Interview: Are we any closer to identifying the origin of leg pain?




Marzia LUGLI, MD
Department of Cardiovascular
Surgery, Hesperia Hospital
Modena, ITALY

Are we any closer to identifying the origin of leg pain?


Interview with M. Lugli, Italy



Advances in research have drawn attention to the role of chronic inflammatory processes affecting the valves and walls of veins of all sizes and also in the skin, leading to the development of varicose veins and chronic venous insufficiency. The role of inflammation in the occurrence of venous pain has also been highlighted in recent research and the presence of nociceptors stimulated by inflammatory mediators completes the picture. Investigations into the pathophysiology of chronic venous disease have only focused on the competence of macroscopic valves present in large veins. However, some researchers have recently demonstrated that incompetence of the smaller valves located in the third to sixth generation of tributaries can be involved in the occurrence of chronic venous disease. Small vein incompetence is not necessarily associated with valve incompetence in the main venous trunk, thus justifying the possible occurrence of venous symptoms in patients not affected by varicose veins or axial reflux. Moreover, it is well known that venous symptoms and leg pain are only loosely correlated with alterations in the main venous trunks. Therefore, it can be hypothesized that these symptoms actually stem from incompetence in smaller veins and capillaries.

Medicographia. 2015;37:80-84 (see French abstract on page 84)


Why has venous pain been so poorly studied in the literature?

Venous pain is a very common complaint in chronic venous disorders and its chronic nature greatly worsens the quality of life of affected people. Although frequently encountered in daily practice, venous pain is hard to understand. The wording used by patients to describe leg pain is vague and is associated with other unpleasant sensations, such as feelings of swelling, tension, burning, heaviness, and tingling, etc. Venous pain is diffuse, not localized, and more similar to visceral pain. Frequently, the relatively low intensity of venous pain seems to not justify its impact on quality of life, leading to suggestions that venous pain may be more psychogenic than biological in origin. Consequently, venous pain is difficult to define, identify, locate, and quantify. Moreover, the intensity of venous pain is not related to chronic venous disorder severity, so that suffering patients often present with no clinical or pathophysiological anomalies.

When pain occurs in the context of venous disease, such as postthrombotic syndrome or varicose veins, the pain is usually attributed to the disease itself. This is a common attitude, despite the fact that several well conducted epidemiological stud- ies have shown that the presence and the intensity of pain likely to be related to chronic venous insufficiency are not correlated with the clinical assessment of disease severity. The Edinburgh Vein Study has shown that approximately 40% of asymptomatic patients presented with varicose veins, whereas 45% of patients complaining of pain compatible with chronic venous insufficiency did not present with varicose veins.1 Moreover, no significant correlation was proven between the presence of pain and the presence of superficial and/or deep reflux detected at Doppler ultrasound examination.2

What do we know about the mechanisms at work in venous pain occurrence?

Leg pain is associated with all stages of chronic venous disorders, and has the tendency to increase with severity of disease. However, correlation between pain intensity and severity of venous signs is weak, as is correlation between pain and the presence of inflammatory markers. It is fully accepted that primary chronic venous disorders are caused by the occurrence of venous hypertension determined by reflux through incompetent valves (mostly in superficial veins) and sometimes by primary non-postthrombotic obstruction and reflux in the deep system.3 Venous hypertension is a key point to help understand alterations in superficial veins, deep veins, capillaries, and eventually skin. There is now a body of evidence showing that all stages of primary chronic venous disorders are linked to inflammatory processes that can affect large and small venous vessels and their valves. In patients affected by varicose veins, superficial valves are incompetent and present a highly remodeled wall. Several studies have found that valve flaps are often infiltrated with inflammatory cells, mainly granulocytes and neutrophils. The trigger event for venous inflammation and the cascade of events that leads to valve degradation and disease progression is not clear. It can be hypothesized that the postural pressure changes that are frequent in daily life might lead to vein distension and valve distortion. This could be the starting mechanism of endothelial and leukocyte activation, and consequently of inflammation. Lifelong repeated inflammatory stresses might lead to valve and wall injuries, thus determining reflux and consequently venous hypertension.

