Servier – Phlebolymphology

Abstract

This review presents up-to-date data on the pathophysiology, epidemiology, classification, diagnosis, and treatment of the combination of May-Thurner syndrome (MTS) and pelvic congestion syndrome (PCS). It includes hypotheses to explain the predominant lesion of the pelvic veins in these patients and describes in detail the clinical symptoms of combined lesions of the iliac and pelvic veins. The article discusses modern methods of diagnosis of MTS and PCS, as well as advantages and disadvantages of ultrasound and radiological methods of investigation. It goes further to discuss the issues of choosing a method of treatment for combination of MTS and PCS and highlights the optimal sequence of using endovascular methods of treatment. It presents current data on the efficacy of iliac vein stenting in relieving PCS symptoms and discusses rational use of endovascular treatment methods to avoid unnecessary interventions on the gonadal veins. Altogether, these data indicate the lack of our knowledge both in regard to pathogenesis of the MTS and PCS combination and in determining the optimal set of diagnostic tests for verifying the diagnosis and choosing a treatment method. Multicenter randomized trials are needed to address many of the controversial issues in the diagnosis and treatment of MTS and PCS.

Introduction

Pelvic congestion syndrome (PCS) and May-Thurner syndrome (MTS) are two nosologies that have long been considered separately from each other. This is understandable because PCS is the common cause of chronic pelvic pain (CPP)^1-3 and MTS is a factor in the development of deep-vein thrombosis (DVT), venous claudication, and edema of the left lower extremity.^4,5 The situation changed within the last decade with the publication of studies^6-8 reporting case series of the combination of PCS and MTS; at that time, the main clinical end point was pelvic pain, not the symptoms of chronic venous disease (CVD) or venous thrombosis. The paradigm shift was reflected both in the updated Clinical, Etiology, Anatomic, Pathophysiology (CEAP) classification⁹ and in changes in terminology, as well as in the direction of research.^10,11 The authors proposed use of the umbrella term “pelvic venous disorder” (PeVD) to describe various disorders of the pelvic veins (PCS, MTS, nutcracker syndrome, and ovarian vein syndrome). Despite a significant number of studies on the diagnosis and treatment of MTS and PCS, more and more questions arise about the optimal method for assessing the degree of stenosis of the left common iliac vein (CIV) and the approaches to treatment of patients with a combination of MTS and PCS. This article aims to provide an overview of current trends in the diagnosis and treatment of the combination of MTS and PCS.

Epidemiology

The reported prevalence of MTS varies widely from 4% to 60% depending on the degree of CIV stenosis and the size of the studied population.^12,13 In the study of Kibbe et al, a narrowing of the left CIV of greater than 50% was identified in 24% of patients, and stenosis greater than 25% was diagnosed in 66% of the examined asymptomatic patients.¹⁴ Liu et al reported the presence of MTS in 11% of symptomatic patients.¹⁵ PCS is diagnosed in 15% of women of reproductive age and in 30% of women seeking medical help from a gynecologist for CPP.¹⁶ According to different authors, one in every 10 women has a dilation of the gonadal veins (GV), and 60% of them eventually develop PCS.^17,18

However, the real prevalence of the MTS and PCS combination is difficult to determine, as the screening for pelvic venous disease in a large population requires reliable imaging techniques. Pelvic vein dilation or left CIV stenosis does not necessarily indicate the presence of PCS or CVD.^19,20 As such, the prevalence of combined MTS and PCS is mostly reported for certain groups of patients, most often with CPP or DVT. Thus, in a study of 277 patients with pelvic venous insufficiency, Santoshi et al reported an 80% prevalence of CIV stenosis greater than 50%.⁸ According to data from our clinic, the prevalence of combined MTS and PCS in patients with CPP is 23%, and 8% of patients have a left CIV stenosis greater than 50% as assessed by multiplanar pelvic venography (MPPV).²¹

Pathophysiology

The morphological substrate of MTS is the narrowing of the left CIV lumen due to its pulsatile compression between the overlying right iliac artery and the fifth lumbar vertebrae. To date, it is unclear why some patients with MTS present with CVD symptoms and signs while others develop PCS. Probably, in patients with MTS, the lesion of the left internal iliac veins (IIV), parametrial veins (PV), uterine veins (UV – uterine veins), and GV is one of the variants of the disease course, which is genetically determined (Figure 1). It can be speculated that, in such patients, the valves in IIV, PV, GV are absent or underdeveloped, and with worsening stenosis, blood reflux initially occurs in the left IIV and triggers a cascade of abnormalities in other veins.

