Chronic venous disease (CVD) is clinically classified from C0 to C6, according to the CEAP classification. International clinical guidelines recommend aggressive invasive treatment for symptomatic limbs with clinical class C2 or higher; however, even in C2 patients, invasive treatment is not recommended if there is no leg discomfort (1). Not all patients with varicose veins have leg symptoms; the most common symptoms are swelling, heaviness, itching, pain, numbness, and nocturnal leg cramps. However, it remains unclear whether these symptoms are related to varicose veins (2,3). Studies on the relationship between varicose veins and clinical findings have found that the correlation between clinical findings and leg symptoms is unclear, and that invasive treatment of varicose veins does not necessarily eliminate leg symptoms, as non-vein- related conditions may cause similar symptoms (2,4). To understand the association between leg symptoms and venous disease, it is crucial to determine the presence and extent of lower-extremity venous system dysfunction in patients with leg symptoms. We believe that it is meaningful to analyze the association between leg symptoms and venous dysfunction by identifying objective and detailed venous circulation dysfunction using duplex ultrasound scanning (DUS). Several studies have examined the associa-tions between various leg symptoms and DUS findings. However, they did not examine valvular insufficiency in the deep veins, analyze the relationship between the saphenous vein diameter and reflux duration, or determine the distribu-tion of valvular insufficiency in the saphenous veins (3,5). Leg symptoms were assessed based on the patient's subjective complaints. It is often difficult to determine whether edema or heaviness is associated with chronic venous diseases. For example, edema in the ankle area in the late afternoon after prolonged standing and activity can be understood as physiological rather than pathological.

However, in the case of nocturnal leg cramps, the symptoms are relatively easier to identify compared to other leg symptoms, and there have been no reports on the correlation between duplex ultrasound (DUS) findings and nocturnal leg cramps in patients with chronic venous disease. This study aimed to analyze the association between nocturnal leg cramps and DUS findings in the lower extremities of patients with chronic venous disease to explain the possible association between nocturnal leg cramps and lower extremity venous system dysfunction.

This retrospective study was approved by the institutional review board of our hospital (2021-09-001). Clinical data and DUS results were analyzed using medical records. A total of 1668 limbs of 888 patients with signs and symptoms of chronic venous disease (CVD) were evaluated using DUS from April 2017 to December 2020. Limbs with saphenous vein reflux were selected for this study. Patients with a history of treatment for varicose veins, including sclerotherapy, were excluded from the study.

Patient characteristics such as sex, age, body mass index (BMI), leg symptoms, and medical history were determined during outpatient visits. The clinical findings of venous disease were classified according to the CEAP classification.

DUS was performed on the patient's weight in the lower extremities contralateral to the lower extremities being examined. The ultrasound device used was a LOGIQ5 PRO (GE Healthcare, Sungnam, South Korea) with a 5~12 MHz linear probe. The examination sites were the common femoral vein, popliteal vein, great saphenous vein (GSV), anterior accessory saphenous vein (AASV), and small saphenous vein (SSV). In patients with clinical class C4~C6, the perforating vein was also examined. Limbs with an incompetent AASV were excluded from the analysis of homogeneous data if the AASV was not the main superficial truncal vein. The GSV was examined for valvular insufficiency at the saphenofemoral junction, midthigh, knee, and upper calf levels (10 cm below the knee crease). Valve failure in the GSV above the knee was defined as a reflux flow in at least two of the three examination sites above the knee. The SSV often does not have a saphenopopliteal junction; therefore, a routine analysis was performed to check for valve failure at the knee crease level. Venous reflux was defined as retrograde flow with a duration >0.5 s for saphenous veins and >1.0 s for deep veins after the provocation maneuver (distal compression and rapid release).

Statistical analyses were performed using the Statistical Package for the Social Sciences (IBM SPSS Statistics, version 21; SPSS Inc., Chicago, IL, USA). Differences between groups were analyzed using the Student’s t-test and c² test. The correlation between variables was analyzed using Cramer's V. Statistical significance was considered when the probability value was less than 0.05.

During the study period, 940 limbs of 582 patients were included. Each limb was analyzed as a single case. The sex ratio of the patients was 1:1.9 (199 males and 383 females), with an average age of 55 years (range, 19~86 years). Among the symptomatic lower limbs, 15.6% (147/940) had nocturnal leg cramps. A comparison of the clinical parameters between the limbs with and without nocturnal leg cramps is shown in Table 1. There were no statistically significant differences in the distribution of sex, laterality, and CEAP clinical stage. Age was significantly higher (p=0.02), and BMI was significantly lower cramps (p=0.03) in patients experiencing nocturnal leg cramps in the lower limbs. However, the correlations between age, BMI, and nocturnal leg cramps were very weak.

