Servier – Phlebolymphology

Spiro Koustas, MD
Renaissance School of Medicine at
Stony Brook University, Division
of Vascular and Endovascular
Surgery, New York, USA

Nicos Labropoulos, MD, PhD
Renaissance School of Medicine at
Stony Brook University, Division of
Vascular and Endovascular Surgery,
New York, USA

ABSTRACT

Residual edema is often found after venous interventions. Although several reports mention residual edema, it has not been studied thoroughly and is frequently underreported. There are many reasons for which residual edema occurs and why it is often not emphasized. Such edema is obvious after the intervention, and it can worsen with time. One important reason is the treatment itself that can be inadequate, incomplete, or even inappropriate. Continuity of care, addressing remaining disease, and using compression and medication to reduce inflammation and edema play an important role too. Venous disease may have been long-standing, leading to phlebolymphedema, which is not fully reversible as the lymphatic vessels are permanently damaged. Systemic conditions that are associated with edema are also responsible. Furthermore, patient factors such as lack of physical activity, obesity, and musculoskeletal issues limiting mobility and impairing the muscle pump function contribute as well. Use of different types of medications that are responsible for causing edema should also be considered. The coexistence of lymphedema and lipedema with venous disease can explain the limited response of venous interventions. In a good number of patients, there is idiopathic edema that can be unrelated to venous disease. A good evaluation should be performed, and the practitioners should set the right expectations for patients treated for chronic venous disease.

Introduction

The various treatments for edema in patients with chronic venous insufficiency (CVI) focus mostly on the venous system for resolution. However, residual edema is often found after venous interventions. Although several reports mention residual edema, it has not been studied thoroughly and is frequently underreported. It is important to delve into factors that may contribute to residual edema after venous interventions that may in turn lead to better patient outcomes. CVI has been recognized as a leading cause of secondary lymphedema.¹ This is significant, as even after appropriately treating the venous disease, unabated venous hypertension can cause permanent lymphatic impairment, yielding residual edema.^2,3 Edema has different causes and clinical presentations. It may sometimes regress but in general if there is chronic cause it usually gets worse over time. Even in patients that are properly selected to undergo venous interventions the multitude of causes for edema that coexist with venous disease can make it harder to treat. These are very common, such as obesity, restricted mobility, lymphedema, lipedema, systemic organ failure, vein disease that has not been addressed and of course idiopathic edema where a cause cannot be identified.

CVI is a complex condition characterized by impaired venous return, leading to a spectrum of clinical manifestations. It includes CEAP (clinical-etiological-anatomical pathophysiological classification) classes from C3 to C6.⁴ Consequently, when treating such patients, it is crucial to reduce, and ideally eliminate, the edema.

Although addressing the underlying venous hypertension often leads to improvements in venous-related symptoms, such as claudication and venous ulcers, a notable proportion of patients with CVI may continue to experience persistent swelling. This ongoing edema may indicate the presence of untreated lower-extremity dysfunction. There are several factors associated with residual edema after venous interventions. This paper analyzes when and why residual edema occurs after venous interventions.

Clinical vignette

A 74-year-old female patient presented to our institution with symptomatic varicose veins in her right lower limb; they had been present over the previous 40 years.

Her past medical history included hypertension and hyperlipidemia, both of which were well controlled with medication. She had a body mass index (BMI) of 27, was a nonsmoker and had a maternal history of varicose veins. She had 3 children through normal pregnancies and deliveries. Varicose veins became gradually worse after the pregnancies. She developed discoloration about 10 years ago.

Her symptoms included swelling, itching, heaviness, skin discoloration, and pain, particularly after prolonged standing. The symptoms were most severe at the end of the day when the veins were most enlarged (Figure 1). The left lower limb also had varicose veins, though they were only mildly symptomatic. Her only treatment to date had been compression therapy, though she had not been adherent to this treatment.

The patient came to the clinic because of a bleeding varicosity in the medial malleolus (Figure 2). Discoloration was seen, particularly in the medial aspect of the limb extending from the foot to the upper calf. On palpation, the area in the lower calf and medial malleolus was hard, indicating chronic fibrosis. Clinical examination revealed equal thigh diameters, but the right calf and ankle were 3 cm larger in circumference compared with the left.