Figure 1. Pelvic venography. (A) Direct projection. (B) Lateral projection. 1, dilated left common iliac vein; 2, dilated left internal iliac vein; 3, reflux of contrast media in the left iliolumbar vein; 4, compression of the left common iliac vein by the right common iliac artery.

Classification

The symptomatic and asymptomatic course of MTS is distinguishable, which largely determines treatment strategy. Conventionally, left CIV stenosis is considered hemodynamically significant or insignificant if a reduction in lumen diameter is greater or lesser than 50%, respectively.^8,12 Significant CIV stenosis requires intervention, whereas insignificant CIV does not affect blood outflow from the pelvis and lower extremities. Patients with a combination of MTS and PCS should be classified using the updated revision of the CEAP classification.⁹ Although the clinical part of that classification section does not include symptoms and signs of PCS, the other three parts are quite applicable for such patients. Meissner et al proposed a new classification of pelvic venous disorders (PeVDs),¹¹ which includes the following three domains: Symptoms (S), Varices (V), and Pathophysiology (P), with the pathophysiology domain encompassing the Anatomic (A), Hemodynamic (H), and Etiologic (E) features of the patient’s disease. An individual patient’s classification is designated as SVP A, H, E. For patients with pelvic origin of the lower-extremity signs or symptoms, the SVP classification is complementary to and should be used in conjunction with CEAP classification. Indeed, the development of the SVP classification is an important step forward in the implementation of new terminology and stratification of patients with PeVD. Whereas it is the first that is focused on pelvic venous insufficiency; it does contain controversial statements and generalizations that require further clarification. It is appropriate here to recall the well-known quote from Albert Einstein: “Everything should be made as simple as possible, but no simpler.” Nevertheless, it should be recognized that the foundation for further research has been laid and clinicians now have something to work on.

Clinical manifestations

Regarding clinical manifestations, it’s better to start not with the description of venous-specific symptoms and signs, but with a presentation of the general status of patients with a combination of MTS and PCS. Typically, they are young women aged 25 to 40 years who have given birth several times, who have a low body mass, bad mood, and are presenting numerous emotional complaints. Exaggerating, I would designate three signs of such a woman: young, thin, and angry (or emotionally labile). This is supported by studies that indicate that patients with PCS have a reduced body mass index.²² Behavioral changes are understandable, as long-term pelvic pain affects the personality.²³

Patients with a combination of MTS and PCS most often have symptoms and signs of venous congestion of the pelvic organs, such as pelvic pain, feeling of heaviness or discomfort in the hypogastric region, coital and postcoital pain, urination disorders, vulvar varicose veins, and varicose veins on the posterior surface of the thigh.^24,25 Pelvic venous pain (PVP) is typically described as a constant, dull, and aching pain localized in the hypogastric, left or right iliac regions, which increases in the second phase of the menstrual cycle, after static load or physical exertion, and with intake of gestagenic drugs, and decreases when the patient is in the horizontal position, after a night’s rest, and with use of venoactive drugs. The PVP is characterized most often as a dull and aching feeling; however, a number of patients describe pain as stabbing, burning, or cramping.^26-28 PVP is noncyclic pain lasting more than 6 months and arising with dilation of the pelvic veins, which is localized in the lesser pelvis. It worsens the patient’s quality of life and requires medical or surgical treatment.