Table 1 . Comparison of demographic data between legs with or without night leg cramps.

	Night leg cramps		p	Cramer’s V
	No (%)	Yes (%)
Sex
Male (N=312)	263 (84)	49 (16)	1.00	0.001
Female (N=628)	530 (84)	98 (16)
Age (years)	55±13.3	58±11.5	0.02
<55 (N=410)	364 (89)	46 (11)	0.001	0.11
≥55 (N=530)	429 (81)	101 (19)
BMI	24.0±3.41	23.4±3.84	0.03
<25 kg/m2 (N=651)	537 (82)	114 (18)	0.02	0.08
≥25 kg/m2 (N=289)	256 (89)	33 (11)
Laterality
Left (N=473)	398 (84)	75 (16)	0.86	0.006
Right (N=467)	395 (85)	72 (15)
CEAP
C0∼C1 (253)	212 (84)	41 (16)	0.65	0.03
C2 (641)	540 (84)	101 (16)
C3∼C6 (46)	41 (89)	5 (11)

1) Correlation of nocturnal leg cramps with the distribution of incompetent saphenous vein

The distribution of incompetent saphenous veins between the limbs, with or without nocturnal leg cramps, is shown in Table 2. In limbs with valvular insufficiency localized to the GSV (N=661), there was no statistical difference in the distribution of incompetent segments between limbs with or without nocturnal leg cramps (p=0.57). In limbs with an incompetent GSV combined with an incompetent SSV (N=165), there was no statistically significant difference in the distribution of incompetent segments of the GSV between limbs with or without nocturnal leg cramps (p=0.23). There was no statistically significant difference in nocturnal leg cramps based on the presence of an incompetent SSV (p=0.43). When comparing limbs with valvular insufficiency localized to the GSV or SSV, there was no significant difference in the incidence of nocturnal leg cramps based on the saphenous vein with valvular insufficiency (p=0.67).

Table 2 . Comparison of the distribution of incompetent saphenous veins between limbs with or without night leg cramps.

Incompetent saphenous veins	Nocturnal leg cramps		p	Cramer’s V
	No (%)	Yes (%)
GSV AK (N=276)	238 (86)	38 (14)	0.57	0.04
GSV BK (N=117)	96 (82)	21 (18)
GSV AK and BK (N=268)	228 (85)	40 (15)
GSV AK+SSV (N=61)	49 (80)	12 (20)	0.23	0.13
GSV BK+SSV (N=54)	42 (78)	12 (22)
GSV AK and BK+SSV (N=50)	45 (90)	5 (10)
SSV involvement
Yes (N=279)	231 (83)	48 (17)	0.43	0.03
No (N=661)	562 (85)	99 (15)
Incompetent saphenous vein
GSV only (N=661)	562 (85)	99 (15)	0.67	0.02
SSV only (N=114)	95 (83)	19 (17)

2) Correlation of nocturnal leg cramps with the diameter and reflux time of the GSV at a mid-thigh level

Of the total number of lower extremities with incompetent saphenous veins, 276 had valvular insufficiency localized to the GSV above the knee. Among limbs with valvular insufficiency localized to the GSV above the knee, a comparison of diameter and reflux duration based on the GSV at the mid-thigh level between limbs with or without nocturnal leg cramps is shown in Table 3. There were no significant differences in the diameter and duration of reflux in the GSV at the mid-thigh level between the limbs with and without nocturnal leg cramps.

Table 3 . Comparison of night leg cramps with the diameter and the duration of the reflux of incompetent saphenous veins.

	Nocturnal leg cramps		p
	No	Yes
The GSV at mid-thigh level (N=276)
Diameter (mm)	5.2±1.5	5.1±1.6	0.64
Duration of the reflux (sec)	3.3±6.3	3.5±2.2	0.86
The GSV below the knee (N=117)
Diameter (mm)	2.9±0.6	2.7±0.5	0.19
Duration of the reflux (sec)	1.9±1.6	2.5±2.9	0.22
The SSV at popliteal fossa (N=114)
Diameter (mm)	4.5±1.8	4.7±1.5	0.61
Duration of the reflux (sec)	4.2±2.9	3.9±2.2	0.69

3) Correlation of nocturnal leg cramps with diameter and reflux time of the GSV below the knee

There were 117 limbs with valvular insufficiency localized to the GSV below the knee. A comparison of the diameter and reflux duration of the GSV below the knee between limbs with and without nocturnal leg cramps is shown in Table 3. There were no significant differences in the diameter and duration of reflux in the GSV below the knee between limbs with and without nocturnal leg cramps.

