Which symptoms are more likely to forecast the evolution of chronic venous disease to the advanced stages?



Stavros K. KAKKOS MD, PhD, RVT

Department of Vascular Surgery – University Hospital of Patras – GREECE

Address for correspondence: Stavros K. Kakkos, MD, MSc, PhD, RVT, Department of Vascular Surgery, University Hospital of Patras, Patras, 26504, Greece (email: kakkos@upatras.gr)

 

Abstract

In order to discuss which symptoms may best predict progression of chronic venous disease (CVD) to advanced stages we must first consider the complexity of the disease and the diversity of symptoms, and the terms used to describe these symptoms should be clarified. It is also necessary that leg symptoms can be correctly attributed to venous disorders, as the association of leg symptoms with CVD is known to be difficult. The SYM Vein Group has tackled this challenge, making easier the identification of patients at risk of developing ulcers. Nevertheless, so far there is only preliminary data, which seem to suggest that some venous symptoms can increase the risk of developing chronic venous insufficiency; however, findings are influenced by the methodology used for assessment of venous symptoms in those studies, which were carried out before publication of the SYM Vein consensus statement. Here, we highlight the need for new assessment and new surveys that take each symptom and its severity into account individually.
 

Introduction

Chronic venous disease (CVD) is a common problem affecting a large number of individuals in Western societies, and over at least half a century, heredity, occupation, and pregnancy have been implicated as risk factors.1 Irrespective of its clinical presentation—ie, in asymptomatic patients (though the disease very often still causes cosmetic concerns); in patients with symptoms or signs related to CVD; in patients that have developed specific complications, such as superficial vein thrombosis or external bleeding—both the physician and patients are usually aware of the progressive nature of CVD. This fact in turn aggravates the potential distress associated with CVD because it is seen as a precursor of deterioration in cosmetic appearance, quality of life, and health status in general. It is well-known that progression of CVD occurs rapidly during pregnancy due to hemodynamic and hormonal reasons and that there is potential for regression after delivery.
 

Description of symptoms attributed to CVD

Before making any association between an individual symptom and disease progression in patients with CVD, it is imperative to briefly discuss the symptoms, as described in the 2016 SYM Vein consensus statement developed under the auspices of the European Venous Forum.2 SYM Vein provided the first detailed description and definition of venous symptoms. Venous symptoms have been underestimated for decades, although clearly described in the literature for a long time. 1 This was probably because priority had been given to prevention of leg ulceration, which occurs more frequently in CEAP class C3 and C4 patients (class based on presentation severity in the following areas: C, clinical; E, etiology; A, anatomy; P, pathophysiology) and is not related to the presence of CVD symptoms that are improved with elastic stockings or venoactive drugs.3,4 It is also possible that because of the subjective nature of CVD symptoms, often exaggerated by patients seeking treatment, these symptoms were not taken seriously. Nevertheless, the wide use of minimally invasive methods, such as endovenous methods and foam sclerotherapy, grew to include treatment of patient groups previously turned down for saphenectomy. In the SYM Vein consensus statement, the process of attributing leg symptoms to venous disorders was described, and the pathophysiology of individual venous symptoms was extensively reviewed. Individual symptoms described in SYM Vein were pain or aching, throbbing, tightness, heaviness, fatigue, feeling of swelling, cramps, itching, restless legs, tingling sensation, and heat or burning sensation. Equally important are the secondary symptoms (eg, feelings of disquiet, malaise, insomnia, ill-being, etc) and the specific complaint of venous claudication. In a large study on 6009 patients, the most common symptoms were leg heaviness (70.4%), pain (54.0%), and sensation of swelling (52.7%).5
 
Major issues in the assessment of venous symptoms include the difficulty at times in distinguishing them from symptoms related to other diseases. 6 Furthermore, human factors may influence how both patients and practitioners describe, interpret, express, and use these symptoms, and are clearly discussed in the SYM Vein consensus statement.2 These factors include the following:

      – Language and culture.
      – Levels of tolerance to unpleasant experiences. This determines whether or not a symptom and its level of effect are reported.
      – Previous experience—duration and intensity. This influences the choice of words.
      – Psychosocial gains. This may influence the choice of symptoms reported, in order to obtain empathy and support.
      – Economic gains. This also affects how symptoms are described.
      – A patient’s or practitioner’s belief regarding the relationship of symptoms to a CVD. This influences the symptom described and its severity.
      – The perceived importance of venous disorders.
      – Psychological dysfunction. This may at times contribute to misperceptions of symptom cause and severity.
      – Influence of fear due to family history, for example, a fear of future risk of developing ulceration.