Changes in the hemodynamics of large veins and venous hypertension are transmitted into the microcirculatory level, increasing permeability and leading to the accumulation of fluid, macromolecules, and extravasated red blood cells into the interstitial space. This pathological process results in the production of the interstitial edema. Eventually, the many changes result in the development of venous microangiopathy, which could be due to white blood cell trapping. The last stage in disease progression is venous ulceration.4





When and how does pain occur during this timeline? It is well known that the walls of veins contain unmyelinated C fibers that may play a key role in the onset of pain. Experimentally, C fibers are activated by different types of stimuli (mechanical, thermal, or chemical), thus they are polymodal nociceptors. Venous dilatation, even when severe, is not by itself a significant source of pain in normal subjects. This statement is confirmed by the evidence of absence of pain of arteriovenous fistulae created for hemodialysis. A balloon dilatation is felt as being painful when the diameter of veins reaches a value that is three times that of normal. Such a situation is not likely to occur in chronic venous disorders, because vein dilatation is not of this amplitude, even if vein dilatation is real and can be assessed. Painful sensations related to temperature variations have been studied in human hands before and after blockade of venous afferents. Intravenous cooling or warming of a cutaneous vein segment of the hand was able to evoke pain after numbing the skin, thus confirming that the sensory elements of veins are polymodal nociceptors.5

In chronic venous disorders, the sensation of heat is one of the many complaints expressed by symptomatic patients. Such a sensation is not related to any nociceptive stimuli. Current hypotheses on pain mechanisms in chronic venous disorders are focused on a local inflammatory origin, related to venous stasis. At the end of the full process, inflammatory mediators released by activated leukocytes are strong stimulators of C nociceptors and partly explain why chronic venous disorders can be painful at all disease stages. Interestingly, the same processes assumed to generate pain in venous disease seem to be involved in the long-term period of varicose vein remodeling, defined as the whole qualitative and quantitative alterations in the cellular and matrix components of the venous wall. The starting point for these mechanisms is probably the local hypoxia associated with capillary stasis. A significant fall in the partial pressure of oxygen after 30 minutes in the standing position has been demonstrated in lower-limb veins in venous disease, and several studies have demonstrated that hypoxia induced by capillary stasis has the effect of activating endothelial cells.6

The evidence for an inflammatory reaction playing such a main role in patients with varicose veins has increased dramatically over recent years, and the biochemical changes identified suggest that endothelial cells and neutrophils are the source of this local inflammation. The presence of neutrophils, monocytes, and activated T lymphocytes, the accumulation of macrophages and mast cells, the expression of adhesion molecules on the surface of leukocytes and endothelial cells (lymphocyte function–associated antigen 1 [LFA-1], very late antigen 4 [VLA-4], endothelium leukocyte adhesion molecule 1 [ELAM-1], intercellular adhesion molecule 1 [ICAM-1], vascular cell adhesion protein 1 [VCAM-1]), and the synthesis of cytokines (interleukin 1β [IL-1β], IL-6, tumor necrosis factor α [TNFα]) and prothrombotic factors (von Willebrand factor) are all indicators of inflammation in venous disease.

What is the rationale that led to the suggestion that microcirculatory reflux is involved in the occurrence of symptoms?

The fact that venous pain is not closely correlated with the presence of varicose veins or axial reflux/obstruction suggests that the primary activation site of venous and/or perivenous nociceptors may not be in the large venous vessels. In this regard, the hypothesis of local activation of nociceptors in the microcirculation, where contact between nerve endings, the arterioles, the vein, and the capillaries is probably much closer than at the macrovascular level, seems entirely plausible. Moreover, edema stems from capillary leakages and is painful due to the pressure it exerts on nerve endings.