4) Correlation of nocturnal leg cramps with diameter and reflux time of the SSV

One hundred and fourteen limbs had valvular insuffi-ciency limited to the SSV. A comparison of the diameter and duration of reflux between limbs with and without nocturnal leg cramps in limbs with valvular incompetence limited to the SSV is shown in Table 3. There was no significant difference in the diameter and duration of SSV reflux between limbs with or without nocturnal leg cramps.

5) Correlation of nocturnal leg cramps with deep vein insufficiency

Limbs combined with incompetent saphenous veins and deep venous insufficiency accounted for 15.5% (146/940) in patients with nocturnal leg cramps, and 98.6% (144/146) in patients without nocturnal leg cramps of the deep venous insufficiencies were in the popliteal vein segment. Among the lower limbs with nocturnal leg cramps, 20 (13.7%) had deep vein insufficiency, and 126 (86.3%) did not; therefore, there was no statistically significant difference in deep vein insufficiency between limbs with or without nocturnal leg cramps (p=0.54).

The frequency of nocturnal leg cramps in patients with chronic venous disease is reported to be 24%~42% (2,6), and in this study, 16.7% of all limbs had nocturnal leg cramps, which is relatively low in comparison. The reason for the relatively low prevalence of nocturnal leg cramps is not apparent. The age distribution of the study participants was not significantly different from that of other studies as 70% of the participants were over 50 years old. However, the percentage of limbs with BMI greater than 27 kg/m² in this study was 15.5%, which is much lower than the 33.2% reported by Chiesa et al. (3) Therefore, it is thought that the relatively low proportion of obese patients may also have been a reason for the low frequency of symptoms.

The frequency of lower extremity symptoms increases with age and BMI and is more frequent in women than in men (2,3,5). In this study, the mean age was significantly higher in the limbs with nocturnal leg cramps; however, this correlation was weak. The comparison of BMI showed a significantly lower BMI value in the lower limbs with nocturnal leg cramps, contrary to other reports. However, similar to age, the correlation was weak.

Regarding the correlation between DUS findings and the frequency of nocturnal leg cramps, Labropoulos et al. (6) reported that the longer the segment of saphenous vein valve failure on DUS examination, the more symptoms were present. In this study, the extent and location of the incompetent saphenous veins were not statistically correlated with the frequency of nocturnal leg cramps. There was also minimal correlation between nocturnal leg cramps and incompetent saphenous vein diameter or reflux duration. Bradbury et al. (5) reported that isolated valve failure in the saphenous or deep veins was not associated with symptom presentation. However, valvular insufficiency in the saphenous and deep veins was associated with a higher frequency of most lower-extremity symptoms, including muscle cramps, especially in the left lower extremity. In this study, valve failure in both the saphenous and deep veins did not correlate with the frequency of nocturnal leg cramps, and there was no difference in laterality. However, in the study by Bradbury et al. (5), the criterion of pathologic reflux in a deep vein was 0.5 s or longer, identical to that of the saphenous vein, and the popliteal vein was used to indicate deep vein reflux. Therefore, direct comparison with the results of Bradbury et al. (5) is not appropriate.

Nocturnal leg cramps have no apparent cause, owing to the lack of appropriate diagnostic methods, making it difficult to choose an appropriate treatment. Exercise research has suggested that muscle fatigue may cause leg cramps. Muscle exercises of higher-than-usual intensity are associated with leg cramps; however, the mechanism of action is unclear (7,8). Medical conditions or treatments that may increase the frequency of leg cramps include cancer treatment, cirrhosis, end-stage renal disease, hemodialysis, lumbar canal stenosis, peripheral neuropathy, peripheral vascular disease, and venous insufficiency (9). Although venous insufficiency is associated with leg cramps, there are no reports that leg cramps are caused by tissue hypoxia or toxic metabolites, and there are no reports that the treatment of chronic venous disease improves the symptoms (10).

The limitations of this study are that we did not consider medical conditions, medications other than chronic venous diseases, or professional activity conditions. However, this is beyond the scope of this study. This study is meaningful because there have been no reports on the correlation between the distribution of valve failure in the lower- extremity venous system and nocturnal leg cramps.

In conclusion, the results of this study show that the clinical indicators and distribution of valve failure in the lower-extremity venous system were not correlated with nocturnal leg cramps. In future, it will be necessary to investigate the prognosis of nocturnal leg cramps after treatment for chronic venous disease in a prospective randomized study.

This work was funded by National Health Insurance Service Ilsan Hospital (NHIMC-2021-CR-059). National Health Insurance Service Ilsan Hospital had no involvement in the study design or collection, analysis, and interpretation of data.

None.