 
As a result of the bias introduced, associations between the various venous symptoms and end points of research may not be clearly significant, as a different amount of bias may exist for different symptoms.
 

Pathophysiology insights

Pain or aching, tightness, heaviness, and feeling of swelling are more likely to be the result of venous hypertension, although pain may be the result of coexisting vascular inflammation. On the other hand, cramps, restless legs, tingling sensation, and heat or burning sensation may be related to secondary neuropathy as a result of CVD. Itching and a heat (or burning) sensation are probably related to the local temperature of the skin and might represent localized vascular inflammation aggravated by increased ambient temperature. Leg fatigue is thought to be the end result of the presence of one or more symptoms.2
 
A key component of vascular inflammation leading to certain symptoms is leukocyte-endothelium interaction, which includes a sequence of events, ie, leukocyte trapping/adhesion, migration, endothelial activation, and release of inflammatory mediators in the microcirculation.7 Venous hypertension, venous stasis with hypoxia, and altered shear stress are considered the key reasons responsible for the initiation of the vascular inflammation process described above. Inflammatory mediators such as bradykinin, serotonin, prostaglandin, leukotrienes, platelet-activating factor (PAF), and interleukins secreted by leukocytes have been implicated in the activation of nociceptors, which results in diffuse nonlocalized pain. It is thought that pain is the result of activation of sensory multimodal nociceptors of myelinated Ad and unmyelinated C nerve fibers. Vascular inflammation may be responsible not only for patient symptomatology but also for alterations in the macrocirculation with remodeling of the venous wall and valves (elastic fiber fragmentation, smooth muscle differentiation and migration with extracellular matrix alteration and fibrosis), which in turn aggravates venous hypertension, ie, is related to CVD development and progression. More work on the genetics of varicose veins and progression is required, 8,9as a positive family history of CVD is a predictor of progression.10
 

Ultrasonographic progression

In a prospective study of progression of reflux patterns in saphenous veins of 92 women with chronic venous valvular insufficiency, great saphenous vein segmental reflux was most prevalent initially, progressing to great saphenous vein multisegmental reflux.11 Unfortunately, the frequency and role of symptoms was not reported. In another study, 73 limbs in patients who had venous surgery in the contralateral leg were followed-up for 5 years, and 48 new sites of reflux (affecting the superficial system in 37 cases) were observed in 38 limbs (52%).10 Obesity, prolonged standing, and noncompliance with elastic stockings were independent risk factors for CVD progression. Unfortunately, the correlation between overall venous ultrasound findings (reflux + obstruction) and venous clinical severity score was weak in one study (r=0.23, P<0.0001),12 indicating a poor prognostic role of venous symptoms, a constituent of venous clinical severity. However, another study on the progression of CVD showed that in patients with new signs or symptoms during reexamination, new ultrasound findings were encountered in 54%, compared with 23% in patients without new symptoms (P=0.04), although a predictive role for any baseline symptom was not reported.13 In the same study, progression affected mostly the saphenous trunks or their tributaries.
 

Association of symptomatology with CVD clinical class and severity scoring

In everyday clinical practice, phlebologists and other vascular specialists are faced with the multifaceted presentation of venous disease. Extensive varicosities are very often entirely asymptomatic; on the other hand, relatively small varicosities can cause significant symptoms. Although exaggeration of symptoms may hold true for those patients seeking active treatment (systemic bias) and there may be variability in patient perception (random bias), these are valid observations. Additionally, a seeming paradox may exist: symptoms in patients with CVD occur more frequently in those with advanced stages of CVD, 14,15 but these tend to be less severe in advanced CEAP clinical classes. 16 This apparent paradox is thought to be a result of an altered perception of pain during the course of the disease or to an increased threshold as a result of neuropathy. Furthermore, venous symptoms are not specific and are sometimes difficult to distinguish from symptoms caused by other diseases. It is obvious that all of the above associations, observations, and facts should be viewed as confounders in the quest for candidate symptoms associated with CVD progression. In general, it has been reported that CVD symptoms did not change in a large series of patients awaiting surgery with a high frequency of progression to skin changes and ulceration. 17 However, the association of a specific symptom with progression was not reported.
 