A feature of dyspareunia in PCS is the persistence of pain after intercourse for a period of time lasting from 15 minutes to a day.²⁹ The superficial dyspareunia, which occurs in patients with vulvar varicose veins, is distinguished from deep dyspareunia characteristic of venous congestion of the uterus. The presence of deep dyspareunia is an unfavorable prognostic sign indicating significant pelvic venous congestion.^26,29,30 Vulvar (gluteal, perineal) varicose veins and varicose veins of the posterior surface of the thigh are pathognomonic signs of pelvic vein abnormalities (Figure 2).

Figure 2. Photos of patients with (A) vulvar varicosities and (B) varicose veins on the posterior surface of the thigh at the confluence with the pelvic veins.

Based on experience from our clinic, where, annually, we treat more than 5000 patients with various venous disorders, it can be argued that symptoms and signs of CVD in patients with a combination of MTS and PCS are rare and in 80% of cases are limited to CEAP class C1.²¹

Other clinical manifestations of the combination of MTS and PCS include urination disorders characterized by frequent urge to urinate.²⁶ This is due to the venous congestion of the bladder wall. Women with MTS and PCS often report various irregularities in the menstrual cycle, including irregular heavy and prolonged periods. Venbrux et al have demonstrated the absence of the effect of GV embolization (GVE) on the menstrual cycle in such patients.³⁶ Dysmenorrhea is likely due more to hormonal disorders than PeVD.

Thus, the clinical manifestations of the combination of MTS and PCS are highly variable and nonspecific. Perhaps only vulvar varicose veins can be used as a pathognomonic sign of such combined lesions. Additional diagnostic tests are required for the timely and precise diagnosis of this combined pathology.

Diagnosis

Detection and assessment of pelvic veins is impossible without the use of ultrasound and radiological techniques. This is determined by the deep location of pelvic veins, the nonspecific clinical picture, and the need to obtain accurate information about the diameters of the pelvic, iliac, and renal veins and to establish the presence and duration of pelvic venous reflux in numerous pelvic veins. This is especially true for patients with a combination of MTS and PCS because the disorders of pelvic vein hemodynamics are the most complex in this category of patients.

Duplex ultrasound scanning (DUS)
Duplex ultrasound scanning (DUS) of the pelvic veins is considered the gold standard method for the diagnosis of pelvic varicose veins.^37,38 With DUS it is possible to measure diameters of pelvic (parametrial, uterine, gonadal) veins, establish the presence of reflux and its duration, as well as objectively assess the state of the left renal vein (nutcracker syndrome) and the patency and diameters of the iliac veins.³⁹ Other advantages of DUS include its noninvasiveness, the reproducibility of results, and the absence of radiation exposure. Disadvantages include operator dependence and the need for bowel preparation and following of a diet before the examination for better imaging of the pelvic veins. Whiteley et al report a high informative value of DUS in detecting pelvic-perineal reflux (PPR) and valvular incompetence of the internal pudendal, obturator, and inferior gluteal veins.³⁷ Our experience with DUS in patients with MTS and PCS suggests the opposite: the reliable imaging of the IIV tributaries with DUS is unlikely and, most importantly, is completely unnecessary.⁴⁰ If the treatment of vulvar varicose veins consists of sclerotherapy or excision of the vulvar veins, the presence of reflux in the IIV tributaries makes no difference. But if the task is localization diagnosis of PPR and embolization of IIV tributaries, pelvic venography is essential. Therefore, there is no point in wasting time and effort to identify reflux in the IIV tributaries using DUS. The main purpose of performing DUS in PeVD is to detect pelvic varicose veins and pelvic venous reflux and to assess the left renal vein (Figure 3).

Figure 3. Duplex ultrasound scanning. (A) Arrows indicate dilated parametric veins. (B) Arrows indicate a dilated left gonadal vein.