Interest in the mechanisms underlying symptoms and signs of chronic venous disorders has received new impetus with the increasing recognition of the role of venous valves in small veins and venules. It is known that small superficial veins of the human lower limb contain abundant, typical bicuspid venous valves, with the majority occurring in vessels less than 100 μm in diameter and present in vessels as small as 18 μm.7 Such microscopic valves have also been described in human skin. Their role was believed to resist and prevent blood reflux in small-sized veins, from postcapillary venules to the capillary bed.

A recent study by Vincent et al has confirmed the existence of these microscopic venous valves (MVVs) in the small superficial venous veins of human lower limbs, and has shown that incompetence can occur in the MVVs independent of reflux within the great saphenous vein (GSV) and major tributaries. Reflux in MVVs was associated with tortuosity and distension of varicosities in the skin with a normally functioning GSV.

Using light microscopy in retrograde corrosion casts of legs with venous ulcers, MVVs were found from the GSV through to the sixth-generation tributaries. Indeed, to show reflux from the GSV to the small-vessel networks, the resin has to pass a minimum of three generations of incompetent valves. The last valve generation before resin refluxed into the skin capillary bed was designated as the “boundary valve.” Most of these “boundary valves,” assumed to prevent reflux in the small venous network in the skin, were located in the third generation of tributaries. The authors speculated that skin degenerative changes are worse when refluxes in MVVs from the third generation and in GSV occur together, and this would explain why some patients with longstanding varicose veins develop venous ulcers.8

At the other extremity of the clinical, etiological, anatomical, and pathophysiological (CEAP) classification, individuals with lower-limb symptoms without signs, assigned to CEAP class C0s, are frequently encountered in clinical practice. In the population of the Vein Consult Program, 19.7% of screened individuals had typical chronic venous disorder leg symptoms without signs.2 C0S subjects constitute an excellent population to investigate, since they are purely venous symptomatic.

We hypothesize that incompetence in the MVVs from the third to the sixth generation of tributaries may be responsible for the occurrence of venous symptoms, particularly the early symptoms in the C0S subjects.

What are the current methods used to investigate the microcirculation and what do they assess?

Instrumental investigation of any early chronic venous disorder patients, including C0s subjects, usually performed by duplex ultrasound, often proves negative. In the larger number of cases reflux is not detected, neither in the saphenous veins nor its tributaries. In fact, investigations of pathophysiology of primary chronic venous disorders evaluate only the competence of the macroscopic valves present in large veins, usually the GSV and to a lesser extent, short saphenous vein. Duplex ultrasound investigation is not sensitive enough to detect reflux down to more than one level of tributary generations. It is therefore not known whether C0s subjects present with reflux in the MVVs of the GSV and its subsequent tributaries.

Currently, various methods can be used to explore the microcirculation and its alterations over the course of progression of chronic venous disorders. In my knowledge, none of the current assessment tools have been used with the purpose of finding relationships between the presence of venous symptoms and alterations in the microcirculation.

Regarding the assessment of the microcirculation, the following investigations may be applied:
◆ Videocapillaroscopy: to visualize capillaries in different cutaneous areas of the lateral and medial aspects of the lower leg and in the foot. Some parameters can be measured, such as the capillary density (number of vessels per mm2) and the capillary loop diameter (μ).
◆ Laser Doppler: to quantify skin perfusion after standardized maneuvers such as the venoarteriolar reflex.
◆ Light reflexion rheography (LRR) plethysmography (static or dynamic): the probe applied in the same cutaneous areas as those mentioned above evaluates the lower-limb venous function by measuring the refilling time.

The assessment of reflux in large veins and first generation of tributaries, usually performed by duplex ultrasound examination, can be integrated by adjunctive ultrasound investigations:
◆ B-flow ultrasound: the evaluation of tributaries until the limit of detection of a superficial probe (7.5 to 10 MHz). Exploration can be performed on the whole lower extremity,
◆ Continuous-wave Doppler: with a flat probe applied on visible tributaries to identify flow direction. Continuous-wave Doppler is able to detect small sites of reflux often missed by duplex ultrasound.