Figure 1. Large viscosities present in calf.

Figure 2. Bleeding point on varicose vein (arrow).

She underwent treatment with thermal ablation of the GSV and multiple phlebectomies to address the affected tributaries. The areas of skin damage were subsequently treated with ultrasound-guided foam sclerotherapy (UGFS).

She required additional treatment for the tributaries at 8 and 17 months. At a follow-up 2 years after the initial treatment, she reported symptomatic improvement, and the edema in her right limb was reduced. Before treatment, the right calf and ankle were 3 cm larger than the left in circumference. After the treatment, the right calf was 1.5 cm and the ankle was 2 cm larger than the left. Like many patients treated for CVI, our patient also has residual edema, despite receiving the appropriate care.

Figure 3. Ultrasound images of the great saphenous vein (GSV) and subcutaneous tissues. A) Enlarged GSV diameter in the upper cuff measuring 8.6 mm. The subcutaneous tissues have normal echotexture at this level. B,C) Reflux is shown in a GSV tributary at the medial malleolus. D) GSV in the distal calf was enlarged measuring 4.7 mm. The echotexture of the subcutaneous tissues here is abnormal, showing dense fibrosis. E) Magnified view of the subcutaneous tissues showing dense fibrous tissue and pockets of fat.

Figure 4. CEAP (clinical-etiologicalanatomical-pathophysiological) classification, and duplex ultrasound findings. Red color indicates the vein segments with reflux. Blue color represents normal veins. The GSV diameter ranged between 4.7 mm and 8.6 mm. The GSV at the knee was found to be aplastic (white color). There was long duration of reflux in all vein segments exceeding 5 seconds. The deep veins in the abdomen, pelvis, and lower limb were normal. Abbreviations: IVC: inferior vena cava; SSV: small saphenous vein.

Initial assessment

Lower-limb edema is common and has a wide range of possible causes. This often makes diagnosis challenging, particularly when multiple etiologies coexist. On initial evaluation, a thorough medical history should be taken, along with an assessment for systemic diseases. The laterality of symptoms can aid diagnosis. Unilateral symptoms may suggest causes such as thrombosis, venous insufficiency, or venous and lymphatic obstruction, while bilateral symptoms are more likely to indicate systemic conditions such as heart failure, renal or hepatic disease, thyroid disorders, or sleep apnea.^5-8

A thorough review of medications is necessary to identify potential contributors such as antihypertensives (in particular calcium channel blockers), corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), hormonal therapy, and chemotherapy. The mechanism often involves retention of salt and water with increased capillary hydrostatic pressure or volume depletion seen with diuretics, which stimulates the renin-angiotensin system.⁵

Furthermore, a thorough physical examination should be performed. Assessment of the distribution, extent and severity of the swelling, including ankle, calf, and thigh circumferences, using a standardized method to monitor treatment response, is important. The time of onset and duration is also significant. It is necessary to separate recent onset from chronic swelling and determine their causes. For example, recent-onset swelling is often due to deep venous thrombosis (DVT), whereas postthrombotic changes would be responsible for chronic swelling.

Examination of the skin of the lower extremities can help identify the underlying cause of the edema. Indicators of venous insufficiency include varicose veins, hyperpigmentation, eczema, atrophy blanche, lipodermatosclerosis, and ulcers. Thin, shiny skin with bilateral edema and pretibial myxedema may indicate endocrine disorders. Obesity can also cause bilateral swelling with skin changes similar to venous insufficiency, even without venous disease.⁸ The causes are discussed below.

Venous

Patients with persistent edema after venous interventions may have underlying venous etiologies related to reflux, obstruction, or both.

Residual edema after treating reflux disease may result from ineffective, incomplete, or even inappropriate treatments. In patients for whom conservative care of reflux disease is unsatisfactory, endovenous ablation therapies are recommended. Shutze et al, found that 75.8% of patients experienced a reduction in or resolution of swelling after endovenous laser ablation (EVLA) for saphenous vein reflux.⁹

Additionally, some patients may not report resolution of edema immediately after the intervention, but report a gradual reduction in swelling over time. Studies have shown that this improvement could continue for up to 2 years post treatment.^10,11 However, Proebstle et al demonstrated that when followed-up for up to 4 years, some patients begin to show worsening of symptoms.¹¹

