Vol 37, No.

1, 2015
Medicographia
122
A Ser vier publication

Leg pain: taking center stage in

chronic venous disorders
E DITORIAL
3 Venous pain: more than ever a topic of research
La douleur veineuse : plus que jamais un sujet de recherche
B. Eklf, Sweden

T HEMED ARTICLES
10 Description and definition of venous symptoms in chronic venous
disorders: a review
M. R. Perrin, France

16 The prevalence of lower-limb venous symptoms in recent epidemiological

surveys
E. Rabe, Germany

20 Symptoms and signs of chronic venous disorders: can we put an end

to the controversy?
M. Simka, Poland

26 Leg pain: somatic or psychogenic?

W. Blttler, F. Amsler, Switzerland

32 Pathophysiological underpinnings of lower-limb pain of venous origin

N. Labropoulos, USA

37 Lower-limb venous symptoms and assessment of quality of life: existing tools

F. Mariani, Italy

45 Lower-limb venous symptoms: combining physician and patient reporting tools

M. A. Vasquez, C. Munschauer, D. Panza, USA

50 Management of lower-limb venous symptoms: what the guidelines tell us

Z. Rybak, Poland

Contents continued on next page

Vol 37, No. 1, 2015
Medicographia
122
A Ser vier publication

C ONTROVERSIAL QUESTION
57 Is lower-limb pain reduction a meaningful treatment outcome?
S. Agarwal, India - Y. Akcali, Turkey - M. Bokuchava, Georgia -
D. Branisteanu, Romania - E. Ferreira, Portugal - F. F. Haddad, Lebanon -
D. T. T. Huong, Vietnam - D. Karetov, Czech Republic - G. Lessiani, Italy -
H. Lotfy, Egypt - C. Ruangsetakit, Thailand - C. E. Virgini-Magalhes,
Brazil - I. A. Zolotukhin, Russia

DAFLON 500 MG
71 The place of Daflon 500 mg in recent international guidelines on the
management of symptomatic chronic venous disorders
F. Pitsch, France

I NTERVIEW
80 Are we any closer to identifying the origin of leg pain?
M. Lugli, Italy

F OCUS
85 Risk factors for symptomatic chronic venous disorders: results from the
international Vein Consult Program
D. J. Radak, V. A. Sotirovic, Serbia

A TOUCH OF F RANCE
94 The Savior of ChildrenAlbert Calmette and the BCG vaccine
A. Perrot, France

104 Blighted destinies: arts, artists, and the Romantic Disease in

19th-century France
I. Percebois, France

EDITORIAL
To understand the pathophys-
iology of venous pain, we need to
take into account the properties of
the nociceptors, as well as the in-
flammatory mechanisms that char-
acterize venous disease from its
early stages. The likely trigger for
these mechanisms is local hypox-
ia caused by venous hypertension.
This hypoxia activates endothelial
cells, which results in the synthe-
sis and local release of mediators
that modulate pain through activa-
tion of proinflammatory nocicep-
tors.
Bo EKLF, MD, PhD
Lund University
Lund, SWEDEN
Address for correspondence:
Prof Bo Eklf, Batteritorget 8,
SE-252 70 Helsingborg, Sweden
(e-mail: moboek@telia.com)
Medicographia. 2014;37:3-9
www.medicographia.com
Venous pain: more than ever a topic of research Eklf
Venous pain:
more than ever
a topic of research
b y B . E k l f, S w e d e n
ccording to the VEIN-TERM consensus document, venous symptoms are
A complaints related to venous disease, which may include tingling, aching,
burning, pain, muscle cramps, swelling, sensations of throbbing or heav-
iness, itching skin, restless legs, and leg tiredness and/or fatigue.1 Although
not pathognomonic, these symptoms may be suggestive of chronic venous disor-
ders, particularly if they are exacerbated by heat or dependency, worsened with the
course of the day, and relieved with leg rest and/or elevation. In several epidemi-
ologic surveys, up to 75% of adults complain of venous symptoms, and in the world-
wide Vein Consult Program comprising almost 100 000 individuals, venous symp-
toms were perceived similarly in all regions surveyed, with pain reported in 60% to
77%.2 There is a significant correlation between venous pain/symptoms and wors-
ening of chronic venous disorder signs, with a significant influence on quality of
life (QoL). A particular group of patients complain of symptoms, but have no clinical
signs or venous reflux (C0s according to the class, clinical, etiological, anatomical,
physiological [CEAP] classification). These patients were found to represent about
15% of all patients in several surveys.3 The commonest complaint in chronic venous
disorders is leg pain, which may be difficult to understand because its intensity is
not correlated with the severity of venous disease, and patients sometimes com-
plain of symptoms without signs. A mistaken conception of venous pain is wide-
spread in the medical world and frequently causes misunderstanding in physician-
patient relations.
Focus on leg pain
In this issue of Medicographia, the editor focuses on Leg pain: taking center stage
in chronic venous disorders, inviting European experts (including Nicos Labropoulos,
who originates from Greece) to share their experiences. In 2013, Servier published
a book entitled From Venous Pain to Surgery, where the French neurologist Nicolas
Danzinger from La Piti Salptrire, Paris, wrote an excellent chapter on How to de-
scribe venous pain. In the general mechanisms of venous pain he describes the
anatomy, venous innervation, and physiological properties of venous and perivenous
nociceptors, and the role of neuromediators involved in their activation.4 To under-
stand the pathophysiology of venous pain, we need to take into account the prop-
erties of the nociceptors, as well as the inflammatory mechanisms that character-
ize venous disease from its early stages. The likely trigger for these mechanisms
is local hypoxia caused by venous hypertension. This hypoxia activates endothe-
lial cells, which results in the synthesis and local release of mediators that modu-
late pain through activation of proinflammatory nociceptors. Evidence of such an
inflammatory reaction in the varicose veins of patients has accumulated in recent
MEDICOGRAPHIA, Vol 37, No. 1, 2015 3
EDITORIAL
years, and the biochemical changes identified suggest that
endothelial cells and neutrophils are the source of inflam-
mation. Danzinger questions why pain is not correlated with
clinical severity and refers to Bradburys findings in the Edin-
burgh Vein Study, showing a poor correlation between symp-
toms and the presence or absence of varicose veins.5 He of-
fers an explanation that this lack of correlation suggests that
venous nociceptors may not be activated in the large veins,
but rather in the microcirculation. Venous hypertension is trans-
mitted to the microcirculation, which prompts leucocyte ad-
hesion to the capillary endothelium. This initiates an inflamma-
tory reaction that increases capillary permeability, leading to
interstitial edema. This theory is supported by van Rijs work
on failure of microvenous valves in small superficial veins as a
key to skin changes in venous insufficiency, which may also
explain pain in C0s patients.6
Characterizing venous symptoms
This is difficult and frequently leads to misunderstanding. It is
often difficult for patients to find the right words for their com-
plaints; in addition to heaviness and swelling, other descrip-
tions (such as sensations of tension, aching, congestive pain,
and tired legs) are also encountered. Physicians often under-
estimate the degree of pain that patients suffer and its impact
on their lives. This is especially true if the pain is chronic and
poorly defined, and when no signs of venous insufficiency and
reflux are obvious. Physicians lack tools to measure the de-
gree and impact on patients daily activities. The CEAP classi-
fication should aid the physician in diagnosing the severity of
chronic venous disorders, where clinical class C0 has no vis-
ible or palpable signs of venous disease, up to C6 with an ac-
tive venous ulcer.7 Each clinical class is characterized by S
for symptomatic or A for asymptomatic. The severity of symp-
toms is not assessed and this needs to be addressed at the
next revision of CEAP. In the Venous Clinical Severity Score
(VCSS), with which you can follow the effect of treatment, pain
is categorized into four grades: no pain, 0; mild pain, 1 (oc-
casional pain or other discomfort, ie, not restricting regular
daily activities); moderate pain, 2 (daily pain or other discom-
fort, ie, interfering with, but not preventing, regular activities);
and severe pain, 3 (daily pain or discomfort, ie, limits most
daily activities).8
Patients with venous symptoms only (C0s) and no demon-
strable venous dysfunction will be classified as C0sEp A nPn. A
visual analog scale (VAS) for pain is a useful tool. When the
pain is severe and not proportionate to clinical and duplex
findings, we should consider venous outflow obstruction. This
SELECTED ABBREVIATIONS AND ACRONYMS
CEAP clinical, etiological, anatomical, pathophysiological
VAS visual analog scale
VCSS Venous Clinical Severity Score
4 MEDICOGRAPHIA, Vol 37, No. 1, 2015
can lead to true venous claudication with bursting pain on
walking, and a long resolution time at rest, or venous hyper-
tension causing inflammatory pain. In patients with disabling
pain, the pelvic outflow should be investigated, especially in
patients with posthrombotic disease without any skin changes,
pain out of proportion to the duplex findings, or no detectable
lesions explaining the pain.
Negln et al have reported substantial improvement of pain
after stenting of iliofemoral obstruction using the VAS, con-
firmed by several studies using VCSS.9 Delis reported elim-
ination of venous claudication, evaluated by treadmill in 55
patients with previous iliofemoral deep vein thrombosis (DVT),
after stenting.10 There is no relationship between clinical sever-
ity and magnitude of venous pain, and a poor correlation be-
tween pain and the presence of deep or superficial reflux. How-
ever, QoL questionnaires correlate well with generic and clinical
outcomes.
Socioeconomic impact
In the guidelines according to scientific evidence on manage-
ment of chronic venous disorders of the lower limbs, it is stat-
ed that the considerable socioeconomic impact of chronic
venous disorders is due to the large numbers concerned,
cost of investigations and management, morbidity, and suf-
fering.11 This in turn is reflected in a deterioration in QoL and
loss of working days. The problem is compounded by the
fact that chronic venous disorders are progressive and has
a propensity to recur. Measures to reduce the magnitude of
the problem include increasing the awareness of the problem,
early diagnosis and care, careful consideration of the neces-
sity and choice of investigations, discipline in the choice of
management based on clinical effectiveness, and cost. These
requirements imply specific training in all aspects of this con-
dition. Direct costs are associated with medical, nursing, and
ancillary manpower together with costs for investigation and
treatment, whether in hospital or as an outpatient. Indirect
costs relate to loss of working days. The cost in human terms
must also be considered, and this can be quantified by as-
sessment of QoL. Estimation of the overall annual costs of
chronic venous disorders vary from 600-900 million euros in
Western European countries, representing 1% to 2% of the
total health budget. Indirect costs of venous disease in terms
of working days lost is quoted as the most important cost
factor, amounting to 270 million euros in Germany (1990).
A study from France, 2005, found that about 7% of the work-
ing population is off work because of venous disease. These
costs are higher than the amount spent for arterial disease.
The need to contain the increasing costs of chronic venous
disorders is evident. The methods used, whether aimed at
prevention or treatment, must essentially be shown to be ef-
fective, but must also take into consideration the cost in re-
lation to proven effectiveness. At the present time there is no
way to effectively prevent the onset of varicose veins. Much
Venous pain: more than ever a topic of research Eklf

work has been done to prevent chronic venous disorders de-
veloping in patients with early varicose veins or following DVT,
and all measures that contribute to preventing a venous ul-
cer will have a strong impact on the human and socioeco-
nomic costs.
Further research needed
Despite the increased interest in the pathophysiological mech-
anisms for chronic venous disorders, our knowledge remains
limited according to the above mentioned guidelines. The ge-
netic and molecular determinants for the development of
chronic venous disorders are still largely undetermined. The
relationship between the macrohemodynamics and endothe-
lial function/dysfunction in the vein wall, and the actual im-
pact of flow dynamics on capillary, valve, and vein wall remod-
eling, white-cell activation, smooth muscle cell proliferation
and migration, as well as extracellular matrix alteration, re-
quire further investigation.
Evidence for the role of senescence and apoptosis in the de-
velopment of chronic venous disordersrelated cellular and
molecular alterations in the presence of venous hypertension
remain poorly understood. The variable manifestations of signs
and symptoms in chronic venous disorders among individu-
als with similar reflux sites, extent of disease and global hemo-
dynamic impairment have not been explained. In addition, the
pathophysiological and molecular bases for lipodermatoscle-
rosis and ulceration are only partially understood, and the
pathophysiology behind venous pain in patients without signs
of venous disease or reflux/obstruction also needs further study.
The significance of corona phlebectatica in relation to progres-
sion of chronic venous disorders remains undetermined.
It is critically important that recommendations for change in
the CEAP classification are supported by research, enabling
progress on the level of evidence rather than the level of in-
vestigation. There is a need to include a severity grading of
symptoms, eg, as in the VCSS. The descriptive comparabil-
ity offered by CEAP stratification should be used in associa-
References
1. Eklf B, Perrin M, Delis KT, Rutherford RB, Gloviczki P. Updated terminology
of chronic venous disorders: The VEIN-TERM transatlantic interdisciplinary con-
sensus document. J Vasc Surg. 2009;49:498-501.
2. Rabe E, Guex JJ, Puskas A, Scuderi A, Fernandez Quesada F; VCP coordina-
tors. Epidemiology of chronic venous disorders in geographically diverse pop-
ulations: results from the Vein Consult Program. Int Angio. 2012;31:105-115.
3. Rabe E. The prevalence of lower limb symptoms in recent epidemiological sur-
veys. Medicographia. 2015;37:16-19.
4. Danzinger, N. From venous pain to surgery: How to describe venous pain. In:
From Venous Pain to Surgery. Paris, France: Servier International; 2013:35-44.
5. 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.
6. van Rij AM, Vincent J, Hill G, Jones GT. Failure of microvenous valves in small su-
perficial veins: A key to the development of venous ulcers. J Vasc Surg. 2011;53:
256.
Keywords: CEAP classification; chronic venous disorder; Venous Clinical Severity Score; venous pain; venous symptom
Venous pain: more than ever a topic of research Eklf
EDITORIAL
tion with VCSS and QoL scores as instruments for longitudinal
research that offer objective assessment of outcomes. The
relationship between symptom severity in chronic venous dis-
orders and global venous hemodynamics across the spec-
trum of CEAP is currently unavailable.
Methods to measure the degree of a hemodynamically signif-
icant venous obstruction remains undetermined. There is a
compelling need to introduce a dependable noninvasive test
to detect clinically relevant outflow impairment.
Available studies on the efficacy of venoactive drugs in chron-
ic venous disorders are only rarely comparable due to dis-
parities for inclusion criteria and primary end points. Interna-
tionally accepted reporting standards are required to enable
standardization and comparability of accrued randomized
data. The role that venoactive medication may have for treat-
ing venous symptoms, varicose veins, edema, or venous ul-
cers, and their effect on the natural history of chronic venous
disorders, remains to be determined.
Conclusion
Several epidemiological studies have shown that up to 75%
of adults complain of venous symptoms. There is a significant
correlation between venous symptoms and worsening of the
clinical (C) class of CEAP or QoL. However, 15% of these in-
dividuals complain of symptoms without signs of chronic ve-
nous disorders. The commonest symptom in chronic venous
disorders is pain that is not correlated to the severity of chron-
ic venous disorders. The likely trigger is venous, and probably
capillary, hypertension causing an interaction between leu-
cocytes and the venous endothelium, which results in the syn-
thesis and release of mediators that modulate pain through
activation of proinflammatory nociceptors. Despite the in-
creased interest in the pathophysiological mechanisms for
chronic venous disorders, our knowledge remains limited and
further research is needed. I encourage you to read the fol-
lowing eight themes written by excellent experts in chronic
venous disorders.
7. Eklf B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification for
chronic venous disorders: consensus statement. J Vasc Surg. 2004;40:1248-
1252.
8. Vasquez MA, Rabe E, McLafferty RB, et al. Revision of the venous clinical sever-
ity score: venous outcomes consensus statement: special communication of
the AVF ad hoc outcomes working group. J Vasc Surg. 2010;52:1387-1396.
9. Negln P, Hollis KC, Olivier J, Raju S. Stenting of the venous outflow in chronic
venous disease: Long-term stent-related outcome, clinical, and hemodynamic
result. J Vasc Surg. 2007;46:979-990.
10. Delis KT, Bountouroglu D, Mansfield AO. Venous claudication in iliofemoral throm-
bosis: long-term effects of venous hemodynamics, clinical status and quality
of life. Ann Surg. 2004;239:118-126.
11. Nicolaides AN (Chairman editorial committee). Management of chronic venous
disorders of the lower limbs. Guidelines according to scientific evidence. Int
Angio. 2014;33:87-208.
MEDICOGRAPHIA, Vol 37, No. 1, 2015 5
 DITORIAL

Comprendre la physiopatho-
logie de la douleur veineuse nces-
site que nous prenions en compte
les proprits des nocicepteurs,
ainsi que les mcanismes inflam-
matoires qui caractrisent linsuf-
fisance veineuse, ds ses stades
La douleur veineuse :
prcoces. Le dclencheur de ces
mcanismes est vraisemblable-
plus que jamais un sujet
ment lhypoxie locale provoque
par lhypertension veineuse. Cette
hypoxie active les cellules endo-
de recherche
thliales, ce qui entrane la synthse
et la libration locale de mdiateurs
qui modulent la douleur par lac-
tivation des nocicepteurs pro-in-
flammatoires .
p a r B . E k l f, S u d e

S
elon le document de consensus VEIN-TERM, les symptmes veineux sont
des plaintes lies linsuffisance veineuse, qui peuvent inclure des four-
millements, un endolorissement, des brlures, des douleurs, des crampes
musculaires, un dme, des sensations de pulsation ou de lourdeur, un
prurit, un syndromedes jambes sans repos et une fatigue au niveau des jambes1.
Bien quils ne soient pas pathognomoniques, ces symptmes peuvent suggrer
un trouble veineux chronique (TVC), en particulier sils sont exacerbs par la cha-
leur ou la dclivit, sils saggravent au cours de la journe, et sils sont soulags par
le repos et/ou llvation des jambes. Dans plusieurs enqutes pidmiologiques,
jusqu 75 % des adultes se plaignent de symptmes veineux, et dans le programme
Vein Consult, qui a port sur prs de 100 000 personnes dans le monde, les symp-
tmes veineux ont t perus de manire similaire dans toutes les rgions ayant
rpondu lenqute, la douleur tant mentionne dans 60 77 % des cas2. Il a t
observ une corrlation significative entre la douleur et les symptmes veineux dune
part et laggravation des signes de TVC dautre part, avec une influence significa-
tive sur la qualit de vie (QdV). Toutefois, un groupe particulier de patients se plaint
de symptmes, mais ne prsente ni signes cliniques ni reflux veineux (C0 selon la
classification CEAP [clinique, tiologique, anatomique, physiopathologique]). Il a t
constat que ces personnes reprsentaient environ 15 % de lensemble des patients
dans plusieurs enqutes3. Le symptme le plus frquent de TVC est la douleur des
jambes, qui peut tre difficile comprendre, parce que dune part son intensit ne
montre pas de corrlation avec la svrit de la maladie veineuse, et que dautre part
les patients se plaignent parfois de symptmes sans montrer de signes. Une concep-
tion errone de la douleur veineuse est largement rpandue dans le monde mdi-
cal et provoque frquemment des malentendus dans la relation mdecin-patient.

Analyse de la douleur des jambes

Dans ce numro de Medicographia, consacr au thme Insuffisance veineuse :
les douleurs de jambe au devant de la scne , plusieurs experts europens (no-
tamment Nicos Labropoulos, Grce) partagent leur exprience. En 2013, Servier a
publi un ouvrage intitul De la douleur veineuse la chirurgie, dans lequel le neu-
rologue franais Nicolas Danzinger, de La PitiSalptrire Paris, a crit un excel-
lent chapitre sur le sujet suivant : Comment dcrire la douleur veineuse . Dans la
partie consacre aux mcanismes gnraux de la douleur veineuse, il dcrit lana-
tomie, linnervation veineuse, les proprits physiologiques des nocicepteurs veineux
et priveineux et le rle des neuromdiateurs participant leur activation4. Com-
prendre la physiopathologie de la douleur veineuse ncessite que nous prenions en
compte les proprits des nocicepteurs, ainsi que les mcanismes inflammatoires

6 MEDICOGRAPHIA, Vol 37, No. 1, 2015 La douleur veineuse : plus que jamais un sujet de recherche Eklf

qui caractrisent linsuffisance veineuse ds ses stades pr-
coces. Le dclencheur de ces mcanismes est vraisembla-
blement lhypoxie locale provoque par lhypertension vei-
neuse. Cette hypoxie active les cellules endothliales, ce qui
entrane la synthse et la libration locale de mdiateurs qui
modulent la douleur par lactivation des nocicepteurs pro-
inflammatoires. Des indices dune telle raction inflammatoire
dans les varices de patients se sont accumuls au cours des
dernires annes, et les changements biochimiques identifis
suggrent que les cellules endothliales et les neutrophiles
sont la source de linflammation. Le docteur Danzinger sin-
terroge sur la raison pour laquelle la douleur ne montre pas
de corrlation avec la svrit clinique, et se rfre aux travaux
de Bradbury dans ltude Veineuse ddimbourg (Edinburgh
Vein Study), qui mettaient en vidence une faible corrlation
entre les symptmes et la prsence ou labsence de varices5.
Il suggre que ce manque de corrlation pourrait sexpliquer
par le fait que les nocicepteurs veineux ne seraient pas ac-
tivs dans les veines de gros calibre, mais plutt dans la mi-
crocirculation. Lhypertension veineuse est transmise la mi-
crocirculation, ce qui dclenche ladhsion des leucocytes
lendothlium capillaire. Ce phnomne dclenche une rac-
tion inflammatoire qui augmente la permabilit capillaire, en-
tranant un dme interstitiel. Cette thorie est confirme par
les travaux de van Rij sur linsuffisance des valvules microvei-
neuses dans les petites veines superficielles, qui constitue un
lment essentiel des changements cutans dans linsuffi-
sance veineuse, ce qui pourrait aussi expliquer la douleur chez
les patients de classe clinique C0 6.
Caractrisation des symptmes veineux
Elle savre difficile et conduit frquemment des malenten-
dus. Il est souvent difficile pour les patients de trouver les mots
exacts pour dcrire leurs symptmes ; outre la lourdeur et
ldme, dautres descriptions (notamment des sensations
de tension, de douleur sourde, de douleur congestive et de
jambes fatigues) sont galement entendues. Les mdecins
sous-estiment souvent le degr de douleur que ressentent
les patients ainsi que son impact sur leur vie. Cela est parti-
culirement vrai si la douleur est chronique et mal dfinie, et
lorsquaucun signe dinsuffisance veineuse ni de reflux nap-
parat de manire manifeste. Les mdecins ne disposent pas
doutils permettant de mesurer le degr et limpact sur les ac-
tivits quotidiennes des patients. La classification CEAP doit
aider le mdecin diagnostiquer la svrit du TVC, de la
ABRVIATIONS ET ACRONYMES PRINCIPAUX
CEAP clinical, etiological, anatomical, pathophysiological
[clinique, tiologique, anatomique, physiopathologique]
TVC trouble veineux chronique
EVA chelle visuelle analogique
VCSS Venous Clinical Severity Score [Score de Svrit
Clinique Veineux]
La douleur veineuse : plus que jamais un sujet de recherche Eklf
DITORIAL
classe clinique C0 , sans signe visible ou palpable dinsuffi-
sance veineuse, jusqu C6 qui se caractrise par la prsence
dun ulcre veineux actif 7. Chaque classe clinique est carac-
trise par une lettre S pour symptomatique ou A pour asymp-
tomatique. La svrit des symptmes nest pas value et
cela ncessitera dtre pris en compte lors de la prochaine
rvision de la classification CEAP. Dans le cadre du Score de
Svrit Clinique Veineux ( Venous Clinical Severity Score,
VCSS), qui permet de suivre les effets du traitement, la dou-
leur est classe en quatre grades : aucune douleur, 0 ; dou-
leur lgre, 1 (douleur ou autre gne occasionnelles, cest-
-dire ne limitant pas les activits quotidiennes rgulires) ;
douleur modre, 2 (douleur ou autre gne quotidiennes,
cest--dire interfrant avec les activits rgulires, mais ne
les empchant pas) ; et douleur svre, 3 (douleur ou gne
quotidiennes, cest--dire limitant la plupart des activits
quotidiennes)8.
Les patients prsentant uniquement des symptmes veineux
(C0 ), mais chez lesquels aucun dysfonctionnement veineux
ne peut tre mis en vidence, sont classs C0s Ep A n Pn. Une
chelle visuelle analogique (EVA) est un outil utile pour la dou-
leur. Lorsque la douleur est svre et non proportionne aux
rsultats cliniques et lcho-Doppler, nous devons envisager
une obstruction du dbit veineux. Cela peut conduire une
claudication veineuse relle avec des lancements doulou-
reux lors de la marche, et un temps de rsolution prolong au
repos, ou bien une hypertension veineuse provoquant une
douleur inflammatoire. Chez les patients prsentant une dou-
leur invalidante, le dbit pelvien doit tre explor, en particu-
lier chez les patients atteints dune maladie post-thrombotique
sans aucun changement cutan, se plaignant dune douleur
hors de proportion par rapport aux rsultats de lcho-Dop-
pler ou ne prsentant aucune lsion dtectable expliquant
la douleur.
Negln et al ont observ une amlioration substantielle de
la douleur en utilisant une EVA, aprs avoir mis en place une
endoprothse sur une obstruction iliofmorale, ces rsultats
tant confirms par plusieurs tudes utilisant le VCSS 9. Delis
a rapport la suppression dune claudication veineuse, va-
lue par tapis roulant chez 55 patients prsentant des ant-
cdents de thrombose veineuse profonde (TVP) iliofmorale,
aprs la mise en place dune endoprothse10. Il nexiste au-
cune relation entre la svrit clinique et lamplitude de la dou-
leur veineuse, et seule une faible corrlation est constate
entre la douleur et la prsence dun reflux profond ou super-
ficiel. Cependant, les questionnaires de QdV montrent une
bonne corrlation avec les rsultats gnraux et cliniques.
Impact socio-conomique
Dans le document de consensus tout juste publi dans Int
Angiol (2014;33(2):87-20811) : Management of Chronic Ve-
nous Disorders of the Lower Limbs : Guidelines According
to Scientific Evidence [Prise en Charge de lInsuffisance Vei-
MEDICOGRAPHIA, Vol 37, No. 1, 2015 7
DITORIAL
neuse Chronique des Membres Infrieurs : Directives Bases
sur les Donnes Scientifiques], il est indiqu que limpact so-
cio-conomique considrable du TVC est d au grand nom-
bre de patients concerns, au cot des investigations et de la
prise en charge, la morbidit et la souffrance11. Ces l-
ments se refltent dans la dtrioration de la QdV et la perte
de jours de travail. Le fait que le TVC soit progressif et pr-
sente une propension rcidiver rend le problme compli-
qu. Les mesures destines rduire lamplitude du problme
comprennent une meilleure prise de conscience, un diagnos-
tic et des soins prcoces, lexamen minutieux de la ncessit
et du choix des investigations, la discipline pour le choix de la
prise en charge bas sur lefficacit clinique et les cots. Ces
exigences impliquent une formation spcifique dans tous les
aspects de cette maladie. Les cots directs sont associs au
personnel mdical, infirmier et auxiliaire ainsi quaux cots des
investigations et des traitements, quils soient dlivrs au cours
dune hospitalisation ou en consultation externe. Les cots
indirects sont lis la perte des jours de travail. Le cot en
termes humains doit galement tre pris en compte, et celui-
ci peut tre quantifi par lvaluation de la QdV. Lestimation
des cots annuels globaux du TVC varie de 600 900 mil-
lions deuros dans les pays dEurope de lOuest, ce qui repr-
sente 1 2 % du budget total de la sant. Les cots indirects
de la maladie veineuse en ce qui concerne la perte des jours
de travail sont qualifis de plus important facteur de cot ,
atteignant 270 millions deuros en Allemagne (1990). Une tude
franaise de 2005 a observ quenviron 7 % de la popula-
tion active ne travaillait pas cause de la maladie veineuse.
Ces cots sont suprieurs la somme dpense pour les
maladies artrielles. La ncessit de limiter laugmentation
des cots du TVC apparat vidente. Les mthodes utilises,
quelles soient destines la prvention ou au traitement, doi-
vent se caractriser essentiellement par une efficacit dmon-
tre, mais elles doivent galement prendre en considration
le cot par rapport celle-ci. lheure actuelle, il nexiste au-
cun moyen de prvenir efficacement la survenue de varices.
Beaucoup defforts ont t consacrs pour la prvention du
dveloppement du TVC chez des patients prsentant des
varices prcoces ou des antcdents de TVP, et toutes les
mesures qui contribueront la prvention dun ulcre veineux
exerceront un impact important sur les cots humains et so-
cio-conomiques.
Ncessit de recherches complmentaires
Malgr lintrt croissant que suscitent les mcanismes phy-
siopathologiques du TVC, notre connaissance reste limite
selon les directives mentionnes ci-dessus. Les dterminants
gntiques et molculaires du dveloppement du TVC sont
encore largement mconnus. La relation entre les paramtres
macrohmodynamiques et le fonctionnement ou le dysfonc-
tionnement endothlial dans la paroi veineuse, ncessite des
investigations complmentaires tout comme limpact rel de
la dynamique des flux sur le remodelage capillaire, valvulaire
8 MEDICOGRAPHIA, Vol 37, No. 1, 2015
et de la paroi veineuse, lactivation des globules blancs, la pro-
lifration et la migration des cellules musculaires lisses, et lal-
tration de la matrice extracellulaire.
Les preuves du rle de la snescence et de lapoptose dans
le dveloppement des altrations cellulaires et molculaires
lies au TVC en prsence dune hypertension veineuse restent
mal comprises. Les manifestations variables des signes et des
symptmes dans le TVC chez les personnes prsentant des
sites de reflux similaires, une ampleur comparable de la ma-
ladie et une altration hmodynamique globale quivalente
nont pas t expliques. En outre, les bases physiopatholo-
giques et molculaires de la lipodermatosclrose et de lulc-
ration ne sont que partiellement explicites, et la physiopatho-
logie sous-jacente de la douleur veineuse chez les patients
ne prsentant aucun signe de maladie veineuse ou de reflux/
obstruction doit galement faire lobjet dtudes supplmen-
taires. La signification de la corona phlebectatica en relation
avec la progression du TVC reste mal dtermine.
Il est essentiel que les recommandations relatives au change-
ment de la classification CEAP soient soutenues par des re-
cherches, afin de permettre des progrs concernant le niveau
de preuve plutt que le niveau dinvestigation. Il est ncessaire
dinclure une cotation de la svrit des symptmes, comme
dans le VCSS par exemple. La comparabilit descriptive per-
mise par la stratification CEAP doit tre utilise en association
avec les scores VCSS et de QdV, lesquels sont des instru-
ments pour des recherches longitudinales offrant une valua-
tion objective des rsultats. La relation entre la svrit des
symptmes dans le TVC et les paramtres hmodynamiques
veineux globaux dans tout le spectre de la classification CEAP
ncessite dtre tudie plus avant. Les mthodes permet-
tant de mesurer le degr dune obstruction veineuse signifi-
cative sur le plan hmodynamique restent dterminer. Lin-
troduction dun test non invasif fiable permettant de dtecter
une altration cliniquement significative du flux constitue un
besoin important.
Les tudes disponibles sur lefficacit des phlbotropes dans
le TVC sont rarement comparables compte tenu des dispari-
ts au niveau des critres dinclusion et des critres dvalua-
tion principaux. Des normes de notification internationalement
acceptes sont ncessaires pour permettre la standardisa-
tion et la comparabilit des donnes randomises accumu-
les. Le rle que les phlbotropes peuvent avoir dans le trai-
tement des symptmes veineux, des varices, de ldme ou
des ulcres veineux, et de leurs effets sur lhistoire naturelle du
TVC, doit encore tre dfini.
Conclusion
Plusieurs tudes pidmiologiques ont montr que jusqu
75 % des adultes prsentent des symptmes veineux. Il existe
une corrlation significative entre les symptmes veineux et
laggravation de la classe clinique ( C ) de la classification
La douleur veineuse : plus que jamais un sujet de recherche Eklf
 DITORIAL

CEAP ou de la QdV. Cependant, 15 % des personnes se plai-
gnant de symptmes ne prsentent aucun signe de TVC. Le
symptme le plus frquent du TVC est la douleur, et elle ne
prsente pas de corrlation avec la svrit du TVC. Son d-
clencheur probable est une hypertension veineuse et proba-
blement capillaire, provoquant une interaction entre les leuco-
cytes et lendothlium veineux, qui entrane la synthse et la
libration de mdiateurs modulant la douleur par lactivation
de nocicepteurs pro-inflammatoires. Malgr lintrt croissant
port aux mcanismes physiopathologiques du TVC, notre
connaissance reste limite et des recherches complmen-
taires sont ncessaires. Je vous encourage vous plonger
dans ce numro de Medicographia rdig par dexcellents
experts du TVC.

Mots cls : classification CEAP ; trouble veineux chronique ; Score de Svrit Clinique Veineux ; douleur veineuse ; symp-
tme veineux

La douleur veineuse : plus que jamais un sujet de recherche Eklf MEDICOGRAPHIA, Vol 37, No. 1, 2015 9

LEG PA I N : TA K I N G C E N T E R S TA G E I N C H R O N I C V E N O U S D I S O R D E R S

very few books or treatises

dedicated to chronic venous dis-
orders give a precise description
and definition of so-called venous
symptoms. This may be due to
difficulty in defining these symp-
Description and definition of
toms, as they are not pathogno-
monic. This point increases the
difficulty of attributing a venous
venous symptoms in chronic
etiology or cause to these symp-
toms, knowing that all classes of
venous disorders can be associ-
venous disorders: a review
ated with venous symptoms.

b y M . R . Pe r r i n , Fra n c e

T
he precise description of venous disorders is lacking in most books or
treatises devoted to venous disorders, and confusingly, there are times
when both signs and symptoms are included within the same heading
of symptoms. The absence of an accurate description may be related to the
fact that most venous symptoms are nonspecific, and more or less identical
to symptoms arising from nonvenous causes. Symptoms listed in various ve-
nous classifications are often not the same, and the different terms are some-
times difficult to describe accurately. Some frequently noted symptoms may
also be difficult to differentiate, as they are very similar to each other, for ex-
ample, pain and aching. This review aims to, firstly, describe symptoms as pre-
Michel R. PERRIN, MD cisely as possible and, secondly, define the circumstances favoring their oc-
Unit de pathologie vasculaire
currence. The relationship between symptoms and signs, reflux, quality of life,
Jean Kunlin, Lyon
FRANCE venous clinical score, and inflammatory markers is reviewed. Some attempts
to better ascribe leg symptoms to venous etiology are analyzed, and their val-
ue is questioned. In conclusion, an international consensus concerning the
definition of venous symptoms and causes is recommended, with the knowl-
edge that this should, in turn, improve the management of patients.
Medicographia. 2015;37:10-15 (see French abstract on page 15)

onfusingly in English literature, signs and symptoms sometimes appear un-

C der the same heading of symptoms. In this article, the term symptom only
incorporates unpleasant phenomenon felt by the patient that arise from and
accompany a particular disease or disorder. Consequently, the presence and sever-
ity of symptoms is subjective.

Venous symptoms remain a challenge to deal with for multiple reasons. Firstly,
very few books or treatises dedicated to chronic venous disorders give a precise
description and definition of so-called venous symptoms. This may be due to
difficulty in defining these symptoms, as they are not pathognomonic. This point
increases the difficulty of attributing a venous etiology or cause to these symp-
toms, knowing that all classes of venous disorders (from C0s to C6 of the clinical,
etiological, anatomical, pathophysiological [CEAP] classification) can be associat-
ed with venous symptoms. Secondly, there is a nonconstant correlation between
Address for correspondence:
Michel R. Perrin, 26 Chemin de
symptoms and signs, and routine instrumental investigations.
Decines, F-69680 Chassieu, France
(e-mail: m.perrin.chir.vasc@wanadoo.fr)

www.medicographia.com

10 MEDICOGRAPHIA, Vol 37, No. 1, 2015 Venous symptoms in chronic venous disorders Perrin
 LEG PA I N : TA K I N G
List of venous symptoms
u CEAP classification
The CEAP classification includes aching, pain, tightness, skin
irritation, heaviness, muscle cramps, and other complaints at-
tributable to venous dysfunction in its list of venous symptoms.1
u VCSS classification
The Venous Clinical Severity Score (VCSS) reports pain or oth-
er discomfort (ie, aching, heaviness, fatigue, soreness, and
burning) presumed of venous origin.2 Interestingly, the symp-
tom list is not limited as it is in the CEAP classification, as ve-
nous dysfunction may be identified (which is not always pos-
sible in daily practice). In the VCSS, the symptoms described
are reported as possibly venous, which is not discriminative
as it depends how venous function is investigated.
u Bonn Vein Study
The Bonn Vein Study (BVS) recognizes symptoms such as
swelling; feeling of swelling, tightness, and heaviness; pain dur-
ing prolonged walking, sitting, or standing; cramps; itching;
and restless legs.3,4
u VEINES-QoL/Sym questionnaire
The subscale of the VEnous INsufficiency Epidemiological
and economic Study (VEINES) called VEINES-Quality of life/
Symptoms (VEINES-QoL/Sym) listed nine venous symptoms:
heavy legs, aching legs, swelling, night cramps, heat or burn-
ing sensation, restless legs, throbbing, itching, and tingling
sensation. Although built to evaluate the quality of life in pri-
mary chronic venous disorders,5 the tool has been mainly
used to assess the quality of life of patients with postthrom-
botic syndrome.6 From this bibliographic research, it appears
that the term venous symptoms needs to be better deter-
mined and clarified.
Description of venous symptoms
As previously mentioned venous symptoms are nonspecific,
but there are some features that may help to attribute them
to a venous origin.
u Pain or aching
Venous pain may take on the following patterns:
Pain along the varicose vein course (phlebalgia) and, more
frequently, diffuse pain in the lower leg, mainly in the calves.
Venous claudication due to an obstructive lesion of the deep
vein usually located in the iliocaval axis.7 Intermittent claudi-
SELECTED ABBREVIATIONS AND ACRONYMS
BVS Bonn Vein Study
CEAP clinical, etiological, anatomical, pathophysiological
DS duplex scanning
VCSS Venous Clinical Severity Score
VEINES VEnous INsufficiency Epidemiological and
economic Study
Venous symptoms in chronic venous disorders Perrin
CENTER STA G E IN CHRONIC VENOUS DISORDERS
cation is defined as the outcome of a painful or bursting sen-
sation that occurs only when the patient is walking or run-
ning and is located either in the lower limb or in the buttock.
This pain disappears progressively when the patient stops,
or by leg elevation that allows differentiating from arterial
claudication and nonvenous neurologic compression. Ac-
cording to Blttler and Blttler, pure venous claudication re-
lated to axial vein obstruction can be distinguished from ve-
nous neurogenic claudication caused by dilated veins in the
spinal canal that arise from the collateral circulation, by mag-
netic resonance imaging or contrast enhanced computed
tomography. Both are cured by venous stenting.8
Presence of painful lipodermatosclerosis or an open ulcer.
u Throbbing
This infrequent symptom is depicted by patients as a pulsing
pain along the pathway of varices, mainly the incompetent
saphenous trunks or their major tributaries.
u Tightness
Tightness is a term rarely used by patients, but may corre-
spond to the feeling that their leg is caught in a stranglehold.
u Heaviness
This symptom is described as heavy legs occurring in a long-
term standing or seated position.
u Fatigue
This symptom is a little bit different from heaviness and is de-
scribed by patients as a feeling of tiredness, occurring after
any kind of activity using the lower limb, but also after pro-
longed motionless standing.
u Impression of swelling
This symptom is different from the sign edema, which can be
measured. Some patients describe the impression of swelling
with no evident edema on clinical examination.
u Cramps
Cramp is an involuntary, painful, contraction of muscles. Ve-
nous cramps are usually located in the calf (gastrocnemius
and soleus muscles) and occur at night.
u Itching
Itching may be present in a number of different circumstances,
such as in association with: (i) dermatitis (including stasis der-
matitis and contact eczema); and (ii) noncomplicated varices.
Duque et al showed that in the latter group, 97% complained
of itching in the evening and night, 50% had some difficulty
falling asleep almost every night, and 40% were awakened
by itching. Itching is a frequent and intense symptom.9
u Restless legs
This symptom, usually quoted as restless legs syndrome, is
described by patients as a disagreeable and indefinable feeling,
MEDICOGRAPHIA, Vol 37, No. 1, 2015 11
LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC
frequently reported as having the fidgets in the lower limb,
and accompanied by an irresistible need to move the legs.
u Tingling
This symptom is described as a sensation of prickling or sting-
ing in the leg.
Methods allowing identification of venous etiology
In some cases, symptoms or physical signs are highly sus-
pect for venous etiology, but most often, circumstance of ap-
parition and instrumental investigations are crucial for attribut-
ing a venous cause to symptoms.
u Clinical circumstances of appearance
There is a consensus for agreeing that venous symptoms:
Are influenced by the standing position, which is often con-
sidered as a trigger, or immobility in orthostatic position.
Worsen progressively during the course of the day and are
worst in the evening.
Are exacerbated by warmth or when the ambient tempera-
ture and atmospheric humidity are high (eg, during the sum-
mer season, hot baths, floor-based heating systems, or hot
waxing to remove body hair), but less intense in winter and/
or with cold temperatures.
Are exacerbated during the luteal phase of the menstrual
cycle, in other words, more intense during the period im-
mediately prior to menstruation, and may decrease once
menstruation begins.
May occur with hormonal therapy (eg, oral contraceptive,
or hormone replacement therapy), but disappear with dis-
continuation of such treatment.10-12
Consequently, when symptoms occur or are enhanced by the
circumstances described above, a venous origin is highly prob-
able. Nevertheless, instrumental investigations are undertak-
en to identify venous pathophysiological anomalies, in order
to objectively diagnose venous etiology.
u Instrumental investigations
Instrumental investigations are often carried out in all patients
presenting with any kind of venous disorder from C0s to C6.
u Duplex scanning
Duplex scanning (DS) is the first-line investigation for suspect-
ed venous disorders. This noninvasive investigation explores
saphenous trunks and their first order tributaries, lower-limb
deep axial veins, as well as deep femoral, gastrocnemius veins,
and lower-limb perforators. Conversely, tributaries beyond the
first-generation tributaries and the iliac vein in obese patients
are either impossible or difficult to investigate in routine DS
examination.
u Venography
Venography includes ascending or descending phlebography,
with or without lower-limb tourniquet use. This investigation
explores the same veins, but less precisely in terms of patho-
physiological disorders such as reflux.
12 MEDICOGRAPHIA, Vol 37, No. 1, 2015
VENOUS DISORDERS
u Computed tomography and magnetic resonance imaging
These two investigations are rarely used in primary chronic ve-
nous disorders, except in pelvic congestion syndrome com-
bined with varices or when non-postthrombotic suprainguinal
vein obstruction is suspected.
u Iliac vein intravascular ultrasound examination
This investigation is only undertaken in primary venous dis-
orders, in patients presenting with severe symptomatology
without severe varices and in the absence of postthrombot-
ic syndrome.13
u Microcirculation investigations
Microcirculation is not investigated routinely in the presence
of primary venous disease, except in the few cases of se-
vere chronic venous insufficiency.
u Conclusion
Venous investigations, particularly DS, are very useful in pa-
tients for attributing symptoms to venous etiology in the CEAP
C2 class, although there is a weak correlation between varices
and symptom severity. Conversely in C0s patients, who rep-
resent 19.6% of the Vein Consult Program,12 venous valve
competence of the second to the sixth generation are not
investigated. We know that microscopic venous valves in
the small superficial venous veins of human lower limbs can
be incompetent, independent of reflux into the great saphe-
nous vein and major tributaries (Figure 1).14,15 A plausible hy-
pothesis is that symptoms present in C0s patient might be
caused by reflux in the second to sixth generation of micro-
valves. Such microrefluxes are not currently assessable by
physical examination or by DS investigation.
Relationship between symptoms and/or signs,
and other markers
u Venous symptoms and reflux
Pain is particularly poorly associated with the presence or
absence of trunk varices and reflux, according to the Edin-
burgh Vein cross-sectional survey. Firstly, in men, only itch-
ing was significantly related to the presence and severity of
trunk varices. In women, the correlation between symptoms
and trunk varices is better: heaviness or tension (P<0.001),
aching (P<0.001), and itching (P<0.005).16 Of note, this cor-
relation was established only for saphenous varices, Pr2 to
Pr4 according to the CEAP classification.16 The highest preva-
lence of symptoms was found when varices and telangiec-
tasias were both present.17 Secondly, reflux in the saphenous
trunks was not correlated with venous symptoms in men. In
women, only heaviness (P<0.025) and itching (P=0.002; left
leg) are correlated with saphenous reflux.18
Chiesa et al showed that approximately 80% of subjects with
no visible signs of venous disease, including absence of varices,
complain of symptoms. In contrast to the Edinburgh Vein cross-
sectional survey, reflux related to valve incompetence corre-
lated positively with worsening symptoms.19
Venous symptoms in chronic venous disorders Perrin
 LEG PA I N : TA K I N G
u Venous symptoms and venous disease severity
There is a significant correlation between venous symptoms,
particularly pain and worsening of clinical chronic venous dis-
order signs (CEAP classes), in many articles.20-23 Conversely,
Howlader and Smith found no correlation between symp-
toms and clinical classes (CEAP classification C2 to C5).24
u Venous symptoms and health-related quality of life
Impact of venous symptoms on health-related quality of life
has been clearly established in noncomplicated varices (CEAP
classification C2). To assess quality of life, Duque et al curious-
ly used a specific dermatologic questionnaire (Skindex-16),9
while Darvall et al used the generic Short Form 12 (SF-12).25
u Venous symptoms and inflammation
According to Howlader and Smith, there is no correlation be-
tween levels of inflammatory mediators and venous symp-
toms.24 However, Danziger, in his article on venous pain patho-
physiology, underlines that capillary and venule stasis activates
A
B DS. Secondly, the same difficulty exist in patients with non-
Figure 1. Patterns of retrograde resin casting in limbs assigned
CEAP C0 or C1.
All limbs had competent great saphenous veins (GSVs) as determined by ultra-
sound. The proximal end of the cast is to the right-hand side. A) Multiple terri-
tories of small vein network filling and dilated tortuous (arrow) veins. Of note, the
GSV was intact with numerous competent valves and tributaries (arrowheads).
B) Extensive filling of the superficial venous network. Note the straight course of
the GSV (between the two arrows), presence of competent GSV valves (arrow-
head), and high degree of variability in small vessel filling in these limbs with no
major, ultrasound-detected, superficial reflux.
Abbreviation: CEAP, clinical, etiological, anatomical, pathophysiological
From reference 15: Vincent JR, Jones GT, Hill GB, van Rij AM. J Vasc Surg.
2011;54:62S-69S. 2011, Society for Vascular Surgery.
Venous symptoms in chronic venous disorders Perrin
CENTER STA G E IN CHRONIC VENOUS DISORDERS
endothelial cells, resulting in the synthesis and local release
of inflammatory mediators such as bradykinin, platelet-acti-
vating factor, prostaglandins, and leukotriene B4, etc. In turn,
these inflammatory mediators activate C nociceptors in the
capillary and vein walls, resulting in diffuse pain often described
as discomfort, tightness, or heaviness.26,27
Attempts to better ascribe leg symptoms to
venous etiology
As venous symptoms are often nonpathognomonic and non-
specific, the task of attributing these symptoms to venous
etiology is not easy. Carpentier et al suggested the creation
of a diagnostic score in order to facilitate this process, by clas-
sifying the patients in two groups.28 The first group includes
patients presenting with leg symptoms and no clinical evi-
dence of arterial, rheumatic, or neurological disorders, but with
venous dysfunction documented both clinically and by DS ex-
amination. This group was named CVD+. The second group
included patients with leg symptoms and documented ar-
terial, rheumatic, or neurological disorders, but no signs of clin-
ical disorders or venous reflux at DS examination. This group
was identified as CVD .
In a validation series of 92 patients (67 CVD+ and 25 CVD ),
Carpentier et al found that the combination of four symptoms,
worsened by circumstances of apparition, was reliable in terms
of high specificity (0.95) and fair sensitivity (0.75) for identi-
fying chronic venous disorders. Unfortunately, no other pa-
per using this score has been reported and consequently the
score proposed by Carpentier and al has not yet been vali-
dated. In theory, the Carpentiers evaluation has two biases:
firstly C0s patients are difficult to classify, as they have no ve-
nous dysfunction identifiable by clinical examination or routine
thrombotic iliac vein obstructive lesions, which are not iden-
tified by DS examination according to Neglen.29
Another approach to identifing venous responsibility has re-
cently been used. In 2013, the BVS was reanalyzed to try to
distinguish between a psychic component and somatic com-
ponent by using a short questionnaire; the psychic vs somat-
ic venous disease questionnaire (PsySoVDQ).30 The conclu-
sion of this study is that the PsySoVDQ identified somatic and
psychic components of the widespread and frequently re-
ported leg symptoms in the general population. Nevertheless,
in the majority of subjects, symptoms remained unexplained.
The authors suggest a neuropsychological and neurobiolog-
ical hypothesis.
Conclusion
Precise definition and description of venous symptoms are
suggested in this review, in order to identify a venous origin
of the so-called venous symptoms. This is crucial in provid-
ing better care for symptomatic patients. However, there are
several issues that still need to be clarified.
MEDICOGRAPHIA, Vol 37, No. 1, 2015 13
LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC
Firstly, it is still unclear whether venous symptoms are caused
by a primary etiology in alterations of the major veinsrelat-
ed to reflux in superficial or/deep veins or compression above
the inguinal ligament axial veinsor in anomalies within the
veinules or capillaries. Secondly, it is still unclear whether the
presence or severity of symptoms independently of signs al-
lows us to forecast worsening venous disease. If we rely on
VCSS, the maximum score attributed to symptoms is only
3/30; in other words venous symptoms count for very little in
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1. Eklf B, Rutherford RB, Bergan JJ, et al; American Venous Forum Internation-
al Ad Hoc Committee for Revision of the CEAP Classification. Revision of the
CEAP classification for chronic venous disorders: consensus statement. J Vasc
Surg. 2004;40:1248-1252.
2. Vasquez MA, Rabe E, Mc Lafferty RB, et al. Revision of the venous clinical
severity score: Venous outcomes consensus statement: Special communica-
tion of the American Venous Forum Ad Hoc Outcomes Working Group. J Vasc
Surg. 2010;52:1387-1396.
3. Rabe E, Pannier-Fischer F, Bromen K, et al. Bonner Venenstudie der deutschen
Gesellschaft fr phlebologie. Epidemiologische Untersuchung zur Frage der
Hufigkeit und Ausprgung von chronischen venenkrankheiten in der stdtis-
chen und lndlichen Wohnbevlkerung. Phlebologie. 2003;32:1-14.
4. Rabe E, Pannier F. What we have learned from the Bonn Vein Study. Phlebo-
lymphology. 2006;13:186-191.
5. Lamping DL, Schroter S, Kurz X, Kahn SR, Abenhaim L. Evaluation of outcomes
in chronic venous disorders of the leg: Development of a scientifically rigorous,
patient-reported measure of symptoms and quality of life. J Vasc Surg. 2003;
37:410-419.
6. Kahn SR, Lamping DL, Ducruet T, et al; VETO Study investigators. VEINES-
QOL/Sym questionnaire was a reliable and valid disease-specific quality of life
measure for deep venous thrombosis. J Clin Epidemiol. 2006;59:1049-1056.
7. Delis KT, Bjarnason H, Wennberg PW, Rooke TW, Gloviczki P. Successful iliac
vein and inferior vena cava stenting ameliorates venous claudication and im-
proves venous outflow, calf muscle pump function, and clinical status in post-
thrombotic syndrome. Ann Surg. 2007;245:130-139.
8. Blttler W, Blttler IK. Relief of obstructive pelvic venous symptoms with endo-
luminal stenting. J Vasc Surg. 1999;29:484-488.
9. Duque M, Yosipovitch G, Chan YH, Smith R, Levy P. Itch, pain, and burning sen-
sation are common symptoms in mild to moderate chronic venous insufficien-
cy with an impact on quality of life. J Am Acad Dermatol. 2005;53:504-508.
10. Ramelet AA, Perrin M, Kern P, Bounameaux H. Symptoms in chronic venous dis-
ease. In: Phlebology. 5th ed. Paris, France: Elsevier Masson; 2008:97-103.
11. Carpentier PH, Maricq HR, Biro C, Ponot-Makinen OC, Franco A. Prevalence,
risk factors and clinical patterns of venous insufficiency of lower limbs: a popu-
lation-based study in France. J Vasc Surg. 2004;40:650-659.
12. Rabe E, Guex JJ, Puskas A, et al. Epidemiology of chronic venous disorders in
geographically diverse populations: results from the Vein Consult Program. Int
Angiol. 2012;31:105-115
13. Raju S, Neglen P. High prevalence of nonthrombotic iliac vein lesions in chron-
ic venous disease: a permissive role in pathogenicity. J Vasc Surg. 2006;44:
136-143.
14. Phillips MN, Jones GT, van Rij AM, Zhang M. Micro-venous valves in the super-
ficial veins of the human lower limb. Clin Anat. 2004;17:55-60.
15. 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
Keywords: CEAP classification; chronic venous disease; chronic venous disorder; varices; Venous Clinical Severity Score;
venous symptom
14 MEDICOGRAPHIA, Vol 37, No. 1, 2015
VENOUS DISORDERS
venous disorder scoring.2 Venous symptoms in epidemiolog-
ical studies are very common; in the BVS more than half of the
1800 participants reported such symptoms.3,4 We know that
operative treatment, particularly in noncomplicated, but symp-
tomatic, varices does not relieve venous symptomatology in
many cases. It would be a step forward to identify the patients
that could potentially experience improved symptoms follow-
ing operative treatment. Patients that are unlikely to improve
should be recommended an alternative treatment. n
Surg. 2011;54:62S-69S.
16. Bradbury A, Evans C, Allan P, Lee A, Ruckley CV, Fowkes FG. What are the
symptoms of varicose veins? Edinburgh vein study cross sectional population
survey. BMJ. 1999;318:353-356.
17. Ruckley CV, Evans CJ, Allan PL, Lee AJ, Fowkes FG. Telangiectasia in the Edin-
burgh Vein Study: Epidemiology and association with trunk varices and symp-
toms. Eur J Vasc Endovasc Surg. 2008;36:719-724.
18. Bradbury A, Evans CJ, Allan PA, Lee AJ, Ruckley CV, Fowkes FG. The rela-
tionship between lower limbs symptoms and superficial and deep venous re-
flux on duplex sonography: The Edinburgh Vein Study. J Vasc Surg. 2000;32:
921-931.
19. Chiesa R, Marone EM, Limoni C, Volonte M, Petrini O. Chronic venous disor-
ders: correlation between visible signs, symptoms, and presence of functional
disease. J Vasc Surg. 2007;46:322-330.
20. Carpentier PH, Cornu-Thenard A, Uhl JF, Partsch H, Antignani PL. Appraisal
of the information content of the C classes of CEAP clinical classification of
chronic venous disorders: A multicenter evaluation of 872 patients. J Vasc Surg.
2003;37:827-833.
21. Carpentier PH, Maricq HR, Biro C, Ponot-Makinen OC, Franco A. Prevalence
risk factors and clinical patterns of population-based study in France. J Vasc
Surg. 2004;40:650-659.
22. Kahn SR, MLan CE, Lamping DL, Kurz X, Berard A, Abenhaim LA; VEINES Study
Group. Relationship between clinical classification of chronic venous disease
and patient-reported quality of life: results from an international cohort study.
J Vasc Surg. 2004;39:823-828.
23. Langer RD, Ho E, Denenberg JO, Fronek A, Allison M, Criqui MH. Relationships
between symptoms and venous disease. Arch Int Med. 2005;165:1420-1424.
24. Howlader MH, Smith PD. Symptoms of chronic venous disease and associa-
tion with systemic inflammatory markers. J Vasc Surg. 2003;38:950-954.
25. Darvall KAL, Bate GR, Adam DJ, Bradbury AW. Generic health-related quality
of life is significantly worse in varicose vein patients with lower limb symptoms
independent of CEAP clinical grade. Eur J Vasc Endovasc Surg. 2012;44:341-
344.
26. Danziger N. [Pathophysiology of pain in venous disease]. J Mal Vasc. 2007:32;
1-7.
27. Danziger N. How to describe venous pain? In: From Venous Pain to Surgery.
1st ed. Paris, France: Servier Publisher; 2013:35-44.
28. Carpentier PH, Poulain C, Fabry R, et al. Ascribing leg symptoms to chronic ve-
nous disorders: the construction of a diagnostic score. J Vasc Surg. 2007;46:
991-996.
29. Neglen P. Chronic deep venous obstruction: definition, prevalence, diagnosis,
management. Phlebology. 2008;23:149-157.
30. Amsler F, Rabe E, Bltter W. Leg symptoms of somatic, psychic, and unex-
plained origin in the population-based Bonn Vein Study. Eur J Vasc Endovasc
Surg. 2013;46:255-262.
Venous symptoms in chronic venous disorders Perrin
 LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC VENOUS DISORDERS