Multispiral computed venography (MSCV)
Multispiral computed venography (MSCV) has been successfully used in the diagnosis of venous pelvic disorders. MSCV provides reliable visualization of GV, PV, UV, inferior vena cava, iliac, and renal veins.^30,42-44 MSCV does not allow detection of venous reflux and measuring blood flow velocity; however, it shows venous anatomy very well (Figure 4). The possibility of obtaining frontal, sagittal, transverse, and three-dimensional images also contributes to a qualitative assessment of the status of pelvic veins and to the accurate assessment of the degree of left CIV stenosis. Many authors report a high accuracy of MSCV in the verification of MTS and PCS, as well as the correlation between the results of computed venography and intravascular ultrasound (IVUS).⁴⁵ According to Jayaraj and Raju, three-dimensional computed venography represents a noninvasive and accurate technique for measuring the degree of left CIV stenosis and can be successfully used to determine the required caliber and length of the stent.⁴⁶ It should be noted that the results of MSCV are very indicative in the nutcracker syndrome, and native computed tomography can reveal the pathology of organs and tissues of the abdominal cavity and pelvis.^47,48 This is important for differential diagnosis of the causes of CPP. The disadvantages of the techniques are radiation exposure and the need to use contrast media.

Figure 4. Computed venography. (A) Arrow indicates a dilated left gonadal vein. (B) Arrows indicate compression of the left common iliac vein.

Ovarian venography (OV) and multiplanar pelvic venography (MPPV)
Despite the availability of such high-tech modalities as MSCV, MRI, and IVUS, conventional venography has not lost its relevance to date.^53,54 Until embolization and stenting of veins are used, it will not be possible to refuse venography because it is a part of these procedures. The classic venographic sign of pelvic venous congestion is reflux of the contrast media in the left or right GV with the cross flow of contrast agent to the opposite side through the incompetent PV and UV. Renal venography always precedes left GV imaging in order to detect or exclude stenosis of the left renal vein. Pelvic venography in patients with MTS should be performed in frontal and lateral views. This provides the most accurate assessment of the degree of left CIV stenosis. Signs of hemodynamically significant MTS are narrowing of the left CIV in combination with its prestenotic dilation, substantial reflux of contrast media into the left IIV and visualization of pelvic collaterals, and reflux of the contrast media into the dilated left iliolumbar vein (Figure 5). In addition, during venography, it is possible to measure the pressure in pre- and post-stenotic parts of the left CIV. A pressure gradient greater than 2-4 mm Hg is considered a sign of hemodynamically significant stenosis of the left CIV.⁵⁵

Figure 5. Ovarian and pelvic venography. (A) Arrows indicate dilated left and right gonadal veins. (B) Arrow indicates compression stenosis of the left common iliac vein.

In other studies, the authors report a high correlation between data, obtained by MPPV, MSCV, and IVUS, and indicate the need for the combined use of venography and IVUS.^46,55,60 Forauer et al state that IVUS provides a more precise placement of the stent into the iliac veins, minimizing the risk of developing a jailing effect (overlapping of the contralateral CIV by the stent).⁶¹ However, IVUS also has drawbacks. In particular, the IVUS findings of a significant iliac vein lesion are sometimes not accompanied by any clinical manifestations. Birn and Vedantham propose to match ultrasound and clinical data in order to determine the optimal treatment for a patient with iliac vein lesion.⁵⁵

Therefore, a variety of diagnostic tests including DUS, MSCV, and venography with or without IVUS should be used in patients with concurrent MTS and PCS. IVUS is not a panacea. Our experience suggests that successful diagnosis and treatment of patients with a combination of MTS and PCS is possible without the use of IVUS. Severe symptoms of venous congestion of the pelvic organs and disturbances of pelvic venous blood flow, according to DUS, MSCV/MRV, and venography, substantiate the need to restore blood flow in the pelvic and iliac veins.

Treatment

Regarding a combination of MTS and PCS, we a priori consider symptomatic patients, as PCS cannot exist without pelvic pain, dyspareunia, etc. Furthermore, in such patients, the disturbances in venous outflow from the pelvis are significant, consistently confirmed by the results of ultrasound and radiopaque methods. When choosing a technique for restoring venous outflow from the pelvis in patients with MTS and PCS, the main factors are: (i) the degree of left CIV stenosis; (ii) involvement of GV, as PCS may be a result of an isolated PV and UV dilation without ovarian venous insufficiency; and (iii) the presence of vulvar/gluteal varicose veins, varicose veins on the posterior surface of the thigh, and detection of PPR by imaging.

