	2.3 (1.9-12.3)
Iron free level (40-150 μg/dL)	26.5 (12-89)
Ferritine (20-200 ng/mL)	235 (126-456)
Vitamin B12 ( 205-870 pg/mL)	189 (121-245)
Vitamin D-OH25 (30-100 ng/mL)	41 (12-130)

Table 3 Synopsis of the tests at baseline

Test (range)	Results
Hamilton rating scale (0-66)	18.5 ± 4.5
PSQI (0-5)	3.4 ± 0.5
ESS (0-24)	11 ± 2.1
IRLSSG	Fulfillment of criteria:
	211/211
IRSL (0-40)	0-10 (mild) = 22
	11-20 (moderate) = 76
	21-30 (severe) = 109
	31-40 (very severe) = 4

ESS: Excessive diurnal sleepiness; IRLS: International RLS severity scoring system; IRLSSG: International Restless Legs Syndrome Study Group evaluation; PSQI: Depression, sleep quality assessment.

Table 4 Synopsis of pramipexole titration

Patients	Baseline	75th day	105th d	135th day	165th day	205th day
211	0.18 mg
211		0.7 mg
211			0.88 mg
170				1.4 mg
134					1.4 mg
36					0.88 mg
110						1.4 mg
60						0.7 mg

Table 5 Synopsis of gabapentin titration

Patients	45th day	75th day	105th day	135th day	165th day	205th day
41	100 mg
41		300 mg
35			300 mg
6			400 mg
30				300 mg
11				500 mg
27					300 mg
14					600 mg
16						300 mg
25						600 mg

Table 6 Results for pramipexole therapy during follow-up of 170 patients

Test (range)	135th day	165th day	205th day
Hamilton rating scale (0-66)	9.2 ± 0.1	8.7 ± 1.3	9.0 ± 1.1
	(-9.3 ± 3.0; < 0.01)	(-9.8 ± 1.7; < 0.01)	(-9.5 ± 0.2; < 0.01)
PSQI (0-5)	2.2 ± 0.7	1.9 ± 0.7	2.3 ± 0.7
	(-1.2 ± 0.2; < 0.05)	(-1.32 ± 0.2; < 0.05)	(-1.1 ± 0.2; < 0.05)
ESS (0-24)	8. 3 ± 0.7	8. 5 ± 0.4	8 .7 ± 1.1
	(-7.1 ± 0.4; < 0.01)	(-7.3 ± 0.7; < 0.01)	(-7.7 ± 0.2; < 0.01)
IRSL (0-40)	0-10 (mild) = 51	134	110
	11-20 (moderate) = 100	12	45
	21-30 (severe) = 19	14	15
	31-40 (very severe) = 0	0	0

Within-group analysis was done by comparing results at each day’s visit vs baseline. ESS: Excessive diurnal sleepiness; IRLS: International RLS severity scoring system; PSQI: Depression, sleep quality assessment.

Table 7 Results for gabapentin therapy during follow-up of 41 patients

Test (range)	135th day	165th day	205th day
Hamilton rating scalec(0-66)	9.7 ± 0.4	9.7 ± 0.5	10.0 ± 0.7
	(-9.8 ± 0.2; < 0.01)	(-9.8 ± 0.3; < 0.01)	(-9.9 ± 1.2; < 0.01)
PSQI (0-5)	2.7 ± 0.7	2.9 ± 0.3	3.0 ± 0.5
	(+ 0.7 ± 0.2; NS)	(+0.5 ± 0.2; NS)	(+0.6 ± 0.3; NS)
ESS (0-24)	9 9 ± 0.7	9. 5 ± 0.4	12 .7 ± 1.1
	(-0.7 ± 1.0; NS)	(-0.5 ± 0.1; NS)	(-3.3 ± 0.1; < 0.05)
IRSL (0-40)	0-10 (mild) = 21	18	17
	11-20 (moderate) = 14	19	22
	21-30 (severe) = 6	4	2
	31-40 (very severe) = 0	0	0

Within-group analysis was done by comparing results at each day’s visit vs the 45^th day results. ESS: Excessive diurnal sleepiness; IRLS: International RLS severity scoring system; NS: Nonsignificant; PSQI: Depression, sleep quality assessment.

Table 8 Analysis of factors for association with the presence of augmentation

Factor	n	Univariate		Multivariate
		OR (95%CI)	P value	OR (95%CI)	P value
Age	170	1.07 (0.7-1.2)	0.24	1.1 (0.9-1.3)	0.20
BMI	170	1.3 (0.9-1.5)	0.45	1.6 (1.0-1.9)	0.40
IRLS	170	1.5 (1.1-2.2)	0.36	1.7 (1.2-2.2)	0.57
Alcohol abuse	139	2.3 (0.9-4.1)	< 0.001	3.75 (2.7-6.2)	< 0.001
Daily pramipexole	170	3.6 (2.1-6.8)	< 0.001	7.2 (4.1-15.2)	< 0.001
Treatment duration, > 75 d/< 75 d	170	2.3 (1.3-4.2)	0.036	6.6 (3.1-11.2)	0.01
ALT	170	1.3 (0.9-1.6)	0.21	3.1 (1.7-3.9)	0.54
AST	170	1.6 (0.8-1.7)	0.50	2.7 (0.7-4.2)	0.76
Iron-free level	170	2.9 (0.9-4.1)	0.01	5.05 (1.1-12.2)	0.06
Vit. B12	170	4.25 (1.3-9.7)	0.01	6.9 (4.7-7.6)	0.01
Folate	170	4.1 (3.1-13.6)	0.01	5.7 (4.2-8.2)	0.01
Vit. D-OH25	170	4.8 (3.4-12.9)	0.01	5.67 (2.4-8.9)	0.01

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BMI: Body mass index; CI: Confidence interval; IRLS: International restless leg syndrome severity; OR: Odds ratio; Vit.: Vitamin.