DESCRIPTION ET DFINITION DES SYMPTMES VEINEUX

DANS LA MALADIE VEINEUSE CHRONIQUE : MISE AU POINT
La plupart des ouvrages consacrs aux troubles veineux ne les dcrivent pas prcisment et parfois, les signes et les
symptmes sont regroups de faon confuse sous la mme rubrique symptmes . Cette absence de description
prcise peut tre lie la non-spcificit de la majorit des symptmes veineux et leur relative similarit avec des
symptmes qui sont dus des causes non veineuses. Les symptmes numrs dans les classifications veineuses
multiples sont souvent diffrents et les termes utiliss pour dcrire les symptmes dans lesdiffrentes classifica-
tions des affections veineuseschroniques ne sont pas toujours les mmes. Certains symptmes frquemment rap-
ports peuvent tre difficiles diffrencier car trs similaires comme, par exemple, la douleur et lendolorissement.
Cet article dcrit tout dabord les symptmes aussi prcisment que possible, pour ensuite dfinir leurs circons-
tances de survenue. Les relations entre les symptmes et les signes, le reflux, la qualit de vie, le score veineux cli-
nique et les marqueurs inflammatoires sont tudies. Les tentatives dune meilleure attribution dun symptme du
membre infrieur une tiologie veineuse sont analyses et leur valeur est discute. Pour conclure, nous recom-
mandons un consensus international sur la dfinition des causes et des symptmes veineux dont la connaissance
pourra, en retour, amliorer la prise en charge des patients.

Venous symptoms in chronic venous disorders Perrin MEDICOGRAPHIA, Vol 37, No. 1, 2015 15

Recent epidemiologic stud-
ies show that venous symptoms
defined in the updated CEAP clas-
sification are very common in the
general population. These symp-
toms, eg, feeling heaviness, swell-
ing, and pain in the legs, are more
prevalent in the female population,
compared with the male popula-
tion. They increase with age and
are more frequent in higher clinical
stages of chronic venous disorders,
except for restless legs and simi-
lar complaints.
Eberhard RABE, Prof Dr. med
Department of Dermatology
University of Bonn
GERMANY
Address for correspondence:
Prof Dr. med. Eberhard Rabe,
Emeritus President Union, internatio-
nale de Phlbologie, Department of
Dermatology, University of Bonn,
Sigmund-Freud-Str. 25, 53105 Bonn,
Germany (e-mail:
eberhard.rabe@ukb.uni-bonn.de)
www.medicographia.com
16 MEDICOGRAPHIA, Vol 37, No. 1, 2015
LEG PA I N : TA K I N G C E N T E R S TA G E I N C H R O N I C V E N O U S D I S O R D E R S
The prevalence of lower-
limb venous symptoms in
recent epidemiological surveys
by E. Rabe, Germany
T
he clinical class, C, of the clinical, etiological, anatomical, pathophys-
iological (CEAP) classification divides cases into symptomatic and asymp-
tomatic, with symptoms including aching, pain, tightness, skin irritation,
heaviness, and muscle cramps, particularly if they are exacerbated, eg, by
heat or during the course of the day, or relieved with leg rest or elevation. In
recent epidemiological studies, it could be shown that these symptoms are
very frequent in the general population and may not be specific for venous
disease. Their prevalence increases with age and is higher in women. How-
ever, these symptoms are significantly associated with venous pathology and
their frequency also increases with higher C stages. Venous symptoms in
individuals without clinical signs of chronic venous disorders may indicate hid-
den structural or functional venous pathology, such as postthrombotic changes
or obesity-induced venous obstruction. However, other reasons for leg symp-
toms, such as orthopedic disease or a psychogenic component, should not be
neglected.
Medicographia. 2015;37:16-19 (see French abstract on page 19)
Introduction
hronic venous disorders of the lower limbs are amongst the most common
C diseases all over the world.1,2 in contrast to older studies, recent epidemi-
ological studies have used the clinical, etiological, anatomical, pathophys-
iological (CEAP) classification to make results more comparable.2-9
The CEAP classification of chronic venous disorders, in its updated version from 2004,
gives clear definitions of venous findings and specifies venous symptoms.10 All clin-
ical classes can be asymptomatic (A) or symptomatic (S). Symptoms include aching,
pain, tightness, skin irritation, heaviness, muscle cramps, and other complaints at-
tributable to venous dysfunction.10 The subjective symptomatic course can point to
a venous etiology, particularly if the abovementioned symptoms are exacerbated,
eg, by heat and/or the course of the day, or relieved with leg rest and/or elevation.11
Lower-limb symptoms may be associated with venous pathology, but may not be
specific for venous disease. Van der Velden recently found that other leg diseases
like arterial occlusive disease, knee or hip arthrosis, or spinal disc herniation may be
associated with identical symptoms as venous disease.12 in the Edinburgh Vein
Study, Bradbury found that the correlation of trunk varices with venous symptoms
is weak13 and that venous symptoms do not correlate well with venous reflux.14 How-
The prevalence of lower-limb venous symptoms in recent epidemiological surveys Rabe
 LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC VENOUS DISORDERS

part of the standard interview, participants were asked if they

Symptom All (%) Men (%) Women (%) had any kind of venous symptoms in the past or present. The
most frequent symptom was aching (17.7%), followed by
Heaviness 18.2 11.1 23.8 cramping (14.3%), tired legs (12.8%), and feeling of swelling
Tension 12.6 9.1 15.3 (12.2%) (Table II).6
Swelling 11.4 5.7 15.8
Aching on standing 19.9 14.4 24.2 Symptoms were more common in the female population com-
Aching on walking 11.6 11.3 11.8 pared with the male population. Except for restless legs, all
itching 9.5 10.3 8.9 symptoms increased with the severity of the disease. The
Cramps 25.5 21.9 28.2 prevalence of all symptoms, except of restless legs, was sig-
Restless legs 9.6 6.4 12.1 nificantly higher in participants with trophic venous changes.

Table I. Leg symptoms in the Bonn Vein Study I.
Modified from reference 4: Rabe E et al. Phlebologie. 2003;32:1-14. 2003,
Schattauer GmbH.
ever, Darvall showed a worsening of health-related quality of
life with the number of reported venous symptoms.15 The aim
of the paper is to review venous symptom findings in recent
epidemiologic studies that used the CEAP classification.
The Italian Study
in italy, Chiesa and coworkers published the 24-cities cohort
study on venous diseases, including 4457 women and 730
men aged 18 to 90 years.7 The participants were selected
during spring and summer 2003 by advertising on television,
in newspapers, and by leaflets in 24 italian cities. Only 22.7%
had no clinical signs of chronic venous disease (CVD). A total

The Bonn Vein Study

The Bonn Vein Study investigated 3072 partic- Symptom All (%) No CVD (%) C1 (%) VV (%) TC (%)
ipants aged between 18 and 79 years, select- Heaviness 7.5 4.4 6.7 11.8 16.0
ed by a simple random sample from population
Swelling 12.2 7.2 10.1 19.1 35.7
registers of the city of Bonn and two rural town-
Tired legs 12.8 10.6 11.1 18.3 21.1
ships.4 The overall prevalence of varicose veins
Aching 17.7 14.2 15.7 25.5 29.1
was 23.2% (19.8% in men, 25.8% in women),
itching 5.4 4.0 4.3 8.7 13.1
and of chronic venous insufficiency (C3 to C6)
Cramps 14.3 12.9 13.2 17.7 19.7
17% (15.4% in men, 18.3% in women). A total
Restless legs 7.4 5.8 7.5 9.0 8.0
of 56.4% of the participants claimed leg symp-
toms assignable to chronic venous disorders in
Table II. Percentage of participants with leg symptoms in the San Diego Population
the prior 4 weeks (Table I).4 Venous symptoms
Study by visible disease.
were more frequent in the female population Abbreviations: CVD, chronic venous disease; C1, telangiectasias or reticular veins; VV, varicose
(62.1%) compared with the male population veins; TC, trophic changes.
(49.1%). A total of 53.9% of the rural population Modified from reference 6: Langer RD et al. Arch Intern Med. 2005;165(12):1420-1424. 2005,
American Medical Association.
and 57.9% of the city population had venous
symptoms. The prevalence of symptoms increased with age of 64.8% had telangiectasias or reticular veins, 29.4% had vari-
and with the clinical class according to the CEAP classification. cosities other than saphenous veins, and 13.6% saphenous
Venous symptoms were present in 43.4% of the C0 popula- varicose veins. in the C3 class, 13.6% had edema, 13.4% ve-
tion, whereas 85.1% of the C4 population were symptomatic. nous eczema, and 8.6% preulcer skin changes like white at-
rophy and dermatoliposclerosis, or healed or active venous
The San Diego Population Study ulcers. Venous symptoms were reported in 96.3% of the
The San Diego Population Study investigated 2408 men and women and 90.1% of the men. The authors suspected that
women, aged between 29 to 91 years, who were employees, this high prevalence might be partly due to the method of
retirees, or spouses of a large state university. This population recruitment for the study.7 There were no differences in preva-
was randomly selected within strata by age, sex, and ethnic- lence by age or by region of living for most of the symptoms.
ity.6 in the whole population, 23.3% had varicose veins (15% The most frequent complaints were tired legs (77.5%) and
in men, 27.7% in women).5 Trophic changes were present in heavy legs (75.5%). Except for tingling sensation, women re-
6.2% of the population (7.8% in men, 5.3% in women). As a ported symptoms significantly more often than men (Table III,
page 18).7
SELECTED ABBREVIATIONS AND ACRONYMS
The Polish Study
CEAP clinical, etiological, anatomical, pathophysiological in this multicenter cross-sectional study, 803 participating pri-
CVD chronic venous disease mary care physicians in Poland screened 40 095 consecutive
patients using a standardized interview and assigned them to

The prevalence of lower-limb venous symptoms in recent epidemiological surveys Rabe MEDICOGRAPHIA, Vol 37, No. 1, 2015 17
LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC VENOUS DISORDERS

practitioners in Western, Central, and Eastern Europe, Lat-

Symptom All (%) Men (%) Women (%) in America, and the Middle East screened 91 545 consec-
utive patients for the presence of chronic venous disorders.
Heaviness 75.5 57.4 78.5 The mean age was 50.6 years, with 16.4% of all participants
Swelling 53.9 36.4 56.8 in an asymptomatic C0 class and 19.7% with venous symp-
Tired legs 77.5 66.0 79.4 toms, but no clinical signs of chronic venous disorders (C0s).
Pain 53.0 42.9 54.6 A total of 21.7% had reticular veins or telangiectasias, 17.9%
Heat sensation 40.1 27.0 42.3 were in class C2, 14.7% in C3, 7.5% in C4, 1.4% in C5, and
Tingling sensation 38.4 37.7 38.5 0.7% in C6. The majority of the population screened had ve-
nous symptoms, the most prevalent being heavy legs (72.4%)
Table III. Percentage of participants with leg symptoms in the Italian and pain (67.7%) (Table IV).
24-cities cohort study.
Modified from reference 7: Chiesa R et al. Eur J Vasc Endovasc Surgery. 2005;
30:422-429. 2005, Elsevier Ltd.
in the majority, symptoms increased at the end of the day.
Venous symptoms were more prevalent in the female pop-
a clinical class, C, according to the CEAP classification.8 Of ulation and the prevalence increased with higher C classi-
the participants, 16% were men and 84% were female. The fication.
age ranged from 16 to 97 years with a mean of 44.8 years. A
total of 51.1% were assigned to C0, 16.5% to C1, 21.8% to Discussion
C2, 4.5% to C3, 4.6% to C4, 1% to C5, and 0.5% to C6. Recent epidemiologic studies show that venous symptoms
defined in the updated CEAP classification are very common
in patients assigned to the clinical levels C1 to C6, symptoms in the general population.10 These symptoms, eg, feeling heav-
like heaviness, cramps, and aching were very frequent com- iness, swelling, and pain in the legs, are more prevalent in the
pared with those assigned to C0 (heaviness 73.7% vs 23.3%, female population compared with the male population. They
cramps 57.5% vs 20.0%, aching 75.7% vs 27.5%, respec-
tively). in the chronic venous disorder group (CEAP C1 to C6 ),
in most cases the symptoms intensified at the end of the Symptom All (%) Men (%) Women (%)
day (73.4%), during standing position (67.4%), and during Heaviness 72.4 64.1 75.2
summer time (66.1%), compared with the C0 patients, where Swelling 52.7 42.4 56.3
this dynamic could only be observed in the minority of par- Aching 67.7 62.5 69.4
ticipants (24.6%, 20.0%, 19.5%, respectively). in the chron-
Cramps 44.3 42.9 44.8
ic venous disorder population, the symptoms were chronic
itching 23.6 22.4 24.0
in 23.8%, whereas this was only the case in 4.4% of the C0
group. Heat sensation 29.0 23.6 30.9
Pins and needles 37.0 33.9 38.2
The Brazilian Study
Table IV. Percentage of participants with leg symptoms in the Vein
From March 1998 to December 2000, in the cities of Soro-
Consult Program (unpublished data).
caba and Campinas, 2104 consecutive patients from gener-
al ambulatory departments in the University Hospital and from increase with age and are more frequent in higher clinical
the Public Health Centers were screened for venous disease stages of chronic venous disorders, except for restless legs
and assigned to the C class of CEAP.9 They were asked about and similar complaints. These symptoms increase during the
the presence of subjective symptoms such as feelings of heav- course of the day and with warm temperatures in the chron-
iness in the legs, edema, tired legs, burning feet, and pares- ic venous disorder population.2,8,12
thesia. in the female age group of 14 to 22 years, 12.29% were
symptomatic, in the age group of 23 to 48 years, 37.53% had These symptoms are not limited to venous disease alone.
venous symptoms, and in those older than 48 years, 62.7% As Van der Velden showed, similar symptoms may also be
were classified as symptomatic. in the male population, only present in other pathologies, such as orthopedic back and
13.97% were classified as symptomatic. knee diseases, and arterial occlusive disease.12 However, in
these cases the typical dynamics with increased intensity dur-
The Vein Consult Program ing the course of the day and during warm periods may not
The most recent data derive from the Vein Consult Program be present.8,12
(VCP).2 The VCP is a large international observational pros-
pective survey that has been carried out on the initiative of Even in the C0 patients without any clinical signs of CVD so-
the Union Internationale de Phlbologie (international Union called venous symptoms may be present. it is possible in
of Phlebology) to raise awareness of CVD, thanks to an un- these cases that the symptoms are definitely not of venous
restricted grant from Servier, France. A total of 6232 general origin and therefore may have an alternative cause. However,

18 MEDICOGRAPHIA, Vol 37, No. 1, 2015 The prevalence of lower-limb venous symptoms in recent epidemiological surveys Rabe
 LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC VENOUS DISORDERS

the clinical level C0 does not mean that no venous patholo-
gy exists. One such example is of postthrombotic patients
with obstruction or valve incompetence in the deep venous
system, but without varicose veins, edema, or skin changes.
in these patients, the symptoms are even part of the Villalta
Score to classify postthrombotic syndrome.16 Feelings of heav-
iness, swelling, or pain, like venous claudication, may also be
symptoms of primary or secondary iliac vein obstruction with-
out visible signs of chronic venous disorders.17 in addition,
obese patients may develop a functional venous disease with-
out reflux, but with nonpermanent iliac vein obstruction during
sitting periods.18 They may also develop venous symptoms
without clinical signs of chronic venous disorders. We have to
consider that there may also be a psychogenic component of
leg symptoms, as reported by Amsler and coworkers in 7.3%
of the Bonn Vein Study symptomatic participants.19 n

References
1. Beebe-Dimmer JL, Pfeifer JR, Engle JS, Schottenfeld D. The epidemiology of
chronic venous insufficiency and varicose veins. Ann Epidemiol. 2005;15:175-
184.
2. Rabe E, Guex JJ, Puskas A, Scuderi A, Fernandez Quesada F; VCP Coordina-
tors. Epidemiology of chronic venous disorders in geographically diverse pop-
ulations: Results from the vein consult program. Int Angiol. 2012;31:105-115.
3. Evans CJ, Fowkes FG, Ruckley CV, Lee AJ. Prevalence of varicose veins and
chronic venous insufficiency in men and women in the general population: Ed-
inburgh vein study. J Epidemiol Community Health. 1999;53:149-153.
4. Rabe E, Pannier-Fischer F, Bromen K, et al. Bonner Venenstudie der Deutschen
Gesellschaft fr Phlebologie. Phlebologie. 2003;32:1-14.
5. Criqui MH, Jamosmos M, Fronek A, et al. Chronic venous disease in an ethni-
cally diverse population: The San Diego population study. Am J Epidemiol. 2003;
158:448-456.
6. Langer RD, Ho E, Denenberg JO, Fronek A, Allison M, Criqui MH. Relationships
between symptoms and venous disease: The San Diego population study. Arch
Intern Med. 2005;165(12):1420-1424.
7. Chiesa R, Marone EM, Limoni C, Volont M, Schaefer E, Petrini O. Chronic ve-
nous insufficiency in italy: The 24-cities cohort study. Eur J Vasc Endovasc Surg.
2005;30:422-429.
8. Jawien A, Grzela T, Ochwat A. Prevalence of chronic venous insufficiency in men
and women in Poland: multicenter cross-sectional study in 40095 patients.
Phlebology. 2003;18:110-122.
9. Scuderi A, Raskin B, Al Assal F, et al. The incidence of venous disease in Brazil
based on the CEAP classification. Int Angiol. 2002;21:316-321.
10. Eklof B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification for
chronic venous disorders: Consensus statement. J Vasc Surg. 2004;40:1248-
1252.
11. Eklof B, Perrin M, Delis KT, et al. Updated terminology of chronic venous dis-
orders: The VEiN-TERM transatlantic interdisciplinary consensus document.
J Vasc Surg. 2009;49(2):498-501.
12. Van der Velden SK, Shadid NH, Nelemans PJ, Sommer A. How specific are ve-
nous symptoms for diagnosis of chronic venous disease? Phlebology. 2014:
29(4):580-586.
13. Bradbury A, Evans C, Allan P, Lee A, Ruckley CV, Fowkes FG. What are the
symptoms of varicose veins? Edinburgh vein study cross sectional population
survey. BMJ. 1999;318:353-356.
14. Bradbury A, Evans CJ, Allan P, Lee AJ, Ruckley CV, Fowkes FG. The relation-
ship between lower limb symptoms and superficial and deep venous reflux on
duplex ultrasonography: The Edinburgh Vein Study. J Vasc Surg. 2000;32(5):
921-931.
15. Darvall KA, Bate GR, Adam DJ, Bradbury AW. Generic health-related quality of
life is significantly worse in varicose vein patients with lower limb symptoms in-
dependent of CEAP clinical grade. Eur J Vasc Endovasc Surg. 2012;44(3):341-
344.
16. Kahn SR. Measurement properties of the Villalta scale to define and classify the
severity of the post-thrombotic syndrome. J Thromb Haemost. 2009;7:884.
17. Negln P, Raju S. Balloon dilation and stenting of chronic iliac vein obstruc-
tion: technical aspects and early clinical outcome. J Endovasc Ther. 2000;7:79-
91.
18. Gstl K, Obermayer A, Hirschl M. Pathogenese der chronisch vensen insuf-
fizienz durch Adipositas Aktuelle Datenlage und Hypothesen. Phlebologie.
2009;38:108-113.
19. Amsler F, Rabe E, Blattler W. Leg symptoms of somatic, psychic, and unex-
plained origin in the population-based bonn vein study. Eur J Vasc Endovasc
Surg. 2013;46:255-262.

Keywords: CEAP classification; chronic venous disease; chronic venous disorder; venous symptom

LA PRVALENCE DES SYMPTMES DES MEMBRES INFRIEURS

DANS LES TUDES PIDMIOLOGIQUES RCENTES
La classe clinique C de la classification CEAP (clinique, tiologique, anatomique, physiopathologique) divise les
cas en symptomatiques et asymptomatiques, les symptmes comprenant douleur, raideur, irritation de la peau, lour-
deur et crampes musculaires, en particulier sils sont exacerbs par exemple par la chaleur ou au cours de la jour-
ne, ou soulags par llvation ou le repos des jambes. Dans des tudes pidmiologiques rcentes, ces symptmes
sont trs frquents dans la population gnrale et ne sont pas spcifiques de la maladie veineuse. Leur prvalence
augmente avec lge et elle est plus leve chez les femmes. Ces symptmes sont cependant significativement as-
socis une pathologie veineuse et leur frquence augmente aussi avec les stades C plus levs. Les symp-
tmes veineux chez ceux qui nont pas de signes cliniques de maladie veineuse chronique (MVC) peuvent voquer
une pathologie veineuse structurelle ou fonctionnelle cache, comme des modifications post-thrombotiques ou une
obstruction veineuse induite par lobsit. Il ne faut cependant pas ngliger les autres raisons des symptmes de
jambes, comme les maladies orthopdiques ou linfluence psychique.

The prevalence of lower-limb venous symptoms in recent epidemiological surveys Rabe MEDICOGRAPHIA, Vol 37, No. 1, 2015 19

from a practical point of
view, it is important to distinguish
patients with actual symptomatic
varicosities from those patients
with other sources of pain and oth-
er venous complaints. If such pa-
tients are initially not properly di-
agnosed, it is inevitable that some
of them will be dissatisfied by the
treatment for varicose veins, since
the real cause of their complaints
(eg, hip arthrosis) will not be ad-
dressed by a vascular procedure.
Marian SIMKA, MD, PhD
College of Applied Sciences
Department of Nursing
Ruda lska, POLAND
Address for correspondence:
Marian Simka, ul. Jednosci 20,
43-245 Studzionka, Poland
(e-mail: mariansimka@poczta.onet.pl)
www.medicographia.com
20 MEDICOGRAPHIA, Vol 37, No. 1, 2015
LEG PA I N : TA K I N G C E N T E R S TA G E I N C H R O N I C V E N O U S D I S O R D E R S
Symptoms and signs
of chronic venous disorders:
can we put an end
to the controversy?
b y M . S i m k a , Po l a n d
A
ssociation of so-called venous symptoms (aching, itching, tingling, burn-
ing sensation, swelling, easily fatigued legs, leg heaviness, and leg rest-
lessness) with chronic venous disease (CVD) still remains a controver-
sial issue. Although these symptoms and decreased quality of life are common
in patients with venous incompetence, and are even more frequent in those
with a history of venous thrombosis or recurrent and bilateral varicose veins,
research has actually revealed that these complaints are poorly correlated
with objective signs of venous insufficiency. A venous source for these com-
plaints is quite obvious in patients with advanced CVD, but a substantial part
of venous symptoms, especially in patients with telangiectasias and uncompli-
cated varicose veins, is actually not of venous origin. In addition, such symp-
toms can be reported by many patients presenting with nonvenous diseases,
while uncomplicated varicose veins can cause few symptoms or be asymp-
tomatic. In many venous patients these symptoms are not permanent, but
can only be seen at the end of the day. Therefore, it is important to consider
and investigate an alternative cause of such venous complaints, especially
because other pathologies can accompany CVD and produce similar symp-
toms. The most common pathologies that may be responsible and should be
taken into account include: spinal disc herniation, hip and knee arthrosis, pe-
ripheral arterial disease, joint and ligament overload due to obesity, peripher-
al neuropathy, and adverse drug reactions.
Medicographia. 2015;37:20-25 (see French abstract on page 25)
here is a great deal of controversy surrounding association of so-called ve-
T nous symptoms with chronic venous disease (CVD). An uncertain associa-
tion of the presence of uncomplicated varicosities with these symptoms has
even lead some health care providers to restrict access to treatment for asympto-
matic varicose vein patients or those experiencing few symptoms.1 Clinical symptoms
that are thought to be caused by chronic venous insufficiency include: aching leg
pain, itching, tingling, burning sensation, swelling, easily fatigued legs, leg heaviness,
and restlessness. All of these symptoms typically worsen as the day progresses.2
The presence of such complaints usually correlates with a decreased quality of life
(QoL). An association of these symptoms with CVD is not as obvious as is usually
believed. While some researchers found significant correlations between venous
symptoms and the signs of CVD (venous reflux revealed by means of Doppler sono-
graphy, visible varicose veins, or skin changes typical for venous incompetence [hy-
perpigmentation, lipodermatosclerosis, and ulcers]), others argued that these symp-
Symptoms and signs of chronic venous disorders Simka
 LEG
D A
C find significant differences it terms of venous symptoms be-
Figure 1. The most common nonvenous causes of the so-called
venous symptoms.
(A) spinal disc herniation; (B) hip and knee arthrosis; (C) peripheral arterial disease;
(D) peripheral neuropathy; (E) adverse drug reactions (calcium channel blocker
or other medications).
toms were actually poorly correlated with clinical signs of ve-
nous insufficiency. In this review, I will summarize the research
related to this problem in an attempt to explain conflicting re-
sults and interpretations of the studies.
Correlating symptoms and signs
u Severe chronic venous disease
The majority of patients with severe forms of CVDthose with
leg edema (C3 according to the clinical, etiological, anatom-
ical, pathophysiological [CEAP] classification), skin changes
(C4 ), and venous ulcers (C5 and C6 )present with some of
the above symptoms. The proportion of patients with venous
symptoms significantly increases with the C class of the
CEAP classification.3 Usually, in patients with advanced CVD
SELECTED ABBREVIATIONS AND ACRONYMS
CEAP clinical, etiological, anatomical, pathophysiological
CVD chronic venous disease
QoL quality of life
VEINES VEnous INsufficiency Epidemiologic and economic
Study
Symptoms and signs of chronic venous disorders Simka
PA I N : TA K I N G CENTER STA G E IN CHRONIC VENOUS DISORDERS
an association of these symptoms with venous incompetence
is not questioned, even if other pathologies can accompany
chronic venous insufficiency and may produce similar symp-
toms. Also, it has been demonstrated that these patients pres-
ent with decreased QoL, with progressive impairment of QoL
from C3 to C5/C6.2,4,5
u Less severe chronic venous disease
Venous background of clinical symptoms in patients with less
severe forms of CVD, C1 and C2, remains controversial. Many
of these patients are asymptomatic despite the presence of
an obvious venous pathology.3,6-10 In many C1/C2 patients
B these complaints may actually be rooted in another coexist-
ing pathology, such as osteoarticular, neurologic, or arterial
pathology (Figure 1). For example, in the VEnous INsufficiency
Epidemiologic and economic Study (VEINES; 1531 patients
with CVD and 1313 controls assessed) the authors did not
tween the controls and patients with varicose veins (C2). Thus,
the authors speculated that clinical symptoms in varicose
E vein patients probably resulted from concomitant aspects of
CVD and not from varicosities, per se.9
u Poor correlation between symptoms and signs
In the Edinburgh Vein Study (a cross-sectional population
study, 1566 individuals assessed) the authors did not demon-
strate an association between lower-limb symptoms (leg heav-
iness, aching, and itching) and the presence of visible varicose
veins.11 Nor did they reveal a significant correlation between
venous reflux and lower-limb symptoms.12 Consequently they
concluded that most of these symptoms probably had a non-
venous cause.11 A similar conclusion came from another study,
where itching and burning sensations in the legs were not
correlated with the severity of venous insufficiency.13 Also, an
observational study by Howlager et al, looking at patients at-
tending a vascular clinic (132 individuals assessed), did not
reveal an association between severity of the symptoms and
anatomic distribution of venous reflux.14
u Potential correlation between symptoms and signs
On the contrary, in the San Diego population study (a cross-
sectional study on 2209 individuals) the researchers revealed
an association between clinical symptoms and the presence
of venous disease. Leg edema was the most specific symp-
tom related to venous incompetence. Other symptoms, com-
prising leg heaviness, aching, and itching, although more com-
mon in the patients with venous disease, were also found quite
often (5% to 15%) in individuals without CVD.15
Similar results were demonstrated by a recent Dutch study.
The authors revealed small andexcept for swelling of the leg
and itchingnonsignificant differences in prevalence of ve-
nous symptoms between the patients with CVD and those
suffering from other pathologies (arthrosis, peripheral arterial
disease, or spinal disc herniation). However, the patients with
MEDICOGRAPHIA, Vol 37, No. 1, 2015 21
LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC
venous incompetence were more likely to experience symp-
toms at the end of the day, which was atypical in patients with
other pathologies.2
In another study, the researchers found more frequent venous
symptoms among patients with telangiectasias, and even
more such symptoms in patients with varicose veins. How-
ever, a substantial proportion of the individuals without ve-
nous disease also reported venous complaints (heaviness,
swelling, aching, restless legs, cramps, itching, and tingling)
and differences between the subjects with no visible venous
pathology and those with either telangiectasias or varicose
veins were modest.16
Much the same conclusions came from another survey. The
authors of this cross-sectional study revealed venous symp-
toms in 60% of patients with varicose veins and demonstrat-
ed that this association was statistically significant. However,
33% of subjects without varicose veins also suffered from ve-
nous symptoms. Risk factors that were significantly associat-
ed with these symptoms included prolonged sitting or stand-
ing, and history of thromboembolism. These symptoms were
more common in older women and in tall (height >175 cm)
and overweight (body mass index [BMI] >25 kg/m2 ) men. Con-
sequently, the authors concluded that varicose veins were
not the only cause of venous symptoms. Other factors, prima-
rily prolonged sitting and standing, could be a source of such
symptoms, and improper clothes and shoes may also play a
role. Of note, the researchers did not demonstrate a statis-
tically significant correlation between these symptoms and a
history of osteoarthritis. Still, venous symptoms were more
common in such patients (20% vs 15% in patients with a neg-
ative history of osteoarthritis). Notably, in this study the pa-
tients were not clinically examined to reveal an osteoarticular
pathology.8
In another cross-sectional study on clinical features of CVD in
Italian patients (16 251 individuals assessed) the researchers
found a statistically significant positive correlation between
the symptoms (such as tired and heavy legs, leg pain, or leg
edema) and severity of venous disease (defined by the C
grade of CEAP). These venous symptoms were more preva-
lent in women and in patients with an increased BMI. How-
ever, almost all participants of this survey reported some com-
plaints and only about 10% of the individuals surveyed were
free of venous symptoms. An actual venous background of
these complaints in the population studied remains question-
able. Moreover, it was likely that relevant selection bias oc-
curred in this study, since the individuals attending this sur-
vey were attracted by means of advertising in mass media.
Therefore, the population was probably skewed towards peo-
ple with somenot necessarily vascularleg complaints.10
To add to the confusion, in one study patients with benign ve-
nous disease (C2/C3) reported more symptoms than those
with complicated varicose veins (C4/C5).14
22 MEDICOGRAPHIA, Vol 37, No. 1, 2015
VENOUS DISORDERS
Venous background of leg symptoms in patients with telang-
iectasias and small epifascial veins (C1 in the CEAP classifica-
tion) is even less certain. In a cross-sectional study aimed at
the evaluation of the clinical impact of small cutaneous veins,
researchers found that venous symptoms, comprising leg ede-
ma, muscle cramps, and restless legs, were more common
in patients with small varicosities in comparison with healthy
controls (C0), except for itching, which was less prevalent in
the individuals with dilated veins. However, when adjusted for
age and sex, these differencesexcept for leg swellingwere
no longer statistically significant. Thus, the authors concluded
that although venous symptoms were quite common, also in
the C1 class patients, patients age (older subjects) and sex
(women) seemed to be a better explanation for these com-
plaints than the presence of small cutaneous varicosities. Leg
swelling can be related to such dilated veins, yet their clinical
relevance in the development of this symptom seemed to be
low (odds ratio, 1.3).17
Chronic venous disease and quality of life
u Clinical stage
There are also conflicting results for studies on QoL in early
stages of CVD. In the San Diego population study the presence
of venous disease, even of uncomplicated varicose veins, was
associated with significant limitations of all functional scales
(physical functioning, role functioning, pain, and general health
perception) of the Short Form 36 (SF-36) QoL questionnaire.5
In another study, female sex was associated with a worse QoL
in the patients referred to the varicose vein clinic, but this ef-
fect was no longer seen when only C2 patients were analyzed.7
Similarly, the VEINES study did not reveal significant differences
in QoL between C2 patients and controls,9 and there was no
association between the C class and QoL impairment in a
study assessing the patients qualified for surgical treatment of
varicose veins.7 Also, an observational study on patients as-
sessed in vascular laboratories did not demonstrate a de-
creased QoL in the individuals with C1 and C2 classes. Some
QoL scores were even higher in varicose vein patients than in
healthy people.4,18 Likewise, in a study evaluating patients qual-
ified for invasive varicose vein treatment, the authors found
an impaired QoL that was independent of the clinical stage of
venous disease.19 However, a similar cross-sectional study
(570 venous patients from Serbia) revealed a progressive wors-
ening of QoL from C1 to C6 class. Even those patients pre-
senting with C1 and C2 classes reported an impairment of QoL
and did not consider their venous incompetence as a benign
cosmetic problem, but rather as a real disease.20 Worsening
of QoL in C3 to C6 patients compared with the C1/C2 classes
was also found in another study.21
u Venous reflux and inflammatory markers
Similarly, a correlation between the degree of venous reflux
with QoL reduction is uncertain. Although one would expect
profound venous reflux or an increased diameter of incompe-
Symptoms and signs of chronic venous disorders Simka
 LEG PA I N : TA K I N G
tent saphenous trunk to be associated with more severe clin-
ical symptoms and decreased QoL, research does not always
confirm such a relationship. In one study, incompetence of
the great or small saphenous veins had a greater impact on
QoL than nonsaphenous varicosities.7 Another study revealed
either a weak or no correlation between the diameter of in-
competent great saphenous vein and impaired QoL in patients
with varicose veins.22 Similarly, there was no association be-
tween venous symptoms and systemic inflammatory markers,
such as von Willebrand factor, intercellular adhesion mole-
cule 1 [ICAM-1], vascular cell adhesion protein 1 [VCAM-1],
E-selectin, P-selectin, L-selectin, vascular endothelial growth
factor [VEGF], interleukin 1a (IL-1a), IL-1b, IL-6, and tumour
necrosis factor a (TNF-a).14
u Interventions
Some studies examined the impact of interventions aimed at
the reduction of venous incompetence (compression therapy
or ablation of varicose veins) on venous symptoms and QoL.
It might be assumed that if the symptoms were indeed pro-
duced by venous disease, then such treatments should re-
sult in fewer complaints and a better QoL. However, only some
of the patients studied were free of symptoms after otherwise
successful treatment of varicose veins.23-25 On the other hand,
a recurrence of venous incompetence was not always accom-
panied by a return of the symptoms.26,27
u Compression stockings and radiofrequency ablation
As expected, wearing compression stockings resulted in im-
proved QoL, not only in advanced (C3 to C5) venous patients,
but also in those with early (C2) disease.18 A similar improve-
ment of QoL was demonstrated by another study in patients
with incompetent great saphenous veins (clinically C2 to C4).
The authors of this study revealed that improvement of QoL
was mainly due to the relief of venous symptoms. In this study,
an invasive treatment (radiofrequency ablation of the great
saphenous vein together with phlebectomies of superficial
varicosities) resulted in an even greater improvement of QoL.
An important finding of this study was that relief of symptoms
by compression therapy was a good predictor of successful
surgical treatment. Patients who improved their symptoms
with compression therapy were more likely to experience fur-
ther clinical improvement after ablation of varicose veins. How-
ever, a substantial proportion of patients who did not improve
their QoL after compression therapy benefited from surgical
treatment of varicose veins. Thus, not all clinical symptoms of
CVD could be relieved by compression alone.28
u Surgical excision
In another interventional study, QoL significantly improved
(71% of the patients got better) after surgical excision of vari-
cose veins. Patients with uncomplicated (C2 to C3) and com-
plicated (C4 to C6) venous disease experienced a similar im-
provement in their QoL. In this study the patients with a poorer
QoL before surgery were more likely to benefit from the treat-
Symptoms and signs of chronic venous disorders Simka
CENTER STA G E IN CHRONIC VENOUS DISORDERS
ment.29 Similarly, in an observational study on patients receiv-
ing ultrasound-guided foam sclerotherapy of symptomatic
incompetent great or small saphenous veins (patients with
asymptomatic varicosities were not included) there was a
significant improvement of QoL after the treatment. This im-
provement was seen in both C2 to C3 and C4 to C5 patients.
Improvement of QoL was similar in patients with great and
small saphenous vein varicosities. Also, considering mental
domains of the QoL questionnaire, there was no difference in
terms of QoL according to whether uncomplicated (C2 to C3)
or complicated (C4 to C5) varicose veins were treated. On the
contrary, physical aspects of QoL were significantly worse in
patients with C4 to C5 venous disease. Interestingly, regard-
ing physical domains of QoL, the patients with uncomplicat-
ed varicosities benefited more from the treatment in compar-
ison with those with complicated varicose veins.6
u Other influencing factors
It seems that CVD is not a uniform clinical entity in terms of clin-
ical symptoms and impaired QoL. Thrombotic events, bilater-
al varicosities, and the recurrence of varicose veins significantly
affect natural history of the disease. In the VEINES study, a
multivariable regression analysis revealed that previous ve-
nous thromboembolism was a predictor of poorer QoL, inde-
pendent of variables such as age, sex, country of residence,
education, BMI, duration of CVD, and the presence of comor-
bidities.30 In this study, an analysis adjusted for the CEAP clin-
ical class confirmed a previous thromboembolism as an inde-
pendent predictor of decreased QoL.30,31 Bilateral varicose
veins were demonstrated to be associated with worse QoL
than unilateral venous incompetence,7 while some studies
demonstrated that QoL was significantly reduced in patients
with recurrent varicosities in comparison with those with pri-
mary varicose veins.6,32 In one study, QoL impairment was no
worse in recurrent varicosities than primary varicosities.7
Conclusion
A reasonable explanation of the enigma of venous symptoms
considering inconsistent results of the above-presented stud-
iesis not easy. Certainly, in many of these studies a selection
bias took place, either skewing the cohorts studied towards
the patients presenting with real symptomatic CVD (clinical
symptoms indeed caused by venous disease), or towards the
patients suffering from alternative sources of complaints, pri-
marily osteoarticular pathologies. The first scenario was more
likely if the patients qualifying for surgical treatment of varicose
veins were evaluated, since they were initially screened by an
experienced clinician and those with nonvenous complaints
were not very likely to enter such a study. A second scenario
could take place in the surveys that used advertising in mass
media to select participants, thus mostly attracting people
with pain or other leg symptoms primarily associated with neu-
rological and orthopedic problems, and not with venous in-
competence. Some researchers speculated that differences
between the studies in terms of association of venous symp-
MEDICOGRAPHIA, Vol 37, No. 1, 2015 23
LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC
toms with CVD could result from different expressions of such
complaints in particular languages, making a comparison of
the studies conducted in different countries difficult.8
Nonetheless, venous symptoms seem to be nonspecific for
CVD and can also be reported by patients presenting with
other diseases. Many uncomplicated varicose veins can in-
deed be asymptomatic or cause very few symptoms.3,6-10 In
some varicose vein patients, the symptoms and impaired QoL
may result from concomitant components of venous disease,
such as inflammatory skin changes, and are not directly caused
by dilated veins. In many of these patients, clinical symptoms
are not permanent, but can be seen at the end of the day
(when clinical trials are not routinely performed) or only during
hot periods of the year (again, not a typical season to perform
studies). Moreover, the research is telling us that a large pro-
portion of venous symptoms have their sources in coexisting
nonvenous pathologies.2,11,15 This is of particular importance
in patients in classes C1 and C2, since those with more severe
forms of venous incompetence usually experience symptoms
caused by venous disease. The majority of symptoms in the
patients with telangiectasias and uncomplicated varicose veins
do not seem to be of venous origin. Rather, especially if such
symptoms are severe, an alternative cause should be con-
sidered.
Unfortunately, available QoL questionnaires do not include
questions that facilitate recognition of the real cause of symp-
toms. Also, a thorough medical history and clinical examina-
tion, together with vascular sonographic assessment, were not
used by most of the studies that evaluated an association of
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Keywords: chronic venous disease; chronic venous disorder; quality of life; venous symptom

SIGNES ET SYMPTMES DE LA MALADIE VEINEUSE CHRONIQUE :

PEUT- ON METTRE FIN LA CONTROVERSE ?
Lassociation de la maladie veineuse chronique (MVC) ce que lon appelle les symptmes veineux (douleur, dman-
geaison, picotement, sensation de brlure, gonflement, fatigue et lourdeur des jambes et syndrome des jambes
sans repos) est toujours un problme controvers. Ces symptmes et la diminution de la qualit de vie sont courants
chez les patients ayant une incontinence veineuse, et sont mme plus frquents chez ceux ayant des antcdents
de thrombose veineuse ou de varices bilatrales ou rcidivantes, mais daprs la recherche, ces plaintes sont trs peu
lies des signes objectifs dinsuffisance veineuse. Pour les patients ayant une MVC avance, une cause veineuse
ces plaintes est presque vidente, mais une partie importante des symptmes veineux, en particulier chez les pa-
tients ayant des tlangiectasies et des varices non compliques, nest en fait pas dorigine veineuse. De plus, de nom-
breux patients ayant des maladies non veineuses peuvent avoir de tels symptmes, tandis que des varices non com-
pliques peuvent nentraner que de lgers symptmes ou tre asymptomatiques. Chez de nombreux patients ayant
des symptmes veineux, ceux-ci ne sont pas permanents, mais peuvent ntre vus qu la fin de la journe. Il est donc
important denvisager et de rechercher une cause alternative de telles plaintes, en particulier parce que dautres
pathologies peuvent accompagner la MVC et provoquer des symptmes similaires. Les pathologies les plus courantes
pouvant tre responsables et qui devraient tre prises en compte sont : hernie discale, arthrose de la hanche et du
genou, maladie artrielle priphrique, surcharge aux niveaux articulaire et ligamentaire due lobsit, neuropathie
priphrique et vnements indsirables dus aux mdicaments.