The indication for endovascular intervention on the left CIV depends on the severity of its stenosis. Carr et al argue that narrowing the left CIV to 4 mm increases the risk of DVT and requires CIV stenting.⁶² Ahmed et al expressed the same opinion about stenting in MTS.⁷ Daugherty and Gillespie considered the following indication for stenting: reduction in CIV lumen diameter to 2–6 mm and stenosis area from 65% to 99% by IVUS.31 For patients in our clinic with a combination of MTS and PCS, we consider compression stenosis of the left CIV greater than 50%, as assessed by venography, to be an absolute indication for stenting.²¹

GV reflux is a significant factor in the development of severe venous congestion of the pelvic organs. Therefore, reduction in blood flow through GV is one of the necessary steps in PeVD treatment. However, in patients with combined MTS and PCS, the role of ovarian venous insufficiency may be secondary. It was shown that isolated excision of varicose tributaries of the great saphenous vein or crossectomy in combination with excision of tributaries (ASVAL [Ambulatory Selective Varicose vein Ablation under Local anesthesia] and CHIVA [Conservatrice Hémodynamique de l’Insuffisance Veineuse en Ambulatoire] methods) is accompanied by restoration of great saphenous vein valvular function in 60% to 70% of cases.^63,64 It is likely that the restoration of normal blood flow in the left CIV would reduce reflux in the left GV. In patients with PCS, we observed the elimination of the dilation of PV and UV and the restoration of their valvular function after GVE.⁶⁵

In patients with PeVD, the occurrence of vulvar varicosities (VV) and varicose veins on the posterior surface of the thigh is associated with reflux in the IIV tributaries (internal pudendal, obturator, and inferior gluteal veins).^66,67 Vulvar vein dilation most often occurs during pregnancy; the rate of its detection in pregnant women ranges from 10% to 20%.⁶⁸ However, in two-thirds of these women, VV disappears after childbirth without any treatment. This suggests that IIV reflux is reversible. Khan et al presented the case of a woman with combined MTS, PCS, and VV⁶⁹ and who had no detectable images of IIV tributaries or PPR on venography despite a severe VV. Our experience shows that the reflux in the IIV trunk, internal pudendal vein, and obturator vein is found in only 8%, 8%, and 6% of patients with VV, respectively.⁴⁰ These data should be taken into account when choosing a method for eliminating VV.

Stenting or embolization?
What is the first intervention to perform in patients with a combination of MTS and PCS? Is it really necessary to perform GVE? Should the IIV inflows be embolized in patients with a combination of MTS, PCS, and VV? These and a number of other questions arise for surgeons when taking into account clinical, ultrasound, and radiological data in this cohort of patients.

Findings from recent studies suggest that CIV stenting is the first intervention on the pelvic veins to perform in patients with concomitant MTS and PCS. Daugherty and Gillespie reported elimination of PCS symptoms in 79% of patients after CIV stenting.³¹ Santoshi et al successfully used isolated CIV stenting in 22% of patients with combined MTS and PCS.⁸ Ahmed et al managed to relieve symptoms of venous congestion of the pelvic organs in 68% of patients with MTS and PCS via stenting and without GVE.⁷ A study by Gavrilov et al showed complete relief of PCS symptoms in 17% of patients with left CIV stenosis.²¹ Lakhanpal et al noted a significant reduction or complete relief of PCS symptoms in 76% of patients.⁷⁰ These data indicate the possibility of curing patients who have a combination of MTS and PCS through CIV stenting alone, without GVE.