What would be an ideal investigation procedure to assess leg pain in symptomatic patients?

Current methods to assess the microcirculation are not sensitive enough to detect symptomatic subjects such as those in class C0S, since these people probably have subliminal perturbations of the capillary bed.

The orthogonal polarization spectral imaging technique used in the CytoScan® has raised hope to better study patients suffering from chronic venous disorders. The CytoScan® has a small handheld probe which can be noninvasively applied to all body surfaces. Chronic venous disorders were previously studied using the orthogonal polarization spectral technique. Five microcirculatory parameters were correlated with CEAP classification (C0 to C5). Moderate microangiopathy was found among all CEAP classes, and microcirculatory alterations were not assessable before CEAP class C2. No microangiopathy could be found in C0.9

MVVs have never been studied in vivo. Previous work has studied MVVs on cadavers’ legs. We plan to perform a pilot study aimed at investigating the function of MVVs from the third to the sixth generation of saphenous tributaries in individuals classified C0s and in healthy subjects. The sample size will probably not be sufficient to prove any association, but will be used to guide future studies. It will help select the most relevant variables for future projects, given the cost and time required to perform the various microcirculatory investigations that are mandatory before finding the one that could fit the purpose.

The first observations from this work might shed some light on the underlying mechanisms at work in the occurrence of pain in venous disease,particularly at an early stage, and thereby explain why pain is neither correlated with clinical signs of venous disease nor with reflux. It may be that valve incompetence occurs in small superficial veins in the absence of reflux in the GSV and at an early stage, in the absence of any visible signs. In patients with skin changes or ulcers, both the macro- and the microcirculation should be disturbed, confirming the observations described by Philips et al.

If results meet our expectations, they could explain the role of venoactive drugs such as Daflon 500 in venous symptom relief. Further explorations using drug therapy could be performed in the future. Our exploratory study could therefore open a new perspective for further studies, with the ambition to clear up some unanswered clinical questions, and to better understand the role and/or limitations of available treatments for venous disease. ■


References
1. Bradbury A, Evans C, Allan P, et al. What are the symptoms of varicose veins? Edinburgh vein study cross sectional population survey. BMJ. 1999;318:353-356.
2. Rabe E, Guex JJ, Puskas A, Scuderi A, Fernandez Quesada F; VCP coordinators. Epidemiology of chronic venous disorders in geographically diverse populations: results from the Vein Consult Program. Int Angiol. 2012;31(2):105-115.
3. Perrin M, Ramelet AA. Pharmacological treatment of primary chronic venous disease: rationale, results and unanswered questions. Eur J Vasc Endovasc Surg. 2011;41:117-125.
4. Eberhardt RT, Raffetto JD. Chronic venous insufficiency. Circulation. 2005;111: 2398-2409.
5. Klement W, Arndt JO. Pain but no temperature sensations are evoked by thermal stimulation of cutaneous veins in man. Neurosci Lett. 1991;123:119-122.
6. Danziger N. Pathophysiology of pain in venous disease. Phlebolymphology. 2008; 15:107-114.
7. Caggiati A, Phillips M, Lametschwandtner A, Allegra C. Valves in small veins and venules. Eur J Vasc Endovasc Surg. 2006;32:447-452.
8. Vincent JR, Jones GT, Hill GB, van Rij AM. Failure of microvenous valves in small superficial veins is a key to the skin changes of venous insufficiency. J Vasc Surg. 2011;54(6 suppl):62S-69S.
9. Virgini-Magalhaes CE, Lascasas Porto CL, Fernandes FFA, Dorigo DM, Bottino DA, Bouskela E. Quantification of microangiopathy in chronic venous disease. Phlebolymphology. 2007;14(3):129-134.


Keywords: chronic venous disorder; leg pain; microvalve; reflux; vein incompetence; venous disease; venous valve