Symptoms and signs of chronic venous disorders Simka MEDICOGRAPHIA, Vol 37, No. 1, 2015 25

The most interesting finding
gathered from persons at risk of
developing venous leg symptoms
was the response to wearing light
compression stockings for three
weeks in a randomized crossover
trial. The stockings not only re-
duced feelings of heaviness and
pain in the legs, but also reduced
sleep disturbance, depression, and
the feeling of having unattractive
legs. This improvement was ac-
companied by a reduction of low-
er-leg volume.
Werner BLTTLER, MD
Angiologie Graubnden
Chur/Schiers, SWITZERLAND
Felix AMSLER, MSc
Amsler Consulting, Basel
SWITZERLAND
Address for correspondence:
Werner Blttler, MD,
Einsiedlerstrasse 8,
CH-8820 Wdenswil,
Switzerland
(e-mail: w.blaettler@gmail.com)
www.medicographia.com
26 MEDICOGRAPHIA, Vol 37, No. 1, 2015
LEG PA I N : TA K I N G C E N T E R S TA G E I N C H R O N I C V E N O U S D I S O R D E R S
Leg pain:
somatic or psychogenic?
b y W. B l t t l e r a n d F. A m s l e r, S w i t z e r l a n d
T
he authors studies on an eventual psychic cause of venous-type leg
symptoms are reviewed. Construction of the nine-item psychic vs so-
matic venous disease questionnaire (PsySoVDQ) is described. The in-
strument has been applied to participants of the population-based Bonn Vein
Study (BVS) II and found able to group 77.3% of the 962 subjects with symp-
toms according to the presence of a psychic cause or a somatic cause of the
symptoms. The groups showed different demographic and disease-related
characteristics. Elevated scores in the psychic component (PC) were correlat-
ed with the absence of true venous disease. Elevated scores in the somatic
component (SC) showed high sensitivity and specificity for true venous dis-
ease. The PsySoVDQ clearly recognizes the particularities of subjects with a
somatic and a psychic condition behind their symptoms. However, it has a lim-
ited discriminatory power. This is due to the fact that subjects with an emo-
tional or psychic problem use the same expressions for their feelings as those
with clear organic venous disease. This is an inalterable phenomenon imply-
ing that questionnaires may not be appropriate tools to assess feelings.
Medicographia. 2015;37:26-31 (see French abstract on page 31)
Data of studies on symptoms of leg swelling, heaviness,
tension, and pain
he hallmark of venous-type leg symptoms are feelings of swelling and heav-
T iness, and poorly located pain that is difficult to explain. In addition, a wide
spectrum of individual complaints are brought up by afflicted persons.1-4 The
various symptoms show a high inter-item consistency and a strong correlation of
each with the core symptoms.5 The symptoms are poorly associated with venous
disease severity and clearly have a good prognosis. This is discordant with the im-
paired quality of life readily observed in
individual patients and documented in
many observational studies. SELECTED ABBREVIATIONS AND ACRONYMS
BVS Bonn Vein Study
We studied the many aspects of the CEAP clinical, etiological, anatomi-
disorder in four cohorts: (i) patients who cal, pathophysiological
consulted because of symptoms, with PC psychic component
no objective signs and laboratory find- PsySoVDQ psychic vs somatic venous
ings of venous or any other disease; disease questionnaire
(ii) healthy persons at a presumed el- SC somatic component
evated risk of becoming symptomatic
Leg pain: somatic or psychogenic? Blttler and Amsler
 LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC VENOUS DISORDERS

A 0.1 Compression first (n=35) 1.4

Compression second (n=63) Volunteers
Change of pain and feeling

P=0.015 Patients
0 1.2
of swelling (score)

P<0.001

of swelling and heaviness

0.1 1.0

Intensity of feelings
P=0.155

0.2 0.8

P=0.005
0.3 0.6

0.4 0.4
Visit 1 Visit 2 Visit 3
B 10 0.2

P=0.142
0 0.0
1 2 3 4 5
Change of lower leg

P=0.007
P=0.155
GSV reflux No Yes No Yes Yes
volume (mL)

10
Fears to get
No No Yes Yes
varicose veins
20
n 162 39 43 10 40
P=0.001 Swelling and
30 heaviness 0.26 0.56 0.73 0.95 0.73
intensity (0.51) (0.72) (0.77) (0.98) (0.91)
(meanSD)
40
Visit 1 Visit 2 Visit 3
Figure 2. Correlating symptoms and disease.
Figure 1. Medical compression stockings and lower limb symptoms. Feelings of leg swelling and heaviness in healthy volunteers with a fear of devel-
(A) Pain and feeling of leg swelling and (B) change of lower leg volumeduring oping varicose veins (bar 3); with reflux in the great saphenous vein (GSV) un-
the period of awaiting the designated use of low-strength medical compression known at the time of the study (bar 2); with both features (bar 4); with neither
stockings (in dotted lines) and during the period of wearing them (in plain lines). feature (bar 1); and in patients with GSV varicose disease (bar 5).
Data of a crossover trial in hairdressers. Abbreviation: SD, standard deviation.
Adapted from reference 5: Blazek C et al. Phlebology. 2013;28(5):239-247. Adapted from reference 10: Blttler W et al. Phlebology. 2013;28(7):347-352.
2013, SAGE Publications. 2013, SAGE Publications.

because of their occupation; (iii) healthy subjects who served
as controls in a study on normal anatomy of veins; and (iv)
subjects from the general population.
u Symptoms only
In-depth psychiatric work-up of patients showed a high inci-
dence of feelings of heaviness of legs, tiredness, and sleep-
lessness (73%, 88%, and 65%, respectively) and no other
somatic symptoms of above normal prevalence or intensity. The
psychic syndrome featured hypochondria, anxiety, distur-
bance of vital feelings (85%, 77%, and 73%, respectively) and
depression (84% overall, 42% severe depression). Psychiatric
analysis revealed a low self-esteem, high dependence on the
opinion of others, a wish to run away, and the inability to attrib-
ute to the legs their libidinous role, among others.6-9
We conclude that leg symptoms can be associated with char-
acteristic and comprehensible psychiatric symptoms and frank
depression.
u At-risk population
The most interesting finding gathered from persons at risk of
developing venous leg symptoms was the response to wear-
ing light compression stockings for three weeks in a random-
ized crossover trial.5 The stockings not only reduced feelings
of heaviness and pain in the legs, but also reduced sleep dis-
turbance, depression, and the feeling of having unattractive
legs. This improvement was accompanied by a reduction of
lower-leg volume (Figure 1).5 We also found that both the
psychic and somatic end points were improved at the end of
the period during which the persons were not wearing com-
pression stockings, but were looking forward to using them.
The phenomenon was understood as a Hawthorne effect. The
term labels the pervasive phenomenon that any promise of
change for the better results in feelings of hope and faith, and
thereby leads to an improvement in the symptoms.
We conclude that leg symptoms are related to leg volume and
can be prevented with light leg compression. The expectation
of such treatment already exerts a positive effect on both so-
matic and psychic phenomena.
u Healthy controls
The examination of healthy volunteers participating in a pop-
ulation-based cross-sectional study on normal vein anatomy
revealed that leg symptoms were equally prevalent in sub-
jects with fears of one day developing varicose veins, in sub-
jects with a refluxing great saphenous vein that was only un-
covered during the study, and in patients who consulted a vein
clinic for overt venous disease (Figure 2).10

Leg pain: somatic or psychogenic? Blttler and Amsler MEDICOGRAPHIA, Vol 37, No. 1, 2015 27
LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC VENOUS DISORDERS

We conclude that leg symptoms of similar intensity can be score (receiver operating characteristic [ROC] analysis, area
caused by specific fears, the presence of a previously unknown under the curve 0.604 and 0.627 respectively, both P<0.001).
and clinically undetectable varicose great saphenous vein, and Elevation of the SC score did not depend on the presence of
a varicose disorder for which treatment is deemed necessary. varices, but on the presence of edema (P<0.001).

u General population The use of the questionnaire as an algorithm to identify the

u The psychic vs somatic venous disease questionnaire
(PsySoVDQ)
Based on both our psychometric and psychoanalytical data6-9
and in due consideration of the literature, we worked out a
comprehensive questionnaire (62 items) and used it in a pre-
vious study.5 A version shortened to 12 items was applied to
participants in the Bonn Vein Study (BVS) II,11 the follow up of
the BVS I.12 Finally, a nine-item questionnaire was constructed
with the data gathered in this large population-based study. The
statistical methods applied were a factor analysis of principal
components with varimax rotation and Cronbach a calcula-
tion to assess inter-item consistency. This version was labeled
the PsySoVDQ and used to distinguish between a psychic and
a somatic cause of the symptoms on the basis of symptoms
alone (Table I).11 The BVS symptom score, used for compari-
son, took the presence of signs into account.
The PsySoVDQ was administered to 1 800 subjects of which
962 (53.4%) had an elevated BVS symptom score and 1 111
(61.7%) had an elevated PsySoVDQ score. The psychic com-
ponent (PC) score alone was elevated in 437 subjects (24.3%)
and not correlated with an elevated BVS symptom score.
Subjects with CEAP (clinical, etiological, anatomical, patho-
physiological) class C0 or C1 showed higher PC scores than
those with C2 or C3; indeed, an elevated PC score showed a
negative predictive value for the presence of C2 or C3 disease
(P<0.001). The somatic component (SC) score alone was el-
evated in 395 subjects (21.9%). It showed the same predic-
tive value for the presence of C2 or C3 as the BVS symptom
cause of the symptoms was reasonably limited in subjects
who experienced symptoms in the recent past (Figure 3).11 Of
the 607 subjects with an elevated SC score, 59% had a nor-
mal PC score, while 41% had an elevated PC score at the
same time. The concomitant increase of the PC score reduced
the likelihood of a somatic origin (C2/C3) of the symptoms from
58% to 45%. Of the 355 subjects with a normal SC score,
39% had an elevated PC score. Thus, 58% had a psychic ori-
gin of their symptoms, while 42% had a somatic origin. In the
subjects with normal SC and PC scores, the origin of the symp-
toms remained unexplained in 61% and were attributed to a
somatic condition in 39%.
The personal and disease-specific data of subjects scoring
high on either component of the PsySoVDQ differed signifi-
cantly from the data obtained from asymptomatic study par-
ticipants and formed two distinct groups (Table II).11 The typi-
cal interviewees with an elevated PC score were younger, slim
women, with a higher education and social status, who felt that
their general health was jeopardized and that their psychic
quality of life reduced. The symptoms were of the same type
as those reported by the subjects scoring high in the SC, but
were much less intense.
We conclude that the PC of the PsySoVDQ identified subjects
with the psychiatric syndrome, as described in the previous
studies. Thus, this particular dysfunction is present subcon-
sciously in some healthy subjects with venous-type leg symp-
toms. The SC identified the subjects with C2/C3 disease as

Factor loadings Internal Descriptive statistics Table I. Items

consistency of the psychic
Factor 1 Factor 2
(PC) (SC) Cronbach Mean SD Median component (PC)
and somatic
Psychic component (PC) 0.73 0.76 0.54 0.8 component (SC)
1. Melancholic person 0.79 0.03 0.51 0.69 0 of the PsySoVDQ.
2. Anxious person 0.74 0.08 0.63 0.75 0 Factor analysis with
varimax rotation
3. Feels like running away 0.65 0.08 0.49 0.70 0 (n=1800).
4. Stressed because of unresolved issues 0.62 0.03 1.07 0.89 1 Abbreviations: SD,
standard deviation;
5. Interested what other people think of me 0.53 0.10 1.11 0.88 1 PsySoVDQ, psychic
vs somatic venous
Somatic component (SC) 0.67 0.40 0.62 0.0 disease questionnaire.
6. Feelings of leg heaviness 0.01 0.79 0.45 0.79 0 Adapted from refer-
ence 11: Amsler et al.
7. Feelings of leg swelling 0.02 0.78 0.45 0.80 0 Eur J Vasc Endovasc
8. Leg pain at various sites 0.03 0.62 0.52 0.98 0 Surg. 2013;46(2):255-
262. 2013, Euro-
9. Leg pain at one site 0.16 0.57 0.40 0.87 0 pean Society for
Vascular Surgery.
Possible answers: Questions 1-7: 0=never, 1=rarely, 2=often, 3=very often; Questions 8-9: 0=never, 1=monthly, 2=weekly, 3=daily Published by Elsevier
Elevated scores defined as PC 1 and SC >0 Ltd. All Rights
Reserved.

28 MEDICOGRAPHIA, Vol 37, No. 1, 2015 Leg pain: somatic or psychogenic? Blttler and Amsler
 LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC VENOUS DISORDERS

Figure 3. Use of the PsySoVDQ as an

BVS participants
algorithm to explain the cause of symp-
C0 /C3; n=962 toms in participants of the Bonn Vein
Study (BVS) II.
Organic (C2/C3) Any leg symptoms Nonorganic (C0/C1) Use: Symptomatic subjects, consider somatic
n=461; 48% n=962; 53% n=501; 52% component (SC) first and consider psychic com-
ponent (PC) second. Interpretation: SC+/PC+, no
separation of the two components possible (the
SC+ SC SC is less strong); SC+/PC-, elevation of the SC
n=607; 63% n=355; 37% score with no elevation of the PC score speaks
for the presence of an organic venous condition;
SC-/PC+, elevation of the PC score with no eleva-
PC+ PC PC+ PC tion of the SC score speaks for the presence of a
n=251; 26% n=356; 37% n=137; 14% n=218; 23% psychic condition; SC-/PC-, normal values of both
components mean that the PsySoVDQ cannot iden-
Psychic Psychic Psychic Unexplained tify the cause of the symptoms in these subjects.
symptoms symptoms symptoms symptoms Some subjects have asymptomatic C2 /C3 disease.
(C0 /C1); 55% (C0 /C1); 42% (C0 /C1); 58% (C0 /C1); 61% Abbreviation: PsySoVDQ, psychic vs somatic ve-
Organic Organic Organic Organic nous disease questionnaire.
symptoms symptoms symptoms symptoms Adapted from reference 11: Amsler et al. Eur J
(C2 /C3 ); 45% (C2 /C3 ); 58% (C2 /C3 ); 42% (C2 /C3 ); 39% Vasc Endovasc Surg. 2013;46(2):255-262.
2013, European Society for Vascular Surgery.
Published by Elsevier Ltd. All Rights Reserved.

well as the comprehensive BVS questionnaire administered

PC SC separately and serving for comparison. However, the discrim-
Item Pearsons r Pearsons r inatory power of the two components is low, as many sub-
Personal data jects had both an elevated PC and SC (858 of 962; 89%). As
Women +0.18**** +0.17**** will be discussed below, many subjects take certain notice of
Age 0.19**** +0.10**** phenomena going on in their peripheral veins. The intensity of
BMI 0.11**** +0.15**** the bodily signal depends on the shape of the venous system
School certificate +0.14**** 0.07** and its environment, while the intensity of the mental reaction
Working hours +0.10**** 0.11**** depends on momentary emotions and the individuals psy-
Job exhausting 0.07* +0.10** chic condition. The PsySoVDQ covers the two extremes of this
Fears losing job +0.09** continuum. Other questionnaires will undoubtedly encounter
General health the same facts.
Reduced +0.08** +0.24****
Getting worse +0.06* +0.09**** The PsySoVDQ was administered to the whole BVS cohort,
and not only to the symptomatic participants. Under this con-
Symptoms last 3 weeks
dition, its potential to diagnose a venous disorder with a psy-
Any symptoms +0.05* +0.50****
chic or somatic origin was found to be very low. We conclude
BVS symptom score +0.08*** +0.67****
that the PsySoVDQ is of no use to assess a cohort that in-
Restlessness of legs +0.05* +0.35****
cludes asymptomatic patients.
Feelings of swelling +0.05* +0.51****
Feelings of heaviness +0.09*** +0.58****
Feelings of tension +0.08*** +0.45**** A hypothesis on the origins of symptoms of
leg swelling and heaviness
CEAP classification Venous leg symptoms investigated in multiple studies world-
C0-C3 0.07** +0.24**** wide and in all imaginable situations turned out to be the same
VCSS classification everywhere, and merit the label of a somatoform or function-
Pain ns +0.36**** al disorder as they are capable of affecting the subjects self.
Varices 0.06** +0.12**** Often dismissed as just feelings, the symptoms mimic true
Edema 0.05* +0.30**** venous disease, but remain medically unexplained in many
Compression therapy ns +0.18****
Handicap score ns +0.41**** Table II. Univariate correlations of the psychic component (PC)and
somatic component (SC) with personal and disease-related findings
CIVIQ Quality of Life
(n=1800). *P<0.05; **P<0.01; ***P<0.001; ****P<0.0001.
Pain +0.05* +0.45****
Abbreviations: BMI, body mass index; BVS, Bonn Vein Study; CEAP, clinical,
Somatic ns +0.37**** etiological, anatomical, pathophysiological; CIVIQ, ChronIc Venous Insufficiency
Social ns +0.32**** Questionnaire; ns, nonsignificant; PsySoVDQ, psychic vs somatic venous disease
questionnaire; VCSS, Venous Clinical Severity Score.
Psychic +0.26**** +0.36****
Adapted from reference 11: Amsler et al. Eur J Vasc Endovasc Surg. 2013;46(2):
CIVIQ total +0.15**** +0.44**** 255-262. 2013, European Society for Vascular Surgery. Published by Elsevier
Ltd. All Rights Reserved.

Leg pain: somatic or psychogenic? Blttler and Amsler MEDICOGRAPHIA, Vol 37, No. 1, 2015 29
LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC
Personal structure
Situation:
venous - psychic - environmental
Lower leg muscle activity
Venous return
Venous hypervolemia
Microcirculatory stasis Large vein dilation
Activation:
blood components - endothelium
Activation of C fibers
Nociceptive substances
Spinal cord
Leg movements:
automatic, unrecognized
cases.13,14 Feelings are the highest manifestation of the home-
ostatic control, clearly a mental endeavor providing aware-
ness of something potentially noxious threatening the body
from inside or out.15 A hypothesis shall be set forth on how ve-
nous function is connected with the emergence of feelings.
Involved in the process are the venous circulation, where the
bodily signal is produced, the peripheral nervous system, which
carries the message, and the central nervous system, which
modifies the information on its way to the insular cortex, from
where the feelings are expressed.
In a resting person, venous return stagnates because of inac-
tivity of the muscle pump. Although arterial inflow is reduced
simultaneously because of low demand, increase of blood vol-
ume in the legs inevitably occurs. Standing immobile after ris-
ing from the supine or sitting position leads to an increase of
leg volume by an average of 30 mL within a few seconds16 and
by about 150 mL, or 2.5%, within 9 minutes (Figure 3).11,17,18
The rapid and readily reversible volume load is attributed to
dilatation of veins rather than to fluid extravasation.19 Vein dis-
tension or wall stretch can activate vegetative sensory nerves
(unmyelinated C fibers, sympathetic nerve fibers) whose end-
ings are located within the vein wall.20 Prolonged venous sta-
sis can activate leukocytes, which release nociceptive sub-
stances.21 Chronic venous hypertension will occur when the
venous capacity reaches its limits regularly or permanently.
These phenomena are associated with feelings of discomfort
illustrating the fact that the information is transported to the
central nervous system. On their way to the brain, bodily sig-
nals are subject to continuous modification by interopercep-
tion, until they ultimately arrive at the specific somatosensory
30 MEDICOGRAPHIA, Vol 37, No. 1, 2015
VENOUS DISORDERS
Insular cortex
Feelings
Neuronal fibers:
Physical fitness
Psychic condition
Emotions
Exteroperception
Somatoperception
Figure 4.
Sketch of
the hypothe-
sis of how a
hypoactivity-
associated
volume over-
load of veins
may cause
awkward
Leg movements:
conscious, commented
feelings of
swelling and
heaviness.
areas of the brain cortex that are mainly located in the insu-
la.15,23 The primarily unconscious process is subject to much
interference from other sources as well (exteroperception) and
to comparisons with the body image created by somatoper-
ception. Interference can bring about defensive reactions, from
repetitive leg movements to polite excuses like I have to move
my legs for a moment. Reasons for (mis)perceptions con-
tributing to negative feelings can be either amplified bodily sig-
nals (as in physical deconditioning) or decreased filter activity
(as in anxiety and depressive moods). Feelings conveyed with
words like heaviness and tension, rightly put emphasis on the
somatic origin of the problem, and not on their aggravating
modification by emotions and psychic conditions. In some cas-
es, however, patients may well use expressions that allow one
to elucidate the autobiographic context of their complaints
(such as the feeling to have to run away). The hypothetical con-
cept of venoneuronal coupling is depicted in Figure 4.
Recognition of the venoneuronal coupling has
therapeutic implications
Feelings of venous origin are empathized if they are reported
in association with a visible venous pathology. If no somatic
problem can be identified, the model of venoneuronal cou-
pling can offer an explanation that even low-strength signals
from the peripheral venous system can be perceived as nox-
ious and described with appropriate terms. Using a colloquial
expression, one could say that these persons hear the grass
grow. Successful therapeutic intervention with this oversen-
sitivity requires an in-depth diagnosis, which includes both a
venous workup and the search for the presence of a psychic
problem. Treatment with light compression stockings allevi-
Leg pain: somatic or psychogenic? Blttler and Amsler
 LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC VENOUS DISORDERS

ates the symptoms reliably by reducing the venous distension
and/or by direct action on the afferent nerves that control the
input from the venous milieu. Empathy of the consulted per-
son toward the symptomatic subject plays an important role.
The fact that anticipation of a benefit can give relief already
shows that changing emotions (eg, from fears to hope) can be
a worthwhile strategy. Never again, should a symptomatic pa-
tient be dismissed with the information nothing is wrong, just
feelings! Prescribing compression stockings or a venotropic
drug should be accompanied with good words. As demon-
strated, the Hawthorne effect adds to the effect of the pre-
scribed treatment. Clearly, neither the nature of the venous
signal is sufficiently understood nor is the neuropsychological
interpretation backed by hard facts. The hypothesis is a clar-
ion call for the cooperation of two sciences that have not know-
ingly interacted so far. Awaiting results, we are left with the
modest message of this review, which lays emphasis on the
complexity of the intrinsically coherent venous leg symptoms
that may herald a severe psychiatric condition or a yet to be
diagnosed venous disorder, but in many cases will remain
medically unexplained. Acceptation of the fact that feelings
originating in the body are meaningful, and should help to ward
off misunderstandings of the cause of the symptoms and over-
estimations of the efficacy of interventions on veins. n

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Keywords: chronic venous disease; chronic venous disorder; PsySoVDQ; venoneuronal coupling; venous symptom

DOULEURS DE JAMBES : SOMATIQUES OU PSYCHOGNES ?

Nous analysons les tudes dauteurs sur une ventuelle cause psychique des symptmes de jambes de type vei-
neux. Nous dcrivons la mise en place du questionnaire psychique vs somatique 9 items sur la maladie veineuse
(PsySoVDQ). Cet outil a t appliqu aux participants de ltude BVS II (Bonn Vein Study) base sur la population et
capable de grouper 77,3 % des 962 personnes ayant des symptmes selon la prsence dune cause psychique ou
somatique des symptmes. Les groupes ont montr diffrentes caractristiques dmographiques et lies la ma-
ladie. Des scores levs de la composante psychique (CP) sont corrls labsence de vritable maladie veineuse.
Des scores levs de la composante somatique (CS) montrent une sensibilit et une spcificit leves pour une v-
ritable maladie veineuse. Le questionnaire PsySoVDQ reconnat clairement les particularits des personnes ayant
une pathologie somatique ou psychique derrire leurs symptmes. Il a cependant une puissance discriminatoire li-
mite car les personnes ayant un problme motionnel ou psychique utilisent les mmes expressions pour leurs sen-
sations que ceux ayant une maladie veineuse organique vidente. Ce phnomne non modifiable montre que les
questionnaires ne sont pas des outils appropris pour valuer les sensations.

Leg pain: somatic or psychogenic? Blttler and Amsler MEDICOGRAPHIA, Vol 37, No. 1, 2015 31

The reasons for which pa-
tients develop symptoms, and
more importantly pain, are largely
unknown. It is interesting to see
that two different patients with a
similar history, duration, and ex-
tent of chronic venous disease,
and the same age and sex, can
present very differently. One could
have itching along the varicose
veins and the other, leg heaviness
and pain. This is a frequent sce-
nario that leads us to question
why this occurs and what trig-
gers symptoms to be present.
Nicos LABROPOULOS, PhD,
Stony Brook University Medical
Center, Stony Brook
New York, USA
Address for correspondence:
Dr Nicos Labropoulos, Professor
of Surgery and Radiology
Director, Vascular Laboratory,
Department of Surgery,
HSC T19 Rm94, Stony Brook
University Medical Center, Stony
Brook, NY 11794-8191, USA
(e-mail: nlabrop@yahoo.com)
www.medicographia.com
32 MEDICOGRAPHIA, Vol 37, No. 1, 2015
LEG PA I N : TA K I N G C E N T E R S TA G E I N C H R O N I C V E N O U S D I S O R D E R S
Pathophysiological
underpinnings of lower-limb
pain of venous origin
b y N . L a b ro p o u l o s , U S A
P
atients with chronic venous disease (CVD) present with a variety of signs
and symptoms. Pain, and similar symptoms such as the feeling of burst-
ing, tiredness, and a burning sensation, is very common in these pa-
tients. Many epidemiological and clinical studies have demonstrated that
there is a high prevalence of such symptoms and that these symptoms are
found in all clinical stages of CVD. The feeling of the symptoms is evident in
multiple studies showing that different types of treatment such as medica-
tions, compression, and surgical procedures can improve or alleviate pain. The
range of pain sensation varies from mild to severe and can be present at rest
or during physical activity. The association of pain intensity with the clinical
severity of CVD may be weak, as many factors determine the development
of pain sensation. The mechanisms of venous pain are not well understood.
However, inflammatory mediators seem to have an important role in the ac-
tivation of the nerve endings. Many inflammatory cells and molecules have
been found in the venous wall and perivenous space, both in experimental ani-
mal studies and in humans. As inflammation is found in early stages of venous
disease this could explain why patients in classes C0 and C1 (clinical, etiolog-
ical, anatomical, pathophysiological [CEAP] classification) report pain. The
diffuse character of venous pain makes it difficult for the patient to define and,
therefore, to describe. This is a significant challenge for the practitioners who
deal with venous disease. More studies are needed in order to elucidate the
strength of the association of pain in CVD and unravel its pathways.
Medicographia. 2015;37:32-36 (see French abstract on page 36)
hronic venous disease (CVD), as shown by many epidemiological studies,
C has a high prevalence with a significant socioeconomic impact.1-3 This is due
to the signs and symptoms of CVD that affect a great number of patients.3,4
These vary from cosmetic issues and minor complaints, to venous ulceration and
pain.3,5 Signs and symptoms develop from venous hypertension at a local or more
diffuse area in the lower limb. Increased venous pressure occurs from reflux and
obstruction, or a combination of the two. The major contributing factors of CVD and
its severity are depicted in Figure 1. Together with reflux and obstruction, the effi-
ciency of the foot and calf muscle pump, the cellular biology and soft tissue re-
sponses, risk factors, and genetic predisposition, are all important factors in the de-
velopment of signs and symptoms of CVD.6-8 The development and progression of
CVD is influenced by many factors, to which it is difficult to assign a specific weight
as these factors have never been studied properly in a longitudinal manner.9
Pathophysiological underpinnings of lower-limb pain of venous origin Labropoulos
 LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC VENOUS DISORDERS

sus were on the following: heaviness, tightness,

feeling of swelling, pain after standing, pain dur-
Distribution and extent of reflux
ing walking, cramps, itching, and restless legs.
Foot and calf muscle The prevalence of the symptoms (each exam-
Amount of reflux pump efficiency ined alone) ranged from 9.5% to 25%, with
women being affected more often. Risk factors
Risk factors Venous wall and soft
for developing these symptoms were female
Genetic predisposition
Chronic venous tissue cellular biology sex, higher age, obesity, and a sitting or stand-
disease
Rate of progression Local responses ing profession. It was stated that symptoms of
patients with CVD are not very specific and thus
it is essential to differentiate them from other
Severity of obstruction Lymphatic compensation
Ability to remove excess fluid causes. The association of symptoms in the
early stages of CVD has been a controversial
Distribution and extent of obstruction topic. In our clinics, we have evidence from
many patients that pain is present in a good
number of patients at the early stages of CVD,
Figure 1. Factors and pathological features that are responsible for the develop-
ment of chronic venous disease. after having excluded other causes for pain.
However, the degree of this association is not
Therefore, when discussing the signs and symptoms of CVD, known, since we did not study it in an objective manner. Mul-
and pain in particular, clear associations and evidence-based tiple studies, both epidemiologic and clinical, have indicat-
studies are lacking. Pain is a very common symptom in pa- ed that such an association exists and therefore cannot be
tients with CVD, but it is poorly understood. It ranges from mild ignored.14-17
aching usually found in patients with early stages of CVD, to a
significant level of pain in patients with venous claudication.10-12 In patients in CEAP class C2, pain is reported more often. Typ-
This paper focuses on the pathophysiological underpinnings ically, such pain is located along the varicose veins and is
of pain of venous origin in order to elucidate what is known more often perceived below the knee. In patients who have
and define the questions that we still need to answer. pelvic congestion syndrome and present with C2 disease, the
pain may sometimes be localized only to the area of varicosi-
Definition of pain and its relation to chronic ties in the groin and perineum. Pain in the pelvis alone may
venous disease also be found in patients with pelvic congestion syndrome
Pain has been defined by the International Association for the that is associated with the reflux in varicosities after all other
Study of Pain (IASP) as an unpleasant sensory and emotion- causes have been excluded.18,19 Multiple studies have report-
al experience associated with actual or potential tissue dam- ed relief of pain after treatment with medication, elastic com-
age, or described in terms of such damage. They also wrote pression stockings, or invasive procedures. The greatest re-
that Pain is always subjective. Each individual learns the lief has been achieved with the latter, which also has the sup-
application of the word through experiences related to injury port of many prospective randomized trials.20-23
in early life.13 The sensation of pain appears early in life in
order to serve as a signaling system for tissue damage.13 In In patients with C3 to C6 disease, pain is often seen and can
patients with CVD, pain is a very common symptom with dif- be independent of the presence of varicose veins, as deep
ferent degrees of intensity. As the perception of pain is sub- vein obstruction and postthrombotic luminal damage are
jective and the thresholds vary significantly among individu- more common in these patients.24 Obviously, many of these
als, the clinical presentation and extent of underlying venous patients have varicose veins as well and the pain is most like-
disease do not correlate well with the level of pain. ly a result of both pathologies. When both reflux and obstruc-
tion are present, the chance of developing signs and symp-
In a recent consensus document from the Union Internatio- toms of CVD is higher.24-26 Pain intensity is usually higher in
nale de Phlbologie (UIP; International Union of Phlebology) this group of patients. In fact, venous claudication is exclu-
the venous symptoms in patients with clinical, etiological, sively seen in patients with proximal venous obstruction, par-
anatomical, pathophysiological (CEAP) classification C0 and C1 ticularly when the iliofemoral veins are involved.12,27,28 Also, the
disease were discussed.11 The data presented in the consen- distribution of pain is more extensive and can be found in both
the calf and the thigh.
SELECTED ABBREVIATIONS AND ACRONYMS
Representative images of patients with CVD and pain, with
CEAP clinical, etiological, anatomical, pathophysiological the location and daily presentation, are seen in the examples
CVD chronic venous disease of Figure 2 (page 34). It needs to be emphasized that although
the majority of CVD patients present with symptoms, a large

Pathophysiological underpinnings of lower-limb pain of venous origin Labropoulos MEDICOGRAPHIA, Vol 37, No. 1, 2015 33
LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC
number of them are asymptomatic. This is also true for pa-
tients who present with ulcers. The reasons for which patients
develop symptoms, and more importantly pain, are largely
unknown. It is interesting to see that two different patients
with a similar history, duration, and extent of CVD, and the
same age and sex, can present very differently. One could
have itching along the varicose veins and the other, leg heavi-
ness and pain. This is a frequent scenario that leads us to
question why this occurs and what triggers symptoms to be
present. Precise history and clinical examination are impor-
tant before assigning certain signs and symptoms to patients
with CVD. It is not uncommon to see patients presenting with
joint or sciatic pain that is unrelated to CVD.
A B
Clinical relevance of pain in patients with chronic
venous disease
One of the most common complaints of patients with CVD is
pain. Patients describe different types of pain and in different
locations, with variable extent and intensity in the lower ex-
tremities. The importance of pain in patients with CVD, de-
spite the lack of understanding of its origin, is well perceived,
as all instruments of evaluation such as scales, clinical severi-
ty scores, and quality of life questionnaires have included pain
assessment. In most published reports, pain has been the
most significant factor affecting the health-related instruments
mentioned above. Studies in multiple countries have demon-
strated that CVD has a major socioeconomic impact, affect-
ing millions of patients worldwide. One of the most frequent
symptoms involved in these studies is pain. Despite the sub-
jectivity in reporting and describing pain, it is still the dominant
symptom that affects most patients quality of life. This is clear-
ly evident from all the clinical trials where treatment has re-
duced or abolished pain and has significantly improved most
measurements, as recorded by the different instruments of
pre- and posttreatment assessment.20-23,29,30
Pain and inflammation
Venous pain is closely linked to inflammation. Multiple stud-
ies have shown that CVD is an inflammatory disease. The
inflammation is evident in the vein wall and the perivenous
34 MEDICOGRAPHIA, Vol 37, No. 1, 2015 Pathophysiological underpinnings of lower-limb pain of venous origin Labropoulos
VENOUS DISORDERS
space.31,32 Infiltration of monocytes/macrophages in the prox-
imal vein wall, wall base of valve leaflet, and in the valve sinus
has been demonstrated, while macrophage-monocytes and
mast cells were found widely distributed throughout the vein
wall.33,34 Endothelial cell activation, with expression of sever-
al molecules and inflammatory infiltrates, has been found in
several papers.35-37 These inflammatory changes are more
pronounced in patients with skin damage, ie, CEAP classes
C4 to C6. It has been shown that inflammation parallels the
severity of CVD.7,38 Significant changes are observed in small
venous networks and capillaries, which are more apparent in
patients with skin damage.39 The venous flow in areas of in-
flammation becomes more pulsatile.
Figure 2. Examples of patients
with chronic venous disease
and different types of symptoms.
(A) Male patient with varicose veins in
the medial and posterior calf. He had
itching only, at the mid-calf at the area
of the bulging varicosities. (B) Female
patient who presented with varicose
veins in the anterior and medial thigh.
She had mild pain along the lower part
of the varicosities of the leg, with an
itching and burning sensation. (C) Male
patient with extensive skin damage. He
had previous thrombosis with partial
recanalization in the deep veins. Axial
reflux was found in the deep superficial
veins and two pathological perforator
C veins were found in the calf.
When inflammation is more intense, the cutaneous and per-
forating arteries have a high flow with increased diastolic ve-
locity and loss of the reverse flow component.7 There are also
more lymph nodes, which are enlarged, seen in the groin.7
The skin blood flux is increased and the ability to increase
the local flow to thermal stimuli is reduced.38 A schematic dia-
gram of the role of inflammation on the development of CVD
is shown in Figure 3.31
Venous pain is linked to the activation of nerve endings that
are found on the venous wall and are called nociceptors.40
Perivascular nerves terminating on the adventitia layer of the
veins in animal preparations have been mapped. Although,
nerve fibers have been illustrated in a few papers in the low-
er extremity of patients with CVD, the nerve pathways, precise
architecture, and function have not been reported. Therefore,
the description and associations for venous pain are based
on hypothesis and indirect relations. The current hypothesis
on the mechanisms of venous pain emphasizes an inflamma-
tory reaction and an interaction on venous nociceptors.40 The
association of pain with other unpleasant sensations that are
related to nociception such as tightness, feeling of swelling,
heaviness, and cramps is very common in patients with CVD,
regardless of the clinical class. This may explain why it is dif-
ficult to assess how symptoms are related to CVD. Current-
ly, the hypothesis on the mechanism of development of pain
 LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC VENOUS DISORDERS

Figure 3. The vicious circle of venous hyper-

tension and venous inflammation, empha-
Risk factors for chronic venous disease
sizing the importance of inflammation.
Adapted from reference 31: Bergan JJ et al. N Engl
Venous hypertension J Med. 2006;355:488-498. 2006, Massachusetts
Venous dilation Medical Society.
Increased
hypertension

Valve distorsion and leakage Clinical implications

Valve reflux Venous pain may resemble visceral
pain. When compared with pain in the
Valve and
wall changes
Altered blood flow and shear stress cutaneous space, the nociceptive mes-
sages that are developed at a visceral
level are less localized, may have the
Capillary hypertension INFLAMMATION Skin changes Ulcer
same pain intensity, can be perceived as
more unpleasant, and may have a more
Capillary leakage Edema significant emotional impact. The diffuse
character of venous pain, with the feel-
ing of aching, tiredness, tightness, dis-
and unpleasant perception of the other symptoms discussed comfort, bursting, heaviness, and burning sensation, which is
may be described as follows. Venous stasis, genetic predis- difficult for the patient to define and thus challenging for the
position, and environmental factors lead to altered shear physician to deal with, has a significant impact on patients
stress and wall behavior, which results in the activation of en- quality of life. There is a need to enhance our knowledge of
dothelial cells and leucocytes. This in turn promotes secretion these associations, and better define venous pain and relat-
of algogenic and proinflammatory mediators that induce local ed symptoms. We need to improve the instruments of eval-
inflammation, which stimulates the nerve endings and leads uation, and further understand the ultrastructural and func-
to a pain sensation. tional changes observed at the microcirculation. Moreover, a
more detailed workup is needed to define the nerve pathways
The degree of stimulation may depend on the status of the and their function in the lower-limb veins.
nerve endings (healthy, damaged, nonfunctional) and on tran-
sient stimuli, for example, at the end of the day, menstrual cy- Conclusion
cle, prolonged standing or sitting. The condition of the nerve It is evident from many epidemiological and clinical studies
endings and degree of stimulation may explain why there can that venous pain is found in all stages of CVD. The intensity
be a disparity among pain intensity and severity of CVD. In of pain may not correlate with CVD severity, as many factors
patients with C4b to C6 disease, where heavy infiltration of fi- play a role in the development and sensation of pain. The un-
brous tissue in the perivenous space and in the vein wall is derlying mechanisms of pain are not well understood. How-
found, nerve endings may become less functional and there- ever, inflammatory mediators seem to have an important role.
fore the pain intensity could be less comparable to those with As inflammation starts early in venous disease, this could ex-
earlier stages of CVD. In contrast, some patients with ad- plain why patients in CEAP classes C0 and C1 may have pain.
vanced CVD have more pain than usual and can be sensitive Experimental studies, together with functional and clinical
to touch, without having an infection. This could be explained studies, are needed to further elucidate pain development
by partial nerve damage that may lead to a reduction of the and its association with CVD. This will help us to better man-
threshold of pain. age patients with CVD and improve their quality of life. n

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Keywords: CEAP classification; chronic venous disease; venous pain; venous symptom

FONDEMENTS PHYSIOPATHOLOGIQUES DE LA DOULEUR DES MEMBRES INFRIEURS

Les signes et symptmes des patients atteints de maladie veineuse chronique (MVC) sont varis. La douleur et les
symptmes similaires, comme la sensation de brlure, de fatigue et limpression de chaleur sont trs courants chez
ces patients. De nombreuses tudes pidmiologiques et cliniques ont montr la haute prvalence de ces symptmes
et leur prsence tous les stades cliniques de la maladie. Diffrents types de traitement comme les mdicaments,
la compression et les interventions chirurgicales peuvent amliorer ou soulager la douleur, comme le montrent de
nombreuses tudes dans lesquelles les symptmes sont ressentis. La gamme des sensations de douleur varie de
lgre svre et peut se retrouver au repos ou pendant une activit physique. De nombreux facteurs dterminant
le dveloppement et la sensation de douleur, lassociation de lintensit de la douleur la svrit clinique de la MVC
peut tre faible. Les mcanismes de la douleur veineuse ne sont pas bien compris. Les mdiateurs inflammatoires
semblent cependant avoir un rle important dans lactivation des terminaisons nerveuses. Chez les humains comme
dans les tudes exprimentales animales, la paroi veineuse et lespace priveineux contiennent de nombreuses cel-
lules et molcules inflammatoires. Les patients des classes C0 et C1 de la CEAP (classification clinique, tiologique,
anatomique, physiopathologique) rapportent des douleurs, qui peuvent sexpliquer par une inflammation retrouve
aux stades prcoces de la maladie veineuse. Le patient dfinit et donc dcrit difficilement la douleur veineuse cause
de son caractre diffus. Traiter la maladie veineuse est un enjeu significatif pour les mdecins. Il faut dautres tudes
pour clairer lassociation de la douleur dans la MVC et claircir son parcours.