In the presence of hemodynamically significant CIV stenosis in these patients, the treatment of choice is stenting of the iliac veins (Figure 6). At the same time, there is a certain proportion of patients (from 30% to 70%) in whom stenting does not significantly improve PCS symptoms. Various explanations include a long history of the disease (more than 5-7 years), incorrectly chosen stent size, and erroneous stent implantation in patients with hemodynamically insignificant stenosis of the iliac veins. Persistence of PCS symptoms after CIV stenting is an indication for GVE.

Figure 6. Pelvic venography (A) before and (B) after stenting of the left common iliac vein. The arrows indicate a stenosis of the left common iliac vein and stents in the lumen of the left iliac veins.

Figure 7. Pelvic venography of a patient with unresolved compression stenosis of the left common iliac vein (indicated by an arrow) after embolization of the left gonadal vein. Marked pelvic collaterals and reflux of the contrast media into the dilated left internal iliac vein are visualized.

Another issue in choosing an optimal stent is braiding and length. A wide range of venous stents have been developed to date. They are distinguished by flexibility, strength, and radial resistance force, and they have various braiding, etc.⁸⁰ The authors recommend using Z-stents. The length of iliac vein stents should be at least 90 mm. The experience of our clinic is based on the use of Wallstent stents (Boston Scientific). These devices have been used in the treatment of MTS for 15 years, and there have been no cases of reported breakage, migration, or thrombosis of these stents.⁷¹

Placement of the stent in the CIV lumen should also be touched on. The ideal position is placement within the immediate area of confluence of the iliac veins. However, this is almost impossible to achieve in real practice because stent placement within the same plane as the CIV orifice is associated with a risk of proximal residual stenosis after stenting. Therefore, most authors recommend placing a stent in a vein so that it protrudes 0.5-1 cm into the lumen of the inferior vena cava.⁷⁸ Other authors point out that even 2-cm displacement of the stent in the inferior vena cava should not be regarded as a serious defect in stenting technique.⁷⁸ The “jailing” effect leads to thrombosis of the contralateral OPV in no more than 1% of cases.⁸¹ This is demonstrated by tomograms of a patient with MTS and PCS who underwent CIV stenting with two stents in our clinic 15 years ago (Figure 8). PCS symptoms were completely eliminated and are absent to date; stents remain completely patent; and there have been no episodes of thrombosis of the iliocaval segment.

Venoactive drugs (VAD) in the treatment of patients with a combination of MTS and PCS
When using endovascular methods of treatment, it should be understood that CIV stenting and/or GVE does not result immediately in a decrease in the diameter of the pelvic veins, elimination of reflux in them, and restoration of venous outflow from the pelvic organs. Given this fact, patients should be advised to take venoactive drugs (VADs); these have a beneficial effect on the walls of the pelvic veins and improve microcirculation in the pelvic organs. The only VAD studied in PCS patients is the micronized purified flavonoid fraction (MPFF). Several studies have shown a positive effect of MPFF on venous outflow from the pelvis, pelvic pain, and other symptoms of the disease.^82-85 This drug is characterized by high efficacy and safety in the treatment of patients with PCS. The use of MPFF in the pre- and postoperative period provides early relief of symptoms of the disease and facilitates rehabilitation of patients with MTS and PCS after endovascular treatment.

Figure 8. Computed tomography in a patient who underwent stenting of the left iliac veins with two Wallstent stents and embolization of the left gonadal vein with coils. (A) Sagittal projection. (B) Frontal projection. The stents are patent. The arrow indicates the “jailing” effect.

Conclusion

It is difficult to address all the issues and nuances of diagnosis and treatment of patients with a combination of MTS and PCS in one review; there are many anatomical and clinical variants of the course of this combined pathology. MTS and PCS are the most common causes of pelvic vein disease. The main directions of research are clear, focusing on the study of pathophysiological processes in PeVD, adequate and reliable diagnosis of disease, and determination of optimal approaches and methods for correction of venous outflow disturbances in MTS and PCS. It is also obvious that these issues are impossible to resolve without international consolidation of the efforts of surgeons, phlebologists, vascular, and interventional surgeons. Large multicenter studies are needed, sharing international experience in the diagnosis and treatment of PeVDs.



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