A possible explanation for the residual edema could be the presence of deep venous reflux as shown by Puggioni et al.¹² Another reason for residual edema is incomplete treatment of saphenous tributaries, accessory, and nonsaphenous veins. For example, if the reflux involves the anterior accessory saphenous vein (ASV) instead of or in addition to the GSV, then performing laser ablation to the GSV may be inadequate.^13,14 Moreover, failure to identify central obstruction or postthrombotic vein disease, is a common cause for residual edema even when reflux is eliminated in all the superficial veins. In such cases, wrong expectations may be set for the patient.¹⁴ Recanalized vein segments with reflux may also be responsible for the residual edema. Therefore, evaluation of patients for suspected vein disease both in the limbs and suprainguinal veins is warranted as often can be treated. Additionally, development of new disease may worsen existing edema.⁹

When treating patients with venous obstruction, common pitfalls resulting in residual edema include inappropriate selection of patients, incomplete treatment, failure to identify anatomical variants, and recurrence of disease. In patients with inferior vena cava (IVC) or iliac vein obstruction, the primary treatment strategy focuses on treating the obstruction. This intervention is targeted in patients for whom the edema is symptomatic, impacting their quality of life, and who do not effectively respond to conservative management. Anomalies of the IVC and its tributaries is reported to affect 0.3% to 10.14% of the population. Patients with IVC hypoplasia and aplasia are frequently associated with lower-limb edema. Such patients often develop DVT at a young age, which is an additional factor for edema. Through awareness and detection of such anomalies, one can alter treatment strategies to better manage the patient.¹⁵ Patients with nonthrombotic obstruction often have positional iliac vein stenosis, and stenting of these patients is inappropriate.^16,17 Other cases of inappropriate treatment include placing stents in patients with primary lymphedema or in patients with systemic causes of edema such as heart failure. Furthermore, patients with poor inflow may not respond well when treated with stents, resulting in high failure rates. Even if central vein obstruction is appropriately treated, edema may persist due to chronic postthrombotic changes in the infrainguinal veins. It should be noted that errors in diagnosis and treatment strategies are common and thus the patients need to be carefully reevaluated to treat all the underlying causes.

Lymphedema

Although the treatment of underlying venous hypertension can lead to the alleviation of venous-related symptoms, such as claudication and venous ulcers, a considerable proportion of patients may experience residual edema, indicative of possible untreated lymphatic disease.¹⁸

Increased hydrostatic venous pressure results in the accumulation of fluid in the interstitial tissue that relies on lymphatics for drainage. Under normal conditions, the lymphatic vessels manage this fluid by maintaining higher interstitial pressure, compared with luminal pressure, facilitating drainage. Edema occurs when the accumulation of fluid surpasses the lymphatic system’s drainage capacity.^19,20 In early stages, the edema can be reversible. However, when these conditions persist over time, as in CVI, irreversible lymph vessel damage may ensue. This condition is known as phlebolymphedema and is common in patients with long-standing CVI.

Previous reviews have demonstrated that up to 35% of patients with lower-extremity edema continue to experience residual persistent edema after venous stent placement. The implementation of lymphedema-specific treatment in these patients demonstrated significant benefits with improvement of symptoms and a decrease in lymphedema associated complications.^18,21 Other studies observed that a delay in initiating lymphedema treatment after venous intervention suggested underrecognition of coexisting lymphedema and may explain the limited response of venous interventions.¹⁸

Lymphedema management should be considered for patients with residual edema that persists despite adequate venous therapy, particularly when accounting for other comorbidities. Further research is needed to determine the optimal treatment approach for patients with CVI-associated lymphedema (CVI-LED).

On some occasions, patients with primary lymphedema may have varicose veins. When the latter is treated, residual edema is present due to the former pathology.

Obesity

Obesity is increasingly recognized as a significant risk factor for lymphedema, as it can lead to damage of the lymphatic vasculature and impair lymphatic function.²² The mechanisms behind this impairment include an increase in inflammatory cells around lymphatic vessels, elevated levels of T cells, and higher nitric oxide synthase activity.²³

An increasing BMI is associated with a higher risk of developing lymphedema. Research suggests that there may be a specific threshold of BMI beyond which lymphatic dysfunction in the lower extremities becomes more prevalent.²⁴

In a large-cohort study completed by van Rij et al, CVI was more severe in the obese, and ulcer disease was more frequent. In their smaller study group, weight correlated positively with the diameter of the femoral vein, ambulatory venous pressure, venous filling index, and calf pump ejection volume.²⁵ All of these would additionally contribute to the presentation of edema.