36 MEDICOGRAPHIA, Vol 37, No. 1, 2015 Pathophysiological underpinnings of lower-limb pain of venous origin Labropoulos

An instrument is reliable when
it consistently produces the same
results when applied to the same
subjects with no evidence of
change. One way to assess relia-
bility is to determine the internal
consistency reliability coefficient,
which reflects the degree of re-
latedness between the individual
items that make up a scale. The
items should all measure the same
concept, and therefore be corre-
lated with each other.
Fabrizio MARIANI, MD
Department of Vascular Surgery
Valdisieve Hospital
Pontassieve, Florence
ITALY
Address for correspondence:
Prof Fabrizio Mariani, Angiomedica
Medical Institute, Loc. Belvedere n99,
Colle di Val dElsa, Siena, Italy
(e-mail: brtma@tin.it)
www.medicographia.com
Lower-limb venous symptoms and assessment of quality of life: existing tools Mariani
LEG PA I N : TA K I N G C E N T E R S TA G E I N C H R O N I C V E N O U S D I S O R D E R S
Lower-limb venous
symptoms and assessment of
quality of life: existing tools
b y F. M a r i a n i , I t a l y
C
hronic venous disease (CVD) may affect several aspects of quality of
life (QoL). These functional effects are usually operationalized as (lim-
itations in) physical, psychological, and social functioning. CVD can
negatively affect patients QoL, as it is a painful and disabling disease that can
restrict physical functioning and mobility, and that is associated with depres-
sion and social isolation. Instruments used to measure QoL can be classified
into generic instruments and disease-specific instruments. A number of good
evaluative instruments exist that can monitor changes in patients status over
time and are responsive to disease progression or therapeutic intervention.
Each instrument should be carefully studied to ensure that it is valid (capable
of quantifying what it is intended to measure), reliable (produces consistent
results when used repeatedly on stable subjects), and responsive (capable of
detecting clinically important changes). Objective outcome measures and
guidelines for the management of patients with venous disease are more im-
portant now than ever and will assume even greater importance in the future.
Management of patients with CVD is rapidly evolving, and to assess whether
a particular treatment is appropriate, reliable, standardized, and objective, eval-
uation instruments are required. It would be helpful to promote and validate
new specific assessment tools about the medical procedures and QoL in ve-
nous leg ulcers, in postthrombotic syndrome and in CVD. Specific tools capa-
ble of assessing the full spectrum of CVD, its signs and symptoms, impact
on QoL, and treatment effects are key to the efficient management of the dis-
ease. Secondly, there should be a focus on longitudinal research about the
long-term effect of CVD on QoL and on the effect of CVD on the well-being of
the partners of the affected individual. In future, it will be necessary to pro-
mote an international consensus to approve the same instruments for all clin-
ical studies on CVD/QoL.
Medicographia. 2015;37:37-44 (see French abstract on page 44)
uality of life (QoL) can be defined as the functional effect of an illness and
Q its consequent therapy upon a patient, as perceived by the patient.1 Chron-
ic venous disease (CVD) may affect several aspects of QoL.
These functional effects are usually operationalized as (limitations in) physical, psy-
chological, and social functioning. CVD can negatively affect patients QoL, as it is
a painful and disabling disease that can restrict physical functioning and mobility, and
that is associated with depression and social isolation.2
MEDICOGRAPHIA, Vol 37, No. 1, 2015 37
LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC
In consequence, CVD can result in limitation to daily activities,
decreased productivity at work, and patients needing to take
sick leave, as well as having a negative effect on their self-es-
teem. The higher the clinical, etiological, anatomical, patho-
physiological (CEAP) clinical class, the poorer the disease-
specific QoL, as demonstrated by low scores for physical and
social functioning in QoL questionnaires.2 QoL is increasing-
ly seen as an important outcome measure because of the
publication of several clinical trials showing that it is respon-
sive to important clinical changes.3
In addition to relieving clinical symptoms and prolonging sur-
vival, the primary objective of any health care intervention should
be the enhancement of the QoL of the patient.4 Instruments
used to measure QoL can be classified into generic instru-
ments and disease-specific instruments.5 Generic instruments
allow comparison across populations of patients with differ-
ent diseases, whereas disease-specific instruments are sen-
sitive to key dimensions of QoL that are impaired by specific
diseases. A number of good evaluative instruments exist that
can monitor changes in patients status over time and are re-
sponsive to disease progression or therapeutic intervention.
Each instrument should be carefully studied to ensure that
it is valid (capable of quantifying what it is intended to meas-
ure), reliable (produces consistent results when used repeat-
edly on stable subjects), and responsive (capable of detecting
clinically important changes).6
Objective outcome measures and guidelines for the manage-
ment of patients with venous disease are more important now
than ever and will assume even greater importance in the fu-
ture. Management of patients with CVD is rapidly evolving and
to assess whether a particular treatment is appropriate, reli-
able, standardized, and objective, evaluation instruments are
required. Patients should be objectively classified according to
the CEAP classification and a validated QoL instrument com-
SELECTED ABBREVIATIONS AND ACRONYMS
AVVQ Aberdeen Varicose Vein Questionnaire
CEAP clinical, etiological, anatomical, pathophysiological
CIVIQ ChronIc Venous Insufficiency quality of life
Questionnaire
CVD chronic venous disease
MF micronized flavonoids
PTS postthrombotic syndrome
QoL quality of life
SF-36 Short Form 36
VAS visual analogue scale
VEINES VEnous INsufficiency Epidemiological and economic
Study
VCSS Venous Clinical Severity Score
VSS Venous Severity Scoring
VUQ Venkatraman Ulcer-specific quality of life Questionnaire
38 MEDICOGRAPHIA, Vol 37, No. 1, 2015 Lower-limb venous symptoms and assessment of quality of life: existing tools Mariani
VENOUS DISORDERS
Appropriateness The content of the instrument corresponds to
the intended purpose of their specific trial
Acceptability This instrument is acceptable to patients
Feasibility The impact of different measures upon staff
and researchers in collecting and pro-
cessing information
Interpretability The meaning of the instruments score
Precision The capacity of the instrument to make
numerous distinctions
Reliability The reproducibility and internal consistency
of the instrument, it assesses the extent
to which the instrument is free from
random error
Responsiveness The ability of the instrument to detect impor-
tant clinical changes
Validity The assessment of the extent to which the
instrument measures what it is supposed
to measure
Table I. Main features of an assessment tool instrument.
bining generic and disease-specific instruments.2 Following
treatment at appropriate time intervals, evaluative and QoL
measures should be repeated.
Review of available instruments
An instrument is reliable when it consistently produces the
same results when applied to the same subjects with no ev-
idence of change (Table I).7 One way to assess reliability is to
determine the internal consistency reliability coefficient, which
reflects the degree of relatedness between the individual items
that make up a scale.7 The items should all measure the same
concept, and therefore be correlated with each other. A mea-
sure of overall internal consistency reliability is the Cronbach
a coefficient; in general, for comparing groups a reliability co-
efficient higher than 0.70 is acceptable.8 Validity of a QoL mea-
sure is usually determined by examining correlations between
conceptually-related measures and by studying associations
between the measure and various clinical characteristics.7 The
tools can be summarized as9:
clinical, CVD-related signsassessed by the physicians
(CEAP and VSS [Venous Severity Scoring]);
functional (measuring QoL) or CVD-related symptoms
the symptoms are self-assessed, using patient-related out-
come or patient-reported outcome tools.
The VEIN-TERM10 consensus document has clarified venous
terminology; venous symptoms may include tingling, aching,
burning, pain, muscle cramps, swelling, sensations of throb-
bing or heaviness, itching skin, restless legs, and leg tiredness,
and/or fatigue. Although not pathognomonic, these may be
suggestive of CVD, particularly if they are exacerbated by heat
or worsen during the course of the day, and are relieved by
leg rest and/or elevation.
 LEG PA I N : TA K I N G
u Clinical investigations
There are three main clinical investigation methods: CEAP,
VSS, and Villalta Scale, specific for postthrombotic syndrome
(PTS). The CEAP classification was first developed in 1995.11
The original classification was modified in 2004,12 since at the
time it was not adequately dynamic nor did it adequately cor-
relate with symptoms. The modified version continued to be
physician-centered and hence did not always correlate with
patient symptoms. Furthermore, the symptoms related to
lymphatic failure in CVD are not considered in the classifica-
tion. This is a pitfall in all the cases in which the patients have
edema of the lower limb. The CEAP classification is descrip-
tive, but many of its components are static and do not change
in response to treatment. A disease severity scoring scheme
needs to be quantifiable, with gradable elements that can
change in response to treatment. The American Venous Fo-
rum developed the VSS,13 which was designed to supplement
CEAP scoring and to provide a method for serial assess-
ment. VSS is mainly used for longitudinal follow-up of a pa-
tients condition during and following treatment, it has recent-
ly undergone a revision to increase its sensitivity and value.14
The VSS scoring system has three components:
Venous Disability Score (VDS)this component evaluates the
level of work-based disability, disability is scored from 0 to 3;
Venous Segmental Disease Score (VSDS)this is based
on anatomical and pathophysiological components of CEAP,
obstruction, and reflux;
Venous Clinical Severity Score (VCSS)this is a dynamic
form of CEAP evaluation that has been designed to include
ten hallmarks of the most severe complications of CVD, each
hallmark is scored on a severity scale ranging from 0 to 3;
VCSS is an easy-to-apply, stand-alone scoring system.
A number of clinical tools or scales have been used in clini-
cal investigations to measure the PTS. The International So-
ciety on Thrombosis and Haemostasis recommended that
the Villalta Scale be adopted in clinical studies to diagnose
and grade the severity of PTS.15 The Villalta Scale is a reliable
and valid clinical scoring system that is based on severity rat-
ings of PTS symptoms and signs.
u Functional investigation
These are generic and disease-specific assessments of QoL.
The generic assessments are Short Form 36 (SF-36; 36-item
health survey),16 SF-12 (12-item health survey), and EuroQol 5
Dimension (EQ-5D; mobility, self-care, usual activities, pain/
discomfort, anxiety/depression health survey).17 The disease-
specific assessments include the Aberdeen Varicose Vein
Questionnaire (AVVQ),18 Specific Quality of life and Outcomes
Response-Venous (SQOR-V), ChronIc Venous Insufficiency
quality of life Questionnaire (CIVIQ),19 and VEnous INsufficien-
cy Epidemiological and economic Study (VEINES).20 Since
the latter ones are more specific in their scope, they have be-
come more popular in evaluating CVD management.
Lower-limb venous symptoms and assessment of quality of life: existing tools Mariani
CENTER STA G E IN CHRONIC VENOUS DISORDERS
u Generic instruments
u SF-36
The SF-36 is a valid assessment of QoL. The scoring system
is based on two types of health aspects: physical health and
mental health. The former is assessed via the patients level
of functioning, whilst the latter is assessed via an indicator of
well-being. These two types include eight domains: assess-
ment of physical and social functioning, role limitations due
to physical and emotional problems, mental health, pain, vi-
tality, and health perception. The survey generates a score
ranging from 0 to 100, with higher scores indicating better
general health perception. The SF-36 is a good way of assess-
ing changes in QoL in CVD.
u Nottingham Health Profile
The Nottingham Health Profile (NHP)21 is intended for primary
health care to provide a brief indication of a patients perceived
emotional, social, and physical health problems. It consists of
two parts. Part I contains 38 yes/no items in six domains: pain,
physical mobility, emotional reaction, energy, social isolation,
and sleep. Part II contains seven general yes/no questions
concerning problems of daily living.
u Disease-specific instruments
u CIVIQ
The CIVIQ was developed and validated (relevance, accept-
ability, reliability, construct validity, and sensitivity) by a French
group in 1996.19 The CIVIQ is a 20-item self-reported instru-
ment that includes four categories of questions: physical (4
items), psychological (9 items), social (4 items), and pain (3
items). Its score ranges from 0, the worst score, to 100, the
best. There are five possible answers (from 1 to 5) to describe
each symptom and the sensation of discomfort.
In a great number of patients the CIVIQ showed good inter-
nal consistency, reliability (above 0.80), and discriminating
power of items. Factor analysis identified physical, psycholog-
ical, and pain factors as important, but revealed instability of the
social factor. The CIVIQ was highly sensitive to changes in the
QoL of patients clinically improved after drug treatment.22
The first version of the CIVIQ questionnaire, CIVIQ 1 (where
1 denotes the first draft) included different numbers of ques-
tions in each category. The second version, the CIVIQ 2 (where
2 denotes the second draft of the same questionnaire), pro-
vides a global score covering all aspects of the questionnaire
and weighs the categories equally. Recently, a new short form
of the CIVIQ with a stable factorial structure was validated;
the CIVIQ-14 (14-item QoL questionnaire).23,24
The RELIEF (Reflux assEssment and quaLity of lIfe improvE-
ment with micronized Flavonoids) study,25 which was con-
ducted in 23 countries worldwide and included the partic-
ipation of more than 10 000 patients suffering from CVD,
validated the CIVIQ, the first QoL scale specific to CVD, and
MEDICOGRAPHIA, Vol 37, No. 1, 2015 39
LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC
assessed changes in the QoL of patients suffering from CVD,
with or without venous reflux, treated with micronized flavo-
noids (MF).
The DECIDE study26 evaluated the predictive value of a symp-
tom checklist for CVD in patients seen by general practition-
ers. The secondary objectives were to assess the relationship
between the checklist data and the patients QoL evaluated
using the CIVIQ, and to monitor the medium-term evolution
of this relationship amongst patients prescribed a venoactive
drug. A total of 13 131 patients were included, whose accept-
ance of the symptom checklist was good, since the com-
pletion rate was high. The correlation between a positive diag-
nosis of CVD and positive answer to the symptom checklist
was 98.9% (95% confidence interval [CI], 98.3% to 99.3%),
indicating that the symptom checklist is of predictive value for
CVD. The CIVIQ-20 was of discriminatory value since there
was a 12-point difference between patients with and without
CVD (64.417.9 vs 76.216.4, respectively; P<0.001).
Of 9953 patients followed up for an average of 63 days, 88.7%
received MF 500 mg, 5.1% received another venoactive drug,
and 3.5% were left untreated. After the 63-day follow-up, a sig-
nificant decrease in CVD symptoms was observed in all pa-
tients treated with MF 500 mg. Amongst the 7103 patients to
whom the CIVIQ-20 was readministered, a significantly greater
improvement in QoL was seen in the group treated with MF
compared with the other treatment groups.
The Vein Consult Program,27 which started in 2009, is an inter-
national observational, multicenter, descriptive survey of CVD.
In step two of the program, the patients were asked to com-
plete the CIVIQ-14. A total of 69 866 subjects were screened
for the first 13 countries participating in the program. It is
demonstrated that there is good correlation between two vein-
specific QoL tools (AVVQ and CIVIQ-14) across the whole
spectrum of disease severity.28
The CIVIQ and CIVIQ-14 have been used extensively as re-
ported in numerous studies, some of which included large
samples of patients, and have been validated in seventeen
linguistic versions.29
u VEINES-QoL/Sym
The VEINES,20 an international prospective cohort study con-
ducted in Belgium, France, Italy, and Canada, has developed
the VEINES-QoL/Sym to evaluate QoL and symptoms across
the range of conditions (eg, telangiectasias, varicose veins,
edema, skin changes, leg ulcers) in CVD. It consists of 35
items distributed in two categories to generate two summa-
ry scores: the questionnaire comprises 25 items that estimate
the effect of disease on QoL, and 10 items that measure symp-
toms. The focus of this instrument is on physical discomfort as
opposed to psychological and social aspects. This measure
of QoL and symptoms is available in four languages (Eng-
40 MEDICOGRAPHIA, Vol 37, No. 1, 2015 Lower-limb venous symptoms and assessment of quality of life: existing tools Mariani
VENOUS DISORDERS
lish, French, Italian, and Canadian French). Compared with the
CIVIQ, this method focuses more on symptoms than the psy-
chological and social aspects of the disease; furthermore, it
was validated for DVT symptoms.30
u Phleboscore
The Phleboscore is an 11-item self-administered question-
naire that helps predict the risk of developing CVD.31 It includes
questions about risk factors as well as questions about the
frequency of symptoms and the circumstances in which symp-
toms worsen (heat, contraceptive pill, long-distance travel).
The scores range from 0 to 31. A score >12 identifies pa-
tients at risk of CVD, while a score >23 pinpoints a need for
venous investigation.
u AVVQ
The AVVQ18 addresses multiple aspects of varicose disease,
including physical symptoms, social issues, and the cosmet-
ic manifestations of treatment outcomes. The overall evaluation
consists of a score with a range of 0 to 100. The AVVQ is a
13-question survey addressing multiple elements of varicose
vein disease. Physical symptoms and social issues, includ-
ing pain, ankle edema, ulcers, compression therapy use, and
limitations on daily activities are examined, as well as the cos-
metic effect of varicose veins. The questionnaire is scored from
0 (no effect) to 100 (severe effect). A high correlation was found
between the AVVQ and the SF-36 for CVD patients, with
health perception lower in patients with varicose veins than in
the general population. Two recent studies32,33 show that the
AVVQ may be the preferred method of rationalizing patients
for varicose vein surgery. It could be used to help inform a
patient pathway for referral and treatment of varicose veins.
u Charing Cross Venous Ulcer Questionnaire (CXVUQ)
The CXVUQ was developed to provide a valid QoL measure-
ment of venous ulcers. This method may be combined with
the SF-36 to generate valuable information on the progres-
sion of ulcers and their treatment. This questionnaire has been
mainly designed for patients with venous ulcers.34 Although it
can be intuitively assessed that venous stasis ulcers negative-
ly affect patient QoL, there was no reliable instrument to eval-
uate the effects of venous ulcer therapies.
u Venkatraman Ulcer-specific QoL Questionnaire (VUQ)
In 2005, a cross-sectional survey35 conducted on a represen-
tative sample of patients suffering from venous leg ulcers was
published. A self-administered six-page questionnaire, Frei-
burger Lebensqualitts Questionnaire Assessment (FLQA),
was used to collect data. The pilot survey showed the relia-
bility and the reproducibility of the questionnaire and indicat-
ed that the VUQ is suitable and has the potential to reflect
the perspective on compression therapy and overall QoL of
patients suffering from venous leg ulcers. The VUQ was test-
ed in some randomized studies to evaluate compression ther-
apy for venous ulcers or venous surgery, and QoL.36,37
 LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC VENOUS DISORDERS

Discussion
A number of findings stand out when reviewing the topic of
QoL in patients with CVD:
patients with varicose veins report a real impairment of QoL;
patients with venous leg ulceration report impairment of
their physical functioning and mobility similar to patients suf-
fering from congestive heart failure,38 and suffer from negative
emotions and social isolation;
patients with venous thrombosis and PTS report pain and
impairment of their physical functioning, they also report low
health perceptions and high health distress;
improvement of QoL in CVD after treatment with MF is well
demonstrated.
The majority of studies about PTS applied generic QoL meas-
ures, in particular the SF-36, which provide the possibility to
characterize patients with deep venous thrombosis (DVT) in
comparison with other clinical samples and the healthy pop-
ulation. However, the SF-36 could not detect any differences
between patients with and without PTS,39 whereas the VEINES-
QoL/Sym did detect some differences. The generic measure,
SF-36, is also not sensitive to any specific effects of compres-
sion therapies. Some studies about the effects of compression
and QoL used disease-specific measures, but only a few have
been adequately validated in large groups of patients. In most
of these instruments, the social dimension has been neglect-
ed or only partially captured. Because we feel that this is an
important issue, we recommend the use of an instrument
that also assesses this domain and that is well validated,
such as the CIVIQ, VEINES-QoL/Sym, and VUQ, in associa-
tion with CEAP classification and the VSS system. There are
recognized limitations in questionnaire studies including pa-
tients with low literacy skills or poor eyesight who might not be
able to complete them, and that long and demanding ques-
tionnaires might reduce compliance. In addition, the respons-
es on questionnaires that were administered retrospective-
ly could suffer from a response bias, and most of the used
questionnaires have not been formally evaluated for reliability

The following questions are concerned with your views on compression therapy (bandages or elastic stockings). Please put a cross in the box provided
to indicate your feelings ( *scores).

Not at all Sometimes Occasionally Always

(1)* (2)* (3)* (4)*

1 Do you experience pain when compression is applied?

2 Do you experience pain when compression is removed?

3 Do you experience pain when wearing shoes with compression?

4 Do you experience pain when walking wearing compression?

5 Do you have painful constrictions after wearing compression ?

6 Does wearing compression prevent you from normal activities?

8 Does wearing compression prevent you from visiting friends and families?

9 Do you feel any discomfort while wearing compression during the day?

7 Do you wear compression when you are asleep?

11 Do you feel any discomfort while wearing compression when you are asleep?

10 How many times do you wear compression?

14 Does your compression device slip?

12 Do you have dryness of the skin?

13 Do you feel itching?

15 Do you wear compression at all times or when the nurse or families help you?

What is your opinion about the compression therapy?

It helps to improve It does not improve It prevents my It helps to heal It does not improve It is
my symptoms (1)* my symptoms (4)* symptoms (1)* my ulcer (1)* my ulcer (4)* comfortable (1)*

Table II. A proposal for a modified Venkatraman Ulcer-specific Questionnaire (VUQ) for compression therapy.

Lower-limb venous symptoms and assessment of quality of life: existing tools Mariani MEDICOGRAPHIA, Vol 37, No. 1, 2015 41
LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC
and validity. Furthermore, no symptoms seemed to vary ac-
cording to the severity of varicose veins and the complaints
related to CVD. They can be very complex to detect at the
first stages of the CEAP classification and they can have many
pathological causes (eg, edema or pain). Early stages of CVD
are difficult to assess objectively, particularly in C0s to C1 pa-
tients, as symptoms are by definition subjective.
The QoL of CVD patients is greatly affected by pain, the com-
plaint that most often leads to the diagnosis of venous disease.
The intensity of pain can also fluctuate, from patient to patient
or in the same patient with progression of the disease over a
period of time. A causal relationship between CVD and pain
of venous origin remains difficult to clarify. In the Edinburgh
Vein Study,40 the correlation observed between pathologic su-
perficial venous reflux and sensation of swelling, heaviness, or
tension was low. In addition, this correlation was limited either
solely to men (sensation of swelling) or solely to women (sen-
sation of heaviness or tension). No significant correlation was
observed between superficial or deep venous reflux and ve-
nous symptoms or pain. Furthermore, no statistical relation is
found between the pain score or heaviness score of a patient,
evaluated on a 10-point visual analogue scale (VAS), and the
clinical severity of venous disease.41,42 There are multiple mea-
sures available to assess pain in adult populations.43 Each
measure has its own strengths and weaknesses. The VAS
and the Numeric Rating Scale for Pain (NRS) are unidimen-
sional single-item scales that provide an estimate of patients
pain intensity. The VAS is usually a horizontal or vertical line,
10 cm in length, anchored by word descriptors at each end.
On this line, the patient marks the point that they feel rep-
resents their perception of their current state. To evaluate the
multiple dimensions of acute and chronic pain, a number of
Physical Mental
condition condition Mobility Activity
Very bad (1) Stupororous (1) Immobile (1) Bedfast (1)
Poor (2) Confused (2) Very limited (2) Chairbound (2)
Fair (3) Apathetic (3) Slighty Walks with
impaired (3) help (3)
Good (4) Alert (4) Full (4) Ambulant (4)
Table III. Norton Scale. All rights reserved.
valid and reliable questionnaires are available. The McGill Pain
Questionnaire (MPQ) is a generic pain measure useful largely
for research purposes to describe not only the quantity (inten-
sity), but also the quality of the patients pain. The Chronic Pain
Grade Scale (CPGS) is similarly a generic pain measure use-
ful for research purposes to describe, evaluate, and compare
chronic pain severity across groups and in response to treat-
ment effects. The third generic multidimensional pain measure,
the SF-36 Bodily Pain Scale (SF-36 BPS) is useful in evalu-
ating pain in the context of overall health status, and there-
42 MEDICOGRAPHIA, Vol 37, No. 1, 2015 Lower-limb venous symptoms and assessment of quality of life: existing tools Mariani
VENOUS DISORDERS
fore most suitable for use in making comparisons across pop-
ulations and between subgroups within populations. The VAS
and SF-36 BPS are the preferred generic assessment instru-
ments for pain. Regarding CVD, since pain is mostly below
the half scale, the adequacy of the VAS may be questioned
because the amplitude of pain may not be large enough in
CVD to assess the therapeutic effects using such means. The
CIVIQ questionnaire evaluates pain in CVD with a specific ap-
proach, but for everyone involved in CVD, pain is difficult to
measure.
Another important question is to distinguish the psychic from
somatic components in CVD symptoms. Recently the psychic
vs somatic venous disease questionnaire (PsySoVDQ) was
applied to 1800 participants of the Bonn Vein Study II.44 Fac-
tor analysis of the PsySoVDQ distinguishes a psychic com-
ponent separate from a somatic component. The PsySoVDQ
identified somatic and psychic components of the widespread
and frequently reported leg symptoms in the general popu-
lation.
Conclusion
It would be helpful to promote and validate new specific as-
sessment tools for the medical procedures and QoL in ve-
nous leg ulcers, PTS, and CVD. We propose to assess a mod-
ified VUQ for compression therapy (Table II, page 41). The
section of the questionnaire regarding compression therapy
is modified and could be validated for the general assessment
of QoL with compression bandages and stockings. This ques-
tionnaire could be used in association with the Norton Scale
(for mental state and joint mobility; Table III ),45 the CIVIQ (or
VEINES) and CEAP/VSS classification to assess, at the same
time, CVD and the effects of compression therapy on QoL.
Specific tools capable of assessing the full
spectrum of CVD, its signs and symptoms,
Incontinence impact on QOL, and treatment effects are
key to the efficient management of the dis-
Urinary and
fecal (1) ease.
Usually urinary (2)
The European Organization for Research
Occasional (3)
and Treatment of Cancer (EORTC) took the
initiative to develop a QoL instrument for pa-
None (4)
tients with cancer, the QLQ-C30, which is
validated in 81 languages and used in more
than 3000 studies worldwide. It would be
an idea for the future if a similar instrument was developed
for patients with CVD and applied as a standard measure-
ment in all clinical studies. Until that day, a combination of well-
validated clinical investigations and disease-specific meas-
ures would be the preferred approach. Secondly, there should
be a focus on longitudinal research on the long-term effect of
CVD on QoL and on the effect of CVD on the well-being of the
partners of the affected individual. In future, it will be neces-
sary to promote an international consensus to approve the
same instruments for all clinical studies on CVD/QoL. n
 LEG PA I N : TA K I N G
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19. Launois R, Reboul-Marty J, Henry B. Construction and validation of a quality
of life questionnaire in chronic lower limb venous insufficiency (CIVIQ). Qual Life
Res. 1996;5(6):539-554.
20. Kurz X, Lamping DL, Kahn SR, et al; VEINES Study Group. Do varicose veins
affect quality of life? Results of an international population-based study. J Vasc
Surg. 2001;34:641-648.
21. Vasquez MA, Munschauer CE. Venous clinical severity score and quality of life
assessment tools: application to vein practice. Phlebology. 2008;23:259-275.
22. Launois R, Mansilha A, Jantet G. International psychometric validation of the
chronic venous disease quality of life questionnaire (CIVIQ-20). Eur J Vasc En-
dovasc Surgery. 2010;40(6):783-789.
23. Launois R, Le Moine JG, Lozano FS, Mansilha A. Construction and internation-
al validation of CIVIQ-14 (a short form of CIVIQ-20), a new questionnaire with a
Keywords: CEAP classification; primary venous disorder; varices; Venous Clinical Severity Score; venous symptom
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CENTER STA G E IN CHRONIC VENOUS DISORDERS
stable factorial structure. Qual Life Res. 2012;21:1051-1058.
24. Radak DJ, Vlajinac HD, Marinkovi JM, Maksimovi M, Maksimovi ZV. Qual-
ity of life in chronic venous disease patients measured by short Chronic Venous
Disease Quality of Life Questionnaire (CIVIQ-14) in Serbia. J Vasc Surg. 2013;
58(4):1006-1013.
25. Jantet G. Chronic venous insufficiency: worldwide results of the RELIEF study.
Reflux assEssment and quaLity of lIfe improvEment with micronized Flavonoids.
Angiology. 2002;53(3):245-256.
26. Pitsch F. Results of the DECIDE survey: appraisal of the predictive value for
chronic venous disease of a symptom checklist. Phlebolymphology. 2011;18(3):
140-148.
27. Pitsch F. VEIN CONSULT Program: interim results from the first 70 000 screened
patients in 13 countries. Phlebolymphology. 2012;19(3):132-137.
28. Kuet ML, Lane TR, Anwar MA, Davies AH. Comparison of disease-specific qual-
ity of life tools in patients with chronic venous disease. Phlebology. 2014;29(10):
648-653.
29. Launois R, Mansilha A, Lozano F. Linguistic validation of the 20 item-chronic ve-
nous disease quality-of-life questionnaire (CIVIQ-20). Phlebology. 2013;29(7):
484-487.
30. Kahn SR, Shbaklo H, Lamping DL, et al. Determinants of health-related quality
of life during the 2 years following deep vein thrombosis. J Thromb Haemost.
2008;6(7):1105-1112.
31. Blanchemaison P. Evaluation pratique du risque veineux: le Phlboscore. Act
Vasc Int. 2000;81:12-16.
32. Lattimer CR, Kalodiki E, Azzam M, Geroulakos G. The Aberdeen varicose vein
questionnaire may be the preferred method of rationing patients for varicose
vein surgery. Angiology. 2014;65(3):205-209.
33. Staniszewska A, Tambyraja A, Afolabi E, Bachoo P, Brittenden J. The Aberdeen
varicose vein questionnaire, patient factors and referral for treatment. Eur J
Vasc Endovasc Surg. 2013;46(6):715-718.
34. Smith JJ, Guest MG, Greenhalgh RM, Davies AH. Measuring the quality of life
in patients with venous ulcers. J Vasc Surg. 2000;31:642-649.
35. Venkatraman PD, Anand SC, Dean C, Nettleton R, EL Sawi A, Afify S. Pilot study
investigating the feasibility of an ulcer-specific quality of life questionnaire. Phle-
bology. 2005;20:14-27.
36. Mariani F, Mattaliano V, Mosti G, et al. The treatment of venous leg ulcers with
a specifically designed compression stocking kit. Comparison with bandaging.
Phlebologie. 2008;37:191-197.
37. Mariani F, Marone EM, Gasbarro G, et al. Multicenter randomized trial com-
paring compression with elastic stocking versus bandage after surgery for vari-
cose veins. J Vasc Surg. 2011;53:115-122.
38. Allegra C. Updating guidelines in chronic venous disease: what is needed?
Medicographia. 2011;33(3):238-243.
39. Kahn SR, Hirsch A, Shrier I. Effect of post-thrombotic syndrome on health-re-
lated quality of life after deep venous thrombosis. Arch Intern Med. 2002;162:
1144-1148.
40. Bradbury A, Evans CJ, Allan P, Lee AJ, Ruckley CV, Fowkes FG. The relation-
ship between lower limb symptoms and superficial and deep venous reflux
on duplex ultrasonography: The Edinburgh Vein Study. J Vasc Surg. 2000;32:
921-931.
41. Howlader MH, Smith PD. Symptoms of chronic venous disease and associa-
tion with systemic inflammatory markers. J Vasc Surg. 2003;38:950-954.
42. Allaert FA. Evolution des tableaux cliniques de linsuffisance veineuse chro-
nique en fonction de son anciennet. Angiologie. 2002;54:1.
43. Jensen MP, Karoly P. Self-report scales and procedures for assessing pain in
adults. In: Turk DC, Melzack R, eds. Handbook of Pain Assessment. 2nd ed.
New York, NY: Guilford Press; 2001:15-34.
44. Amsler F, Rabe E, Blttler W. Leg symptoms of somatic, psychic, and unex-
plained origin in the population-based Bonn vein study. Eur J Vasc Endovasc
Surg. 2013;46(2):255-262.
45. Perneger TV, Gaspoz JM, Ra AC, Borst F, Hliot C. Contribution of individual
items to the performance of the Norton pressure ulcer prediction scale. J Am
Geriatr Soc. 1998;46(10):1282-1286.
MEDICOGRAPHIA, Vol 37, No. 1, 2015 43
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SYMPTMES VEINEUX DES MEMBRES INFRIEURS ET

VALUATION DE LA QUALIT DE VIE : LES OUTILS EXISTANTS
La maladie veineuse chronique (MVC) peut influer sur plusieurs aspects de la qualit de vie (QdV), les effets sur le
fonctionnement tant habituellement concrtiss comme des limitations physiques, psychologiques et sociales. La
MVC, maladie douloureuse et handicapante pouvant restreindre le fonctionnement physique et la mobilit, influe n-
gativement sur la QdV et sassocie la dpression et un isolement social. Les instruments de mesure de la QdV
peuvent tre classs en instruments gnraux et instruments spcifiques de la maladie. Certains bons instruments
dvaluation peuvent suivre les changements de ltat des patients dans le temps et ragissent la progression de
la maladie ou au traitement. Chaque instrument devrait faire lobjet dune tude soigneuse pour sassurer de sa va-
lidit (capable de quantifier ce quil est suppos mesurer), de sa fiabilit (fournit des rsultats rguliers lorsquil est
utilis de faon rpte chez des sujets stables), de sa ractivit (capable de dtecter cliniquement des changements
importants). Des mesures objectives des rsultats et des recommandations pour la prise en charge des patients at-
teints de maladie veineuse sont plus importantes maintenant que jamais, et le seront encore plus dans lavenir. La prise
en charge des patients souffrant de MVC volue rapidement et des instruments dvaluation fiables, standardiss et
objectifs sont ncessaires pour juger de la pertinence dun traitement particulier. Promouvoir et valider de nouveaux
outils dvaluation spcifiques sur les procdures mdicales et la QdV dans les ulcres veineux de jambe, le syndrome
post-thrombotique et la MVC, seraient dune grande aide. Des outils spcifiques dvaluation de la gamme complte
de la MVC, de ses signes et de ses symptmes, de son impact sur la QdV et des effets des traitements sont des l-
ments cls de la prise en charge efficace de la maladie. Leffet long terme de la MVC sur la QdV et sur le bien-tre
des partenaires des sujets atteints devrait tre tudi de faon longitudinale. lavenir, un consensus international
dapprobation des mmes instruments pour toutes les tudes cliniques sur la MVC et la QdV sera ncessaire.

44 MEDICOGRAPHIA, Vol 37, No. 1, 2015 Lower-limb venous symptoms and assessment of quality of life: existing tools Mariani

LEG
There are a range of valid, re-
liable assessment instruments to
measure chronic venous disease
symptoms and results of treatment.
New modalities of treatment are
ever present. Comparison of abla-
Lower-limb venous symptoms:
tion outcomes is best performed
when the same outcome measures
are used no matter what the mode
of treatment. Physician assessment
and patient self-assessment serve
complementary functions and
should be combined to provide a
more accurate clinical scenario.
R
Michael A. VASQUEZ, MD
Cary MUNSCHAUER, BA
Danielle PANZA, RPA-C
Venous Institute of Buffalo
Buffalo, New York
USA
Address for correspondence:
Michael A. Vasquez, MD,
The Venous Institute of Buffalo,
Clinical Assistant Professor of
Surgery, SUNY Buffalo Department
of Surgery, 415 Tremont St,
North Tonawanda, NY 14120, USA
(e-mail:
mvasquezmd@venousinstitute.com)
www.medicographia.com
Lower-limb venous symptoms: assessing the assessment tools Vasquez and others
PA I N : TA K I N G C E N T E R S TA G E I N C H R O N I C V E N O U S D I S O R D E R S
combining physician and
patient reporting tools
b y M . A . Va s q u e z , C . M u n s c h a u e r,
a n d D . Pa n z a , U S A
ecent developments in the number and quality of treatment modalities
have increased health provider interest in appropriate outcome assess-
ment. Uniform outcome data are also desirable to establish medical ne-
cessity for third party payers. A valuable assessment tool will measure and
stratify venous symptoms and elucidate the results of therapy. While general
categories of physician-assessed or patient-reported instruments form the
framework for evaluation, specific tools have emerged as valid, reproducible
methods for the continuum of diagnosis, treatment, and follow-up. Physician-
generated instruments including the clinical, etiological, anatomical, patho-
physiological (CEAP) classification and Venous Clinical Severity Score (VCSS)
measure objective data. The revised VCSS is now the most widely used physi-
cian-derived assessment tool in chronic venous disease. More subjective pa-
tient-reported assessments have also increased in popularity. There are four
measurement tools frequently referenced in venous literature and one prom-
ising newcomer. The VEnous INsufficiency Epidemiological and economic
Study Quality of Life/Symptoms (VEINES-QoL/Sym), ChronIc Venous Insuf-
ficiency quality of life Questionnaire (CIVIQ), Aberdeen Varicose Vein Ques-
tionnaire (AVVQ), Charing Cross Venous Ulcer Questionnaire (CXVUQ), and
some modifications are reviewed. The Varicose Vein Symptom Questionnaire
(VVSymQ) is introduced. The novel idea of combining physician-generated
and patient-reported assessment instruments is being explored. The benefit of
a combination approach to following outcomes may be a more accurate eval-
uation of both symptoms and treatment results in the same patient. A model
that combines the elements attributed to symptoms, treatment results, and ul-
trasound findings may lay the framework for medical necessity and reimburse-
ment in the future.
Medicographia. 2015;37:45-49 (see French abstract on page 49)
he number of available outcome assessment tools has increased dramati-
T cally in recent years. There is a genuine interest in following the results of the
increasing modalities of treatment available. Arising with this are the demands
of an increasingly restrictive payer network. The end result is a tangle of similar, yet
different, assessment tools that reflect what is meant to be measured. We will at-
tempt to sift through the currently available, validated tools for the assessment of
symptoms and manifestations of chronic venous disease (CVD), focusing on instru-
ments that evaluate the results of therapy. Beyond a systematic review of outcome
assessment, we will address the predicted future value of these instruments in light
of emerging therapies.
MEDICOGRAPHIA, Vol 37, No. 1, 2015 45
LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC VENOUS DISORDERS

Attribute Absent (0) Mild (1) Moderate (2) Severe (3)

Pain or other discomfort None Occasional pain or other Daily pain or other discom- Daily pain or dis-
(ie, aching, heaviness, fatigue, discomfort (ie, not restrict- fort (ie, interfering with, comfort (ie, limits
soreness, burning), presumed ing regular daily activity) but not preventing regu- most regular daily
venous origin lar daily activities) activities)

Varicose veins None Few: scattered (ie, isolated Confined to calf or thigh Involves calf and
Varicose veins must be branch varicosities or clus- thigh
3 mm in diameter to qualify ters), also includes corona
phlebectatica (ankle flare)

Venous edema None Limited to foot and ankle Extends above ankle, but Extends to knee
Presumed venous origin area below knee and above

Skin pigmentation None or Limited to perimalleolar Diffuse over lower third Wider distribution
Presumed venous origin, does focal area of calf above lower third
not include focal pigmentation of calf
over varicose veins or pigmen-
tation due to other chronic
diseases (ie, vasculitis purpura)
A
Inflammation None Limited to perimalleolar Diffuse over lower third Wider distribution
More than just recent pigmen- area of calf above lower third
tation (ie, erythema, cellulitis, of calf
venous eczema, dermatitis)

Induration None Limited to perimalleolar Diffuse over lower third Wider distribution
Presumed venous origin of area of calf above lower third
secondary skin and subcuta- of calf
neous changes (ie, chronic
edema with fibrosis, hypoder-
mitis), includes white atrophy
and lipodermatosclerosis

Number of active ulcers None 1 2 3

Duration of active ulcer None <3 months >3 months, but <1 year Not healed for >1
(longest active) year

Size of active ulcer None Diameter <2 cm Diameter 2-6 cm Diameter >6 cm B
(largest active)

Use of compression therapy None Intermittent use of Wears stockings most Full compliance
stockings days with stockings

Table I. The revised Venous Clinical Severity Score (VCSS) is intuitive and easy to follow.
Before endovenous ablation (red): clinical, etiological, anatomical, pathophysiological (CEAP) classification score 4, VCSS score 7, see inset (A). After endovenous
ablation (green): CEAP score 4, VCSS score 3, see inset (B).
Adapted from reference 3: Passman et al. J Vasc Surg. 2011;54:2S-9S. 2011, Society for Vascular Surgery.

Currently available assessment tools
Things have certainly changed in the 6 years since we were
first asked to write a review of outcome assessment meth-
ods in venous disease. While the two broadest categories of
physician-assessed or patient-reported instruments remain,
the tools available have increased and undergone further val-
idation. They have been used in numerous studies and have
benefited from increased exposure and discussion. We now
have a clearer picture of the specific benefits and drawbacks
of many of the instruments. We also have models for combin-
ing assessment tools to gather as much relevant information
as possible from patient and physician perspectives.
With so many instruments available, one important question
is how to best choose the tool to provide the desired infor-
mation without it becoming cumbersome to complete and
onerous to evaluate. With this in mind, many clinicians forego
the generic quality of life (QoL) instruments, including the Short
Form 36 (SF-36). While this survey has been well validated, it
yields mainly population-based data and collective treatment
results.1,2 With more attention being paid to combining physi-
cian-generated tools and patient-reported outcomes (PRO) in-
struments, the focus seems to have settled on combining in-
struments that are specific for venous disease symptoms and
course of therapy.

46 MEDICOGRAPHIA, Vol 37, No. 1, 2015 Lower-limb venous symptoms: assessing the assessment tools Vasquez and others
 LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC VENOUS DISORDERS

Several physician-generated instruments are ideally suited

to provide valid, reliable data on the objective criteria of ve-
nous disease. The clinical, etiological, anatomical, pathophys-
iological (CEAP) classification and Venous Clinical Severity
Score (VCSS) both provide measurement of clinical param-
eters in the progression of venous disease (Table I).3 CEAP is
foremost only a classification tool and a less responsive peri-
procedural representation of CVD. The revised VCSS is a
more dynamic representation of the course of venous dis-
ease through serial reporting.3 Both of these instruments have
gained acceptance due to the common descriptive platforms
they provide and their ease of use. Both also have strong rec-
ommendations for use in the clinical practice guidelines of the
Society for Vascular Surgery and the American Venous Forum.
The CEAP classification is not to be used to assess treatment
results as a stand-alone tool. CEAP has limited responsive-
ness to changes in condition with therapy, especially at the C4
and C5 levels. The original VCSS was criticized early on for
the precision of language used and the degree of interobserv-
er variability. The VCSS was revised in 2010, and has been
widely regarded as improved in specificity of language, nomen-
clature, and observer variability, especially with regards to pig-
mentation change. It is intuitive and is now the most widely
used physician-derived venous score to date, and has been
incorporated into European and American venous registries. It
is made readily available on the American Venous Forum Web
site. There remains debate about whether the VCSS should
include the largely subjective category of compression thera-
py use, and this may be addressed in future revisions.1,3
Patient-reported, venous diseasespecific outcome-report-
ing tools have gained popularity recently as a subjective meas-
ure of the benefits of therapy.2 The five assessments that we
encounter most often are the VEnous INsufficiency Epidemi-
ological and Economic StudyQuality of Life/Symptoms
(VEINES-QoL/Sym), the ChronIc Venous Insufficiency qual-
SELECTED ABBREVIATIONS AND ACRONYMS
AVVQ Aberdeen Varicose Vein Questionnaire
CEAP clinical, etiological, anatomical,
pathophysiological
CIVIQ ChronIc Venous Insufficiency quality of life
Questionnaire
CVD chronic venous disease
CXVUQ Charing Cross Venous Ulceration
Questionnaire
MPFF micronized purified flavonoid fraction
PRO patient-reported outcomes
QoL quality of life
VCSS Venous Clinical Severity Score
VEINES-QoL/Sym VEnous INsufficiency Epidemiological
and Economic StudyQuality of
Life/Symptoms
VVSymQ Varicose Vein Symptom Questionnaire
Dimension Items
Pain Pain in the legs
Impairment at work
Sleeping poorly
Standing for long periods of time
Physical Climbing several floors
Squatting/kneeling
Walking at a good pace
Doing the housework
Psychological Feeling nervous
Having the impression of being a burden
Being embarrassed to show legs
Becoming irritable easily
Having the impression of being disabled
Having no desire to go out
Having to take precautions
Getting tired easily
Difficulty in getting going
Social Going to parties
Performing athletic activity
Traveling by car, plane, etc
Table II. Dimensions and items used in the ChronIc Venous Insuf-
ficiency quality of life Questionnaire (CIVIQ)-20.
After reference 5: Pitsch F. http://www.civiq-20.com/?page_id=45. 2014,
Les Laboratoires Servier.
ity of life Questionnaire (CIVIQ), the Aberdeen Varicose Vein
Questionnaire (AVVQ), the Charing Cross Venous Ulceration
Questionnaire (CXVUQ)1 and the VVSymQ Score (Varicose
Vein Symptom Questionnaire). All of these PRO instruments
are focused primarily on symptoms as opposed to assess-
ing or comparing therapies. As they measure symptoms at
a given point in time, they are effective measures for evaluat-
ing the effects of treatment.
CIVIQ has been validated and is used effectively as a global
measure of venous disease. Some critics have said that it does
not address the specific manifestations of venous disease,
but is more valuable in the overall assessment of venous dis-
ease.1 However, CIVIQ has been linguistically validated in 17
versions.4 There are two versions of CIVIQ: the CIVIQ-14 and
the CIVIQ-20. For CIVIQ-20, patient-generated reports of signs
and symptoms of venous disease were specifically used to
generate the questionnaire. The final 20-item questionnaire
shows a comprehensive collection of relevant parameters:
pain, physical, psychological, and social (Table II).5 Patient re-
call of symptoms was set at 4 weeks.
CIVIQ-20 was felt to be incomplete in assessing social fac-
tors in divergent populations, so a new questionnaire, the
CIVIQ-14 was developed, which combined social factors with
pain to yield three categories: pain, physical, and psychologi-
cal (Table III, page 48).5 This questionnaire was validated across
international lines.

Lower-limb venous symptoms: assessing the assessment tools Vasquez and others MEDICOGRAPHIA, Vol 37, No. 1, 2015 47
LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC
Dimension Items
Pain Pain in the legs
Impairment at work
Sleeping poorly
Physical Climbing several floors
Squatting/kneeling
Going to parties
Performing athletic activities
Psychological Feeling nervous
Having the impression of being a burden
Being embarrassed to show legs
Becoming irritable easily
Having the impression of being disabled
Having no desire to go out
Table III. Dimensions and items used in the ChronIc Venous Insuf-
ficiency quality of life Questionnaire (CIVIQ)14.
After reference 5: Pitsch F. http://www.civiq-20.com/?page_id=45. 2014,
Les Laboratoires Servier.
The issues addressed in the CIVIQ questionnaire assess pa-
tients across the spectrum of venous disease, through to C6,
although CIVIQ-20 targets C0 to C4. Patients with ulcers are
excluded, since factors relevant to patients in the earlier stages
of chronic vascular disease may not be relevant to patients
with ulceration, including questions relating to participation
in sports or limitations on social activities. CIVIQ-20 showed
a strong ability to track changes following therapy. This has
been validated through its use in comparing treatment meth-
ods and conservative therapies.5
VEINES-QoL/Sym is applicable in a wide range of clinical con-
ditions. It focuses on the underlying condition and changes in
associated symptoms, not on the therapy itself. It has proven
useful in elucidating symptomatic changes in studies utilizing
multiple treatments. However, because it focuses on diag-
nostic elements, it is difficult to assess change in response to
a specific therapy. Also, there is less focus on anatomic and
physiologic elements, which also might clarify beneficial treat-
ment options.1
AVVQ considers all elements of venous disease, including
cosmetic manifestations. Because of this wide-reaching ap-
proach, AVVQ is useful in many applications and in consider-
ation of many venous disease findings. However, because of
this wide focus, it lacks some sensitivity in elucidating change
over time in individual patients, especially those with milder
disease.1
CXVUQ is an instrument that considers venous stasis ulcers
and their course. Because of its specific focus, it is a consis-
tent measure of QoL factors in patients with venous ulcers,
regardless of the treatment option selected. However, large-
ly because of this specificity, in order for CXVUQ to give a
48 MEDICOGRAPHIA, Vol 37, No. 1, 2015 Lower-limb venous symptoms: assessing the assessment tools Vasquez and others
VENOUS DISORDERS
complete venous disease assessment in patients with ulcers
it probably needs to be combined with a traditional clinical
outcome measure or a generic instrument.1
The new kid on the block is the VVSymQ Score. It is a symp-
tom-focused PRO instrument that was designed to evaluate
the symptom burden of varicose veins before and after treat-
ment of the great saphenous vein in the BTG Varithena (poli-
docanol injectable foam) randomized controlled trials. In fact,
it is the only PRO instrument that meets the exacting stan-
dards set out in the US Food and Drug Administration (FDA)
guidance document titled Patient-Reported Outcome Meas-
ures: Use in Medical Product Development to Support Label-
ing Claims.6 The VVSymQ score is based on daily patient as-
sessment of the varicose vein symptoms determined through
research to be most important to patients: heaviness, ach-
iness, swelling, throbbing, and itching (Table IV).7
There is a demonstrated intercorrelation with known instru-
ments such as the VCSS, VEINES-QoL, and CIVIQ-20. In the
Varithena trials, VVSymQ, VCSS, and VEINES-QoL were
highly sensitive to change.7 The moderate correlation with
VCSS seems to indicate that both instruments measure dif-
ferent aspects of the same disease. This falls in line with our
understanding of the complementary nature of physician-gen-
erated and patient-reported tools.
The VVSymQ Score is captured via a 7-day electronic daily
diary. This proved valuable in allowing proper completion of the
questionnaire without outside influence. However, the 7-day
coverage period may be problematic for patients without elec-
tronic skills or for physicians with busy practices. Addition-
ally, the VVSymQ is proprietary to BTG and not as yet avail-
able for broader use.
With regards to venoactive drug use in a patient with CVD,
key assessment tools have been used to assess efficacy. The
most commonly used include CIVIQ-14, CIVIQ-20, and the
10-point Visual Analog Scale (VAS) which assesses pain in-
tensity. CEAP has been used to classify patients in these stud-
ies. The revised VCSS has not been directly used with venoac-
tive drugs to date. The investigators of the studies found that
the use of valid, reliable assessment tools was very useful in
determining both the clinical effect of venoactive drug thera-
py and to measure the QoL of a venous disease patient us-
ing venoactive drug therapy.8,9
Dimension Items
Symptoms Heaviness
Achiness Table IV. Dimensions
Swelling and items used in the
Varicose Vein Symptom
Throbbing
Questionnaire
Itching (VVSymQ).
Data from reference 7.
 LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC VENOUS DISORDERS

One thought-provoking combined study, the DECISION study, Conclusion

evaluated whether the addition of micronized purified flavonoid
fraction (MPFF) to patients undergoing endovenous treatment
for varicose veins of the lower extremities improves postop-
erative symptoms and signs of CVD and patient QoL.10 They
found that the reduction in VCSS score during the first 2 weeks
after the endovenous procedure was significantly greater in
the MPFF group compared with the control group. The rea-
son for this is not entirely clear and elicits further questions.
What changes would be seen if MPFF were used along with
medical compression? A valid alternative may be offered for
those patients with symptomatic deep reflux or postthrom-
botic syndrome.
There are a range of valid, reliable assessment instruments
to measure CVD symptoms and results of treatment. New
modalities of treatment are ever present. Comparison of ab-
lation outcomes is best performed when the same outcome
measures are used no matter what the mode of treatment.
Physician assessment and patient self-assessment serve
complementary functions and should be combined to provide
a more accurate clinical scenario. We will even go so far as to
profess that a combined scoring system, inclusive of duplex
findings, would be a preferred manner to establish medical
necessity for those considering treatment and insurance re-
imbursement. n

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ity of life: the DELTA study. Phlebolymphology. 2014;21(3):146-151.
9. Jantet G. Chronic venous insufficiency: worldwide results of the RELIEF study.
Reflux assessment and quality of life improvement with micronized flavonoids.
Angiology. 2002;53:245-256.
10. Bogachev VY, Golovanova OV, Kuznetsov AN, Sheokyan AO; DECISION In-
vestigators group. Can micronized purified flavonoid fraction (MPFF) improve
outcomes of lower extremity varicose vein endovenous treatment? First re-
sults from the DECISION study. Phlebolymphology. 2013;20(4):181-187.

Keywords: CEAP; chronic venous disease; CIVIQ; CXVUQ; lower limb; VCSS; venous symptom

SYMPTMES DES MEMBRES INFRIEURS :

ASSOCIER LES OUTILS D ' VALUATION DU MDECIN ET DES PATIENTS
Les soignants sintressent de plus en plus une valuation approprie des rsultats grce aux progrs rcents du
nombre et de la qualit des modalits de traitement. Des rsultats homognes sont aussi souhaitables pour tablir
la ncessit mdicale des payeurs tiers. Un outil dvaluation trs utile permettra de mesurer et de stratifier les symp-
tmes veineux et dclairer les rsultats des traitements. ct des catgories gnrales dinstruments dvaluation
par les mdecins ou auto-rapports par les patients comme cadre de lvaluation, des outils spcifiques sont appa-
rus comme des mthodes valables et reproductibles pour le continuum du diagnostic, du traitement et du suivi. Des
instruments labors par les mdecins, dont la classification CEAP (Clinique, tiologique, Anatomique, Physiopatho-
logique) et le VCSS (Score de Svrit Clinique Veineux) mesurent les donnes objectives. Le VCSS rvis est main-
tenant loutil dvaluation des mdecins le plus largement utilis dans la maladie veineuse chronique. Des valuations
plus subjectives, rapportes par les patients, ont aussi acquis une notorit. Quatre outils de mesure sont frquem-
ment rfrencs dans la littrature veineuse et un nouveau venu est prometteur. Nous passons en revue le VEINES-
QOL/Sym (VEnous Insufficiency Epidemiological and Economic Study-Quality of Life/Symptoms), le questionnaire
CIVIQ (Chronic Venous Insufficiency Questionnaire), le questionnaire AVVQ (Aberdeen Varicose Vein Questionnaire),
le questionnaire CXVUQ (Charing Cross Venous Ulceration Questionnaire) ainsi que quelques modifications. Nous
introduisons le questionnaire VVSymQ (Vein Symptom Questionnaire). Nous explorons la nouvelle ide dassocier
des instruments labors par les mdecins et rapports par les patients, qui permet une valuation plus prcise des
rsultats des symptmes et des traitements pour le mme patient. Un modle associant les lments attribus aux
symptmes, aux rsultats des traitements et aux rsultats de lchographie pourrait servir de cadre aux besoins et
remboursements mdicaux dans le futur.