Frequency of progression

In a study involving 304 patients with varicose veins, 4% of
them developed venous ulceration and 22%, skin changes while on the waiting list for a median of 4 years.17 In a crosssectional study in 114 patients with venous ulcers and a control group of 352 patients with varicose veins and without leg ulceration, venous ulceration developed mainly due to primary varicose veins, and its risk increased with age. 18 In the Edinburgh Vein study in 334 subjects with varicose veins followedup for 13 years, progression was observed in 58% (4.3% per year). 19 Assuming that the last study included mostly asymptomatic individuals with a CVD, the lower rate of progression than that observed in the previously mentioned study on symptomatic patients (6.5%)17 indicates that progression of varicose veins occurs irrespectively of the presence or absence of symptoms, albeit at a higher rate in the former group, acknowledging the fact that these two studies are not directly comparable. As a result, the asymptomatic individuals may still be offered regular follow-up appointments or at least warned to come back if they experience deterioration of their clinical status, including development of symptoms. This otherwise simplistic observation requires confirmation before formal advice is given to stakeholders and interested individuals.
 
Bonn Vein Study I, conducted in the year 2000, included 3072 participants—aged 18 to 79 years—of the general population of the city of Bonn and two rural townships. Participants were selected by simple random sampling from the registries of residents. In this follow-up study, 6.6 years later, the same population was investigated again to identify the incidence of newly developed CVD and of progression of preexisting CVD. Between May 2007 and September 2008, all Bonn Vein Study I participants were invited for a reinvestigation. The response at follow-up after 6.6 years was 84.6%, and 1978 participants were reinvestigated. The incidence for new varicose veins was 13.7% per 6.6 years, and for new chronic vein insufficiency (CVI), it was 13% per 6.6 years.20 The authors concluded that there was a high incidence of about 2% per year for varicose veins and for CVI.
 

Factors associated with progression of CVD

It is very important to clearly define the baseline CVD stage of patients who progress, and it is equally essential to report the CVD stage these patients progress to, as previously reported by others. 10,13Therefore, C0s and C1s patients may progress to C2s disease. Similarly, C2s patients may progress directly to C3, C4, or C6 disease; C3s patients may progress to C4 or C6 disease, and C4s patients may progress to C6 disease. Obviously, in very few patients, symptoms may fade away after evolution, which explains the absence of a designation for symptoms after progression in these examples.
 
Although not explicitly stated in studies on CVD progression, the presence of edema, which is the hallmark of C3 disease, is usually accompanied by patient complaints, including sensation of leg edema and heaviness. C3 patients, including those with sensation of leg edema and heaviness, are prone to develop progression to a venous ulcer. A well-known source of information on progression of varicose veins is the waiting list for surgery21; however, this is biased because of the selected population. Having said that, these lists mostly contain symptomatic patients, and it is a pity that specific information in the form of stratification by type of symptoms was not provided.21
 
In a case-control study involving 120 patients with an active or healed venous leg ulcer and 120 controls with varicose veins and no history of venous ulceration, skin changes including lipodermatosclerosis, corona phlebectatica, and eczema; higher body mass index (BMI); and popliteal vein reflux remained independently associated with increased risk of ulceration. .22 On the other hand, good dorsiflexion of the ankle and an effective calf muscle pump remained protective factors. Obviously, these predictors should be verified in a longitudinal study, which should additionally evaluate the predictive role of venous symptoms.
 
In a prospective 5-year study of 96 limbs, the progression of CVD was reported to be more rapid in postthrombotic limbs than in those with primary CVD. Prognostic factors for progression to advanced CVD were the combination of reflux and obstruction, ipsilateral recurrent deep venous thrombosis (DVT), and multisegmental involvement.23
 
In the large Edinburgh Vein study in 334 subjects with varicose veins followed-up for 13 years, family history was the only independent risk factor for progression in patients with varicose veins at baseline.19 The presence of reflux in the superficial system increased the possibility of progression, particularly when it was combined with deep reflux and affected the small saphenous vein.24 Again, baseline symptoms were not reported.
 