This is also evident in the outcomes of chronic venous disease (CVD) treatments. Research indicates that a progressive increase in BMI adversely affects treatment outcomes for CVD. Deol et al, found that outcomes, as measured by the revised venous clinical severity score (rVCSS) and CEAP classification (both of which assess edema), deteriorate significantly when BMI exceeds 35, and are markedly poor with a BMI above 46. The venous interventions in that study included endovenous thermal ablation (TA), phlebectomy, or UGFS.²⁶

Consequently, weight loss strategies are often recommended as a preliminary approach before pursuing other treatment options.²⁶

Musculoskeletal

Immobility and gait disturbances can contribute to lower-limb edema. A sedentary lifestyle, where the lower limbs remain stationary for extended periods without active movement, can lead to venous stasis.²⁷ Anatomical problems affecting the calf muscle pump can further increase venous hypertension. Dysfunction of the calf muscle pump is a recognized factor in CVI. Back et al²⁸ and Williams et al²⁹ found that limbs affected by CVI exhibit significantly reduced ankle range of motion (ROM), reduced calf muscle ejection fraction, and an increased venous filling index. This becomes more pronounced as CVI severity progresses. The increased swelling along with valvular incompetence, which result in reduced plantar flexion and dorsiflexion, are linked to impaired calf muscle pump function in CVI-affected limbs.^28,29

Additionally, static foot disorders (SFD) can be an important risk factor that adversely affects CVI and edema. When the sole of the foot contacts the ground, the lateral plantar veins are emptied, returning blood up into the posterior tibial veins. Uhl et al, showed a significant relation between the severity of CVI and patients with SFD such as hollow and flat feet, highlighting the role of the foot venous pump which is crucial in patients with edema.³⁰

Diagnostic investigations are often limited, and the condition is typically diagnosed by exclusion after ruling out anatomical venous issues.

Postoperative care

Several mechanisms have been proposed to explain the development of lower-limb edema following intervention. Post operative care is crucial in reducing complications, including edema, and may even prevent the onset of new edema.

Graduated compression is universally recommended for both surgical and nonsurgical treatment of venous pathologies.³¹ Most guidelines recommend posttreatment compression after venous interventions, such as high ligation and stripping, endovenous thermal ablation, and sclerotherapy. Weiss et al showed a decrease in the incidence of side effects including bruising, telangiectatic matting, hyperpigmentation, ulceration, and edema after sclerotherapy.^32,33 The degree and type of compression used have also been discussed as possible causes of persistent edema.

However, the optimal duration of compression therapy remains unclear. As venous interventions have become increasingly minimally invasive, the expected side effects have decreased, making the need for prolonged compression less certain. Nonetheless, studies suggest that compression therapy still provides benefits during the first week after most interventions.³⁴

Overall, adherence to postoperative instructions—such as the use of compression stockings, leg elevation when feasible, participating in postoperative exercise programs, and adhering to antithrombotic therapy when appropriate— contributes to the management of edema.

Conclusion

Residual edema is often found after venous interventions. The diagnosis and evaluation of lower-extremity swelling require a comprehensive approach including a thorough patient history, physical examination, laboratory tests, and imaging workup. It is essential to employ efficient and accurate strategies to diagnose its underlying cause(s) and provide evidence-based treatment recommendations. This in turn may reduce the incidence of residual edema after an intervention.

It is vital to have open discussions with patients regarding the potential outcomes of CVD treatments. As discussed, the reason for residual edema is often multifactorial and it can be difficult to cure by treating only one underlying cause. Clinicians should set realistic expectations for patients undergoing such treatments.



CORRESPONDING AUTHOR
Prof Nicos Labropoulos
Division of Vascular and Endovascular
Surgery, Department of Surgery, Health
Sciences Center T19-090, Stony Brook
Medicine, Stony Brook, NY 11794-8191,
USA
EMAIL: nlabrop@yahoo.com


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