Lower-limb venous symptoms: assessing the assessment tools Vasquez and others MEDICOGRAPHIA, Vol 37, No. 1, 2015 49

The major symptom in C0s
patients, pain, can be alleviated
by venoactive drugs (VADs). The
role of VADs in the management of
chronic venous disease (CVD) in
the 2014 guidelines is described
as central and unique. These
guidelines also advocate lifestyle
modification in C0s patients, but
call for further assessment of com-
pression therapy. Treatment regi-
mens in CVD should be based on
VADs, like micronized purified fla-
vonoid fraction, with higher levels
of guideline recommendation.
Zbigniew RYBAK, MD, PhD
Department for Experimental
Surgery and Biomaterials
Research, Wrocaw Medical
University, Wrocaw
POLAND
Address for correspondence:
Prof dr hab. Zbigniew Rybak,
Head of Department, Department
for Experimental Surgery and
Biomaterials Research, Wrocaw
Medical University, Rektorat,
wybrzee Ludwika Pasteura 1,
50-367 Wrocaw, Poland
(e-mail: zrybak@poczta.onet.pl)
www.medicographia.com
50 MEDICOGRAPHIA, Vol 37, No. 1, 2015
LEG PA I N : TA K I N G C E N T E R S TA G E I N C H R O N I C V E N O U S D I S O R D E R S
Management of
lower-limb venous symptoms:
what the guidelines tell us
b y Z . R y b a k , Po l a n d
V
enoactive drugs (VADs) are an integral part of the treatment of symp-
tomatic chronic venous disease (CVD), especially in early stages. Rec-
ommendations for the use of VADs for the symptomatic treatment of
CVD have evolved greatly in the past ten years. Landmark events in the de-
velopment of todays recommendations include the 2005 Cochrane review,
2005 International Consensus Statement, 2008 guidelines for the manage-
ment of chronic venous disorders of the lower limbs, 2011 Perrin and Ramelet
review, and most recently, the current 2014 guidelines. At each step, new ev-
idence has been added and the status quo reassessed. Most VADs improve
venous tone, scavenge free radicals, and reduce capillary leakage, while a
few reduce capillary permeability, prevent skin degeneration, improve lym-
phatic drainage, and reduce blood viscosity and/or erythrocyte aggregation.
VADs have also been shown to diminish pain in CVD. Pain, which is induced
by inflammation and/or vein wall distension, is a major symptom in C0s pa-
tients, symptomatic patients with no visible or palpable sign of venous dis-
ease. A fifth of CVD patients could be clinical, etiological, anatomical, patho-
physiological (CEAP) grade C0s . While patient reassurance and lifestyle
modification could also be useful in these patients, the rationale for compres-
sion therapy suffers from a weak evidence base. The 2014 guidelines empha-
size the central and unique role of VADs, particularly in early CVD. VADs with
higher levels of guideline recommendation should be used preferentially.
Medicographia. 2015;37:50-55 (see French abstract on page 55)
Development of chronic venous disease
hronic venous disease (CVD) is a common conditionassociated with de-
C pression, social isolation, and reduced quality of lifewhose prevalence in-
creases with age.1 The main cause of CVD is venous hypertension, which
over time leads to the extravasation of macromolecules into dermal interstitium
and to chronic inflammation.2 Initially, venous hypertension dilates veins and causes
valve leaflets to deform, resulting in valve loss and valve failure.
Valve failure in turn leads to turbulent flow, blood stasis, or reflux, all of which can
provoke local inflammatory and thrombotic responses. These responses include
the production of prothrombotic agents (monocyte chemoattractant protein 1 and
vascular cell adhesion molecule 1) and growth-promoting agents (angiotensin II,
endothelin 1, and platelet-derived growth factor), leukocyte and neutrophil migra-
tion, and promotion of apoptosis.2
Management of lower-limb venous symptoms: what the guidelines tell us Rybak
 LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC VENOUS DISORDERS

Target
Venous Venous Capillary Lymphatic Hemorheological Free radical
Venoactive drug Category tone wall/valve leakage drainage disorders scavengers

Micronized purified flavonoid fraction Flavonoid (g-benzopyrone) + + + + + +

Nonmicronized or synthetic diosmins* Flavonoid (g-benzopyrone)
Rutin and rutosides O-(b-hydroxyethyl)-
Flavonoid (g-benzopyrone) + + + + +
rutosides (troxerutin, HR)
Anthocyans (Vitis vinifera) Flavonoid (g-benzopyrone) +
Proanthocyanidins (Vitis vinifera) Flavonoid (g-benzopyrone) + +
Coumarin a-benzopyrone + +
Horse chestnut seed extract; escin Saponin + + +
Ruscus extract Saponin + +
Gingko extracts* Other plant extract
Calcium dobesilate Synthetic product + + + + +
Benzarone* Synthetic product
Naftazone* Synthetic product

Table I. Evidence-based modes of action of the main venoactive drugs.

Abbreviation: HR, hydroxyethylrutoside. *No data available.
Modified from reference 1: Int Angiol. 2014;33:87-208. 2014, Edizioni Minerva Medica.

Chronic reflux, along with venous hypertension, raises blood
pressure in capillaries of the microcirculation. Capillary hy-
pertension leads to a vicious circle of leakage, edema, and
inflammation, which ultimately result in pathological skin
changes and venous ulceration.2 Chronic reflux, which is evi-
dent before large veins become visible, is a preclinical sign
of CVD in at-risk individuals.3 As CVD progresses, common
symptoms that manifest include aching legs, heaviness, ten-
sion, cramp, swelling, itching, and restless legs.2 The clinical,
etiological, anatomical, pathophysiological (CEAP) classifica-
tion is today used worldwide to classify CVD.1,4
Development of current chronic venous disease
guidelines
As CVD symptoms can appear in the absence of clinical signs
of venous disease and at every clinical stage of CVD,1 symp-
tom control in CVD is critical. Venoactive drugs (VADs), of
which there are different types with different effects (Table I),
are one of the pillars of the symptomatic management of CVD
in the latest guidelines.1 The way in which evidence quality
and recommendations for VADs are determined has evolved
greatly over the last decade.
homogeneous results), B (randomized clinical trials with small
sample sizes, single randomized trial only), or C (other con-
trolled trials, nonrandomized controlled trials).
On this basis, micronized purified flavonoid fraction (MPFF),
calcium dobesilate, and hydroxyethylrutosides were classi-
fied grade A, horse chestnut seed extract and Ruscus extract
grade B, and other VADs grade C. These experts also con-
cluded that VADs should be indicated to relieve symptoms in
all clinical classifications of CVD, from class C0s to C6s.6
Guidelines in 2008 amalgamated the grade recommenda-
tions of the 2005 International Consensus Statement with
the drug indications of the 2005 Cochrane review.7 The 2008
guidelines also provided more information on the use of VADs
in C6 patients and safety of VADs. Importantly, they proposed
that VADs could be used as a first-line treatment for symp-
toms and edema in CVD. In 2011, a new set of recommen-
dations for the use of VADs, based on the Grading of Rec-
SELECTED ABBREVIATIONS AND ACRONYMS

CEAP clinical, etiological, anatomical, pathophysiological

In 2005, a Cochrane review of 59 randomized controlled tri-
als showed that treatment with VADs reduced most symp- CVD chronic venous disease
tomatic CVD outcomes without increasing the incidence of GRADE Grading of Recommendations Assessment,
adverse events vs placebo.5 In the same year, a panel of CVD Development, and Evaluation
experts set out to determine the efficacy of VADs by assess-
MPFF micronized purified flavonoid fraction
ing 83 randomized controlled trials and meta-analyses in the
literature.6 Evidence quality was graded A (randomized clini- VAD venoactive drug
cal trials with large sample sizes, meta-analyses combining

Management of lower-limb venous symptoms: what the guidelines tell us Rybak MEDICOGRAPHIA, Vol 37, No. 1, 2015 51
LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC VENOUS DISORDERS

Indication Venoactive drug Recommendation Evidence quality Code

Micronized purified flavonoid fraction Strong Moderate 1B

Nonmicronized diosmins or synthetic diosmins Weak Poor 2C
Relief of symptoms Rutosides (O-b-hydroxyethyl) Weak Moderate 2B
associated with CVD in
Red vine leaf extracts (Vitis vinifera) Weak Moderate 2B
patients in CEAP classes
C0sto C6s and in those Calcium dobesilate Weak Moderate 2B
with CVD-related edema
Horse chestnut seed extract Weak Moderate 2B
(CEAP class C3)
Ruscus extracts Weak Moderate 2B
Gingko biloba Weak Poor 2C
Other VADs Weak Poor 2C

Table II. Summary of the present guideline recommendations for the use of venoactive drugs for symptom relief, according to the
GRADE system.
Abbreviations: CEAP, clinical, etiological, anatomical, pathophysiological; CVD, chronic venous disease; GRADE, Grading of Recommendations Assessment, Develop-
ment, and Evaluation; VAD, venoactive drug.
Modified from reference 1: Int Angiol. 2014;33:87-208. 2014, Edizioni Minerva Medica.

ommendations Assessment, Development and Evaluation
(GRADE) system, was tentatively proposed.8 The GRADE sys-
tem differed from the earlier 2005 International Consensus
Statement and 2008 guidelines in that treatment recommen-
dation and quality of evidence were assessed independently.
Treatment recommendation was classified as strong (grade 1)
or weak (grade 2), while quality of evidence was classified as
high (grade A), moderate (grade B), or low (grade C).
The 2011 review of Perrin and Ramelet, which accepted the
fact that evidence of moderate or high quality could originate
from large observational studies,8 included evidence for the
longer-term safety of MPFF, which was ascertained in a large
population in the open-label observational study RELIEF
(Reflux assEssment and quaLity of lIfe improvEment with mi-
cronized Flavonoids).9 It also highlighted negative concerns
about the benefit-risk balance of calcium dobesilate, due
to reports of agranulocytosis. MPFF and rutosides were giv-
en strong recommendations based on moderate evidence
(grade 1B for both drugs) with GRADE.8
The latest 2014 guidelines entitled Management of Chronic
Venous Disorders of the Lower Limbs: Guidelines According
to Scientific Evidence, an update of the 2008 guidelines,7 have
retained the GRADE system to evaluate the efficacy of VADs
for the relief of CVD symptoms.1 In these new guidelines,
MPFF has kept its 1B classification, while that of rutosides has
been downgraded to 2B (Table II); other VADs were classi-
fied 2B or 2C.1 No VAD yet has a GRADE rating with a high
quality of evidence. Evidence is still needed to confirm that
treatment with VADs may prevent progression towards com-
plications of CVD. Nevertheless, the 2014 guidelines not only
restate the 2008 conclusions that VADs can be used to re-
lieve CVD-associated symptoms and edema at any clinical
stage of CVD, but also emphasize the central and unique
role of VADs in treating symptoms in patients in the initial
stages of CVD.1 Advice on the management of C0s patients,
symptomatic patients with no visible or palpable sign of ve-
nous disease, was introduced in the 2014 guidelines.
u The C0s patient
The revised 2004 CEAP classification first drew attention to
the existence of C0s patients, or more specifically C0sEn A nPn
patients, with no detectable reflux or visible signs.1,10 This pa-
tient profile is very commonly encountered in clinical practice,
as seen in the recent Vein Consult Program epidemiological
survey.11,12 Nearly a fifth (15 290/77 716) of patients in this
survey were CEAP grade C0s.12 Compared with 46 451 oth-
er symptomatic or asymptomatic patients with clinical CVD
(C1 to C6), C0s patients were more likely to be younger (55.5
15.3 vs 48.616.7 years) and male (22.6% vs 33.5%) (both
P<0.0001).
The overall prevalence of CVD symptoms in C0s patients was
less common: 58.5% vs 80.0% for pain in the legs; 52.4% vs
73.9% for sensation of swelling; and 29.1% vs 62.7% for night
cramps (all P<0.0001). C0s patients also present with fewer
symptoms (2.11.1 vs 3.11.0; P<0.0001). The overall popu-
lation in the Vein Consult Program was much more likely to re-
ceive VADs (39.7% vs 7.9%), compression therapy (24.4% vs
1.4%), or lifestyle advice (51.6% vs 13.1%) than C0s patients.12
Pain, which is induced by inflammation and/or vein wall dis-
tension, is one of the most oppressive symptoms in C0s pa-
tients.2,13 Numerous different factors can provoke venous in-
flammation: oxidative stress,14 shear stress,15 toxicity, bacterial
infection, venous hypertension, hypoxia,16 and mechanical in-
jury, among others. These factors are often silent and difficult
to detect. Excessive distension of veins can be due to pro-
longed standing, pregnancy, heavy labor, or hereditary defi-
ciency of elastic and/or muscular vein wall components. Dis-
tension and inflammation lead to the activation of nociceptors

52 MEDICOGRAPHIA, Vol 37, No. 1, 2015 Management of lower-limb venous symptoms: what the guidelines tell us Rybak
 LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC VENOUS DISORDERS

(sympathetic C fibers) found in venous intima and media. Man- and many also improve symptoms (Table III). The flavonoids
agement of pain and other CVD symptoms in C0s patients in red vine leaf extract have been shown to improve venous
includes oral VADs, compression hosiery, and patient reas- blood flow, while those in MPFF improve quality of life, ul-
surance and lifestyle modification.1 cer healing, and clinical severity of CVD (reduction in CEAP
class).
u Oral venoactive drugs
VADs have been shown to be an effective way of alleviating VAD mixtures are common; examples include MPFF, Gingko
pain in CVD and of treating nearly all CVD symptoms.1,5 Most extracts, and Ruscus extracts. MPFF is made of a 90%/10%
VADs have been shown to reduce capillary leakage and im- micronized mixture of the flavonoid diosmin and other flavo-
prove venous tone (Table I).1 Agents
that improve venous tone act by
Product Origin Active ingredient Clinical benefits
modulating noradrenergic signal-
ing, either by reducing noradrenaline Micronized purified Hesperedin leg edema

Rutacea aurantiae
metabolism (MPFF and hydroxy- flavonoid fraction Diosmin CEAP class
ethylrutosides) or by stimulating ve- quality of life

nous a1-adrenergic receptors (Rus- ulcer healing
cus extracts). Horse chestnut seed
Oxerutin Oxerutin symptoms

Sophera japonica
extract has a different mechanism of
Eucaliptus spp leg edema
action for improving venous tone,
Fagopyrum esculentum
inducing calcium-dependent con-
Moench
tractions in vena cava in a rat model.
Most VADs also have free-radical symptoms

b-hydroxyethyl- Sophera japonica b-hydroxyethyl-
scavenging properties and have rutosides Eucaliptus spp rutosides leg edema
now been demonstrated to have Fagopyrum esculentum
anti-inflammatory effects in CVD; Moench
several acting at more than one step
Read vine leaf Quercetin glucoside symptoms

Vitis vinifera
of inflammatory pathways.17,18 extract Quercetin glucuronides leg edema
Kaempferol glucoside blood flow

VADs can also reduce capillary per-
meability,19 prevent skin degenera- Pycnogenol Maritime pine Proanthocyanidins leg edema
tion related to abnormal capillaries,
improve lymphatic drainage, and Table III. Flavonoid products prescribed for the treatment of chronic venous disorders and
reduce blood viscosity and/or ery- chronic venous insufficiency and their origins, active ingredients, and clinical benefits.
throcyte aggregation.1 Fewer VADs Modified Abbreviation: CEAP, clinical, etiological, anatomical, pathophysiological.
from reference 1: Int Angiol. 2014;33:87-208. 2014, Edizioni Minerva Medica.
(flavonoids, a-benzopyrones, and
calcium dobesilate) have been shown to have an effect on noids (hesperidin, diosmetin, linarin, and isorhoifolin). Gingko
lymphatic drainage or hemorheological disorders (Table I),1 extracts contain Gingko biloba, heptaminol, and troxerutin;
while only MPFF has been shown to prevent the degradation and Ruscus extracts contain Ruscus aculeatus, hesperidin,
of venous wall and venous valves. VADs also have a role in methyl chalcone, and ascorbic acid.
chronic venous insufficiency (CEAP C4 to C6 ). MPFF used
alongside compression and local wound care has been VADs are an integral part of treatment in symptomatic venous
shown to increase the rate of healing of larger ulcers (5 cm to disease, particularly during the early stages. VADs are partic-
10 cm) and established ulcers (6 months to 12 months) vs ularly useful in patients with pruritic symptoms, in hot coun-
standard wound treatment alone.20 tries, and in patients reluctant to use compression therapy.
VADs should also be considered when surgical treatment of
There are five main categories of VAD: flavonoids (g-benzopy- CVD is unsuitable (eg, fear, previous negative experience). Al-
rones), a-benzopyrones, saponins, other plant extracts, and though good evidence exists for recommending the use of
synthetic products (Table I).1 The largest of these categories VADs in CVD, in order to strengthen the scientific rationale for
is the flavonoids (hesperidin, diosmin, oxerutins, b-hydroxy- their use, larger study populations (>200 patients), compre-
ethlyrutosides, quercetin, kaempferol, and proanthocyanidins), hensive patient description using CEAP classification, choice
which are known to have potent antioxidant properties. Flavo- of outcome measures, the use of validated tools, and long-
noids prevent the production of oxidizing agents, scavenge term studies should be the focus of future research activi-
free radicals (thus avoiding cellular damage), block the prop- ty.25 Preference should be given to those treatments with es-
agation of oxidative reactions, and strengthen inherent cellu- tablished evidence of efficacy and those recommended by
lar antioxidant capacity.21-24 All flavonoids reduce leg edema current guidelines.

Management of lower-limb venous symptoms: what the guidelines tell us Rybak MEDICOGRAPHIA, Vol 37, No. 1, 2015 53
LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC
u Compression therapy
Medical compression therapy is also considered an option
in C0s patients,12 and the rationale for its use is explained in
the 2014 guidelines.1 However, a recent review of the litera-
ture highlighted the lack of good quality evidence for deter-
mining the effectiveness of compression stockings or for mak-
ing comparisons between the different types available.26
Furthermore, more data are needed to show that the real-life
efficacy of compression therapy is comparable with that ob-
served in trials, as treatment compliance may be an issue.27,28
u Topical treatment and lifestyle
The cooling sensation of topical preparations containing VADs
or heparinoids can sometimes provide relief for symptoms of
heaviness or swelling.1 Although there is no evidence to sub-
stantiate the benefit of modifying lifestyle, the everyday expe-
rience of phlebologists indicates that many simple measures
could reduce symptoms in C0s patients. Measures such as
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symptom
54 MEDICOGRAPHIA, Vol 37, No. 1, 2015 Management of lower-limb venous symptoms: what the guidelines tell us Rybak
VENOUS DISORDERS
weight loss, raising the legs at night or during breaks, swim-
ming, substituting walking for driving, and calf exercises
could all play a valuable role.
Conclusion
Over the last decade, a constant message has emerged in
chronic venous disorder guidelines, reviews, and consensus
statements: VADs are effective for controlling symptoms at
all stages in CVD. This includes the earliest stage of chronic
venous disorders, where patients show no visible or palpable
signs of venous disease (C0s ). The major symptom in C0s pa-
tients, pain, can be alleviated by VADs. The role of VADs in the
management of CVD in the 2014 guidelines is described as
central and unique. These guidelines also advocate lifestyle
modification in C0s patients, but call for further assessment
of compression therapy. Treatment regimens in CVD should
be based on VADs, like MPFF, with higher levels of guideline
recommendation. n
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ic venous disease: Insights from animal models of venous hypertension. J Vasc
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17. Shukla VK, Sethi AK, Garg SK, Ganguly NK, Kulkarni SK. Effect of venoruton on
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flavonoids: recommendations for treatment and further studies. Phlebology.
2013;28:308-319.
26. Shingler S, Robertson L, Boghossian S, Stewart M. Compression stockings for
the initial treatment of varicose veins in patients without venous ulceration. Coch-
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27. Kahn SR, Shapiro S, Wells PS, et al. Compression stockings to prevent post-
thrombotic syndrome: a randomised placebo-controlled trial. Lancet. 2014;
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ease: patient compliance and efficacy. Ann Vasc Surg. 2007;21:790-795.
 LEG PA I N : TA K I N G CENTER STA G E IN CHRONIC VENOUS DISORDERS

PRISE EN CHARGE DES SYMPTMES VEINEUX DES MEMBRES INFRIEURS :

QUE NOUS DISENT LES RECOMMANDATIONS ?
Les phlbotropes (ou veinotoniques) font partie intgrante du traitement de la maladie veineuse chronique symp-
tomatique (MVC), surtout aux stades prcoces. Ces 10 dernires annes, les recommandations sur lutilisation des
phlbotropes pour le traitement symptomatique de la MVC ont considrablement volu. Les vnements marquants
du dveloppement des recommandations actuelles sont les suivants : la revue Cochrane 2005, la dclaration de
consensus international 2005, les recommandations 2008 pour la prise en charge des troubles veineux chroniques
des membres infrieurs, la revue Perrin et Ramelet 2011 et plus rcemment, les recommandations actuelles 2014.
chaque tape, de nouvelles donnes ont t ajoutes et le statu quo rvalu. La plupart des phlbotropes am-
liorent le tonus veineux, pigent les radicaux libres et rduisent la fuite capillaire, tandis que trs peu dentre eux di-
minuent la permabilit capillaire, empchent la dgnrescence cutane, amliorent le drainage lymphatique et di-
minuent la viscosit sanguine et/ou lagrgation rythrocytaire. Les phlbotropes diminuent aussi la douleur dans la
MVC. La douleur, induite par linflammation et/ou la distension de la paroi veineuse, est un symptme majeur des pa-
tients C0s , patients symptomatiques sans signe visible ou palpable de maladie veineuse. Un cinquime des patients
MVC pourrait appartenir au stade C0s de la CEAP (Clinical, tiological, Anatomical, Physiopathological). Le rcon-
fort et les modifications du style de vie peuvent aussi tre utiles ces patients, mais largumentaire du traitement par
compression se fonde sur de faibles donnes. Les recommandations de 2014 soulignent le rle central et unique
des phlbotropes, en particulier dans la MVC prcoce. Il faut utiliser de prfrence les phlbotropes de haut niveau
de recommandation.

Management of lower-limb venous symptoms: what the guidelines tell us Rybak MEDICOGRAPHIA, Vol 37, No. 1, 2015 55
 THE QUESTION CONTROVERSIAL QUESTION

ower-limb pain of venous ori-

L gin and clinical/investigation

findings have often been
shown to be incongruous, yet it is
acknowledged that this symptom
greatly worsens patients quality of
Is lower-limb pain reduction
life. The question is, is there appro-
priate emphasis placed on the re-
duction of lower-limb pain symp-
a meaningful treatment
toms in the treatment of chronic
venous disorders and is this ulti-
mately a meaningful treatment out-
outcome?
come?

1. S. Agarwal, India

2. Y. Akcali, Turkey

3. M. Bokuchava, Georgia

4. D. Branisteanu, Romania

5. E. Ferreira, Portugal

6. F. F. Haddad, Lebanon

7. D. T. T. Huong, Vietman

8. D. Karetov, Czech Republic

9. G. Lessiani, Italy

10 . H. Lotfy, Egypt

11. C. Ruangsetakit, Thailand

12 . C. E. Virgini-Magalhes, Brazil

13 . I. A. Zolotukhin, Russia

Is lower-limb pain reduction a meaningful treatment outcome? MEDICOGRAPHIA, Vol 37, No. 1, 2015 57
CONTROVERSIAL QUESTION
1. S. Agarwal, India
Sandeep AGARWAL, MS, FIVS
Vice Chairman and Senior Consultant
Department of Vascular and
Endovascular Surgery
Sir Ganga Ram Hospital
New Delhi 110060, INDIA
(e-mail: sagarwal3566@yahoo.com)
T
he syndrome of chronic venous disease (CVD) is com-
mon. In India, about 15% of the population has varicose
veins, and 2.5% venous leg ulcers. However, among
outpatients in the general practice setting, the frequency is
much higher. Leg pain is a major symptom of CVD. In a cross-
sectional survey of 300 patients with CVD, clinical, etiologi-
cal, anatomical, pathophysiological (CEAP) classification C0 to
C4 , 97% complained of lower-limb pain, and their quality of
life (QoL) assessed by a visual analogue scale was reduced
by one-fourth. The most severe pain and loss of QoL is in pa-
tients with leg ulcers (CEAP C5 and C6 ).
The origin of lower-limb pain in CVD is microvascular inflam-
mation. This pathogenic process is initiated by an idiopathic
loss of venous tone or thrombophlebitis involving the veins of
the lower limb. The resulting valvular incompetence and ve-
nous reflux leads to venous hypertension and venous stasis
in the lower limb. Venous stasis acts as a signal for the mar-
ginalization of white cells and their adhesion to the vein wall.
This triggers white-cell activation and release of inflammatory
mediators such as free radicals, thromboxane, and prosta-
glandins. A sterile inflammation develops in the wall of capil-
58 MEDICOGRAPHIA, Vol 37, No. 1, 2015
laries making them more permeable and friable. This micro-
circulatory inflammation gives rise to pain and the other car-
dinal symptoms of CVD, such as heaviness, cramps, and
sensation of swelling in the leg.
The leg pain of CVD is responsive to specific treatment. Meas-
ures to improve venous tone, reduce venous hypertension,
suppress microvascular inflammation, and increase lymphat-
ic drainage are effective. In experimental studies, micronized
purified flavonoid fraction (MPFF) has been shown to signif-
icantly increase venous tone, augment lymphatic drainage,
suppress inflammatory mediators (free radicals, thrombox-
ane B2, and prostaglandins E2 and F2), and reduce capillary
hyperpermeability. When patients with CVD were randomly
treated with MPFF 1000 mg or placebo for 3 months, there
was a significant improvement in lower-limb pain together
with plathesmographic increase in venous tone with MPFF
1000 mg treatment compared with placebo. This has since
been demonstrated in several studies. In India, QoL was first
assessed in a 6-month study on patients with CVD (CEAP
C0 to C4 ) in 1998. Treatment with MPFF 1000 mg together
with leg elevation reduced pain by 76%, and improved QoL
by 65%.1
Against this background of high prevalence, and availability
of effective treatment, it is worthwhile to treat leg pain due
to CVD.
Reference
1. Pinjala R. Long-term treatment of chronic venous insufficiency of the leg with
micronized purified flavonoid fraction in the primary care setting of India. Phle-
bology. 2004;19(4):179-184.
Is lower-limb pain reduction a meaningful treatment outcome?

2. Y. Akcali, Turkey
Yigit AKCALI, MD
Cardiothoracic and Vascular Surgeon
Department of Cardiac and Vascular Surgery
Erciyes University Medical Faculty
Kayseri, TURKEY
(e-mail: yakcali@erciyes.edu.tr)
V
enous disorders in the legs, which may be considered
a nearly normal part of the aging process, are perhaps
the most common afflictions of the bipedal human.
Venous leg pain is the most important differentiation between
venous disorder and venous disease. Therefore, it should
be systematically asked whether a patient is suffering from
venous leg pain. In the event of a painful leg, other vascular,
neurogenic, orthopedic, or rheumatologic disorders should be
considered as differential diagnoses.
Leg pain related to chronic venous disease (CVD) can be ex-
acerbated by a standing position in the course of the day, im-
mobility (for example, in a prolonged sitting position), warmth,
and menstrual cycle, and can be relieved with resting, leg
elevation, and cold exposure. However, patients complaining
of severe venous pain should be investigated for venous in-
termittent claudication (IC) and coexisting peripheral arterial
disease (PAD).1 Venous IC is a rare consequence following
hemodynamically significant obstruction of the deep venous
system, especially after iliofemoral deep venous thrombosis
(DVT) without adequate collateralization. Patients often expe-
rience severe thigh bursting pain or cramps and the sensa-
tion of tightness with walking or exercise, sometimes mimick-
ing claudication secondary to PAD. However, in contrast to
arterial claudication, 15 to 20 minutes of rest combined with
leg elevation often relieve the pain.
Venous pain, which is the main symptom that guides the di-
agnosis of CVD, has a substantial impact on patients quality
of life.2 Therefore, the absence of venous pain is considered
to be the most important outcome after venous treatment.
Is lower-limb pain reduction a meaningful treatment outcome?
CONTROVERSIAL QUESTION
Pain is a symptom of chronic venous disease, but not of
chronic venous disorder. Most patients who have visible
signs in the leg(s) do not need referral to the hospital. Further-
more, visible signs, pain, or reflux in the affected vein may in-
teract in the pathophysiological process, and consequently,
is as important as the appearance of visible signs on the legs
and reflux in the affected vein. Hence, in my clinical practice
I do not perform surgical or endovenous saphenous ablation
unless all of the following indications are present: (i) clinical
indication: CVD-related symptoms, mainly pain; (ii) anatomi-
cal indication: dilated, tortuous and/or elongated superficial
veins 6 mm; and (iii) pathophysiological indication: reflux in
the affected vein >0.5 seconds. So I consider that pain relief,
disappearance of visible signs on the legs, and the absence
of reflux in the diseased veins after the treatment of CVD are
the most important therapeutic outcomes.
If a patient who has been treated for their diseased veins or
skin (clinical, etiological, anatomical, pathophysiological [CEAP]
class C4 to C6 ) with satisfactory clinical and duplex ultrasound
outcomes continues to complain of leg pain, they should be
re-evaluated meticulously for other vascular or nonvascular
diseases (obesity, calf muscle venous pump dysfunction, etc).
After the diagnosis of coexisting PAD, which increases with
advanced age just as in CVD, have been excluded, the deep
venous system is reinvestigated for thrombotic or nonthrom-
botic insufficiency. Sometimes a saphenous vein can function
as a collateral pathway in a patient who has deep vein apla-
sia or hypoplasia with Klippel-Trenaunay syndrome. Then, if
saphenous ablation is performed without an adequate clini-
cal and radiological evaluation, venous leg pain can continue
and even augment postoperatively. A similar clinical picture
is discussed for postthrombotic syndrome, which is prima-
rily diagnosed on clinical grounds.
References
1. Akcali Y. Vascular leg ulcers. In: Coban YK, ed. Lower Extremity Wounds. Kerala,
India: Transworld Research Network; 2013:59-76.
2. Launois R, Reboul-Marty J, Henry B. Construction and validation of a quality of
life questionnaire in chronic lower limb venous insufficiency (CIVIQ). Qual Life Res.
1996;5:539-554.
MEDICOGRAPHIA, Vol 37, No. 1, 2015 59
CONTROVERSIAL QUESTION
3. M. Bokuchava, Georgia
Mamuka BOKUCHAVA, MD, PhD
President of Georgian Association of
Angiologists and Vascular Surgeons
Deputy Director of N. Bokhua Heart
and Vascular Center Clinic
Tbilisi, GEORGIA
(e-mail: bmamuka@hotmail.com)
L
eg pain is the complaint that occurs in 80% of patients
with chronic venous disease (CVD)1-3 and has a signif-
icant impact on patients quality of life (QoL). This pain
is mostly associated with a feeling of heaviness or tiredness
in the legs, numbness, burning, or a sensation of swelling.4,5
In my clinical practice, the first thing to do is to gain the anam-
nesis of a venous patient and to find out whether there is a
family history of varicose disease, thromboembolism, or throm-
bophilia. I systematically ask patients about leg pain and its
originsymptoms, when and under what circumstances the
pain appears, and its correlation with patients daily activities.
In women, it is important to have information about the num-
ber of pregnancies, and the use of contraceptives and hor-
monal therapy.
Venous pain is usually diffuse, with no clear location. Also, it
is known that the intensity of pain is not correlated with the
severity of venous diseasemany patients suffering from ve-
nous pain have no objective clinical or paraclinical abnormal-
ities.4,6 The pain must be differentiated from other lower-limb
pain of different etiologies: mechanical factors usually relat-
ed to activities and movements such as walking up the stairs
and lifting, intermittent claudication (in patients with chronic
ischemic peripheral arterial disease), or by the pain associ-
ated with joint disease. A complaint of severe venous pain re-
quires further investigation. For me as a specialist, the most
important thing is to adapt the treatment to the patient. For
this purpose we must start with an analysis of the patients
60 MEDICOGRAPHIA, Vol 37, No. 1, 2015
clinical status, taking into account his expectations, and of
course to have a good knowledge of the indications and out-
comes of various treatment options. So, the most important
outcome after CVD treatment is not only the disappearance of
one clinical sign or symptom, but a disappearance of all
visible signs, pain, reflux in the affected vein, and severity of
heavy or tired legs.
In the case of continuous leg pain despite venous pathology
having been successfully treated (including ulcer healing),
with good clinical and duplex ultrasound results, I suggest fur-
ther investigations with other specialists, eg, neurology or or-
thopedics/traumatology, in order to exclude other pathology.
The treatment strategy used for the management of chron-
ic venous pathology is complex, including medical treatment
(such as venoactive drugs to prevent the progression of the
disease and to avoid complications), elastic compression ther-
apy, and surgery.
To conclude, leg pain affects 80% of patients with CVD, so
it is important to consider this kind of venous pain as a ther-
apeutic target to improve the QoL of these patients.2,4
References
1. Bradbury A, Evans C, Allan P, Lee A, Ruckley CV, Fowkes FG. What are the
symptoms of varicose veins? Edinburgh Vein Study cross sectional population
survey. BMJ. 1999;318:353-356.
2. Eklof B, Rutherford RB, Bergan JJ, et al. American Venous Forum International
Ad Hoc Committee for Revision of the CEAP Classification. Revision of the CEAP
classification for chronic venous disorders: consensus statement. J Vasc Surg.
2004;40:1248-1252.
3. Widmer LK, Zemp E. Diagnosis and treatment of varicose veins. Deduction from
on a Basel prospective epidemiological study. Helv Chir Acta.1988;54:531-539.
4. Duque MI, Yosipovitch G, Chan YH, Smith R, Levy P. Itch, pain, and burning sen-
sation are common symptoms in mild to moderate chronic venous insufficiency
with an impact on quality of life. J Am Acad Dermatol. 2005;53:504-508.
5. Bergan JJ, Schmid-Schonbein GW, Smith PD, Nicolaides AN, Boisseau MR,
Eklof B. Chronic venous diseases. N Engl J Med. 2006;355:488-498.
6. Bradbury A, Evans CJ, Allan P, Lee AJ, Ruckley CV, Fowkes FG. The relationship
between lower limb symptoms and superficial and deep venous reflux on du-
plex ultrasonography: The Edinburgh Vein Study. J Vasc Surg. 2000;32:921-931.
Is lower-limb pain reduction a meaningful treatment outcome?

4. D. Branisteanu, Romania
Daciana BRANISTEANU, MD, PhD
Associate Professor
Department of Dermatology
University of Medicine and
Pharmacy "Gr.T.Popa"
Iasi, ROMANIA
(e-mail: debranisteanu@yahoo.com)
V
enous pain was and still is an issue of intense debate
among phlebologists because of its clinical and patho-
physiological particularities. There were, and probably
still are, doctors who believe that leg pain is difficult to attrib-
ute to venous disease. On the other hand, venous pain is dif-
ficult to describe by patients, the sensation of pain being as-
sociated with other multiple symptoms of chronic venous
disease (CVD): cramps, pruritus, sensation of swelling, feelings
of heaviness, tension in the legs, etc.
Recent studies provide information on the physiological mech-
anism underlying venous pain and elucidate some cellular and
biochemical processes. Still, incomplete and even erroneous
concepts of the importance of venous pain persist in the med-
ical community. More precisely, patients find it difficult to de-
scribe and even to realize that leg pain is related to venous
disease. A detailed, targeted history may lead to the active de-
tection of this complex symptom of venous disease.
However, the insidious onset and chronicity of venous pain
means that the importance of venous pain in the diagnosis,
course, and effectiveness of therapy for venous disease is of-
ten underestimated by both patient and doctor.
Venous pain is poorly quantified in the clinical, etiological,
anatomical, pathophysiological (CEAP) classification; there
is no concrete scientific assessment of venous pain intensity,
only the differentiation between the presence or absence of
venous pain. The Venous Clinical Severity Score (VCSS) also
doesnt consider venous pain as a criterion for assessing the
severity of venous disease, although the fact that venous pain
leads to a change in the quality of life of patients with venous
disease is recognized.
Is lower-limb pain reduction a meaningful treatment outcome?
CONTROVERSIAL QUESTION
Practical clinical experience suggests a great diversity of ve-
nous pain expression in patients with venous disease. Thus,
some patients with advanced CVD (CEAP class C4 or C5 )
presenting with significant and diverse trophic skin changes
and severe duplex ultrasound findings do not have significant
venous pain. On the other hand, there are patients who com-
plain of significant leg pain in the absence of consistent clini-
cal or ultrasound changes. These clinical findings suggest that
there is no correlation between the presence and intensity
of venous pain, and between pain and the severity of patho-
physiological, clinical, and ultrasound changes, thus further
complicating the correct diagnosis, and short- and long-term
management of CVD.
In daily practice, active detection of leg pain is very important
in all patients with venous disease. This way, the doctor-pa-
tient relationship related to leg pain as a symptom of venous
disease can be improved. Assessment of leg pain as severe
on the Visual Analogue Scale should prompt the physician
to refer the patient to more complex ultrasound examinations
for an accurate diagnosis.
The most important outcome after venous treatment is halting
the progression of CVD to advanced stages, and even regres-
sion in less severe stages of disease. Given this goal, reduc-
ing venous hypertension in leg circulation and the disappear-
ance of reflux in the affected vein are essential. Depending
on the CVD stage, it is desirable that visible signs on the leg
disappear or diminish. From a patients point of view, I believe
that the most important outcome after venous treatment is
the disappearance, or at least the relief, of CVD symptoms,
especially leg pain, followed by healing of clinical signs visi-
ble on the legs.
If leg pain persists despite correct and complex treatment for
CVD, controlled clinical signs, and satisfactory duplex ultra-
sound results, I think it is appropriate to investigate for other
etiology (eg, arterial, neurological, articular, muscular, infec-
tious, etc). Large epidemiological studies are needed to deter-
mine the true incidence and intensity of venous pain in CVD,
such as detecting the factors that cause variations in pain in-
tensity from one patient to another.
MEDICOGRAPHIA, Vol 37, No. 1, 2015 61
CONTROVERSIAL QUESTION
5. E. Ferreira, Portugal
Emilia FERREIRA, MD
Head of the Angiology
and Vascular Department
Santa Marta Hospital
Rua Conselheiro Lopo Vaz
Lote AB, 7D, 1800-152, Lisbon
PORTUGAL
(e-mail: emiliaferreira@cirurgiavascular.pt)
C
hronic venous disease (CVD) is the most prevalent
vascular disorder in developed countries and is as-
sociated with significant costs (2% to 3% of the health
budget of Western countries). According to the clinical, eti-
ological, anatomical, pathophysiological (CEAP) classification,
all classes of CVD can be associated with symptoms, and
there is no direct relationship between symptoms and stage
of disease.
One of the symptoms of CVD is leg pain. Quality of life (QoL)
has been reported to be negatively affected by leg pain among
patients with CVD. The prevalence of leg pain in CVD is often
underestimated by physicians, since it is difficult to evaluate
and could suggest different diagnoses (rheumatic, orthope-
dic, neuropathic, etc). However, we can describe some fea-
tures that may suggest CVD:
Symptoms worsen towards the end of the day.
Symptoms are more intense during the hot season.
Symptoms show an activity-related variation throughout
the day-night cycle; usually unresponsive to analgesics or non-
steroidal anti-inflammatory drugs.
Venous obstruction or reflux removal, as well as the use of
compression stockings and venoactive drugs, leads to im-
provement.
Until recently, treatment effectiveness did not take into ac-
count patient-centered outcomes such as QoL. Currently,
modern medicine has greatly shifted its focus to the patients
perspective of the disease and it has become indispensa-
62 MEDICOGRAPHIA, Vol 37, No. 1, 2015
ble when treatment outcomes are assessed. So, on the first
contact with the patient, it is essential to clarify the reason for
consultation including cosmetic complaints, symptoms (pain,
edema, restless legs, pruritus), impact on QoL, fear of disease
progression, and patient expectations (this is our most im-
portant outcome measure).
A complete clinical history, physical examination, and a con-
tinuous wave Doppler evaluation, are then performed. Ac-
cording to the findings, we can have a diagnosis, classify the
severity of CVD, and propose a treatment regimen. Duplex
ultrasound is generally reserved for patients with C3 or more
advanced stages of the CEAP classification. Patient educa-
tion on healthy lifestyle is fundamental. The following instruc-
tions must be convincing and regularly repeated to the pa-
tient: (i) walk daily, as often as possible; (ii) elevate legs by 30
during rest periods throughout the day; (iii) elevate the foot of
the bed, 10 cm to 15 cm during the night; (iv) take cold show-
ers; (v) regular participation in sportswalking, cycling, swim-
ming, running, etc; and (vi) regular use of compression stock-
ings.
If leg pain is the main complaint, and if its severity has an
impact on patient lifestyle, venoactive drugs should also be
prescribed.
At this time, according to the CVD classification, sclerothera-
py or classic vs endovenous surgery will be discussed. If a
patient that has been satisfactorily treated (according to clin-
ical and ultrasound results) continues to complain of leg pain,
the physician should investigate further.
Therefore, it is mandatory to confirm if the etiology of the pain
is just a symptom of venous disease or whether there are oth-
er objective causes for these symptoms. If all other causes, in-
cluding psychological, have been excluded, venoactive drugs
are prescribed. The most important outcome after venous
treatment is measured by the satisfaction of the patient.
Is lower-limb pain reduction a meaningful treatment outcome?

6. F. F. Haddad, Lebanon
Fady F. HADDAD, MD, FACS
Associate Professor of Clinical Surgery
Vascular and Endovascular Surgery
Director, the Ismail Khalil Vascular Laboratory
Coordinator Endovascular Program
American University of Beirut Medical Center
LEBANON
(e-mail: fh16@aub.edu.lb)
Pain is a feature of venous disease often
overlooked and commonly undertreated. 1
S
ince before ancient times, mankind described, suffered
from, and treated varicose veins; clearly not all for cos-
metic reasons. The San Diego Population Study report-
ed data on symptoms of venous disease: aching was the most
commonly reported venous symptoms with a prevalence of
17.7% (though swelling was slightly more specific).2 Symp-
toms increased in severity with the increase in functional and
visible disease.
It is established that symptoms in varicose veins play a key
role in overall assessment, as stressed by class C0s in the clin-
ical, etiological, anatomical, pathophysiological (CEAP) clas-
sification; however, pain does not stand out specifically in this
grading. The symptom of pain, despite the mixed reporting in
relation to the physical signs and severity of disease, does
carry serious medical implications. Indeed, recent onset pain,
warmth, and erythema in the distal leg can be signs of early
lipodermatosclerosis at the level of the perforators and a prel-
ude for future ulceration.3 Not surprisingly, in the most recent
NICE guidance, patients are to be referred for vascular spe-
cialist care if varicose veins are associated with any trou-
bleshooting symptoms such as pain.4 In addition, the fact
that venous pain may not be correlated with incompetent
valves or absence of reflux (CEAP class C0s ) supports the find-
ings of microvalvular incompetence at very distal tributaries.5
Failure of microvenous valves in small superficial veins is a key
to the skin changes of venous insufficiency. The ultimate as-
sessment of disease impact and treatment outcomes is qual-
ity of life (QoL); looking at the recently revised ChronIc Venous
Insufficiency quality of life Questionnaire (CIVIQ)14 score,
Is lower-limb pain reduction a meaningful treatment outcome?
CONTROVERSIAL QUESTION
one of the three dimensions of this tool is pain. Currently,
this is one of the most reliable and validated QoL scores in
chronic venous disease.6
Importantly, varicose veins are one of the rare etiologies of
pain in the legs that are actually visualized by the patient.
Hence, any complaint in the presence of varicosities is auto-
matically related to the latter. Having pain assessment and
reassessment, initially and at follow-up, is an important out-
come tool. If this is unchanged after treatment, it is likely that
further investigation is warranted to explore possible etiolo-
gies. Regardless, as with any other pathology, outcome as-
sessment should cover the original complaint that brought
the patient for consult. This issue was addressed partly with
the revised Venous Clinical Severity Score, which is also en-
dorsed by the Society for Vascular Surgery and the American
Venous Forum recommendation.7 This does not, unfortunate-
ly, include staging of the disease, and CEAP classification
would still be in order. Ideally, a single venous assessment
and outcome tool should be available that looks at the pa-
tient stage, well-being, and QoL, with a fair representation of
the pain scale in its component.
References
1. Barron GS, Jacob SE, Kirsner RS. Dermatologic complications of chronic ve-
nous disease: medical management and beyond. Ann Vasc Surg. 2007;21(5):
6526-6562.
2. Langer RD, Ho E, Denenberg JO, Fronek A, Allison M, Criqui MH. Relationships
between symptoms and venous disease: the San Diego Population Study. Arch
Intern Med. 2005;165(12):1420-1424.
3. Bergen J. Symptoms of varicose veins. In: Bergen J, ed. The Vein Book. Cam-
bridge, MA: Elsevier Inc; 2007:122.
4. NICE. Varicose veins in the legs. The diagnosis and management of varicose
veins. NICE clinical guideline 168. http://www.nice.org.uk/guidance/cg168/re-
sources/guidance-varicose-veins-in-the-legs-pdf. Issued July, 2013. Accessed
August 28, 2014.
5. 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.e1-e3.
6. Launois R, Le Moine JG, Lozano FS, Mansilha A. Construction and internation-
al validation of CIVIQ-14, a new questionnaire with a stable factorial structure.
Qual life Res. 2012;21:1051-1058.
7. Gloviczki P, Comerota AJ, Dalsing MC, et al. The care of patients with varicose
veins and associated chronic venous diseases: clinical practice guidelines of the
Society for Vascular Surgery and the American Venous Forum. J Vasc Surg.
2011;53(5 suppl):2S-48S.
MEDICOGRAPHIA, Vol 37, No. 1, 2015 63
CONTROVERSIAL QUESTION
7. D. T. T. Huong, Vietnam
Dinh Thi Thu HUONG, PhD
National Cardiology Institute
Hanoi Medical University
Hanoi, VIETNAM
(e-mail: thuhuong60@gmail.com)
A
s a cardiovascular doctor, I have to examine patients
who have heart and vascular diseases. While exam-
ining these patients, I tend to investigate potential risk
factors for these diseases. Clinical practice has shown that
many patients suffering unpleasant sensations in their legs
(including heaviness, cramps, and tension) at the end of the
day show absence of reflux in the superficial or deep veins on
duplex ultrasound.
In contrast, patients with varicose veins often do not complain
about leg pain. It is clear that there is no correlation between
the clinical state and the presence of reflux, or between the
intensity of the pain and the severity of venous disease.
In practice, while examining patients, I often concentrate on
asking them to describe and rate the intensity and the prop-
erty of pain, and clarify whether their pain is stimulated by
physical activities or not. These questions help to differentiate
leg pain due to venous disease from leg pain caused by oth-
er stimuli, such as arthropathy, nervous pain, etc.
Careful investigation is essential in examining venous disease.
Many patients are still diagnosed as having chronic venous
disease by general practitioners, even though they do not have
chronic varicose veins, and vice versa. For all patients who
complain about leg pain, to orientate medical treatment, inter-
vention, or surgical treatment, I always ensure a duplex ultra-
64 MEDICOGRAPHIA, Vol 37, No. 1, 2015
sound scan is carried out by vascular ultrasound specialists.
I believe the quality of evaluation of treatment results depends
on numerous criteria:
For young women with high esthetic requirements, it is im-
portant to provide a treatment that improves the esthetics of
the legs.
For the vast majority of patients, the absence of leg pain,
which thus enables them to enjoy daily life without the feel-
ing of heaviness or cramps at the end of the day, is the best
treatment outcome.
For patients with varicose veins treated with radiofrequency
or laser, the good treatment outcome is no reperfusion or re-
flux in the treated veins.
However, in clinical practice there are many patients who,
after being treated by a cardiovascular intervention or surgery,
still complain of leg pain, despite the absence of clinical signs
or duplex ultrasound results of varicose. These patients still
need to continue using venotonic drugs, because the mech-
anism of venous pain is complex. Studies on the mechanism
of skin pain have clearly shown that inflammatory mediators
may activate nociceptors in the skin. Among the peripheral
mediators involved, protons, bradykinin, serotonin, prosta-
glandins, and leukotrienes appear to be the most potent ac-
tivators of cutaneous nociceptors. Other substances, such as
platelet-activating factor, histamine (pruriginous at low con-
centration, painful at high concentration), certain interleukins,
and neuropeptides also play a major role in the activation of
cutaneous nociceptors. These data on cutaneous nociceptors
have led to several studies of the neuromediators involved
in the activation of venous and perivenous nociceptors in hu-
man subjects. Study of the painful feeling induced by brady-
kinins intravenous or perivenous application unambiguously
shows that bradykinin is involved in the generation of venous
pain. In view of this response to chemical stimulation, venous
nociceptors can be considered to be chemoreceptors.
Is lower-limb pain reduction a meaningful treatment outcome?