Additional information may be taken from studies on the general risk factors for development or recurrence of varicose veins. In a study on risk factors, female sex, increasing age, a reported positive family history for varicose veins, increasing number of births, standing posture at work, and increased weight and height were associated with varicose veins.25 In the Edinburgh Vein Study, the incidence of CVI increased consistently with age and obesity, and participants with a family history of venous disease were more likely to develop C2 varicose veins.26 Residual, uncorrected venous hypertension—in the form of a failed open surgery or endovascular ablation of the superficial venous system, intentionally untreated saphenous stems27,28or deep vein incompetence or obstruction—is strongly correlated with recurrent CVD. These observations strongly support the notion that underlying major hemodynamic mechanisms are related to postintervention recurrent CVD. Similarly, the severity of underlying hemodynamic pathology may be well associated with CVD progression. Having said that, the fast progression of CVD seen during pregnancy is attributed to hemodynamic (and hormonal) reasons, which supports the above statement.
 
A reanalysis of the Basel study (1441 participants with followup in 1982, ie, 11 years after recruitment in 1971) was presented several years ago at the 21st Annual Meeting of the American Venous Forum in Phoenix, Arizona, in the United States and was published in the abstract book of the meeting.29 This study reported that on multivariate logistic regression analysis, venous symptoms predicted the development of venous edema (odds ratio 4.08) but not that of varicose veins in patients we nowadays would call C0s or C1s. Unfortunately, no information was given on the predictive role of specific venous symptoms. Nevertheless, the results are in agreement with the clinical experience of C3 patients without visible or palpable varicose veins; this is probably a result of variation in CVD distribution affecting mainly the large veins. Corona phlebectatica, on the other hand, predicted the development of skin changes. A preliminary analysis of the Bonn Vein study published in an abstract form reported that age, obesity, and hypertension were the only predictors of progression, but it was not specified whether venous symptoms were taken into account.
 
Micronized purified flavonoid fraction (MPFF), consisting of diosmin plus hesperidin, is an effective medication to improve not only patients’ symptoms but also quality of life.30,31 Incompetent valves in small veins and venules may be the target of MPFF and other venoactive medications in order to reduce vascular inflammation related to symptomatology and potentially to CVD progression.32,37 Also, transient venous reflux (ie, reflux observed only in the evening after prolonged periods of standing), which occurs in about 50% of C0s and C1s patients, can be eliminated with MPFF in 93% of all patients, leading to symptomatic improvement in 89%.38 Potentially, progression of venous disease may be halted with MPFF, but obviously, this hypothesis needs formal testing by a double-blind placebo-controlled trial. Similarly, MPFF may be used after ASVAL treatment (ambulatory selective ablation of varices under local anesthesia), known to improve venous function,39 or knee-length stripping of the great saphenous vein, known to be associated with residual reflux below the knee and symptoms,40 in an effort to reduce disease progression, pending proper testing of these hypotheses.
 

Interpretation of the available evidence

Symptoms of CVD have been known for decades if not centuries. However, it is only recently that a systematic description of them was published in the form of a consensus statement.2 Very often, one or more coexisting symptoms are intense enough to affect quality of life, calling for medical, surgical, or endovascular intervention. Since CVD is a progressive disease, patients frequently ask about this risk and if it is associated with existing symptoms in the hope of receiving treatment that eliminates these two issues. So far, there is no direct evidence that the presence of symptoms or the type of symptom is related to progression rates. Patients on a waiting list for saphenectomy17 probably have a higher progression rate than patients who entered the study through screening of the general population,19 indicative of a more active form of disease. C3 patients, with edema, often complain of the sensation of leg edema and heaviness. Such patients seem prone to progression to a venous ulcer, but this common observation requires formal testing. Also, symptomatic C0s and C1s patients have a risk of developing venous edema that is fourfold that observed in C0a and C1a (a, asymptomatic) patients, but no details on specific symptoms were presented. The results of the Bonn Vein study, which will investigate the possible predictive role of venous symptoms on progression of venous disease,41 are eagerly awaited.
 

Conclusions

There is evidence to suggest that venous symptoms in general in patients with CVD are predictors of progression in C0s or C1s patients, but there is no information with regard to a particular type of venous symptom. Sensation of swelling in the subset of C3 patients with venous edema per definition may be viewed as a risk for future ulceration, although this hypothesis should be confirmed by a controlled study. Until a definite study becomes available, the pathophysiology of CVD symptoms and progression should be viewed as distinct steps of the complex process responsible for the development of varicose veins.

 

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