8. D. Karetov, Czech Republic
Debora KARETOV, MD, PhD
Second Department of Medicine
Department of Cardiovascular Medicine
First Faculty of Medicine and
General University Hospital
U Nemocnice 3, 128 08 Prague 2
CZECH REPUBLIC
(e-mail: dkare@lf1.cuni.cz)
C
hronic venous disease (CVD) is often accompanied
by venous pain, which is a consequence of the over-
pressure in microcirculation. Current hypotheses on
pain mechanisms in venous disease are focused on a local
inflammatory origin related to venous stasis, and on a local ac-
tivation of nociceptors in the microcirculation, where contact
between nerve endings and the capillary is probably much
closer than on the macrovascular level. The diminution of pain
in the advanced stages of venous disease may be related to
peripheral sensory neuropathy induced by venous microan-
giopathy.
The chief complaint of pain has a significant impact on patients
quality of life. However, pain is difficult to assess, both be-
cause of its multifaceted nature and because of the lack of a
precise correlation between pain as a symptom and sever-
ity of venous disease. There are at least three other reasons.
First, pain of venous origin is frequently associated with other
unpleasant sensations such as heaviness, cramps, tension in
the legs, or pruritus. It is also often difficult to describe. Sec-
ond, the intensity of pain can fluctuate substantially, both from
patient to patient or in the same patient with progression of
the disease over a period of time. Lastly, although the neuro-
physiological mechanisms of pain of venous origin are better
understood, and some biochemical and cellular processes
involved in varicose vein remodeling have been explained by
recent studies, the causal relationship between CVD and pain
of venous origin remains difficult to understand. The most
obvious symptoms of CVD, except for pain, are tiredness or
heaviness in the legs, sensation of swelling, fullness or even
aching, and later swelling of ankles, especially in the second
part of the day after extended periods of standing. Flaking or
itching skin on the legs could also mimic neuropathy. The sto-
ry of CVD could be quite different in various patients. Some
Is lower-limb pain reduction a meaningful treatment outcome?
CONTROVERSIAL QUESTION
patients present with CVD in the most advanced stage, with
marked skin changes, but without any pain at all. However,
others have very tiny vein changes, but serious pain com-
plaints. Doctors must assess their patients thoroughly to bet-
ter understand and evaluate their pain. For example, differ-
entiating pain of venous origin from neuropathic pain can be
difficult. The two may also coexist and both could be exac-
erbated in the evening hours.
Many scoring systems for evaluation of the severity of CVD
have been developed. Although these systems are used es-
pecially in clinical studies (eg, ChronIc Venous Insufficiency
quality of life Questionnaire [CIVIQ]), they are too complicat-
ed for everyday practice. Instead of these complicated sets
of questionnaires, a much more helpful tool is a set of simple
questions allowing physicians to conclude whether the pa-
tient really suffers from venous hypertension.
Examples of these questions are as follows: Is it more com-
fortable to have your legs up or down? Do you have more pain
in your legs early in the morning or later in the afternoon? Do
you have problems while walking?
The evaluation of these answers is much more important for
the decision of whether to treat CVD than the extent of the
disease determined by physical or ultrasound examination.
Once physicians come to the conclusion that the problem
could be venous hypertension, then therapeutic testing with a
potent venoactive drug, such as micronized purified flavonoid
fraction can be done. The relief of pain is the best proof of hit-
ting the target.
In conclusion, there is a huge discrepancy between the sever-
ity of pain in venous disease based on clinical findings and the
degree of pain reported by patients. This discrepancy compli-
cates the objective evaluation of the result of therapies in ve-
nous disease. The evaluation of leg pain requires a proper his-
tory and physical examination, as well as neurologic evaluation
in some cases. Vascular evaluation should include general
screening with noninvasive vascular studies. The localized re-
lease of proinflammatory mediators seems to play a decisive
role in the activation of venous and perivenous nociceptors
and may account for the occurrence of pain at early stages
of venous disease.
MEDICOGRAPHIA, Vol 37, No. 1, 2015 65
CONTROVERSIAL QUESTION
9. G. Lessiani, Italy
Gianfranco LESSIANI, MD
Angiology Unit
Department of Medicine and Geriatrics
Citt Sant'Angelo Hospital
ITALY
(e-mail: g.lessiani@libero.it)
C
hronic venous disease (CVD) is one of the most wide-
spread conditions afflicting a great part of the worlds
population. The exact prevalence of CVD is difficult to
determine because there is a wide variation in study popula-
tion, selection criteria, and disease definition between different
studies. Generally, symptoms ascribed to CVD are: heaviness,
cramps, aching, itching, feeling of swelling, tingling, etc.
Pain is the most frequent reason for medical evaluation by
patients with CVD, and generally is the complaint that leads
to the diagnosis of venous disease. Quality of life (QoL) of pa-
tients with CVD is greatly affected, especially by pain. How-
ever, pain in CVD is very difficult to understand. Indeed, epi-
demiological studies have established that the presence and
intensity of leg symptoms related to CVD, are not correlated
with the clinical assessment of severity disease. Bradbury et
al showed in the Edinburgh Vein Study that about 40% of
asymptomatic patients had varicose veins on clinical examina-
tion and 45% of the patients complaining of leg pain compat-
ible with CVD had no varicose veins on examination.1 More-
over, no correlation was observed between the presence of
pain and the observation by Doppler ultrasound of superficial
or deep venous reflux. Also, many patients complain of pain at
an early stage of venous disease, when they also have a nor-
mal clinical and Doppler examination. Howlader and Smith
reported no statistical relation between the pain score or heav-
iness score of a patient,2 evaluated with a 10-point visual ana-
logue scale, and the clinical severity of venous disease.
Pain of venous origin is often associated with other disagree-
able sensations that are very difficult to describe (tension in
the leg, pruritus, feeling of heaviness). Pain in venous disease
may vary over time in intensity, within the same patients. Gen-
erally in clinical practice, physicians tend to underestimate the
intensity of pain in venous disease, especially when it is chron-
ic, poorly defined, poorly located, and when underlying mech-
anisms are not clearly identified. Moreover, clinical, etiolog-
ical, anatomical, pathophysiological (CEAP) classification and
the Venous Clinical Severity Score (VCSS) underestimate pain.
The CEAP classification only differentiates between symp-
66 MEDICOGRAPHIA, Vol 37, No. 1, 2015
tomatic or asymptomatic patients, and VCSS defines venous
pain in a generic way. For these reasons, there is a growing
interest in patient-reported outcomes (PROs), which are con-
sidered to be key outcomes that cover several aspects: pref-
erence of care received, outcome of care (health-related QoL,
patient satisfaction, subjective symptoms), and allows mon-
itoring of pain and the progression of the disease.3,4 The use
of QoL questionnaires in patients suffering from CVD can pro-
vide relevant and more complete information, also in relation
to psychology, social aspects, and pain.
Interesting neurophysiological mechanisms of pain in CVD,
and some biochemical and cellular process involved in pain
and vein remodeling have been explained. The strong trigger
for these mechanisms is local hypoxia caused by venous
stasis. The hypoxia activates endothelial cells resulting in the
synthesis and local release of mediators that modulate pain
(activation of venous and perivenous nociceptors) and are pro-
inflammatory. Over time, this process also leads to venous
remodeling characterized by cellular and matrix alterations
resulting in loss of structural integrity of the vein wall and its
elastic properties. Activation of venous and perivenous no-
ciceptors plays a relevant role in determining pain, even in the
early stage of disease.
In clinical practice, we consider it very important to focus on
venous pain during evaluation of the patient, at initial evalua-
tion and on follow-up. For this reason, we systematically per-
form a QoL questionnaire and visual analogue scale for pain.
With a complaint of severe venous pain, we perform a thor-
ough clinical and haemodynamic evaluation, and try to ex-
clude other causes. After venous treatment, we consider rel-
evant outcomes, correction of hemodynamic alterations, and
absence of pain, rather than disappearance of visible signs.
If the patient continues to complain of leg pain despite satis-
factory treatment (clinical and ultrasound results), we re-eval-
uate for other possible causes, and review pharmacological
therapy, taking into account drugs with proven efficacy against
venous pain.
References
1. Bradbury A, Evans C, Allan P, Lee A, Ruckley CV, Fowkes FG. What are the symp-
toms of varicose veins? Edinburgh vein study cross sectional population survey.
BMJ. 1999;318:353-356.
2. Howlader MH, Smith PD. Symptoms of chronic venous disease and associa-
tion with systemic inflammatory markers. J Vasc Surg. 2003;38:950-954.
3. Fung CH, Hays RD. Prospects and challenges in using patient-reported out-
comes in clinical practice. Qual Life Res. 2008;17:1297-1302.
4. Willke RJ, Burke LB, Erickson P. Measuring treatment impact a review of patient-
reported outcomes and other efficacy endpoints in approved product labels.
Control Clin Trials. 2004;25:536-562.
Is lower-limb pain reduction a meaningful treatment outcome?

10. H. Lotfy, Egypt
Hassan LOTFY, MBBCh, MRCS
Faculty of Medicine
Alexandria
EGYPT
(e-mail: hassanlotfy@hotmail.com)
P
ain!! Is it some sort of punishment from God, is it an
evil spirit intruding the body, is it a gift from The Lord
to be able to recognize that there is something going
wrong, or is it due to chemical mediators and noxious stim-
uli either from within or from outside the body? All these ques-
tions have mystified scientists and philosophers over the ages;
each tries to explain pain according to his own point of view.
So, what is pain? Painas we all knowis that unpleasant
sensory and/or emotional feeling caused by an underlying
pathology. Pain can be acute or chronic according to the du-
ration of suffering. It varies in severity from mild discomfort that
may affect the patients quality of life, to severe pain that sig-
nificantly affects normal daily activity and disturbs sleep. The
lower limb is the most common site to experience tiredness
and pain. It is the price paid for the upright position of mankind.
Venous pathology, as a cause for pain, is considered the most
common factor resulting in muscle fatigue and venous con-
gestion after standing idle for a long time.
It is not surprising that pain is the most common complaint of
patients and the most common reason to seek medical ad-
vice. Pain is ranked first in vascular complaints. It may precede
cosmetic concern. In my opinion, vascular surgeons must fo-
cus on the analysis of pain to probe the real cause of pain and
to exclude other causes that mimic venous pain.
Is lower-limb pain reduction a meaningful treatment outcome?
CONTROVERSIAL QUESTION
It is strange to find that different sophisticated scoring systems
for venous disease, such as the clinical, etiological, anatom-
ical, pathophysiological (CEAP) classification and the Venous
Clinical Severity Score (VCSS), do not address pain as a main
component. They just consider whether pain or discomfort
is present, regardless of its severity.
It is not uncommon to find patients with remarkable venous
problems free from pain or discomfort, meanwhile patients
with mild pathology may have pain out of proportion to their
problem. It is essential to investigate the depth of the condi-
tion to find out the actual cause of pain. The most important
issue is to handle the patients complaints in view of the pre-
sented pathology, considering that the most important out-
come is to alleviate pain. It is not worth removing dilated veins
or alleviating venous reflux while the patient is still suffering.
Answering a patients question of How can I reduce my leg
pain? by an answer such as You have had your veins ab-
lated and are free from varicosities, so there is nothing else
that can be doneyou have to live with it, is very frustrat-
ing and disappointing. The patient will certainly wonder why
he has had all these tedious and expensive investigations and
procedures.
A large number of patients go to work in spite of the presence
of pain. This may be attributed to the difference between pop-
ulations with regards to pain threshold. The financial aspect
also plays an important role as many individuals are bread-
winners for their families.
In conclusion, pain relief must be considered as a human right
for every patient to end his suffering and improve quality of
life. Physicians and medical personnel must consider pain
alleviation as the main target that must be achieved while si-
multaneously treating the causative factor.
MEDICOGRAPHIA, Vol 37, No. 1, 2015 67
CONTROVERSIAL QUESTION
11. C. Ruangsetakit, Thailand
Chanean RUANGSETAKIT, MD, FRCS, MSc
Associate Professor
Vascular Surgery Unit
Department of Surgery
Siriraj Medical School
Mahidol University
Bangkok 10700, THAILAND
(e-mail: chaneansi@gmail.com)
T
he incidence and prevalence of chronic venous dis-
ease (CVD) varies widely depending on the definition
of disease and studied geographic area. In Thailand,
the incidence and prevalence have not yet been established.
CVD is a common problem in our vascular clinic, at Siriraj Hos-
pital, Mahidol University, and the patients who visit our clinic
have varied clinical manifestations. Common clinical manifes-
tations are limb swelling, pain, varicose veins, dermatitis, and
venous ulcers. Leg pain in venous patients can be due to ve-
nous or other causes. Other causes may coexist, such as arthri-
tis, neuropathy, claudication, and spinal stenosis. In these pa-
tients, it is important to determine the likelihood that leg pain
is related to venous insufficiency, to enable appropriate ve-
nous management.
For venous patients suffering from leg pain, a physician needs
to study the details of their history and physical examination
to identify the cause. Onset, duration, characteristic of pain,
aggravating and releasing factors, and associated symptoms
all these details of leg pain usually point to the etiology. In
the case of patients where the etiology is not evident from his-
tory and examination, investigations need to be done, espe-
cially in patients with severe venous pain.
Venous physiological tests are very useful for chronic venous
insufficiency. Photoplethysmography can demonstrate the
presence or absence of venous insufficiency. Air plethysmo-
graphy can not only identify venous insufficiency, but also
demonstrates severity of venous insufficiency and the out-
68 MEDICOGRAPHIA, Vol 37, No. 1, 2015
come of venous treatment. Duplex ultrasonography is neces-
sary to identify the cause of venous insufficiency such as deep
vein thrombosis (DVT), the site of reflux, evaluate the deep
and perforator systems, and guide intervention. It is neces-
sary to promptly identify the cause of severe venous pain, as
it may be due to deep vein occlusion or a complication of pri-
mary CVD and can disturb daily activities.
When patients with CVD are diagnosed, they can undergo
treatment. At present, venous treatment can be categorized
into conventional and endovenous treatment for superficial
and deep venous systems. The outcomes after venous treat-
ment depend on the patients symptoms and concerns. These
include leg swelling, leg pain, visible varicose vein, hyperpig-
mentation, dermatitis, and leg ulcers. The disappearance or
improvement of visible signs on the leg and of leg pain are
satisfactory outcomes for the patients. Even though the im-
provement of the patients symptoms and concerns can be
demonstrated, some patients still have reflux in the affected
vein. Conversely, some patients show absent reflux in the af-
fected vein, but still have the symptoms.
I consider that symptoms, concerns, and venous hemody-
namics make patients visit the clinic. In my opinion, the pa-
tients symptoms and concerns are more important than the
absence of reflux in the affected vein. In patients whose clin-
ical and duplex ultrasound results are satisfactory, but who still
continue to complain about leg pain, I explain and discuss the
possible causes of leg pain, and give recommendations about
avoiding or reducing activity that increases venous stasis and
pressure. I also advise regular calf muscle exercises. Occa-
sionally, these patients need muscle relaxants, painkillers, and
venoactive drugs. In my practice, leg pain may improve or dis-
appear in patients who receive treatment. Lower-limb pain in
venous patients can limit their activity and work. Identifying
the cause of pain and managing appropriately could bring
about good outcomes. However, pathogenesis of pain in ve-
nous disease is still not clearly understood.
Is lower-limb pain reduction a meaningful treatment outcome?

12. C. E. Virgini-Magalhes, Brazil
Carlos E. VIRGINI-MAGALHES, MD, PhD
Department of Surgery
Pedro Ernesto University Hospital
State University of Rio de Janeiro,
Rio de Janeiro, BRAZIL
(e-mail: cevirgini@gmail.com)
D
espite recent advances in pathophysiology and mech-
anisms involved in the clinical expression of chronic
venous disorders, scientific understanding is still dis-
appointing. Such deficiency becomes even more expressive
in daily practice, where we are currently challenged with di-
verse clinical presentations. Many patients present with a typ-
ical history and symptoms, but without any objective signs
of chronic venous disorders. On the other hand, some pres-
ent with varicose veins and venous hypertension stigmata
without any clinical complaints.
Leg pain is probably the earliest symptom of chronic venous
disorders. Although many patients with venous disease do
not complain of leg pain, several epidemiological studies in-
dicate that it is a very common symptom, even in the early
stages of the clinical, etiological, anatomical, pathophysio-
logical (CEAP) classification.1-4 It seems intuitive to associate
the degree of the inflammatory process associated to chron-
ic venous disorders to the intensity of pain in these patients,
since pain is a common symptom associated with inflamma-
tion in other medical conditions. However, recent studies failed
to show a clear correlation between pain intensity and venous
disease severity.
The concept of pain relates to an unpleasant sensory and
emotional experience associated with actual or potential dam-
age. Several aspects are involved in the expression and mod-
ulation of pain, which attributes great subjectivity and individ-
uality to this sensation. However, this symptom has a direct
impact on perceived quality of life among these patients, and
this is an important issue that should be considered.5 Lack of
specificity means that venous pain is underestimated by many
physicians, and the eventual absence of a clear anatomical
substrate leads to the neglect of diagnostic investigations or
even disregard of the possibility of treating these individuals.
Certainly, chronic venous disorders have multifactorial caus-
Is lower-limb pain reduction a meaningful treatment outcome?
CONTROVERSIAL QUESTION
es that vary from one individual to another, but a significant
group of patients slowly evolve a vicious cycle fueled by the
inflammatory cascade that gradually promotes remodeling of
macro- and microcirculation, worsening the consequences
of stasis and venous hypertension.
We believe that venous pain is the first clinical evidence of this
inflammatory process. Therefore, the most effective way to
approach chronic venous disorders seems to be the early
identification and management of this inflammatory cascade.
Any patient with typical venous disease complaints associ-
ated with a prolonged orthostatic position such as itching,
burning or swelling should be investigated for chronic venous
disorders. Patients with typical venous pain should have a du-
plex scan study searching for venous truncal reflux, insuffi-
cient tributaries, and perforating veins in the lower limbs.
In addition, leg pain should be considered a therapeutic tar-
get for chronic venous disorder treatment and we believe that
the disappearance of pain should be a good and interesting
parameter to evaluate therapeutic success, as we recurrent-
ly see, for example, patients presenting with painful venous
ulcers that improve after a session of foam sclerotherapy or
saphenous thermal ablation procedure.
It is possible that in a few years we will understand more
about the natural history and evolution of chronic venous dis-
order patients. Meanwhile, it seems reasonable to use clin-
ical parameters such as pain as a therapeutic premise and
as a clinical reference of an ongoing inflammatory process
that may extend over a long period of time, if not treated.
References
1. Carpentier PH, Cornu-Thnard A, Uhl JF, Partsch H, Antignani PL. Appraisal of
the information content of the C classes of CEAP clinical classification of chronic
venous disorders: a multicenter evaluation of 872 patients. J Vasc Surg. 2003;
37(4):827-833.
2. Rabe E, Guex JJ, Puskas A, Scuderi A, Fernandez Quesada F. Epidemiology of
chronic venous disorders in geographically diverse populations: results from the
Vein Consult Program. Int Angiol. 2012;31(2):105-115.
3. Langer RD, Ho E, Denenberg, JO, Fronek A, Allison M, Criqui MH. Relationships
between symptoms and venous disease: the San Diego Population Study. Arch
Intern Med. 2005;165(12):1420-1424.
4. Ruckley CV, Evans CJ, Allan PL, Lee AJ, Fowkes FG. Telangiectasia in the Ed-
inburgh Vein Study: epidemiology and association with trunk varices and symp-
toms. Eur J Vasc Endovasc Surg. 2008;36(6):719-724.
5. Kaplan RM, Criqui MH, Denenberg JO, Bergan J, Fronek A. Quality of life in pa-
tients with chronic venous disease: San Diego population study. J Vasc Surg.
2003;37:1047-1053.
MEDICOGRAPHIA, Vol 37, No. 1, 2015 69
CONTROVERSIAL QUESTION
13. I. A. Zolotukhin, Russia
Igor A. ZOLOTUKHIN, MD, PhD
Department of Angiology
and Vascular Surgery
Pirogovs Russian National Research
Medical University
Moscow, RUSSIA
(e-mail: zoloto70@bk.ru)
T
his topic has been of interest to me for many years and
it is a great idea to raise it in discussion among spe-
cialists in venous diseases. In thinking about what is a
meaningful outcome in chronic venous disease (CVD), I pre-
fer not to refer to reflux at all, as reflux is not a disease, but only
a hemodynamic phenomenon that is quite often not correlat-
ed with the presence and severity of symptoms and signs.
So, the dynamic of symptoms and signs is my choice in es-
timating treatment efficacy. In my point of view, venous pain
is absolutely a meaningful outcome. It should be taken into
account in any case of CVD, regardless of whether or not the
patient has it at the time of consultation, because lack of pain
today does not mean lack of pain tomorrow. Wide accept-
ance of this symptom as a useful tool in clinical practice or
even in clinical trials faces many challenges.
The most important is the precise definition and description of
venous pain. Every patient with CVD that I see in clinic is asked
about symptoms; nearly four out of five are symptomatic. Most
patients with venous symptoms say that they have leg pain.
However, when asked in detail, they frequently say that this
symptom is not exactly pain. They describe it as a complex
sensation consisting of a mix of symptoms such as discom-
fort, heaviness, tiredness, etc. This is not only my observation,
but that of my colleagues too. Maybe the problem is discrep-
ancy in interpretation of the pain in different languages. If it is,
70 MEDICOGRAPHIA, Vol 37, No. 1, 2015
the commonly accepted definition of venous pain may need
validation in different countries, as by the example of quality
of life (QoL) questionnaires.
The next problem is the choice of patients for whom pain
would be a valuable outcome. Some, especially young pa-
tients with both venous pain and cosmetic complaints, look
above all for the disappearance of visible signs. For senior pa-
tients, cosmetic results are usually less meaningful and we
have to concentrate upon eliminating symptoms rather than
signs. Therefore, using the same main clinical outcome in dif-
ferent groups of patients seems to be really controversial.
Rarely, venous pain can be severe. On the one hand, this
helps in differential diagnosticsif a patient has severe lower-
limb pain we should suspect an alternative origin rather than
venous. As a result, we have to make further diagnostic steps
to exclude other pathology. On the other hand, if the pain is
really venous, it rarely exceeds 4 cm to 5 cm on a visual ana-
log scale (VAS) and the next question ariseshow can we
estimate a positive impact of our treatment with such a tool?
Of course, if pain completely disappears after treatment, the
result is undeniably positive. But if we only see the regression
of pain, what should be considered as a success? Is 2 cm
of pain significantly better than 3 cm on the VAS? Other as-
pects that are not usually taken into account are the frequen-
cy of pain and its duration. One patient may have 4 cm of pain
on a VAS, but it appears once or twice a week, while anoth-
er patient may have 2 cm of pain daily. In some patients, 4 cm
of pain starts after several hours of orthostasis, while others
experience such a pain only at the end of the day. Of course,
there are QoL instruments we now use, but they are not ve-
nous pain specific.
It seems that the development of a complex tool for the meas-
urement and estimation of venous pain would be of great val-
ue for both investigators and practitioners.
Is lower-limb pain reduction a meaningful treatment outcome?

Flavonoids are venoactive
drugs (VADs) of particular interest
in the treatment of chronic venous
disorders. Flavonoids were initially
described as vitamin P (for per-
meability) because their deficiency
causes capillary fragility and in-
creases vessel wall permeability.
Flavonoids are naturally occurring
polyphenolic compounds widely
found in nature, especially as plant
pigments.
Franoise PITSCH, Pharm D
Servier International
Suresnes, FRANCE
Address for correspondence:
Franoise Pitsch, Pharm D,
Servier International, 50 rue Carnot,
92284 Suresnes Cedex, France
(e-mail:
francoise.pitsch@fr.netgrs.com)
www.medicographia.com
Daflon 500 mg in guidelines Pitsch
DAFLON 500 MG
The place of Daflon 500 mg
in recent international
guidelines on the management
of symptomatic chronic
venous disorders
b y F. P i t s c h , Fra n c e
U
se of international guidelines for disease description and measure-
ment of treatment outcomes is the first step in the process of imple-
menting evidence-based care. The aim of this review article is to ad-
dress some of the new guidelines that include drug management of chronic
venous disorders. A review of the accepted definitions in the disease field, stan-
dardized nomenclature, patient presentation, severity of venous disease, and
validated outcome measures following therapy are presented. Also, the preva-
lence, burden, and pathophysiological underpinnings of chronic venous dis-
orders, and the classification of the most prescribed venoactive drugs are
broached in the present article. It appears that venous hypertension under-
lies all clinical manifestations of the disease. Inflammation is key in wall remod-
eling, valve failure, and subsequent venous hypertension, which is transmitted
to the microcirculation. This results in capillary alteration leading to edema,
skin changes, and eventually venous ulceration. Venous symptoms may be
the result of interplays between proinflammatory mediators and nerve fibers
located in the periphery of capillaries. Therefore, venous inflammation consti-
tutes a therapeutic target for pharmacological intervention, more particular-
ly for venoactive drugs. A discussion of recent guidelines that have evaluat-
ed the benefits of venoactive drugs (reviews, book chapters, and international
guidelines on the management of chronic venous disorders) follows. Based
on recent studies, reviews, and meta-analyses, a strong recommendation was
given to micronized purified flavonoid fraction (Daflon 500 mg). The conclu-
sion looks at what remains to be done in order to update guidelines on the
management of chronic venous disorders with venoactive drugs, with partic-
ular emphasis on the need for larger and more definitive clinical trials to im-
prove the existing recommendations.
Medicographia. 2015;37:71-79 (see French abstract on page 79)
Introduction
his article addresses some of the newer guidelines on venoactive drugs (VADs)
T in general, and Daflon 500 mg in particular, in the management of chronic
venous disorders, to help clinicians better manage patients with venous dis-
orders of the lower extremity.
Intentionally, only the primary disease will be tackled in this review, putting post-
thrombotic venous disease aside.
MEDICOGRAPHIA, Vol 37, No. 1, 2015 71
DAFLON 500 MG
A common language is needed before building
guidelines in chronic venous disorders
It should first be stressed that no consensus on guidelines is
possible without the use of a common language. A leap for-
ward was recently made thanks to: (i) a common terminolo-
gy on venous anatomy,1 the clinical, etiological, anatomical,
pathophysiological (CEAP) classification proposed by the ad
hoc committee of the American Venous Forum in 1994 and
revised in 2004,2 which was subsequently adopted worldwide
as a basis for improved patient description; and (ii) a consen-
sus on terminology related to chronic venous disorders to
avoid misunderstanding and lack of precision in publications.
The last consensus document (VEIN Term) provides the def-
inition of 33 widely used clinical venous terms and was pub-
lished in The Journal of Vascular Surgery, 2009, under the
aegis of the main American and European scientific societies
(American Venous Forum, American College of Phlebology,
European Venous Forum, Union Internationale de Phlbologie
[UIP; International Union of Phlebology], International Union
of Angiology, and Society for Vascular Surgery).3
The CEAP classification includes a clinical assessment (C), an
etiological assessment of the patients disease (E), an anatom-
ical assessment of location of the pathology (A), and the patho-
physiological basis for the underlying disease (P). It provides
a broad-based, objective, anatomic, and physiologic basis
for classification of venous disease. This is why CEAP has im-
proved standardization, communication, decision making, and
reporting of venous disease.
What does the term chronic venous disorders
cover?
The term chronic venous disorders covers a full spectrum
of venous conditions ranging from patients with symptoms
only (C0s of the CEAP classification) and telangiectasias to the
ultimate complications, venous ulcers. Symptoms are com-
monly associated with signs of chronic venous disorders. Ve-
nous symptoms are defined as tingling, aching, burning, pain,
muscle cramps, swelling, sensations of throbbing or heavi-
ness, itching skin, restless legs, leg tiredness and/or fatigue,
all of which may be exacerbated during the course of the
day or by heat, but relieved with leg rest, elevation, or both.3
Venous signs are visible manifestations of chronic venous
disorders, which include dilated veins (telangiectasias, retic-
ular veins, varicose veins), leg edema, skin changes, and ul-
cers, as described in the CEAP classification.2
SELECTED ABBREVIATIONS AND ACRONYMS
CEAP clinical, etiological, anatomical, pathophysiological
CVD chronic venous disease
UIP Union Internationale de Phlbologie (International
Union of Phlebology)
VAD venoactive drug
72 MEDICOGRAPHIA, Vol 37, No. 1, 2015
Chronic venous disorders include those patients with symp-
toms only, but presenting no signs at clinical examination or
ultrasound investigation (the so-called C0s patients), and those
with venous signs as described in the CEAP classification.
The latter may be either symptomatic or asymptomatic.
The burden of chronic venous disorders
Chronic venous disorders are common conditions in Western
countries that have a significant impact on affected individu-
als and the health care system. In the French survey by Car-
pentier et al,4 the percentage of symptomatic patients with
chronic venous disease (CVD) varied between 25% and 84%,
depending on the severity of the disease (the magnitude of
symptoms increased with severity). According to population-
based epidemiological studies in various countries, telangiec-
tasias and reticular veins are present in approximately 80% of
men and 85% of women, and varicose veins in 25% to 32%
of women and 7% to 40% of men. The prevalence of open
plus healed venous ulceration is estimated at approximately
1% of the population.5
In the recent Vein Consult Program initiated with the UIP, which
surveyed 91 545 subjects of 20 countries worldwide, the
prevalence of chronic venous disorders was 83.6%: 63.9%
of the subjects ranging from C1 to C6, and 19.7% being C0s
subjects. C0s patients were more frequently men, whatever
the age or geographical zone. C1 to C3 appeared to be more
frequent among women, whatever the country, but the rate
of severe stages (C4 to C6 ) did not differ between men and
women.6
The high prevalence of varicose veins and the chronicity of leg
ulcers mean that CVD has a considerable impact on health
care resources. It has been estimated that venous ulcers
cause the loss of approximately 2 million working days and
incur treatment costs of approximately $3 billion per year in
the United States. In European countries, medical care costs
associated with the disease have been estimated to account
for 1% to 3% of total annual health care budgets.7
CVD is associated with a reduced quality of life, particularly in
relation to pain, physical function, and mobility. It is also asso-
ciated with depression and social isolation. The impairment
associated with venous leg ulcers, the most severe manifes-
tation of CVD, has been likened to the impairment associat-
ed with stage II to III of heart failure.8
The main categories of venoactive drugs
VADs, also known as phlebotonic agents, are often used to
treat chronic venous disorders. Main classes of VADs include
coumarin, flavonoids, saponins, and synthetic products (cal-
cium dobesilate, benzaron, and naftazon). On the basis of
randomized controlled trials (RCTs) and meta-analyses, pre-
vious guidelines concluded that VADs should be used as an
adjunct treatment for symptomatic C0 to C6 chronic venous
Daflon 500 mg in guidelines Pitsch
 DAFLON 500 MG

disorders except in specific situations, such as hot climates,
where they may be used in place of compression.9 Flavonoids
are VADs of particular interest in the treatment of chronic ve-
nous disorders. Flavonoids were initially described as vita-
min P (for permeability) because their deficiency causes cap-
illary fragility and increases vessel wall permeability. Flavonoids
are naturally occurring polyphenolic compounds widely found
in nature, especially as plant pigments. Main classes include
flavones, flavonols, flavanes, flavanones, anthocyanadins,
isoflavonoids, and neoflavonoids. Flavonoid products used
for the treatment of chronic venous disorders include mi-
cronized purified flavonoid fraction (MPFF), oxerutin, and O-
(b-hydroxyethyl) rutosides (Table I).5,10
MPFF contains purified flavonoids, mostly hesperidin and dios-
min, from Rutaceae aurantiae (orange) micronized into 2 mm
particles to help improve intestinal absorption. Oxerutin and
O-(b-hydroxyethyl) rutosides are derived by hydroxyethyla-
tion of rutin, a naturally occurring glycoside of quercetin and
the disaccharide rutinose. Red vine leaf extract is a prepara-
tion made from the leaves of wine grape (Vitis vinifera) contain-
ing the flavonols quercetin glucoside, quercetin glucuronides,
and kaempferol glucoside. Pycnogenol is an extract of mar-
itime pine bark containing proanthocyanidins, which are poly-
mers of flavonoids.9
Pathophysiological mechanisms and pharmacological
treatment of chronic venous disorders
Valve and vein wall changes
Results from studies that demonstrate treatment efficacy lead
to guideline recommendations. Ambulatory venous hyperten-
sion is the hemodynamic disease that is related to all symp-
toms and signs of chronic venous disorders, the underlying
components of venous hypertension mainly being failure of
the calf muscle pump, venous valvular incompetence, and lu-
minal obstruction.11,12 Venous hypertension is the underlying
cause of chronic venous disorders and lies in the complex cel-
lular and molecular processes set in motion by abnormal ve-
nous hemodynamics. When venous pressures in the leg reach
higher-than-normal levels and remain elevated for prolonged
periods, a progressive increase in skin damage occurs. Nico-
laides reported that nearly all patients with exercising venous
pressures of >90 mm Hg experienced venous ulceration.13
Primary chronic venous disorders are the result of increased
and unabated venous hypertension caused mostly by reflux
through incompetent valves. To be efficient, any treatment
should prevent or decrease superficial valve incompetency in
order to counteract venous hypertension. It is only recently
that research interest has focused on the action of VADs on
chronic inflammatory processes that can affect large and small
venous vessels and valves of the superficial venous system.

Category Drug Effect on

Venous Venous wall Capillary Lymphatic Hemorheological Free radical

tone and valve leakage drainage disorders scavengers
Micronised purified + + + + + +
flavonoid fraction

Flavonoids (flavons, Nonmicronised or

flavonols, synthetic diosmins*
flavanons)
Rutin and rutosides, + + + + +
O-(b-hydroxyethyl)-
rutosides (troxerutin)

Anthocyans Vitis vinifera extracts*

Vitis vinifera extracts, + +

Proanthocyanidins
grape seed extracts

Coumarin Melilotus officinalis + + +

Horse chestnut seed + + +

extract; escin
Saponins
Ruscus extract + +

Other plant extracts Gingko extracts*

Calcium dobesilate + + + + +

Synthetic products Benzarone*

Naftazon*

Table I. Evidence-based modes of action of the main venoactive drugs.*No data available. Data from references 5 and 10.

Daflon 500 mg in guidelines Pitsch MEDICOGRAPHIA, Vol 37, No. 1, 2015 73

DAFLON 500 MG

Evidence has accumulated over the past years showing that
inflammation could be key in wall remodeling, valve failure, and
subsequent venous hypertension.11,14 Various types of inflam-
matory mediators and growth factors are released (Figure 1),
including vascular cell adhesion molecule 1 (VCAM-1), inter-
cellular adhesion molecule 1 (ICAM-1), transforming growth
factor b1 (TGF-b1), fibroblast growth factor b1 (FGF-b1), and
vascular endothelial growth factor (VEGF). The inflammatory
cascades in the vein wall and venous valves can cause pro-
gressive valvular incompetence and eventual valvular destruc-
tion.12 Once initiated, venous valve damage will be self-rein-
forcing, exacerbating venous hypertension and disturbance
of venous flow, and causing further inflammation. As a result,
reflux appears and may occur in the superficial or deep ve-
nous system or in both.

Venous wall Flavonoids are known to have potent antioxidant properties

Membrane adhesion, that have been investigated in several therapeutic areas oth-
molecule expression
(ICAM-1,
er than CVD, including cancer, arthritis, and cardiovascular dis-
E-selectin...) ease.15 More specifically, the VADs MPFF and rutosides have
Monocyte/lymphocyte shown powerful free-radical scavenging properties in various
rolling, adhesion assay systems,15 and VADs from other groups have also shown
migration

valv
e similar properties, including escins, proanthocyanidines from
ous
Pressure
Ven grape seeds and French maritime pine bark, and calcium
and shear stress, Macrophage dobesilate.5
induced gene
expression
(TNF, IL-1...) In addition to actions that reduce oxidative stress, several

VADs also act at various points in inflammatory cascades. As

Venous wall
Figure 1. Schematic illustration of key events that may lead to
valve damage in primary venous disorders.
Inflammatory gene expression in the endothelium may be induced by a shift in
venous hydrostatic pressure and fluid shear stress. This supports leukocyte
rolling, adhesion, and migration, together with free radical formation, apoptosis,
and tissue necrosis. In the process, macrophages become the instruments of
tissue damage.
Abbreviations: ICAM-1, intercellular adhesion molecule 1; IL, interleukin; TNF,
tumor necrosis factor.
After reference 12: Perrin M, Ramelet AA. Eur J Vasc Endovasc Surg. 2011;
41(1):117-125. 2010 European Society for Vascular Surgery. Published by
Elsevier Ltd. All rights reserved.
examples, grape seed proanthocyanidin reduced expression
of cell adhesion molecules by activated cultured vein endo-
thelial cells, and MPFF decreased expression of adhesion mol-
ecules by neutrophils and monocytes in patients with chron-
ic venous disorders.5
Capillary alteration
Venous hypertension increases hydrostatic pressure in capil-
laries resulting in transcapillary filtration that exceeds lymphat-
ic flow. This contributes to the formation of interstitial edema.
Venous hypertension alters blood flow in capillaries, prompt-
ing leucocyte adhesion to capillary endothelium and initiating
an inflammatory reaction.16 The capillary gaps would become
very large, greatly raising capillary permeability to fluid, macro-
molecules, and extravasated red blood cells, resulting in their
flow into the interstitial space and in edema formation (Fi-
gure 2).12

Fragmentation and destruction of lymphatic vessels may fur-

ther impair drainage from the extremity, whereas dysfunction
of local nerve fibers may alter regulatory mechanisms.11 Giv-
en their antioxidant and anti-inflammatory effects, it is not sur-
prising that many of the major VADs have been shown to re-
duce capillary hyperpermeability, including MPFF, rutosides,
escin, Ruscus extract, grape seed extract, and calcium dobe-
silate.5

Skin changes and venous ulceration

Figure 2. Mechanisms of occurrence of interstitial edema.
Venous hypertension is transmitted to the microcirculation and prompts leuko-
cyte adhesion to capillary endothelium. This initiates an inflammatory reaction
which dramatically increases capillary permeability. When transcapillary filtration
exceeds lymphatic flow, interstitial edema occurs.
Several mechanisms for the development of venous ulcera-
tion have been postulated, of which the theory of leucocyte
trapping is the most likely,17 although challenged today. It is
hypothesised that the primary injury to the skin (which is the
final target of chronic venous hypertension) is extravasation
of macromolecules, such as fibrinogen and a-macroglobulin,

74 MEDICOGRAPHIA, Vol 37, No. 1, 2015 Daflon 500 mg in guidelines Pitsch

 DAFLON 500 MG

and red blood cells into the dermal interstitium. Red blood
cell degradation products and extravasated interstitial pro-
tein are potent chemoattractants and presumably generate
the initial inflammatory signal, which results in leukocyte re-
cruitment and migration into the dermis. Pathologic events
occur during leucocyte migration into the dermis and the end
product of these is dermal fibrosis. A cascade of inflamma-
tory events results in cutaneous changes, which include skin
hyperpigmentation caused by hemosiderin deposition and
eczematous dermatitis. Fibrosis may develop in the dermis
and subcutaneous tissue (lipodermatosclerosis).
Interest in the mechanisms underlying skin changes has re-
ceived new impetus with the increasing recognition of the im-
portance of venous valves in small veins and venules. It is now
appreciated that small superficial veins of the human lower
limb contain abundant, typical bicuspid venous valves, with
the majority occurring in vessels less than 100 mm in diam-
eter and present in vessels as small as 18 mm. A recent study
has shown that incompetence can occur in human small su-
perficial venous valves independently of reflux within the great
saphenous vein and major tributaries. Importantly, degenera-
tive changes and incompetence in these microvenous valves

Pharmacodynamic effects Clinical consequences

MPFF Reduces the number of activated leukocytes in venous valves in an animal Struggles against superficial venous
preserves model of arteriovenous fistula (AVF). hypertension and might hamper disease
valves Maintains the valve diameter in an AVF model. progression.
structure Reduces reflux rate in an AVF model. Compared with control, improves post-
Prolongs the vasoconstrictor effect of noradrenaline (norepinephrine) on operative pain and quality of life of C2 pa-
the vessel wall, reduces gap between valve leaflets, and reduces blood ve- tients having undergone stripping surgery.
nous stasis in vitro.
Increases mechanical tension on bovine metacarpal vein rings in vitro.

As adjunctive treatment to compres-

MPFF Reduces diameter of capillary bulk and diameter of dermal papilla in non-
protects menopausal women compared with placebo, indicating a protective effect sion therapy, accelerates ulcer healing by
microcirculation of MPFF against the morphologic changes that occur in the capillaries and 32% and shortens time to healing by 5
an ability to prevent capillary leaks and edema. weeks in C6 patients.
Shows at least a 25% better decrease
Maintains the number of functional capillaries in nonmenopausal women.
Improves microvascular reactivity and functional capillary density after is-
of ankle edema compared with Ruscus
chemia/reperfusion in hamster cheek pouch. extract, hydroxyethylrutoside, or diosmin
Prevents capillary leakage in a significantly higher proportion than a single
in C3 patients.
Reduces edema by half a liter by lower
diosmin in hamster cheek pouch.
Decreases permeability more than any of its single constituents, showing
limb in C3 patients.
Reduces hematomas by 30% compared
that the flavonoids present in its formulation have a synergistic action in ham-
ster cheek pouch. with controls in C2 patients after stripping
Inhibits the increase in microvascular permeability induced by bradykinin
surgery.
or ischemia in rat cremaster muscle and histamine, bradykinin, leukotriene
B4 ischemia/reperfusion or oxidant challenge in hamster cheek pouch.

MPFF Increases contractility of sheep mesenteric lymphatic collecting ducts in

Significantly ameliorates skin hardness
increases vitro. and heaviness of upper limbs at 6 months
lymphatic Increases the frequency of spontaneous contractions in bovine mesenteric
of treatment in patients with lymphedema.
drainage lymphatics in vitro. Significantly decreases upper-limb cir-
Improves lymphatic drainage in sheep and dogs.
cumference at 6 months of treatment in
Decreases thigh weight, protein concentration in tissue, and fibroblast
patients with lymphedema.
number in rats with acute leg lymphostasis. Improves symptoms in patients with fi-
lariasis.

MPFF Decreases the expression of neutrophils CD11B, monocytes, and neu- Reduces visual analog scale scores of
has potent trophils CD62L in C2 to C6 patients. pain, heaviness, sensation of swelling,
venous anti- Inhibits intercellular adhesion molecule 1 (ICAM-1) expression in ischemia/ cramps, and paresthesia in C2 to C6
inflammatory reperfusion skeletal muscle injury in rats. patients.
effects Inhibits leukocyte adhesion and/or migration after ischemia/reperfusion Halves postoperative pain and signifi-
injury in hamster skin fold or rat skeletal muscle, oxidant challenge in hamster cantly reduces analgesic consumption
cheek pouch, and venular mesenteric occlusion/reperfusion in rats. in C2 patients.
Inhibits oxygenated free radical production in zymosan-stimulated human As adjunctive treatment to compression
neutrophils or mouse macrophages in vitro, and synthesis of prostaglandin therapy, reduces the pain associated with
E2 or F2 and thromboxane B2 in inflammatory granuloma in rats. venous ulcers by 30%.

Table II. Overview of the pharmacodynamics and clinical properties of micronized purified flavonoid fraction (MPFF).
Data from references 12, 15, 17, and 20.

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DAFLON 500 MG
can allow reflux into the microvenous networks in the skin,
which may be critical in the development of severe skin changes
in chronic venous disorders.18
The ability of VADs to reduce inflammation and oxidative stress
could protect small venous valves and prevent reflux, and also
act at the level of preventing the adverse remodeling of skin
tissue that ultimately may lead to the development of active
ulcers in chronic venous disorders.
Symptoms and the role of C nociceptors
Typical leg symptoms of chronic venous disorders are com-
mon in those with even the least severe forms (CEAP C0s and
C1). In a recent report from the Vein Consult Program, a large
cohort of over 90 000 consecutive outpatients from 20 coun-
tries, who were consulting their general practitioner for any
reason, were screened for chronic venous disorders. Of these,
19.7% had typical chronic venous disorder leg symptoms
without signs and were assigned to CEAP class C0s, and a
further 21.7% were assigned to class C1.6 The exact mech-
anisms by which chronic venous disorders, particularly the
earliest stages, give rise to pain and other typical venous
symptoms are not yet understood, but recent studies sug-
gest inflammation plays a key role.19,20 Sympathetic C fibers are
found in the venous intima and media, and wrapped around
cutaneous venules, and act as nociceptors that can respond
to inflammatory mediators.
Inflammatory processes seem to be involved in all stages and
severities of chronic venous disorders, even before obvious
tissue damage has occurred, and could be responsible for
many of the symptoms experienced. Thus, the anti-inflamma-
tory properties of VADs have the potential to improve symp-
toms in patients at all stages of the disease, including those
in CEAP class C0s.
Lymphatic drainage
Lymphatic function is known to be compromised in patients
with especially the more advanced stages of chronic venous
disorders, and has been shown to improve in patients with
varicose veins after reduction of venous reflux by saphenous
vein ablation.21 Several VADs, including alpha-benzopyrones
(coumarin) either alone or combined with rutin,22,23 MPFF,24 and
calcium dobesilate25 have all been shown to improve lymphat-
ic drainage in animal models.
Hemorheological disorders
Hemorheological changes, including increased blood viscosi-
ty and erythrocyte aggregation, are common in chronic venous
disorders. Several VADs have been shown to reduce blood
viscosity and/or erythrocyte aggregation, including MPFF,26
troxerutin27 and calcium dobesilate.28 The pharmacological ef-
fects of VADs are summarized in Table I.5,10 The mode of ac-
tion more specifically related to MPFF is described in Table II
(page 75).12,13,17,20
76 MEDICOGRAPHIA, Vol 37, No. 1, 2015
Based on the authors opinion
Grade of 1 = strong
depending on the balance
between desirable/undesirable
recommendation 2 = weak
effects, cost of treatment, and
patients preferences
A = high Depending on the method-
Quality of
B = medium ological quality of supporting
evidence
C = low evidence
Table III. GRADE: a new system to rate the strength of recom-
mendation.
Abbreviations: GRADE, Grading of Recommendations Assessment, Development,
and Evaluation.
Data from reference 29.
A new grading system for recommendations in
guidelines
The method of determining the strength and quality of the
recommendations in American guidelines deserves mention.
Recommendations are generally accompanied by a number,
which refers to the strength of the recommendation, and a
letter, which refers to the quality of the evidence supporting
the recommendation. Recent guidelines for venous disease
have used two levels for the strength of their recommenda-
tions depending mainly on the benefit/risk ratio: grade 1 for
strong and grade 2 for weak. They further indicate that state-
ments accompanied by a grade 1 level are recommenda-
tions and statements accompanied by a grade 2 level are
suggestions (Table III).29
The quality of evidence upon which the strength of the rec-
ommendation is based ranges from A for high quality, which
is consistent evidence from randomized trials, to B for mod-
erate quality, which is evidence from nonrandomized trials or
inconsistent evidence from randomized trials. Level C is low
quality, which is suggestive evidence from nonrandomized
trials, observational reports, or expert opinion. Writing com-
mittees are increasingly aware of the cost of care and patient
values and preferences, as are physicians. These are also con-
sidered in the strength of recommendation.
The recent guidelines on the management of
chronic venous disorders
Recent reviews and guidelines on chronic venous disorders
have used the Grading of Recommendations Assessment,
Development, and Evaluation (GRADE) system (Figure 3):
The article by Perrin et al published in The European Jour-
nal of Vascular and Endovascular Surgery, 2011, which re-
views the evidence for pharmacological therapies of primary
chronic venous disorders together with the rationale for such
treatment and the questions that remain unanswered.12
The latest (second) edition of The Vein Book edited by Ber-
gan and Bunke, which covers the entire spectrum of venous
conditions from clarification of the pathophysiology of chron-
ic venous disorders, molecular mechanisms in the cause of
Daflon 500 mg in guidelines Pitsch
 DAFLON 500 MG

Details Readership Reference

Educational article. Phlebologists, vascular Reference 12

surgeons.

Bridges the gap between clinical medicine and basic Phlebologists, vascular surgeons, Reference 30
science, suitable both for the seasoned surgeon as well general practice physicians, nurse
as the medical student. practitioners, and medical students
interested in phlebology.

Management of patients with chronic venous disorders has Phlebologists, vascular surgeons, Reference 10
been rapidly evolving from open surgery to endovascular general practice physicians, nurse
techniques and the rise of hybrid procedures in the most practitioners, and medical students
complex forms, prompting updated guidelines and recom- interested in phlebology.
mendations.
Under the auspices of the European Venous Forum (EVF),
the International Union of Angiology (IUA), the Union
Internationale de Phlbologie (UIP; International Union of
Phlebology), and the Cardiovascular Disease Educational
and Research Trust (CDIRT).

Figure 3. Reviews and guidelines on the management of primary chronic venous disorders that have used the Grading of Recommen-
dations Assessment, Development, and Evaluation (GRADE) system.
Data from references 10, 12, and 30.

varicose veins, new treatment options for varicose veins and
spider veins, startling new treatment for venous thromboem-
bolic disease, and effective treatment for leg ulcers.30
The updated recommendations on the management of
chronic venous disorders, results of a consensus conference
inititiated by the European Venous Forum (EVF) and held in
2012 in Cyprus with renown experts. The consensus docu-
ment was published under the auspices of the EVF, the Inter-
national Union of Angiology (IUA), the UIP; and the Cardio-
vascular Disease Educational and Research Trust (CDIRT).10
In summary and based on the quality of evidence, the authors
found it possible to propose a strong recommendation, based
on evidence of moderate quality (1B), for the use of MPFF in
symptoms and edema. Rutosides, horse chestnut seed ex-
tract, and Ruscus extracts have also proven effective against
CVD-related symptoms and lower limb edema, although the
volume and quality of evidence is less than for the previous
drug.
Calcium dobesilate has been associated with a potential safe-
ty concern relating to rare cases of agranulocytosis. Authors of
guidelines have considered that it is only possible to give a
weak recommendation for its use, given the uncertainty over
the balance between benefits and harms (2B). There is ev-
idence from a meta-analysis of RCTs that MPFF is effective
in the healing of venous ulcers. In the absence of important
safety concerns, its use in this indication can be given a strong
recommendation for its use in combination with compression
in long-standing or large venous ulcers of primary etiology (1B;
Table IV, page 78).10
Updating guidelines on chronic venous disorders
An update of the Guidelines for Testing Drugs for Chronic Ve-
nous Insufficiency is needed to allow the pharmaceutical in-
dustry investing the necessary resources to perform large and
definitive clinical trials that could improve the recommenda-
tions, which are useful for clinicians and organizations involved
in decision making in this important field of chronic venous
disorders. Such guidelines could:
Reiterate the basic principles that should prevail when re-
porting from (and setting up) any RCT, using the Consolidat-
ed Standards of Reporting Trials (CONSORT) statement,31 as
for meta-analyses with the QUORUM checklist.32
Comprehensively describe patients at selection in a study,

Daflon 500 mg in guidelines Pitsch MEDICOGRAPHIA, Vol 37, No. 1, 2015 77

DAFLON 500 MG

Recommen- Quality of
Indication VAD dation for use evidence Code

Micronized purified flavonoid fraction Strong Moderate 1B

Nonmicronized diosmins or synthetic diosmins Weak Poor 2C
O-(b-hydroxyethyl) rutosides Weak Moderate 2B
Relief of symptoms associated
Red vine leaf extracts (Vitis vinifera) Weak Moderate 2B
with chronic venous disorders in
patients in CEAP classes C0s to Calcium dobesilate Weak Moderate 2B
C6s and those with CVD-related
Horse chestnut seed extract Weak Moderate 2B
edema (CEAP class C3).
Ruscus extracts Weak Moderate 2B
Gingko biloba Weak Poor 2C
Other venoactive drugs Weak Poor 2C

Healing of primary venous ulcer Micronized purified flavonoid fraction Strong Moderate 1B
(CEAP class C6), as an adjunct to
compressive and local therapy.

Table IV. Summary of the updated recommendations for the use of venoactive drugs, according to the GRADE system.
Abbreviations: CEAP, clinical, etiological, anatomical, and pathophysiological classification; GRADE, Grading of Recommendations Assessment, Development and
Evaluation.
Data from reference 10.

using the advanced CEAP classification,2 which implies that
all classes of the CEAP must be completed, and that duplex
scan investigation, with or without plethysmography (level 2
investigation) is mandatory.
Include larger sample sizes (>200 patients in each group),
having in mind the high incidence of the placebo effect.12 For
instance, the most recent studies on VADs included only be-
tween 30 and 125 patients in each group.9
Promote the use of validated tools to assess symptoms,
edema, and venous leg ulcers, and have a consensus on end
points.33
Encourage the adoption of a simple and universally under-
stood system of grading.29
Perform long-term studies in order to examine the preven-
tion of chronic venous disorder progression and assess the
cost-effectiveness of VADs.9

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view of its use in chronic venous insufficiency, venous ulcers and haemorrhoids.
Drugs. 2003;63:71-100.
16. Boisseau MR. Leukocyte involvement in the signs and symptoms of chronic ve-
nous disease. Perspectives for therapy. Clin Hemorrheol Microcirc. 2007;37:
277-290.
17. Saharay M, Shields DA, Porter JB, Scurr JH, Coleridge-Smith PD. Leukocyte
activity in the microcirculation of the leg in patients with chronic venous dis-
ease. J Vasc Surg. 1997;26:265-273.
18. 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.
19. Danziger N. Pathophysiology of pain in venous disease [in French]. J Mal Vasc.
2007;32:1-7.
20. Vital A, Carles D, Serise JM, Boisseau MR. Evidence for unmyelinated C fibres
and inflammatory cells in human varicose saphenous vein. Int J Angiol. 2010;
19:e73-e77.
21. Suzuki M, Unno N, Yamamoto N, et al. Impaired lymphatic function recovered
after great saphenous vein stripping in patients with varicose vein: venody-

78 MEDICOGRAPHIA, Vol 37, No. 1, 2015 Daflon 500 mg in guidelines Pitsch

 DAFLON 500 MG

namic and lymphodynamic results. J Vasc Surg. 2009;50:1085-1091.
22. Casley Smith JR. Modern treatment of lymphedema. II. The benzopyrones. Aus-
tralas J Dermatol. 1992;33:69-74.
23. Casley Smith JR, Morgan RG, Piller NB. Treatment of lymphedema of the arms
and legs with 5,6 benzo [alpha] pyrone. N Engl J Med. 1993;329:1158-1163.
24. Labrid C. A lymphatic function of Daflon 500 mg. Int Angiol. 1995;14(3 sup-
pl 1):36-38.
25. Piller NB. The lymphagogue action of calcium dobesilate on the flow of lymph
from the thoracic duct of anesthetized and mobile guinea pigs. Lymphology.
1988;21:124-127.
26. Le Dvhat C, Khodabandehlou T, Vimeux M, Kempf C. Evaluation of haemorhe-
ological and microcirculatory disturbances in chronic venous insufficiency: ac-
tivity of Daflon 500 mg. Int J Microcirc Clin Exp. 1997;17 suppl 1:27-33.
27. Boisseau MR, Taccoen A, Garreau C, Vergnes C, Roudaut MF, Garreau-Gomez B.
Fibrinolysis and hemorheology in chronic venous insufficiency: a double blind
study of troxerutin efficiency. J Cardiovasc Surg (Torino). 1995;36:369-374.
28. Benarroch IS, Brodsky M, Rubinstein A, Viggiano C, Salama EA. Treatment of
blood hyperviscosity with calcium dobesilate in patients with diabetic retinopa-
thy. Ophthalmic Res. 1985;17:131-138.
29. Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommen-
dations and quality of evidence in clinical guidelines: report from an American
college of chest physicians task force. Chest. 2006;129;174-181.
30. Perrin M, Ramelet AA. Efficacy of venoactive drugs in primary chronic venous
disease. Survey of evidence, synthesis and recommendations. In: Bergan JJ,
Bunke N, eds. The Vein Book. 2nd ed. New York, NY: Oxford University Press;
2014:514-527.
31. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 Explanation and
Elaboration: updated guidelines for reporting parallel group randomized trials.
BMJ. 2010;340:869.
32. Clarke M. The QUORUM statement. Lancet. 2000;355:756-757.
33. Vasquez MA, Munschauer CE. Venous Clinical Severity Score and quality-of-life
assessment tools: application to vein practice. Phlebology. 2008;23:259-275.

Keywords: chronic venous disease; chronic venous disorder; edema; guideline; management; micronized purified flavonoid
fraction; recommendation; symptom; venoactive drug

PLACE DE DAFLON 500 MG DANS LES RECOMMANDATIONS INTERNATIONALES RCENTES

POUR LA PRISE EN CHARGE DE LA MALADIE VEINEUSE CHRONIQUE SYMPTOMATIQUE
La premire tape dans la mise en uvre de la mdecine base sur les preuves passe par lutilisation des recomman-
dations internationales dont le but est d'valuer les rsultats des diffrentes options thrapeutiques. Le prsent ar-
ticle traite des dernires recommandations relatives du traitement de la maladie veineuse chronique. Nous prsen-
tons ici les dfinitions acceptes dans le domaine de la maladie, la nomenclature standardise, le tableau clinique
du patient, la svrit de la maladie veineuse et les mesures valides de rsultats aprs traitement. Larticle aborde
aussi la prvalence et le cot de la maladie veineuse chronique, ses fondements physiopathologiques et la classifi-
cation des phlbotropes les plus prescrits. Lhypertension veineuse apparait tre la base de toutes les manifesta-
tions cliniques de la maladie. Linflammation joue un rle cl dans le remodelage parital, linsuffisance valvulaire et
lhypertension veineuse qui en rsulte et qui est transmise la microcirculation. Les modifications capillaires qui sen-
suivent entranent un dme, des modifications cutanes et enfin lapparition d'ulcres veineux. Les interactions
entre mdiateurs pro-inflammatoires et fibres nerveuses de la priphrie des capillaires pourraient tre lorigine
des symptmes veineux. Linflammation veineuse est donc une cible thrapeutique, tout particulirement en ce qui
concerne les phlbotropes. Les recommandations rcentes ayant valu le bnfice des phlbotropes (mises au
point, chapitres de livre et recommandations internationales sur la prise en charge des troubles veineux chroniques)
sont analyses. Il ressort des tudes rcentes, des mises au point et des mtaanalyses que le mdicament consti-
tu de la fraction flavonoque purifie micronise (Daflon 500 mg) est celui qui a obtenu la plus forte recommandation.
Larticle conclut sur ce quil reste faire afin dactualiser les recommandations sur la prise en charge des troubles
veineux chroniques par les phlbotropes, en insistant sur la ncessit dtudes cliniques plus importantes et prcises
pour amliorer les recommandations existantes.

Daflon 500 mg in guidelines Pitsch MEDICOGRAPHIA, Vol 37, No. 1, 2015 79


In chronic venous disorders,
the sensation of heat is one of the
many complaints expressed by
symptomatic patients. Such a sen-
sation is not related to any noci-
ceptive stimuli. Current hypothe-
ses 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 media-
tors released by activated leuko-
cytes are strong stimulators of C
nociceptors and partly explain why
chronic venous disorders can be
painful at all disease stages.
Marzia LUGLI, MD
Department of Cardiovascular
Surgery, Hesperia Hospital
Modena, ITALY
Address for correspondence:
Dr Marzia Lugli, Vascular Surgery,
Department of Cardiovascular
Surgery, Hesperia Hospital,
Via Arqu 80/A 41125, Modena, Italy
(e-mail:
lugli@chirurgiavascolaremodena.it)
www.medicographia.com
80 MEDICOGRAPHIA, Vol 37, No. 1, 2015
INTERVIEW
Are we any closer
to identifying the origin
of leg pain?
Interview with M. Lugli, Italy
A
dvances in research have drawn attention to the role of chronic inflam-
matory 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. How-
ever, some researchers have recently demonstrated that incompetence of the
smaller valves located in the third to sixth generation of tributaries can be in-
volved 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 symp-
toms 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?
enous pain is a very common complaint in chronic venous disorders and its
V 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, heavi-
ness, and tingling, etc. Venous pain is diffuse, not localized, and more similar to vis-
ceral 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 de-
fine, identify, locate, and quantify. Moreover, the intensity of venous pain is not re-
lated 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 syn-
drome 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-
Are we any closer to identifying the origin of leg pain? Lugli

ies have shown that the presence and the intensity of pain
likely to be related to chronic venous insufficiency are not cor-
related with the clinical assessment of disease severity. The
Edinburgh Vein Study has shown that approximately 40% of
asymptomatic patients presented with varicose veins, where-
as 45% of patients complaining of pain compatible with chron-
ic 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?
eg pain is associated with all stages of chronic venous
L disorders, and has the tendency to increase with sever-
ity of disease. However, correlation between pain inten-
sity and severity of venous signs is weak, as is correlation be-
tween 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 re-
flux 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 dis-
tortion. 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 ve-
nous hypertension.
Changes in the hemodynamics of large veins and venous hy-
pertension are transmitted into the microcirculatory level, in-
creasing permeability and leading to the accumulation of fluid,
macromolecules, and extravasated red blood cells into the
interstitial space. This pathological process results in the pro-
SELECTED ABBREVIATIONS AND ACRONYMS
CEAP clinical, etiological, anatomical, pathophysiological
GSV great saphenous vein
MVV microscopic venous valve
Are we any closer to identifying the origin of leg pain? Lugli
INTERVIEW
duction 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 signif-
icant source of pain in normal subjects. This statement is con-
firmed 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 block-
ade 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 el-
ements 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. Cur-
rent hypotheses on pain mechanisms in chronic venous dis-
orders 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 stimu-
lators 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 ve-
nous wall. The starting point for these mechanisms is prob-
ably the local hypoxia associated with capillary stasis. A sig-
nificant 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 demon-
strated that hypoxia induced by capillary stasis has the ef-
fect of activating endothelial cells.6
The evidence for an inflammatory reaction playing such a main
role in patients with varicose veins has increased dramati-
cally over recent years, and the biochemical changes iden-
tified 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 functionassociated antigen 1 [LFA-1], very late
MEDICOGRAPHIA, Vol 37, No. 1, 2015 81
INTERVIEW
antigen 4 [VLA-4], endothelium leukocyte adhesion mole-
cule 1 [ELAM-1], intercellular adhesion molecule 1 [ICAM-1],
vascular cell adhesion protein 1 [VCAM-1]), and the synthe-
sis of cytokines (interleukin 1b [IL-1b], IL-6, tumor necrosis
factor a [TNFa]) 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?
he fact that venous pain is not closely correlated with
T the presence of varicose veins or axial reflux/obstruc-
tion 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 leak-
ages and is painful due to the pressure it exerts on nerve end-
ings.
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 ve-
nous valves, with the majority occurring in vessels less than
100 mm in diameter and present in vessels as small as 18 mm.7
Such microscopic valves have also been described in human
skin. Their role was believed to resist and prevent blood re-
flux in small-sized veins, from postcapillary venules to the cap-
illary bed.
A recent study by Vincent et al has confirmed the existence
of these microscopic venous valves (MVVs) in the small su-
perficial 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 trib-
utaries. Reflux in MVVs was associated with tortuosity and
distension of varicosities in the skin with a normally function-
ing 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 cap-
illary 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 gener-
ation of tributaries. The authors speculated that skin degen-
erative changes are worse when refluxes in MVVs from the
82 MEDICOGRAPHIA, Vol 37, No. 1, 2015
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 pop-
ulation of the Vein Consult Program, 19.7% of screened in-
dividuals 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 responsi-
ble 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?
nstrumental investigation of any early chronic venous disor-
I der patients, including C0s subjects, usually performed by
duplex ultrasound, often proves negative. In the larger num-
ber of cases reflux is not detected, neither in the saphenous
veins nor its tributaries. In fact, investigations of pathophys-
iology 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 de-
tect 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 mi-
crocirculation and its alterations over the course of progres-
sion of chronic venous disorders. In my knowledge, none of
the current assessment tools have been used with the pur-
pose of finding relationships between the presence of ve-
nous symptoms and alterations in the microcirculation.
Regarding the assessment of the microcirculation, the follow-
ing investigations may be applied:
Videocapillaroscopy: to visualize capillaries in different cu-
taneous 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 (m).
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.
Are we any closer to identifying the origin of leg pain? Lugli

The assessment of reflux in large veins and first generation
of tributaries, usually performed by duplex ultrasound exam-
ination, can be integrated by adjunctive ultrasound investi-
gations:
B-flow ultrasound: the evaluation of tributaries until the lim-
it of detection of a superficial probe (7.5 to 10 MHz). Explo-
ration can be performed on the whole lower extremity,
Continuous-wave Doppler: with a flat probe applied on vis-
ible tributaries to identify flow direction. Continuous-wave Dop-
pler is able to detect small sites of reflux often missed by du-
plex ultrasound.
What would be an ideal investigation procedure
to assess leg pain in symptomatic patients?
urrent methods to assess the microcirculation are not
C 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 suf-
fering from chronic venous disorders. The CytoScan has a
small handheld probe which can be noninvasively applied to
all body surfaces. Chronic venous disorders were previous-
ly studied using the orthogonal polarization spectral tech-
nique. Five microcirculatory parameters were correlated with
CEAP classification (C0 to C5). Moderate microangiopathy was
found among all CEAP classes, and microcirculatory alter-
ations were not assessable before CEAP class C2. No micro-
angiopathy could be found in C0.9
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 coordina-
tors. Epidemiology of chronic venous disorders in geographically diverse popu-
lations: results from the Vein Consult Program. Int Angiol. 2012;31(2):105-115.
3. Perrin M, Ramelet AA. Pharmacological treatment of primary chronic venous dis-
ease: 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 ther-
Keywords: chronic venous disorder; leg pain; microvalve; reflux; vein incompetence; venous disease; venous valve
Are we any closer to identifying the origin of leg pain? Lugli
INTERVIEW
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 indi-
viduals 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 there-
by explain why pain is neither correlated with clinical signs of
venous disease nor with reflux. It may be that valve incompe-
tence occurs in small superficial veins in the absence of re-
flux 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, con-
firming 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 re-
lief. Further explorations using drug therapy could be per-
formed 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 bet-
ter understand the role and/or limitations of available treat-
ments for venous disease.
mal 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.
MEDICOGRAPHIA, Vol 37, No. 1, 2015 83
INTERVIEW

SOMMES-NOUS PLUS PROCHES DE LIDENTIFICATION

DE L ORIGINE DE LA DOULEUR DES JAMBES ?
Les avances de la recherche ont attir lattention sur le rle des processus chroniques inflammatoires affectant les
valvules et les parois des veines de toute taille et aussi de la peau, entranant le dveloppement de varices et dune
insuffisance veineuse chronique. La recherche rcente a soulign galement le rle de linflammation dans la sur-
venue de la douleur veineuse, la prsence de nocicepteurs stimuls par des mdiateurs inflammatoires compltant
le tableau. Les tudes sur la physiopathologie de la maladie veineuse chronique ne se sont intresses qu la conti-
nence des valvules macroscopiques des grosses veines. Des chercheurs ont nanmoins montr rcemment que lin-
continence des valvules plus petites, situes au niveau des collatrales de 3e 6e gnration, serait implique dans
la survenue de la maladie veineuse chronique. Lincontinence des petites veines nest pas ncessairement associe
une incontinence valvulaire des troncs veineux principaux, ce qui explique lapparition possible de symptmes vei-
neux chez des patients non variqueux ou sans reflux axial. De plus, il est bien connu que symptmes veineux et dou-
leur de jambes sont plus ou moins corrls aux modifications des principaux troncs veineux. On peut donc suppo-
ser que ces symptmes proviennent en fait de lincontinence des veines plus petites et des capillaires.

84 MEDICOGRAPHIA, Vol 37, No. 1, 2015 Are we any closer to identifying the origin of leg pain? Lugli

Under the Vein Consult Pro-
gram (VCP), a Serbian group of
authors showed that the average
number of births was significantly
higher in women in classes C2 to
C3 and C4 to C6 in comparison with
those without the disease. The
higher number of births was a risk
factor for chronic venous disease
(CVD), independent of other ob-
served factors, including age.
Menopause was also independ-
ently related to all clinical classes,
especially C4 to C6.
1 Djordje J. RADAK, MD, PhD
2 Vuk A. SOTIROVIC, MD
1,2 Vascular
surgery Clinic
Dedinje Cardiovascular
Institute, Belgrade, SERBIA
1 School of Medicine
University of Belgrade
SERBIA
Address for correspondence:
Professor Djordje Radak,
Vascular Surgery Clinic,
Dedinje Cardiovascular Institute,
Heroja Milana Tepica 1 Street,
11000 Belgrade, Serbia
(e-mail: radak@ikvbd.com)
www.medicographia.com
Risk factors for symptomatic chronic venous disorders Radak and Sotirovic
FOCUS
Risk factors for symptomatic
chronic venous disorders:
results from the international
Vein Consult Program
b y D . J . R a d a k a n d V. A . S ot i rov i c , S e r b i a
V
enous symptoms are very frequently mentioned during general prac-
titioner or vascular surgeon consultations. Even so, the amount of re-
search conducted on venous sensations is inversely proportional to the
frequency of reported symptoms. Today, there is a lack of epidemiological
studies concerning this issue. The Vein Consult Program (VCP) was started with
a clear mission, with the aim to raise awareness and to deal with a chronic dis-
ease that has reached almost pandemic proportion chronic venous disease
(CVD). The most worrying finding of the VCP is that the majority of subjects
with or without any clinical signs of CVD have symptoms that significantly
affect their daily activities and deteriorate quality of life. Several factors have
been proposed as risk factors for the development of symptomatic CVD: age,
body mass index, sex, family history of CVD, history of previous venous throm-
boembolism, hours spent standing, smoking, and lack of daily exercise. Also,
aside from traditional risk factors, several comorbidities such as high blood
pressure, diabetes mellitus, heart failure, and chronic obstructive pulmonary
disease could have an influence on the development and progression of the
symptoms in patients with CVD. Most of these risk factors cannot be changed,
but a significant number of them could easily be modified. In this article, we
present the latest facts related to venous-related symptoms and risk factors
for the development of such symptoms, based on the results of the VCP.
Medicographia. 2015;35:85-91 (see French abstract on page 91)
eg pain, heaviness, and swelling are symptoms that are very frequently men-
L tioned during general practitioner (GP) or vascular surgeon consultations.1 Even
so, the amount of research conducted on venous sensations is inversely pro-
portional to the frequency of reported symptoms. The risk factors connected to the
development of venous symptoms are still a real mystery. A lack of epidemiologi-
cal studies is frustrating and adds to the unease in the community regarding venous
leg symptoms.
The Vein Consult Program (VCP) is a large international observational prospective
survey investigating chronic venous disease (CVD) in twenty countries, developed
under the auspices of the Union Internationale de Phlbologie (UIP; International
Union of Phlebology). The VCP includes the clinical files of approximately 100 000
subjects, who consulted their GP between October 2009 and July 2011. The VCP
results have helped in resolving many crucial issues and also in initiating further re-
search in the field of CVD.
MEDICOGRAPHIA, Vol 37, No. 1, 2015 85
FOCUS
In this article, we present the latest facts related to venous-
related symptoms and risk factors for the development of such
symptoms, based on the results of the VCP.
The prevalence of CVD and lower-limb symptoms
before the VCP
As there is not yet an established relationship between symp-
toms and signs of CVD, opinions diverge, with some believ-
ing that symptoms such as venous pain, cramps, etc, simply
do not exist, while others believe that all these symptoms
should be treated.
The first step in determining the prevalence of lower-limb
symptoms related to CVD should be to exclude all patients
with symptoms of nonvenous origin. This approach is more
than complex, especially in the group of patients without clear
signs of CVD, or in patients with early stages of visible dis-
ease.
Before the first results of the VCP, the prevalence rate of CVD
and venous-related leg symptoms was based mainly on cross-
sectional epidemiological studies, which were limited to one
region or a single country.2-10 Most of the studies have inhomo-
geneous prevalence rates, due to the different classification
systems used. Today, epidemiological surveys have adopted
the universal clinical, etiological, anatomical, pathophysiolog-
ical (CEAP) classification,10-11 whose purpose is to achieve a
better definition of each disease stage. In addition, by using
this classification system it is much easier to assess the re-
spective frequency of each disease stage. The international
character of the CEAP classification allows precise compar-
isons between countries and between continents.
However, through our daily practice we observed a large num-
ber of limiting factors in the current classification systems. The
CEAP classification does not include any assessment of the
level of the pain, with the classes only categorized as symp-
tomatic or asymptomatic. Due to that, symptoms and their
levels are often underestimated by physicians. These limita-
tions require additional questionnaires to incorporate levels
of symptoms and their change during the time period. In ad-
dition, very few epidemiological studies have actually taken
venous symptoms into account.
Both the Italian 24-cities cohort study6 and the Bonn Vein
Study12 found that patients very frequently reported some ve-
nous symptoms (approximately 56% of subjects). However,
both studies marked one very worrying finding: the vast ma-
jority of subjects with leg symptoms could not be given a
medical explanation for their condition (up to 80% in the 24-
cities cohort study population). Together, these and results of
other studies emphasized a very complex issue of the origin
of venous-type leg symptoms, especially in patients without
any other clinical signs of CVD (C0s) or venous reflux/obstruc-
tion.6,7,13
86 MEDICOGRAPHIA, Vol 37, No. 1, 2015 Risk factors for symptomatic chronic venous disorders Radak and Sotirovic
The VCP was organized within the framework of ordinary con-
sultations, with GPs properly trained in the use of the CEAP
classification. First results show that CVD affects a significant
part of the population worldwide, highlighting the importance
of adequate screening for CVD, and training of both GPs and
specialist physicians. The VCP revealed some key facts, as
presented in the following text.
Better identification of subjects who are more
likely to present with one or several venous leg
symptoms
CVD could be associated with a whole range of symptoms
such as pain, heaviness, restless legs, tingling, aching, burn-
ing, night muscle cramps, swelling, sensations of throbbing
or itching skin, leg tiredness, and/or fatigue (Table I).1,14 In ad-
dition, these symptoms could be a part of other nonvenous
chronic and acute conditions, such as obesity, neurological
disease, a standing or sitting profession, or arterial occlusive
disease.15
Results of the VCP show that venous pain could be found
in approximately 70% of adults, where heaviness and pain
were the most frequent symptoms, mostly affecting women.
Once there are visible signs of CVD (C1 class or higher), asso-
ciated symptoms can be more easily assigned to a venous
cause. The risk of developing symptoms increased signifi-
cantly with disease severity. Individuals with chronic venous
insufficiency, C3 to C6, were 16-fold more likely to be symp-
tomatic than individuals in class C0.14
It is rational to believe that symptoms of CVD will correlate
with Doppler ultrasound findings. However, Chiesa et al6 re-
ported that the occurrence of venous symptoms is independ-
ent of venous reflux, but also that symptoms correlated pos-
itively in both sexes with the CEAP grade, with the exception
of pain (no significant correlation was observed in men). Still,
a Serbian group of authors16 found a significant presence of
both reflux and obstruction in VCP patients in classes C0s to
C1. These findings could justify recommendations for color
duplex ultrasound in all patients with symptoms of CVD, re-
gardless of clinical signs.
Patients with no visible sign of disease, but who are report-
ing venous-like symptoms, represent a real nightmare for
both GPs and vascular surgeons.1,11,17 Identification of C0s pa-
tients could be crucial from a diagnostic and therapeutic point
of view and deserves special attention. Revision of the CEAP
SELECTED ABBREVIATIONS AND ACRONYMS
CEAP clinical, etiological, anatomical, pathophysiological
CVD chronic venous disease
QoL quality of life
VCP Vein Consult Program
 FOCUS

Identification of risk factors that

Total C0s C1 to C3 C4 to C6 influence the appearance of
CEAP class n=77505 n=15290 n=41838 n=7421 symptoms
Risk factors connected to symptomatic CVD
Mean number
of symptoms
2.31.5 3.41.7 4.71.8 are important, from a therapeutic and prognos-
tic point of view. Some risk factors can easily
% Symptomatic be modified in order to slow the development
80.4 100 94.7 96.8
patients
and progression of CVD.
Heavy legs 72.4 58.1 75.0 81.1

Pain in the legs 67.7 52.8 68.3 81.1 The VCP is the first international program that
has involved a large and varied range of coun-
Sensation of swelling 52.7 29.3 56.9 75.3
tries and geographical zones. In total, 91 545
Night cramps 44.3 32.6 43.4 59.6 subjects were involved; 36 004 from Western
Sensation of pins and Europe; 32 225 from Central and Eastern Eu-
37.0 27.4 36.6 50.3
needles in legs rope; 12 686 from Latin America; 3518 from
Sensation of burning 29.0 15.8 29.6 52.3 the Middle East; and 7112 from the Far East
(Table II).13
Itching 23.6 15.3 22.3 42.5

The results of the VCP show that CVD is a glob-

Table I. Distribution of the prevalence of chronic venous disease (CVD) symptoms al phenomenon not solely limited to Western
according to clinical, etiological, anatomical, pathophysiological (CEAP) class.
After reference 14: Phlebolymphology. 2013;20(3):138. 2013, Les Laboratoires Servier.
countries, as is often believed.20,21 The preva-
lence of symptoms in the VCP is high in all ge-
classification brought to the professional public a new pro- ographical areas studied. Moreover, the distribution of symp-
file of patients; those in the C0s class.11 For the first time, the tom prevalence (by decreasing frequency: heavy legs, pain,
results of the VCP13 show a global prevalence of C0s pa- sensation of swelling, night cramps, etc) was similar, whatev-
tients. Approximately 20% of patients with CVD are in the C0s er the area considered. Heaviness and leg pain were found in
class. Also, within the new results from the VCP we expect up to 72% and 68% of VCP participants, respectively. Symp-
a detailed clinical profile of patients in the C0s class, including toms, such as the sensation of swelling, show the greatest
information on the quality of life (QoL) of C0s patients, risk fac- increase between C0s and C4 to C6, and this suggests that
tors, etc. the perception of pain is similar in all studied countries and is
likely to be disconnected from any cultural phenomenon.13
The question still remains: if there is no clinical evidence and Furthermore, the VCP shows that the classification system
functional sign of CVD, do the subjective symptoms have an of CVD is applicable worldwide and this classification allows
objective origin, and if so, are we able to find and treat this the generation and design of a whole battery of new ques-
origin? Several hypotheses have been proposed. Vincent at tionnaires, for better identification of patients and for symp-
al18 analyzed valvular competence in amputated legs with- tom measurement.
out signs of CVD, or evidence of reflux in the deep and super-
ficial venous system (within the great saphenous vein [GSV]).
Central and
The authors showed that microvalvular incompetence could Western Eastern Latin Middle
exist in the small superficial veins of the leg, independent of Europe Europe America East Far East
incompetence in the GSV or its accessories. These findings
n=36004 n=32225 n=12686 n=3518 n=7112
raise some additional arguments for ascending incompetence,
rather than the traditional descending theory and reflux in the France Georgia Brazil Pakistan Indonesia
saphenofemoral junction.18 Incompetence in the microcircu- Spain Hungary Columbia United Arab Singapore
lation along with activation of the inflammatory response and Romania Mexico Emirates Thailand
nociceptors could be the very first manifestation of CVD. Iden- Russia Venezuela Vietnam
tification of these patients seems to be crucial, because not Serbia
only could we identify patients in the early stage of disease, Slovak
but we could also start with some of the treatment options. republic
Slovenia
Van der Velden et al tried to distinguish which symptoms are
19 Ukraine
specific for CVD. However, their results did not have statisti-
cal power due to the low number of patients investigated, and Table II. Vein Consult Program (VCP) study zones with number
of subjects.
the approach and design of the study. This supports the need After reference 13: Rabe E et al. Int Angiol. 2012;31:105-115. 2012, Edizioni
for future large multicenter studies. Minerva Medical.

Risk factors for symptomatic chronic venous disorders Radak and Sotirovic MEDICOGRAPHIA, Vol 37, No. 1, 2015 87
FOCUS

In the VCP population, 56% of patients in the C0s class had

leg pain, while almost 90% of patients in C5 to C6 had signif- Risk Adjusted 95% confidence
factor odds ratio interval
icant leg pain. Still, it is quite interesting that even though there
is a significant increase of symptom prevalence with CEAP Sex; female vs male 2.3 2.2-2.4
class, some patients with severe forms of CVD (C6 and C7) Age (years) 35-50 vs 34 1.7 1.6-1.8
do not report any symptoms (Table I).14
Age (years) 51-64 vs 34 2.3 2.2-2.5

Results of the VCP show that risk factors connected to symp- Age (years) >65 vs 34 2.8 2.6-3.0
tomatic CVD are: age, body mass index (BMI), sex, family BMI (kg/m ) 25-30 vs 24
2
1.3 1.2-1.4
history of CVD, and the patient's history of previous veno- BMI (kg/m ) 30 vs 24
2
1.6 1.5-1.7
thromboembolism (Table III).14 In addition, patient habits play a
Family history of CVD
significant role in the development of venous symptoms, such 2.0 1.9-2.1
vs no family history
as hours spent in an upright position, smoking, and lack of
Personal history of VT
daily exercise (Table IV).14 Together, all of these facts are tra- 2.5 2.1-2.8
vs no personal history
ditionally recognized as risk factors for the development of
CVD in numerous earlier published studies.5,20,22-26 The results Table III. Occurrence of venous symptoms and risk factors in the
of the VCP, for the first time, show the distribution of risk fac- Vein Consult Program (VCP) population ( P<0.05).
tors on a global level, and in populations with different social Abbreviations: CVD, chronic venous disease, VT, venothromboembolism.
After reference 14: Phlebolymphology. 2013;20(3):138. 2013, Les Labora-
habits and economical standards, sometimes living in diamet- toires Servier.
rically different time and weather zones. As we can see from
Table III,14 the sex and age of subjects are two very important
factors for symptomatic CVD. In the VCP, screened subjects Risk Adjusted 95% confidence
factor odds ratio interval
were divided into four age groups: 18 to 34 years, 35 to 50
years, 51 to 64 years, and 65 years. When the CEAP pro- Hours spent standing 5-10 vs <5 1.3 1.2-1.4
file was analyzed according to the age and sex, the authors Hours spent standing >10 vs <5 1.4 1.2-1.5
observed that whatever the age group, there was a signifi-
Hours spent sitting 5-10 or
cant difference between men and women in the classes C0s NS -
>10 vs <5
to C3. With the exception of the C0s class, which was more
Smoker vs nonsmoker 1.3 1.2-1.4
frequent in men than in women after the age of 35, other cat-
egories were more prevalent among women. Next, the preva- Lack of regular exercise
lence of severe CVD (C4 to C6) was found to be similar, what- vs regular exercise 1.3 1.2-1.4
(2 times per week)
ever the sex and age, and to drastically increase with age in
both sexes. C2 and C3 increased with age in both sexes, but Table IV. Occurrence of venous symptoms and risk factors in the
stabilized after the age of 64 years.13,14 Vein Consult Program (VCP) population ( P<0.05).
Abbreviation: NS, nonsignificant.
A number of studies reported an association between obe- After reference 14: Phlebolymphology. 2013;20(3):138. 2013, Les Labora-
toires Servier.
sity and CVD.13,14,27 In the VCP population, mean BMI is sig-
nificantly higher in men compared with women (P<0.0001). nected to the period of day (end of day) and seasons (sum-
Higher values of BMI are reported in Eastern and Central Eu- mer). Even some regions (Middle and Far East) showed a high-
rope (27.345.64) whereas smaller figures appear among er presence of symptoms during the night (52.5% of subjects)
patients in the Far East (22.893.59; P<0.0001). In a part of and a significantly lower presence of venous symptoms dur-
the VCP population, Vlajinac et al28 showed that the CEAP ing the summer (only 5.4% of subjects).14
C categories of CVD were significantly related to being over-
weight or obese, and this association was independent of Up to 65% of participants with CVD in the VCP had a posi-
age, sex, and some other postulated risk factors in this study. tive maternal history of CVD. Also, the role of hormonal factors
Several other habits were confirmed as very strong CVD risk in the development of CVD has been suggested by several
factors, such as smoking and physical inactivity.26 The last investigations. Under the VCP, a Serbian group of authors26
three mentioned factors (obesity, smoking, and physical in- showed that the average number of births was significantly
activity) deserve special attention, since these factors can be higher in women in classes C2 to C3 and C4 to C6 in compar-
easily modified. Standing time increases the risk of sympto- ison with those without the disease. The higher number of
matic CVD, especially if that period is more than 10 hours. births was a risk factor for CVD, independent of other ob-
On the other hand, it seems that sitting time is not a risk fac- served factors, including age. Menopause was also inde-
tor for symptomatic CVD. Lack of regular exercise has been pendently related to all clinical classes, especially C4 to C6.24
observed in 67.4% of subjects. Up to 42% of subjects were The same study showed no existing relationship between
smokers. The appearance of symptoms was strongly con- CVD and either oral contraceptive use or hormonal replace-

88 MEDICOGRAPHIA, Vol 37, No. 1, 2015 Risk factors for symptomatic chronic venous disorders Radak and Sotirovic

ment therapy. On a global level, use of birth control pills is sig-
nificantly more frequent in Western Europe (45.8%, vs 31.1%
for the total population of survey), while that of hormone re-
placement therapy is significantly higher in Latin America
(23.2%, vs 8.2% for the total population; P<0.0001); in the
Far East, HRT use is significantly less frequent than in the oth-
er participating countries (2.3%, vs 8.2% for the overall pop-
ulation of the survey; P=0.0008).13
The risk of developing symptoms increased significantly with
disease severity. When considering individual symptoms ac-
cording to CEAP clinical class, heaviness and sensation of
swelling appeared more related to the C3 class (edema), while
itching was related to skin changes.
Comorbidities as risk factors for symptomatic CVD
There is a lack of evidence on how comorbidities affect the
development and progression of CVD and venous symptoms.
CVD is still often associated with chronic conditions such as
diabetes mellitus, high blood pressure, heart failure, chronic
obstructive pulmonary disease, renal insufficiency, peripheral
arterial disease, and many others.
Our preliminary results of the VCP show that other chronic
diseases are found in a large number of patients with CVD,
primarily in elderly patients. For example, arterial hypertension
can be found in up to 70% of patients aged above 65 years
in CEAP classes C4 to C6. Presence of arterial hypertension,
simultaneously with congestive heart failure, contributes to
edema development and the decrease in local defense ca-
pabilities of already damaged skin and subcutaneous tissue
in patients with severe CVD.
The presence of comorbidities could potentially be a very im-
portant risk factor for symptom development in patients with
CVD, not only in severe cases, but also in the early stages (C0s
to C3 ). These factors could mislead GPs and vascular sur-
geons, especially in subjects without visible signs of CVD (C0s ).
Thus, early recognition and quick treatment of comorbidities
is essential, and could dramatically reduce symptoms and
slow progression of CVD.
The attitude of patients and GPs who manage
venous symptoms
The results of the VCP gave us a clearer picture of how GPs
deal with patients who have CVD, through every stage of the
disease. Two facts have left the strongest impression. First-
ly, subjects with symptoms only are not considered by their
GPs to have CVD. Globally, 63% of screened subjects in the
VCP were considered to have CVD by their GPs. Subjects
with symptoms only (C0s) were less likely to be considered as
having CVD and to be liable for treatment than those with
signs. The presence of a symptom was not the trigger for start-
ing CVD treatment. Secondly, while 63% of screened subjects
were considered to have CVD by GPs, only 22% (one-third)
Risk factors for symptomatic chronic venous disorders Radak and Sotirovic
FOCUS
were referred to venous specialists. Despite this, it appears
that a systematic search for venous symptoms, as was per-
formed in the VCP, could help detect CVD in 6 out of 10 sub-
jects (it is of note that 50% of these were C0s or C1s ).13
Even when venous symptoms are recognized by GPs, the
question still remains: should all symptomatic patients be treat-
ed? The decision is particularly difficult in patients without vis-
ible signs of disease. Yet, it is acknowledged that venous pain
greatly worsens patients QoL. Several questionnaires have
been created to compare the effects of different types of CVD
therapy, as well as for discriminative purpose, and show very
promising results.29-36
In the VCP, subjects diagnosed with CVD after a GP examina-
tion, were requested to complete a self-administered ques-
tionnaire reporting features about their professional activities
and QoL (using the ChronIc Venous Insufficiency quality of life
Questionnaire [CIVIQ]14; 0=poor QoL, 100=very good QoL).
A total of 35 495 questionnaires from 17 countries were an-
alyzed. A total of 7% of patients were hospitalized and 4%
changed their professional activities as a result of CVD. Loss
of work days was reported in 15% of patients.14
Besides the traditional venous leg symptoms, some authors
have identified depression, anxiety, and hypochondria among
patients with CVD.12 The authors concluded that a specially
designed questionnaire, applied to individuals with venous-
type leg symptoms, allows the subjects or patients who have
a distinct psychiatric condition to be distinguished from those
with a true venous disorder.12 The rate of patient referrals to
specialists increases with disease severity: 4.1% at C0s stage
vs 60.2% at C6. In Central and Eastern Europe as well as in
Latin America and the Middle East, patients are referred more
frequently, starting at the C2 stage, than in the Far East, where
even C6 patients are rarely referred.
Conclusion
In conclusion, CVD is a global phenomenon that reaches al-
most pandemic proportions. To deal with this problem, the
VCP was established. The most worrying finding of the VCP
is that the majority of subjects with or without clinical signs of
CVD have symptoms that significantly affect their daily activi-
ties and deteriorate QoL. However, several factors and comor-
bidities have been identified as risk factors for the develop-
ment of venous symptoms, and some of these can be easily
modified, such as BMI, hours spent in an upright position,
smoking, and lack of daily exercise. Results of the VCP also
show the importance of the role of GPs in early recognition and
management of CVD. Venous symptoms may be encoun-
tered in numerous fields and calls for a multidisciplinary ap-
proach (scientific, eg, neurology, molecular biology, psycho-
metrics, etc; clinical, eg, surgery, dermatology, phlebology,
etc) and raised awareness amongst patients and the com-
munity as a whole.
MEDICOGRAPHIA, Vol 37, No. 1, 2015 89
FOCUS
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chronic venous disease quality of life questionnaire (CIVIQ-20). Eur J Vasc
Endovasc Surg. 2010;40:783-789.
36. Radak DJ, Vlajinac HD, Marinkovi JM, Maksimovi MZ, Maksimovi ZV. Qual-
ity of life in chronic venous disease patients measured by short Chronic Ve-
nous Disease Quality of Life Questionnaire (CIVIQ-14) in Serbia. J Vasc Surg.
2013;58:1006-1013.
 FOCUS

FACTEURS DE RISQUE DE LA MALADIE VEINEUSE CHRONIQUE SYMPTOMATIQUE :

RSULTATS DU PROGRAMME INTERNATIONAL V EIN C ONSULT
Les symptmes veineux sont trs frquemment voqus au cours des consultations de mdecine gnrale ou de
chirurgie vasculaire. Pourtant, le nombre de recherches menes sur les sensations veineuses est inversement pro-
portionnel la frquence des symptmes rapports. Nous manquons aujourdhui dtudes pidmiologiques sur
cette question. La mission du programme Vein Consult (VCP) tait claire : augmenter la vigilance et se consacrer
une maladie chronique ayant presque atteint une dimension pandmique, la maladie veineuse chronique (MVC).
Le rsultat le plus proccupant du VCP est la prsence de symptmes affectant significativement les activits quo-
tidiennes et dtriorant la qualit de vie dune majorit de sujets avec ou sans signes cliniques de MVC. Dans les
facteurs de risque de dveloppement dune MVC symptomatique, on retrouve : lge, lindice de masse corporelle,
le sexe, les antcdents familiaux de MVC, les antcdents de thromboembolie veineuse, le nombre dheures en
position debout, le tabagisme et le manque dexercice quotidien. Outre les facteurs de risque traditionnels, il existe
aussi des comorbidits tels une pression artrielle leve, un diabte, une insuffisance cardiaque et une maladie
pulmonaire obstructive chronique qui peuvent influer sur le dveloppement et la progression des symptmes chez
les patients souffrant de MVC. Si la plupart de ces facteurs de risque ne peuvent tre modifis, un nombre significa-
tif dentre eux peut aisment tre chang. Nous prsentons dans cet article, daprs les rsultats du VCP, les der-
niers vnements lis aux symptmes veineux et les facteurs de risque de leur dveloppement.

Risk factors for symptomatic chronic venous disorders Radak and Sotirovic MEDICOGRAPHIA, Vol 37, No. 1, 2015 91
 A TOUCH
OF FRANCE
onsumption (as tuberculo-

C sis was then called) was the

scourge of rapidly industri-
alizing overcrowded cities in 19th-
century Europe. Among its victims,
the disease claimed the lives of
many artists, while also inspiring
their works (see story by Isabelle
Percebois). Tuberculosis triggered
research on an unprecedented
scale. Robert Koch discovered the
culprit, Mycobacterium tuberculo-
sis, in 1882. In 1921, Albert Calmette
and Camille Gurin developed the
vaccine that was to save untold
lives (see story by Annick Perrot),
and the first effective treatment,
streptomycin, was used in 1946. Tu-
berculosis is making a comeback
The Savior of Children:
in Europe due to increased migra-
tory flows and the emergence of
treatment-resistant bacteria.
Albert Calmette and the
BCG vaccine
A . Pe r ro t , F ra n c e
Page 94

Blighted destinies:
arts, artists, and the Romantic
Disease in 19th-century France
I . Pe rc e b o i s , F ra n c e
Page 104

Scanning electron micrograph of Mycobacterium tuberculosis.

2011, Institut Pasteur/Guadagnini (Ultrastructual Microscopy Platform; Marie
Jackson (Mycobacterial Genetics Unit; Jean-Marc Panaud (colorization).
A TOUCH OF FRANCE

Antituberculosis stamp created in 1934, extolling the BCG vaccination and Calmette,
The Savior of Children. The first antituberculosis stamp was issued in Denmark in 1904. France followed
suit in 1927. In France, these stamps played a special educational role, and booklets of stamps were
handed out by schoolteachers to schoolchildren who sold them to the public. The proceeds went
towards the fight against tuberculosis. Themes and slogans changed until 1967,
the last year such stamps were produced.
Comit National contre les Maladies Respiratoires.
 A TOUCH OF FRANCE

almette and Gurin resumed

C their experiments on tuber-

culosis and after 13 years of
unflagging work, using cultures
from 230 passages in the bile/pota- The Savior of Children
to medium, they at last had an ef-
fective means of vaccination using
live attenuated bacillus, thereafter
known as Bacillus Calmette-Gurin
Albert Calmette
(BCG). Satisfied that the BCG vac-
cine was safe, they vaccinated 120 and the BCG vaccine
newborn infants of tuberculous
mothers with three oral doses of
their BCG culture. Thus began the
era of vaccination against tuber-
culosis.
b y A . Pe r rot , Fra n c e

G
raduate of the cole du Louvre, Paris; from 1982 to 2010, curator of the Pasteur Museum (at present honorary
curator) and of the Museum of Applications of Research at the Paris Pasteur Institute. Curated exhibitions on
Louis Pasteur, his disciples, and the Pasteur Institute. Directed the design and creation of the Yersin Museum
in Nha Trang, Vietnam (1996-97), the Museum of the Institut Pasteur in Hanoi, and a permanent exhibition for the In-
stitut Pasteur in Ho Chi Minh City (2006). In 2008, organized an exhibition in Hong Kong: From the Plague to New
Emerging Diseases. A Chronicle of Pasteurian Research in Hong Kong. Took part in events marking major Pasteurian
landmarks (centenaries of the creation of the Pasteur Institute [1987] and of the death of Louis Pasteur [1995]). Gives
talks in France and abroad on the work of the Institut Pasteur. [In French]: coauthored with Maxime Schwartz, former
Director of the Institut Pasteur, a childrens book entitled Pasteur, From Microbes to Vaccine (Casterman, 1999), and
two books published by Odile Jacob: Pasteur and his Lieutenants (2013) and Pasteur and Koch: A Duel of Giants in
the World of Microbes (2014).

rowing up in Nice, in southern France, Albert Calmette (1863-1933) gazed

Annick PERROT,
Honorary curator of the
Pasteur Museum, Paris
FRANCE
Address for correspondence:
Annick Perrot, La Chapelle
41200 Pruniers en Sologne
(e-mail: annick.perrot41@orange.fr)
www.medicographia.com
G across the bay and dreamt of voyages to faraway lands, of sailing oer
the bounding main. Dreams he realized on joining the French navy, not
as a mariner, as in his boyhood musings, but a ships surgeon. He sailed the
China Seas, traveled on assignment to Gabon, and voyaged to Saint Pierre
and Miquelon in the Atlantic Ocean near Canada, where, self-taught, he began
his microbiological research. On his return to France, in 1890, Calmette took
classes at the Pasteur Institute given by mile Roux, with whom over the years
he forged a lasting friendship. On the recommendation of Louis Pasteur, Cal-
mette was sent to Saigon (now Ho Chi Minh City) to set up a laboratory for the
preparation of vaccines against rabies and smallpox. In one year, half a mil-
lion people were vaccinated against smallpox. It was in Saigon that Calmette
oversaw the building of the first Pasteur Institute outside France; the second
one, also in Vietnam, was founded in Nha Trang by Calmettes colleague and
great friend, Alexandre Yersin (today there are 32 Pasteur Institutes through-
out the world). He worked on antisnake venom serum there and later, back
in Paris, developed antivenom serotherapy. Confident in Calmettes organiza-
tional skills, Pasteur entrusted him with setting up and directing a Pasteur
Institute in Lille. Calmette turned it into a model of its kind that played a major
part in the industrial and agricultural development of Northern France and
in the improvement of public health and social hygiene, and above all, in the
fight against tuberculosis. With Camille Gurin, Calmette studied the tuber-
culosis bacillus and developed what came to be known as the BCG vaccine,
which has prevented hundreds of millions of premature deaths ever since.
Medicographia. 2015;37:94-103 (see French abstract on page 103)

Albert Calmette and the BCG vaccine Perrot MEDICOGRAPHIA, Vol 37, No. 1, 2015 95
A TOUCH OF FRANCE
scourge since antiquity, tuberculosis is blind to mere-
A ly mortal distinctions of rank, wealth, and kudos.
From Egyptian pharaohs to crossing sweepers, from
nabobs to panhandlers, over millennia it killed millions. In re-
cent times, tuberculosis was, for more than half a century un-
til the rise of drug-resistant strains in the 1980s, thwarted by
the BCG vaccine. B for Bacillus, C for Calmette, G for Gurin.
BacillusMycobacterium tuberculosisthe foe, needs no
introduction. Gurin (Camille) we will come to shortly. Here,
though, our story is that of Albert Calmette.
Albert Calmette in his laboratory, around 1920-1925.
Photo Ph. Henri Manuel. Institut Pasteur Muse Pasteur.
Albert, his father exulted, was born to the booming of can-
non saluting the seizure of Mexico City (instigated by Em-
peror Napoleon III of France). The year was 1863, the place
Nice, in southern France. Albert was the third son, and the
last, because before he reached two his mother was dead.
Alberts father then embarked with his children on an itiner-
ant life, following the demands of his career as a high-rank-
ing regional civil servant. Albert grew up at a time when
France was building its overseas empire, and his curiosity
plunged him into adventure novels and explorers tales. Ex-
oticism kindled his taste for discovery, and by the age of 13
Albert had made his choice. A life on the high seas.
96 MEDICOGRAPHIA, Vol 37, No. 1, 2015
A vocation sadly that proved short-lived, curtailed by a severe
bout of typhoid fever contracted during his preparatory class-
es for entry to naval school. By the time his long convales-
cence was over, the naval schools doors were closed to him
Albert was already too old. Yet still he dreamed of seeing the
world. So instead, he turned to medicine and in October
1881 entered the naval medical school in Brest. Two years
later, he was appointed physician assistant in the French
navy and enthusiastically wrote to his father: Now the fu-
ture is mine.
His immediate future lay in the China Seas. In November 1883,
he boarded the battleship Victorieuse and later the Triom-
phante in Admiral Courbets squadron, which lay at anchor
in Halong Bay (meaning, in Vietnamese, descending drag-
on bay), with its myriad islets and grottoes in a karst land-
scape (now a UNESCO World Heritage Site). The French
naval division was on a war footing. Calmette had arrived at
a decisive moment of French expansion in the Far East.
China, hostile to the extension to Tonkin of the French pro-
tectorate of Annam, was encouraging acts of piracy to which
the French responded with an iron fist. Tension was high. An-
ticipating trouble, the Triomphante cruised along the coast,
berthing at various ports, where Calmette had his first glimpse
of the vast panorama of Chinese life. Captivated, he observed,
studied, and noted. Everything. At Hong Kong, he met the
Scottish physician Patrick Manson, who had discovered a
developmental phase of filaria in mosquitos. Under the mi-
croscope, Calmette saw the various stages of the life cycle
of the nematode worm that was the cause of elephantiasis.
Tensions between France and China continued to mount and
the failure of diplomatic negotiations triggered the Sino-French
War (August 1884 to April 1885). From his first-aid post, Cal-
mette saw action at the Battles of Fuzhou, on 23 August 1884
(a victory for the French), and Tamsui on 8 October 1884 (a
victory for the Chinese), the occupation of Keelung, and the
capture of the Pescadore Islands. When the signing of a
peace protocol ended hostilities, Calmette was recalled to
France. Before leaving, he visited Saigon, which he said was
the most agreeable town Ive seen in the Far East, adding
wistfully I shall perhaps never return. Little did he know that
Saigon was to play a major part in his career. Back in France,
Calmette completed his medical studies, extending Man-
sons observations in a doctoral thesis on the Etiology and
pathology of tropical diseases caused by filariae in human
blood.
And then a new departure, this time for Africa, Gabon, where
he was to serve aboard the floating hospital the Alceste in
Libreville harbor. The year was 1886, and Savorgnan de Braz-
za, the Italian-born, naturalized French navy officer and ex-
plorer, was deploying his legendary energy in preparing an
expedition. Calmettes brother Gaston, the future director of
Albert Calmette and the BCG vaccine Perrot
 A TOUCH OF FRANCE

French (top) and Chinese (bottom) rendering of the naval battle of Fuzhou, on 23 August 1884, during the Sino-French War,
eyewitnessed by Albert Calmette. Muse de lImage/H. Rouyer /bbs.voc.com.cn. All rights reserved.

Albert Calmette and the BCG vaccine Perrot MEDICOGRAPHIA, Vol 37, No. 1, 2015 97
A TOUCH OF FRANCE
Newlyweds: Albert Calmette donning his naval officer uniform and
his wife Emilie, in 1889. Institut Pasteur Muse Pasteur.
the newspaper Le Figaro, introduced him to this mythical fig-
ure. Calmette was sorely tempted to accept the explorers
offers, but he had recently become engaged to Emilie de la
Salle and was loathe to leave her for an extended period of
uncertain adventuring.
Aboard the Alceste, which was reserved for the hospitaliza-
tion of whites, and ashore, Calmette worked double shifts in
tending to the halt and sick, and also spent time studying lo-
cal diseases like sleeping sickness (African trypanosomiasis)
and blackwater fever. He was shocked by the gulf between
the goals he and others were striving foreconomic develop-
ment, protection of indigenous peoples and of Europeans
and the scarcity of means. While other doctors, faced with
unknown diseases, made do with treating and bandaging,
Calmette saw and acted on the need for improved hygiene
and living conditions, for preventive medicine, convinced that
the civilizing work claimed by the colonialists depended on
the development of health protection among the local popu-
lations. This was prescient, since discoveries at the Pasteur
Institute would soon extend to exotic diseases.
Calmette left Libreville in November 1887 and, after a testing
35-day voyage aboard the Arige, arrived back in France, where
he married Emilie de la Salle in February of the following year.
Young and frail, Emilie over the years to come braved, with
98 MEDICOGRAPHIA, Vol 37, No. 1, 2015
Albert, journeys to exotic lands of icy wastes or sweltering
heat. Their first port of call was Saint Pierre and Miquelon, in
April 1888, an odd destination for the newlyweds, a frozen
and deserted archipelago buffeted by violent storms or smoth-
ered in fog, where cod fishing was the only resource.
At the Naval Hospital, Calmette had his work cut out. Often
unwell (he had caught malaria in Africa), he provided med-
ical care for a local population of 6000, which doubled dur-
ing the fishing season. He cared for the inhabitants in their
homes, the length and breadth of the town, and beyond, de-
livering babies, medicating, performing surgical interventions
everything from amputations to cataracts. He was unfazed by
these numerous initiatives and responsibilities: It was hard
going, but oh so worthwhile in my youthful inexperience! And
on top of all this, he still found the time to fit in two English les-
sons a week and half an hour of fencing every morning. In
the evenings, after a demanding day attending to patients, he
studied and marveled at microbiology by reading the Annales
de lInstitut Pasteur (created in 1887 by the chemist and mi-
crobiologist mile Duclaux), which he had been receiving since
his time in Africa. With an oil immersion objective and an in-
cubator sent from France, he set about his research: without
working, enjoying myself, I gathered together a small collec-
tion of preparations of all kinds of microbes.
To hand there was an intriguing conundrum to be solved:
salted cod heaped up in the holds of ships were turning bright
red. The contaminated flesh was unfit for sale and so the lo-
cal economy was ailing. To study this rouge de la morue
(cod red), Calmette isolated the microbe, reproduced the
spoilage experimentally, proved that the microbe was in the
salt from Atlantic saltworks of Cadiz and Lisbon, and showed
that sodium sulfite has a preventive action.
In the meantime Flix Le Dantec, one of Calmettes colleagues
in the navy health corps, preempted him by publishing identi-
cal results in 1891, without, however, mentioning transmission
by salt. Calmette was only 26 years old and self-taught, yet
already he had accomplished laboratory work of great rele-
vance to public health and with an industrial application, as
long advocated by Pasteur. Even before he entered the Pas-
teur Institute, Calmette was well and truly of the same stripe
as the great man himself.
The French Colonial Medical Service was created in 1890,
and Calmette had no hesitation in joining. His aim was to
work on tropical diseases, and in preparation he wished to
take a 3-month microbiology course at the Pasteur Institute.
Yet word of the courses repute had spread internationally
and no places were left. Calmette, though, came to the atten-
tion of mile Roux, one of Pasteurs closest disciples, who
appreciated his work on cod red, his enthusiasm, scientific
rigor, and technique, and reserved for him a bench in a small
laboratory. Rouxs lab assistant Alexandre Yersin had just left,
Albert Calmette and the BCG vaccine Perrot

Children surround Albert Calmette during a smallpox vaccination session in Saigon in 1891. Institut Pasteur Muse Pasteur.
having succumbed to the call of distant horizons in the Far
East. And so Calmette joined the course which, he later said,
opened up attractive vistas towards which I shall strive.
This was the beginning of a mutual esteem and friendship
between Roux and Calmette that lasted their whole lives.
When the Colonial Medical Service needed someone to set
up a laboratory for the preparation of vaccines against small-
pox and rabies in Indochina, it looked to the Pasteur Institute.
Thus it was that Pasteur summoned Calmette and explained
the mission. Think it over and let me have an answer soon.
To Pasteurs great surprise, the young and eager doctor ac-
cepted forthwith: Theres nothing to think over. Ill leave when-
ever you wish.
In February 1891, Albert and Emilie arrived in Saigon, and Cal-
mette set up his laboratory in two rooms at the military hos-
pital. Great was the contrast after Saint Pierre and Miquelon.
Despite its muggy climate, Saigon appealed to themthe
hospitality of the small French colony, the facilities provided,
their house with the supreme luxury of running water and a
bathroom, plus a garden.
The first problem Calmette faced was storage of his antira-
bies vaccine, which contained attenuated virus taken from the
spinal cord of rabid rabbits. Throughout the long sea voyage,
Albert Calmette and the BCG vaccine Perrot
A TOUCH OF FRANCE
Calmette had maintained the virus by passing it from rabid
rabbit to healthy rabbit, but now his lagomorph population
was running low. So Calmette implemented one of Rouxs dis-
coveries: storage in glycerol of rabbit spinal cord containing
attenuated virus. Before long, people bitten by mad dogs
were sent for treatment to Calmette in Saigon, from all over
Indochina, but also Singapore, Siam, Java, Hong Kong, and
Shanghai.
Calmette also adapted Edward Jenners method of vaccina-
tion against smallpox, which was endemic and widespread in
Indochina. Before the French occupation, smallpox was re-
sponsible for 90% of infant deaths, and those that survived
were badly scarred, and many were blind, to the point that
some villages kept a nearby hamlet of the blind. Calmette
inoculated the skin of local water buffalos with vaccinia virus
and collected vaccine lymph. This method was quickly adopt-
ed over a large area, including the Indonesian peninsula and
southern China, and 500 000 people were vaccinated against
smallpox in just two years.
Calmette pursued his interest in snakebite envenoming and, in
his first paper on the subject, recounted how a source of ven-
om was found. A village in the environs of Bac-Lieu (Cochin-
China) was invaded, in October 1891, at the time of the great
rains, by a swarm of venomous snakes belonging to the
MEDICOGRAPHIA, Vol 37, No. 1, 2015 99
A TOUCH OF FRANCE
Naja tripudians (spectacled cobra), an aggressive snake asso-
ciated with a high rate of lethal snakebites. Color engraving, 1872.
Wellcome Library, London.
species Naja tripudians or cobra capel. These animals, driven
into the native huts by the flood, bit 40 individuals of whom
four, as reported to us, died almost immediately. An Anna-
mite was able to capture and enclose in a barrel 19 of these
cobras and the administrator of the region, M. Sville, kindly
sent them to the laboratory. Fourteen arrived alive. We killed
11 of them immediately to remove their venom glands. Cal-
mette extracted venom from the glands with glycerol and
used the solution to prepare antisnake venom serum.
Calmette also contributed greatly to the local economy, by
investigating the so-called Chinese yeast used to ferment
rice and so produce an alcohol beverage. He doubled the
yield of rice alcohol by means of a fungus which he named
Amylomyces rouxii in honor of his teacher and friend mile
Roux. In this, the heyday of the opium trade, he also showed
that another fungus, Aspergillus niger, shortened the time
needed to ferment opium from one year to 30 days.
And his interests did not stop there. He returned to ideas
first formulated in Gabon and began research work on other
diseases widespread in Indochina: cholera, dysentery, and
filariasis.
100 MEDICOGRAPHIA, Vol 37, No. 1, 2015
The Lille Pasteur Institute, founded by Albert Calmette and
mile Roux in 1899.
Institut Pasteur.
Not content with that, Calmette set up the first Pasteur Insti-
tute outside France (today, the Pasteur Institute in Ho Chi Minh
City). The second, north of Saigon, was the work of Alexandre
Yersin, with whom Calmette struck up a real and lasting friend-
ship when they first met in 1891, as Yersin was setting out on
an expedition to the Annamite Mountains.
This was the dawn of the Pasteurian epic, which in a few years
saw Pasteurs followers reproduce around the world the mod-
el put in place by Calmette, often, like him, in precarious con-
ditions, but always with great adaptability. Researchers, but
also hands-on strategists, and military and civilian doctors, all
trained in the methods of Pasteur, driven by what amounted
almost to fervor. Today, 32 Pasteur Institutes across five con-
tinents continue the good work: public health services for lo-
cal populations, research, and teaching, the only worldwide
network of its kind.
After two and a half years in Saigon, Calmette, weakened by
dysentery, was recalled to France. At just 30 years old he was
appointed a Knight of the Legion of Honor. Keen to continue
his research, he wanted to return to the Pasteur Institute where
the working atmosphere had so impressed him. Alas, regu-
Albert Calmette and the BCG vaccine Perrot
 A TOUCH OF FRANCE

He worked too on hookworm (miners anemia), and on his

new calling, the study of tuberculosis. Although the disease-
causing bacillus (Mycobacterium tuberculosis) had been iden-
tified in 1882 by Robert Koch, no treatment had yet been pro-
duced to stem the progress of the contagion.

The situation was especially bad in industrial towns, where

workers lived in overcrowded, unhealthy conditions. In Lille,
for example, a city of 220 000, some 6000 among the pover-
ty-stricken had tuberculosis, which killed 1000 to 1200 of
them every year. In affected households, infant mortality was
43%. More generally, in early 20th-century France, consump-
tion killed 100 000 to 150 000 people each year, nearly one-
quarter of all deaths. Calmette thereafter single-mindedly pur-
sued the scientific and social fight against tuberculosis until
the end of his days.

His first priorities in Lille were to focus on the environment and

living conditions, to provide the townspeople with safeguards,
and to educate them. He set up the first tuberculosis clinic,
the mile Roux Preventorium (for patients infected by a form
of tuberculosis not yet active) in 1901, the Ligue du Nord
contre la Tuberculose, which raised public awareness and col-
lected funds, a family sanatorium, a school of nursing and
hygiene, and an annex for a nonprofit organization that pro-
tected children from infected households by sending them
to foster homes in the country.

With these treatment and educational networks in place, Cal-

Camille Gurin (standing) and Albert Calmette (sitting), in their mette focused on the prevention of tuberculosis. The odyssey
BCG laboratory, at the Pasteur Institute in 1931. BCG stands for
bacille de Calmette et Gurin. Institut Pasteur Muse Pasteur.
began in 1900, with at his side Camille Gurin, his research
colleague since the early days in Lille. By 1908 they had shown
lations forbade a colonial physician from taking a position that successive cultures of bovine bacilli (Mycobacterium bo-
outside the colonial office, so instead Calmette accepted a vis), on medium containing cooked potato and glycerinated
position of secretary to the board of health, where he was bile, lose their virulence progressively through successive sub-
given a free hand to conduct his personal research in the cultures.
morning. For two years he resumed his studies of antiven-
om serotherapy and worked with Amde Borrel and Yersin
on the preparation of antiplague serum.

Pasteur and Roux then entrusted him with the task of creat-
ing a Pasteur Institute in Lille, in the north of France, at the re-
quest of the board of health and the city council, which, for
this new center of serotherapy, public health, social hygiene,
and research, wanted Mr Rouxs students. Calmette signed
a 10-year contract, but stayed on for a quarter of a century.
Inaugurated in 1899, the institute met the needs of physicians
and hygienists, but also local industrialists, following Pasteurs
advice that pure science, at its noblest, cannot advance a
single step without sooner or later using its precious results
for the good of industrial applications.
Various types of tuberculosis bacteria cultures: human, bovine,
biliary, and aviary tuberculosis on glycerinated potato medium (I
Calmette turned to problems of public health and hygiene, to IV); human, bovines and aviary tuberculosis on glycerinated
and started by developing biological treatments to clean up agar-agar (V to VII). Drawing illustrating Calmettes work, by De-
waste water using trickling filters (also known as biofilters). moulin, 1920. Institut Pasteur Muse Pasteur.

Albert Calmette and the BCG vaccine Perrot MEDICOGRAPHIA, Vol 37, No. 1, 2015 101
A TOUCH OF FRANCE
The Great War and the German occupation of Lille in 1914 in-
terrupted this promising research. During those dark years,
Calmette somehow managed to continue making sera for
serotherapy and vaccines, in spite of having to cope with the
hardships and restrictions imposed by the war and not least
the ordeal of having his wife Emilie being taken hostage in
1918 together with a group of twenty-five prominent women
from Lille, and deported and interned for seven months in a
war prisoner camp in Holzminden, in Lower Saxony.
Cartons of BCG vaccine doses being packed for dispatch throughout the world, at the Pasteur Institute, in 1935.
Institut Pasteur Muse Pasteur.
102 MEDICOGRAPHIA, Vol 37, No. 1, 2015
Oral administration of the BCG vaccine
to a newborn child by Albert Calmette
on 6 June 1931.
Institut Pasteur Muse Pasteur.
The war over, Roux called upon Calmette to
become an assistant director of the Pasteur
Institute in Paris and to run the bacteriology
course there, following the death of the pre-
vious incumbent Ilya Metchnikov, who had
shared the 1908 Nobel Prize in Physiology
or Medicine with Paul Ehrlich for his work on
immunity. Calmette and Gurin resumed their
experiments on tuberculosis and after 13 years
of unflagging work, using cultures from 230
passages in the bile/potato medium, they at
last had an effective means of vaccination us-
ing live attenuated bacillus, thereafter known
as Bacillus Calmette-Gurin (BCG). Satisfied
that the BCG vaccine was safe, they vacci-
nated 120 newborn infants of tuberculous mothers with three
oral doses of their BCG culture. Thus began the era of vacci-
nation against tuberculosis.
But in 1930, as recognition for his work flowed in from all sides,
disaster struck. Terrible news arrived from Lbeck in north-
ern Germany. Seventy-six of 250 children vaccinated with
BCG prepared using a strain sent by Calmette in 1929 died
of tuberculosis. At the resulting trial, which opened in Octo-
Albert Calmette and the BCG vaccine Perrot
 A TOUCH OF FRANCE

ber 1931, it slowly emerged that the tragedy was not attrib-
utable to a recovery of the virulence of BCG, but rather to
mistakes perpetrated at the Lbeck laboratory that prepared
the vaccine.
Calmette was deeply affected by the Lbeck disaster, which,
along with physical exhaustion from years of work and strug-
gle, worsened the heart condition that had afflicted him for
some time. Now 70 years old, Calmette was still paying fre-
quent calls on his ailing friend mile Roux, but declining health
forced him to his bed on 24 October 1933, and he died on
the morning of 29 October, five days before Roux.
Two years before he died aged 70 in October 1933, Albert
Calmette wrote a letter to his children and grandchildren in
which he expressed the wish: I hope that it will be given to
me to work until my eyes are closing to the light and that I will
fall asleep my soul in peace, conscious of having done that
which I have been able. The wish was granted, and since
his death Calmettes main contribution to humanitythe live
BCG vaccinehas protected millions of people around the
world and, together with antibiotics and improved hygiene,
has helped turn the tide against tuberculosis. In its tribute,
the Pasteur Institute said of Calmette: his death deprives
science of one of its most illustrious servants.

LE SAUVEUR DES TOUT PETITS : ALBERT CALMETTE ET LE BCG

Albert Calmette (1863-1933) rvait, enfant Nice, dtre marin, il sera mdecin de la marine. Il rvait de contres loin-
taines, il naviguera sur la Mer de Chine, dans lescadre de lAmiral Courbet, il ira en mission au Gabon, Saint Pierre
et Miquelon o il se distingue par des recherches microbiologiques personnelles. De retour, il suit lenseignement du
Dr Roux lInstitut Pasteur. Une durable amiti va lier les deux hommes. Il est envoy Saigon pour fonder un labo-
ratoire pour la prparation des vaccins contre la rage et la variole. Il pratique en un an 500 000 vaccinations antivario-
liques. Il met au point la srothrapie antivenimeuse. En vritable pionnier, il difie le premier Institut Pasteur Outre-
Mer. Yersin, quil a rencontr en Indochine, et qui lunira une profonde amiti, cre peu aprs le deuxime. Il y a
aujourdhui 32 Instituts Pasteur dans le monde. De retour Paris, confiant dans ses talents dorganisateur, Pasteur
lui confie le soin de crer et diriger un Institut Pasteur Lille. Il en fera un tablissement modle qui participa au d-
veloppement industriel et agricole et au dveloppement de lhygine dans le Nord de la France. Et la lutte contre
la tuberculose, son fer de lance. A Lille, il commence avec Camille Gurin ses recherches sur le bacille de la tuber-
culose qui aboutira la vaccination par le BCG. Ce vaccin, qui devait le rendre clbre dans le monde entier, contri-
buera prvenir de la tuberculose des centaines de millions de personnes de par le monde.

Albert Calmette and the BCG vaccine Perrot MEDICOGRAPHIA, Vol 37, No. 1, 2015 103
 A TOUCH OF FRANCE

n the 1800s, tuberculosis was

I seen as the malady of the cen-

tury and as such echoed the
melancholy of the Romantics and
inspired the Realists. Viewed as the
disease of the poor, in reality tuber-
Blighted destinies: arts, artists,
culosis affected all social classes
and ushered many artists, writers,
and composers into an early grave,
and the Romantic Disease
and into legends of blighted des-
tinies. Tragic stories that fire the
imagination today, just as they did
in 19th-century France
in the heady days of 19th-century
Romanticism.

b y I . Pe rc e b o i s , Fra n c e

sabelle Percebois is Professeur Agrge in Comparative Literature, PhD thesis (Paris IV-Sorbonne University,

I France): Scientific Writings in the European Fantastic Imaginary (1816-1894). Specializes in fantastic literature and
the interactions between science and literature. Main publications (in French): Vienna the scientific at the end
of the 19th century. Germanica. 2008;43:75-84; From tale of marvel to tale of fantasy: the forest in Mrimes Lokis.
Otrante. 2010;27-28:113-120; The cadaver in fantastic literature: place of the body in M. Shelleys Frankenstein and
K. S. Gjalskis Doctor Miics
Dream. Frontires. 2011;23-2:7-13; Mary Shelley: the young girl and science; the im-
print of scientific discourse in Frankenstein. In: Weber AG, Thoizet E, Wanlin N. Literary and
Savant Pantheons: 19th-20th Centuries. Arras, France: Artois Presses Universit; 2012:143-
156. Influence of Pseudo-science in Fantasy Literature: a Scientific Chimera of the 19th Cen-
tury. Oral communication presented at the Symposium: Sciences, Fables, and Chimeras:
Crossings, organized by Toulouse University, 3 June 2011. Proceedings accepted for publi-
cation by Cambridge Scholars Publishing. In English: Humorous duplicity: ironic distance and
fantastic tension in Villiers de lIsle-Adams Claire Lenoir Fastitocalon. 2013;3. In press.

Isabelle PERCEBOIS, PhD
Address for correspondence:
Isabelle Percebois, 8 rue des Fosss,
77000 Melun (e-mail:
percebois.isabelle@wanadoo.fr)
www.medicographia.com
I
n the 19th century, tuberculosis (consumption) struck down countless thou-
sands, acclaimed and nameless alike. Mysterious and incurable, it cut a
swathe through the artistic world in France. Prosper Mrimes letters bear
poignant witness to his fight against the disease; George Sand speaks of
Chopins decline in her autobiographical writings; in Memoirs from Beyond the
Grave, Chateaubriand recounts the consumptive death of his mistress Pauline
de Beaumont. Tuberculosis became a major theme in novels of the day. In the
works of Eugne Sue, Alexandre Dumas, fils, and Victor Hugo, it assumed a
religious character and took the lives of frail heroines seeking to atone for their
misdeeds. Realists like the Goncourt brothers and Emile Zola, on the other
hand, denied tuberculosis any redeeming value and its depiction served an-
ticlerical ends. Few painters portrayed the disease and it was the Norwegian
Edvard Munch, in Paris in 1885, who produced the most explicit and moving
representation in The Sick Child. But it was, above all, opera that placed tuber-
culosis center stage, thereby creating the paradox of the singing consump-
tive. By adapting the novels of French writers Alexandre Dumas, fils and Henry
Murger, the composers Giuseppe Verdi and Giacomo Puccini created La Tra-
viata and La Bohme, two operas whose popularity shows no sign of abating.
Thus, it was that tuberculosis came to serve as an artistic trope in 19th-cen-
tury fiction, painting, and opera, and, latterly, in film adaptations.
Medicographia. 2015;37:104-115 (see French abstract on page 115)

104 MEDICOGRAPHIA, Vol 37, No. 1, 2015 Arts, artists, and the Romantic Disease in 19th-century France Percebois
 A TOUCH OF FRANCE

t plagued 19th-century Europe, sowing death in

I its wake. Phthisis, the wasting disease, graveyard

cough, consumption, call it what you will. Named
or nameless it killed all the same. In a world trans-
formed by the industrial revolution, it spread through
overcrowded towns, taking the lives of unsung and
lauded alike. It was mysterious, hereditary perhaps,
incurable. Potions of dog fat and garlic, seaweed
placed under the sufferers bed, sweltering near a
hot stove, fresh air treatment in sanatoria, all proved
futile. In France, the world of the arts was not spared
and writers, painters, and musicians mythologized
the sickness, putting it at the heart of their works,
seeing it as a source of febrile creativity, as redemp-
tive, as ennobling.

A case in point is Alexandre Dumas 1848 novel La

Dame aux Camlias (The Lady of the Camellias),
which less than five years later inspired Verdi to
compose La Traviata, with Violetta the quintessen-
tial victim of the Romantic Disease. Not until the
end of the 19th century did German microbiologist
Robert Kochs discovery of the tubercle bacillus re-
veal the true face of the disease, thus sounding the
death knell of the consumptive myth and paving
the way to a genuine treatment of what came to be
known as tuberculosis.

The arts in the time of tuberculosis

Before writers and artists in 19th-century France
appropriated it as a fictional device, tuberculosis
figured in their correspondence and autobiograph-
ical writings in all its blood-spitting wretchedness.
Pulmonary tuberculosis, known then as phthisis,
forced the dramatist Prosper Mrimethe author
of Carmen, the basis of Bizets namesake opera
to divide his twilight years between Paris, where
he exercised his office as a senator under the Sec- Cover of journal serializing The Lady of the Camellias, by Alexandre Dumas,
fils, showing Marguerite with her bouquet of white camellias. The novel inspired
ond Empire, and Cannes, where the mild climate
the opera La Traviata, composed by Verdi.
soothed his hacking cough. In his posthumously Bibliothque Nationale de France Bridgeman Art Library.
published Letters to an Unknown Woman, who was
in fact Jenny Dacquin, friend and confidante, Mrime un- The composer Frdric Chopin struggled with consumption
flinchingly related the progress of his sickness. A letter dated for years. His correspondence reveals the daily suffering, but
6 January 1870, less than a year before his death, evoked his also his humor, as in a letter dated 3 December 1838 to his
repeated fits of breathlessness and nights of pain: I have tried friend Julian Fontana (also a Polish pianist and composer, and
all remedies, but always find myself back where I started []. Chopins musical executor). Living at the time on the island of
Im certain a slow and most painful death is approaching.1 Majorca with his lover, the novelist George Sand (pseudonym
used by Amantine Aurore Lucile Dupin), Chopin wrote: Three
Clear-minded, Mrime dwelled less on the disease, with doctorsthe most eminent on the islandexamined me.
which he had learned to live, than on the turbulence of his- One sniffed my spittle, the other tapped to see where the spit
tory that was dragging France into war with Prussia. In the came from, the third palpated me while listening to how I spat.
days following his death, Fanny Lagden, who watched over The first said I was going to die, the second that I was dying,
him till his last breath, wrote that These horrible political events the third that I was dead already.3 George Sand recounted
certainly shortened his life.2 Curtailed perhaps, but Mrime this Majorcan episode in her autobiography Histoire de ma
nonetheless died at 69, an age reached by few consumptives. Vie, where she describes tuberculosis as a wretched disease

Arts, artists, and the Romantic Disease in 19th-century France Percebois MEDICOGRAPHIA, Vol 37, No. 1, 2015 105
A TOUCH OF FRANCE
that provoked the hostility of the islands inhabitants. Scarcely
settled into their lodgings in Palma, the lovers were turfed out
by the owner, who demanded from them a large sum of mon-
ey to disinfect the house soiled by their presence, to white-
wash its walls, and to replace its furniture, which was to be
burned. Treated as plague victims, they found refuge at the
Valldemossa Charterhouse, thanks to help from the French
consul. But Chopins symptoms worsened: Our stay at the
Valldemossa Charterhouse, wrote George Sand, was a tor-
Prosper Mrime (1803-1870), writer and historian. Pastel, 1852,
by Simon Jacques Rochard.
De Agostini Picture Library/G. Dagli Orti/Bridgeman Images.
ture for him and a torment for me.3 The composer seemed
already to be dying, but he lived on for another decade, his
strength sapped by the disease, which gave birth to works
marked by melancholy. In 1849, he died at 39, in his apartment
at the Place Vendme in Paris. His younger sister Emilia too
had been carried off by the same disease 22 years before at
just 15, and they were reunited in death in her tomb at the Pre
Lachaise Cemetery in Paris.
The image of the artistic couple as victims of prophylactic
measures is redolent of the attitude Franois-Ren de Cha-
teaubriand encountered in Rome when looking for a last abode
for his consumptive lover Pauline de Beaumont: a dread among
those renting accommodation of the contagion of chest dis-
eases.4 As a young woman, de Beaumont was well known
in Parisian salons, but only entered the collective memory
after her death in 1803, which Chateaubriand recounted in his
106 MEDICOGRAPHIA, Vol 37, No. 1, 2015
Memoirs From Beyond the Grave. Extracts from her own diary
testify to deep despair: Why do I not have the courage to die?5
Yet her bravery, heroism even, is celebrated by Chateaubriand
when he describes her last moments. While he was in tears,
Pauline greeted death with a resolute spirit shaken only by her
death throes. Chateaubriand pressed a hand on her thin rib-
cage and felt her heart flutter: Oh! Moment of horror and ter-
ror, I felt it stop!5 Dead at 35, in a foreign land, Pauline de
Beaumont, through Memoirs From Beyond the Grave, be-
came a novelistic model for writers like the Goncourt broth-
ers who chose the Eternal City as the setting for their novel
Madame Gervaisais.
Pauline de Beaumonts fate foreshadowed that of Marie Bash-
kirtseff, a Russian painter who died in 1884 aged but 25, in
Paris, where she had come to study art at the Acadmie Ju-
lian. Like Pauline de Beaumont, Marie kept a diary, an emo-
tive account of her losing battle against tuberculosis. In it she
relates what fiction passes over, to wit medical horrors and
treatments that mutilate the female body: I burnt both sides
of my bosomI was unable to wear a low-cut dress for four
months. And these burns have to be repeated from time to
time to keep me alive. Theres no question of getting better. It
seems like I take a dark view of things, but no, its simply true.6
Maries clear-mindedness is striking and a reminder that wis-
dom is not the prerogative of age. This resignation went hand
in hand with unsparing self-criticism because, in her mind,
Marie Bashkirtseff despaired of achieving fame and saw tu-
berculosis as an alternative to mediocrity. In her diary entry for
21 August 1883, she wrote: I want to live. But I have no ge-
nius and it would be better to die.6 These words fail to do jus-
tice to this young polyglot artist and feminist. In a way, Maries
diary summarizes all of 19th-century literature on tuberculo-
sis and through its pages she joins the sisterhood of tragic
heroines of this golden age of the novel.
Tuberculosis as a literary device
Strangely, the consumptive young woman became a pop-
ular heroine in 19th-century writing, as in Eugne Sues Les
Mystres de Paris (1842-1843), one of the founding texts of
the French novel, whose imposing gallery of characters limns
the varied faces of the disease. There is Lorraine, the weep-
ing mother who caught the illness while nursing her child. And
little Adle Morel, the daughter of a poor lapidary, who at just
four years old appears in the story only long enough to die un-
der the eyes of compassionate readers. Sue does not even
spare his heroine, the daughter of the Grand Duke of Gerol-
stein, who believes her to be dead. Abandoned at six by a
moneygrubbing notary public, who passes her off for dead,
maltreated by a one-eyed woman nicknamed La Chouette
(The Owl), she endures loathsome treatment like a saint under
torture. She becomes known as Fleur-de-Marie or Goualeuse
(slang for the Virgin and the singer, respectively) and, in-
evitably, is stricken by tuberculosis. Far from spoiling her beau-
ty, sickness heightens the delicacy of her face and gives it an
Arts, artists, and the Romantic Disease in 19th-century France Percebois
 A TOUCH OF FRANCE

Tomb erected by
Franois Ren de
Chateaubriand,
writer, politician,
and diplomat, and
founder of French
Romanticism,
for his mistress
Pauline de
Beaumont, ne
Montmorin (1768-
1803), who died
of tuberculosis in
Rome. The epitaph
reads: After having
seen her entire
family, father, moth-
er, two brothers,
and sister perish,
Pauline de Mont-
morin, consumed
with a languishing
disease [consump-
tion] came to die
in this foreign land.
F. A. Chateau-
briand erected this
monument in her
memory.
Roger-Viollet.

Arts, artists, and the Romantic Disease in 19th-century France Percebois MEDICOGRAPHIA, Vol 37, No. 1, 2015 107
A TOUCH OF FRANCE
ethereal character: despite the wasted oval
of her face, the expression of her features,
her whole bearing, the grace of her atti-
tude were still worthy of the brushes
of great painters.7 Fleur-de-Marie
may be a fallen woman, her body
may have been sullied, but her
soul is untainted by vice. The more
time she spends with her bene-
factor, the mysterious Rodolphe
(who, unbeknown to both, is none
other than her natural father, the
Grand Duke), the more she be-
comes aware of her degradation
and turns to religion. For Eugne
Sue, tuberculosis stems from want,
but is also a form of atonement where
flesh and spirit merge. Paradoxically, the
illness is a deliverance, which, at the very
moment when she takes her vows as a nun,
enables the heroines final apotheosis and frees
her from an impure body so she can sit with God.
This conception of tuberculosis had a lasting influence on
French writers like Alexandre Dumas, fils, whose The Lady
of the Camellias (1848) was a homage to Marie Duplessis, a
Parisian courtesan of whom he was enamored and who died
of consumption at the age of 23. The novel recounts the trag-
ic passion of the young Armand Duval for the beautiful Mar-
guerite Gautier. The heroine knows only too well, right from
the start of the story, that she is doomed, because she says
I am ill, and with one of those diseases that never relent.8
The giddy round of balls, suppers, and lovers was just a diver-
tissement, as defined by Blaise Pascal: mere entertainment,
a distraction, something that serves only to escape boredom,
to avoid soul-searching, and above all to forget approaching
death. True love alone challenges her licentious behavior, a
bewitching interlude with Armand at Bougival, far removed
from escapades in Paris. But Marguerite is never more mortal
than when she wants to live and regain her health, so as to
live fully this passion in which she had lost faith.
Well before death closes its icy fingers on her breast, it is re-
nunciation that marks her end. By bending to the will of Ar-
mands father, by sacrificing her happiness to the honor of
her beloved, she commits what is tantamount to suicide. She
resumes her life as a courtesan, sells her body to repay debts,
and takes refuge in her inner being, her soul, which she knows
is pure because of the sacrifice of her love. Her fate is akin to
that of Fleur-de-Maries, for in sickness both find a form of
atonement. Love transforms Marguerites heart; tuberculosis
enables the elevation of her soul. The priest who hears Mar-
guerites deathbed confession is in no doubt: She lived a sin-
ner, but will die a Christian.8
108 MEDICOGRAPHIA, Vol 37, No. 1, 2015
Marie Duplessis (1824-1847), mistress to
Alexandre Dumas, fils, inspired the main char-
acter of Marguerite Gautier in La Dame aux
Camlias, published in 1948, adapted to
the stage in 1852, and set to music by
Verdi in 1853 in the opera La Traviata.
From the Journal des Romans, 1905, in which
the novel, still immensely popular more than 50
years after its first publication, was serialized.
Bibliothque Nationale de France/Bridge-
man Art Library.
As Susan Sontag noted in Illness
as Metaphor, Tuberculosis pro-
vided a redemptive death for the
fallen, like the young prostitute
Fantine in Les Misrables.9 Victor
Hugo gives us a religious reading of
the disease. From the outset, Fantines
physiognomy seems to predispose her
to this malady, for Hugo writes she is a
phantom possessed of the form of a nymph.10
Tuberculosis first becomes manifest in Fantines dry
cough, which appears while she is breastfeeding her daugh-
ter Cosette. No longer able to provide for Cosette, Fantine
returns to her birthplace to seek work, confiding her daugh-
ter to the loathsome Thnardiers. Fantine works her fingers
to the bone striving to meet their insistent demands for money
for Cosettes bed and board. Her symptoms worsen: cough-
ing, cold sweats, and the fever which grips her after a bour-
geois amuses himself by thrusting a handful of snow between
her bare shoulders. Hugos portrait of Fantine in the early chap-
ters of the book, praising the beauty of her shock of blond
hair and pearl-like teeth, two of whichthe upper incisors
she later sold in her struggle against destitution, contrasts
starkly with his descriptions of her decline: This creature of
five and twenty had a wrinkled brow, flabby cheeks, pinched
nostrils [] and her golden hair was growing out sprinkled
with gray.10 The realism of this portrait is, however, accompa-
nied by a form of idealization of death since, by dying, Fantine
recovers her lost purity. Like Fleur-de-Marie and Marguerite
before her, the prostitute is transformed into a heavenly crea-
ture and tuberculosis, while it ravages her body, seems also
to reveal the radiance of her soul: Her whole person was
trembling with an indescribable unfolding of wings, all ready
to open wide and bear her away.10 In Hugos romantic vi-
sion, Fantine is no longer the lifeless husk that is tossed into
a common grave, but an angel, as intimated by the metaphor
of wings.
The realistic novels of 19th-century France project a contrast-
ing image of illness, which goes hand in hand with anticler-
icalism and a rejection of the expiatory conception of tuber-
culosis. Madame Gervaisais, the last novel written jointly by
the Goncourt brothers, in 1869, differs in this way from Les
Misrables, which preceded it by just 7 years. As in the works
Arts, artists, and the Romantic Disease in 19th-century France Percebois
 A TOUCH OF FRANCE

considered above, the conversion of the heroine is linked to ed in corporeality. Religion is unable to save Jeanne and in
the advance of her illness, but the Goncourts see in this the Zolas eyes offers nothing more than the mirage of a first com-
defeat of the scientific mind, which seeks refuge in religion as munion, an unattainable dream, the promise of which exac-
death bears down. The mystical fever that grips Madame erbates her nervous disorders. Zolas story describes death,
Gervaisais is also a sickness that gradually isolates her from not as an elevation of a soul finally freed of its earthly shell, but
friends and family. In the last chapters of the book, her life as the end of suffering, the final cure.
is nothing more than mortification and leads to veritable de-
humanization: the increasing disembodiment of the physi- Tuberculosis as depicted in the visual arts
cal being carried her a little closer to the holy madness and One might expect that this theme of tuberculosis, so vivid in
hallucinatory delights of religious love.10 The spiritual impulse the 19th-century novel, would also flourish in the visual arts.
is thus stripped of its aura and constitutes nothing more than Yet few paintings portray the macabre spectacle of the dis-
one of the symptoms of the illness. ease. Marie Bashkirtseff seems to evoke her suffering in the
1883 work Self-Portrait, a Tear, where she turns away from
Anticlericalism is apparent also in the last chapter of Emile the onlooker as if to conceal her pain. Likewise, it would be
Zolas 1878 novel Une Page dAmour (A Love Episode), an vain to search for a self-portrait by Eugne Delacroix that re-
example of French naturalism, when the adulterous passion veals his condition. In his canvasses, as in his letters, Delacroix
between Hlne Grandjean, a wid-
ow with an 11-year-old daughter, and
Dr Deberle is finally consummated.
The daughter, Jeanne, jealous of the
place Dr Deberle increasingly occu-
pies in her mothers affections, will-
fully exposes herself to rain and cold
and contracts phthisis (tuberculosis),
dying just 3 weeks later. At the end
of the novel, the hereditary ill that runs
throughout the Rougon-Macquart
cycle of 20 novels, of which Une Page
dAmour is one, takes a new form.
Symbolically, it is Dr Deberle who pro-
nounces the name of Jeannes incur-
able malady, since in a way he is re-
sponsible for it: It is an acute phthisis,
he murmured at last, [] a case he
had much studied: the miliary tuber-
cles would multiply fast, the fits of
breathlessness would worsen.11

This medical precision is found in

Zolas description of Jeannes death
pangs, which are accompanied by vi-
olent vomiting, a detail authors often
omitted as they deemed it too degrad-
ing. Though Jeanne weakens as the
days pass, she does not acquire the
ethereal character of romantic hero-
ines because her symptoms are root-

Fantine. Oil painting by Margaret

Bernardine Hall (1886). 157116.2 cm,
located at the Walker Art Gallery,
National Museums, Liverpool, UK.
A consumptive Fantine tends her baby
Cosette, in Les Misrables by Victor Hugo.
Walker Art Gallery/National Museums
Liverpool/Bridgeman Images.

Arts, artists, and the Romantic Disease in 19th-century France Percebois MEDICOGRAPHIA, Vol 37, No. 1, 2015 109
A TOUCH OF FRANCE
Study for George Sand and Chopin, by Delacroix (14.312.6 cm)
is at the Louvre Museum, Paris. The original unfinished painting
(1838) was cut up and the portraits were sold separately.
RMN-Grand Palais (Muse du Louvre)/Michle Bellot.
was reticent about the disease to which he succumbed in
1863. Perhaps this was why he asked the photographer Gas-
pard-Flix Tournachon, known as Nadar, not to publish his
portrait, taken in 1858, in which Delacroixs hollow face bears
the stigmata of consumption. There is, however, a work by
Delacroix that suggests the disease: the portrait of his friend
Chopin and George Sand, sketched in 1838, just before the
couple left for Majorca. In this unfinished painting, Delacroix
sought to show the composer at the piano, while the novel-
110 MEDICOGRAPHIA, Vol 37, No. 1, 2015
Portrait of
George Sand
(left) and
Chopin (right),
by Eugne
Delacroix.
George Sand
(9757 cm)
is at the Ordrup-
gaardsamlingen,
Copenhagen.
AKG-images.
Frdric Chopin
(4538 cm) is
at the Louvre
Museum, Paris.
akg-images/Erich
Lessing.
ist seems to be lost in thoughts of love. Much later, in 1874,
the painting was cut in two, perhaps because the then owner
felt that two canvasses would fetch a higher price than one,
thus also materializing, as it were, the rupture between the
lovers, who had separated in 1845. The portrait of George
Sand now hangs in the Ordrupgaard Art Museum in Copen-
hagen, and the Chopin portrait is in the Louvre in Paris, the
shadow of death seemingly flitting over his somber face.
It was a foreign painter staying in Paris who gave us the most
doleful image of tuberculosis. In 1885, Edvard Munch won a
scholarship to travel from his native Norway to study in Paris.
It was there that he developed his ideas for The Sick Child,
which was to become a recurrent theme in his painting. While
Munch seems to come from the line of Norwegian artists like
the naturalist painter Christian Krohg, The Sick Child sets him
apart and is above all autobiographical. Tuberculosis killed
his mother and then his older sister Sophie, who died in 1877
at only 15: Disease, madness, and death were the black an-
gels who leaned over the cradle at my birth,12 he declared.
Munch alludes to Sophie in The Sick Child, by showing a
bedridden girl whose wan face is turned to a distressed moth-
er who hangs her head in distress. Munch painted five other
versions of this canvas, ceaselessly reliving his sisters linger-
ing death while trying to free himself of survivor guilt.
The months that Munch spent in Paris in 1885 were crucial
to the gestation of The Sick Child, which the following year
shocked at the Autumn Exhibition in Kristiania (the then name
of the Norwegian capital), less because of its subject than its
execution. Critics just saw daubings, blobs of paint, where-
as in reality the artists brush retranscribed his deep sorrow.
Arts, artists, and the Romantic Disease in 19th-century France Percebois

The Sick Child, by Edvard Munch, 1907. Oil on canvas, 12.1011.87 cm. Tate Gallery, London.
Derek Bayes/Lebrecht Music & Arts/Lebrecht Music & Arts/Corbis.
Tuberculosis on the operatic stage
In the 19th century, opera turned tuberculosis into a popu-
lar theme, as in La Traviata, the third in Giuseppe Verdis tril-
ogy, after Rigoletto and Il Trovatore. Verdi saw a theater pro-
duction of Alexandre Dumas The Lady of the Camellias in
1852 in Paris, where he was staying with his lover, the oper-
atic soprano Giuseppina Strepponi, who became his second
wife a few years later. If we are to believe his adoptive daugh-
ter, Maria Filomena, as he was leaving the theater Verdi heard
in his mind the opening notes of what was to become La
Arts, artists, and the Romantic Disease in 19th-century France Percebois
A TOUCH OF FRANCE
Traviata. In the depiction of Violetta la traviata (the woman
who strayed or the fallen woman), one sees Giuseppina: she
is this woman of easy virtue condemned by the composers
entourage. Verdi defended Giuseppina in a letter dated 21
January 1852 to his former father-in-law Antonio Barezzi
(whose daughter Margherita was Verdis first wife, who died
suddenly, perhaps of encephalitis, in June 1840 at the age of
26): I have nothing to hide. In my house there lives a lady,
free, independent, like myself a lover of solitude, possessing
a fortune that shelters her from all need. Neither I nor she owes
MEDICOGRAPHIA, Vol 37, No. 1, 2015 111
 Stricken Lady With Camellias
The tragic Romantic myth of the young woman falling prey
to consumption endures: Venera Gimadieva is Violetta in Verdis
opera La Traviata, directed by Tom Cairns and conducted by
Mark Elder at the Glyndebourne Festival, East Sussex, UK,
July-August 2014. The camellia flowers hark back to Alexandre
Dumas novel La Dame aux Camlias, which inspired the opera.
Robbie Jack/Robbie Jack/Corbis.
A TOUCH OF FRANCE
Original 1896 poster for La Bohme, opera by Giacomo Puccini,
which premiered in Turin on 1 February 1896, conducted by Arturo
Toscanini. Fondazione Puccini, Lucca, Italy.
De Agostini Picture Library/A.Dagli Orti/Bridgeman Images.
to anyone at all an account of our actions.13 With La Traviata,
Verdi created a paradox: that of a consumptive woman singing
operatic arias, an incongruity that did not escape the audi-
ences notice. The first performance at La Fenice, in Venice
on 6 March 1853, was a sadly foreseeable fiasco, the word
Verdi himself used. The composer was obliged to transpose
the action to the 17th century to avoid shocking middle-class
sensibilities, and had to come to terms with a singer called
Fanny Salvini-Donatelli whose stoutness and age (she was
38) were at odds with the portrait of a young woman wast-
ing away from consumption. It was not until Verdi reworked
the opera the following year, and then much later when the
role of Violetta was sung by sopranos like Maria Callas, that
La Traviata won acclaim.
Callas also sang the role of the heroine of Puccinis La Bohme,
Mimi, who like Verdis Violetta died of tuberculosis in her prime.
Premiered by Puccini on 1 February 1896, La Bohme is an
adaptation of Scnes de la Vie de Bohme by Henry Murger
(1851), which retraces the precarious existence of four young
114 MEDICOGRAPHIA, Vol 37, No. 1, 2015
Poster for the motion picture Moulin Rouge! starring Nicole
Kidman and Ewan McGregor, released in 2001, the latest avatar
of La Dame aux Camlias, La Traviata, La Bohme.
akg-images/Album/20TH CEN.
Parisian artists. Unlike his contemporaries, Murger describes
a mirthful world of hardship peopled by characters who flit
around and fall in love, while living from hand to mouth,
trusting in Providence. This unrestrained merriment fades at
the death of Mimi, a pretty and flirtatious working-class girl
who drudges as a seamstress. Mimi is the fickle lover of the
poet Rodolfo, whom she leaves for a viscount, tempted by
the hats and dresses he can provide.
Puccinis opera, which over the years has completely eclipsed
Murgers stories, is rooted in this amorous intrigue and ends
with Mimis death, unlike the original text. Study of La Traviata
and La Bohme shows them to be sister works and it is little
wonder they inspired Baz Luhrmann to direct Moulin Rouge!
his award-winning 2001 film. As his heroine, Luhrmann chose
a courtesan called Satine, who is reminiscent of The Lady
of the Camellias, and portrays her Bohemian world in Mont-
martre, peopled by famous figures like the painter Henri de
Toulouse-Lautrec. Her lover, Christian, is modeled on Puccinis
Rodolfo and is the epitome of Murgers definition, in the pref-
Arts, artists, and the Romantic Disease in 19th-century France Percebois
 A TOUCH OF FRANCE

ace to Scnes de la Vie de Bohme, of amateur Bohemians,
who find Bohemian life to be an existence full of appeal.14
In the film, as in Murgers stories or La Bohme, the young
woman perishes at the very moment she is resolved to aban-
don her wicked ways for true love. Thus, we see how from
Murgers Scnes de la Vie de Bohme to Moulin Rouge! the
theme of illness has fascinated through the ages and the arts,
inspiring tragedies timeless in their appeal.
In the 1800s, tuberculosis was seen as the malady of the
century and as such echoed the melancholy of the Roman-
tics and inspired the Realists. Viewed as the disease of the
poor, in reality tuberculosis affected all social classes and
ushered many artists, writers, and composers into an early
grave, and into legends of blighted destinies. Tragic stories
that fire the imagination today, just as they did in the heady
days of 19th-century Romanticism.

References
1. Mrime P. Lettres une Inconnue (Jenny Dacquin), Prcdes dune Etude
sur Mrime. Paris, France: Calmann-Lvy; 1881:359-360.
2. Mrime P. Lettres M. Panizzi: 1850-1870. Vol II. Paris, France: Calmann-Lvy;
1881:444.
3. Chovelon B, Abbadie C. La Chartreuse de Valldemosa: George Sand et Chopin
Majorque. Paris, France: Editions Payot et Rivages; 1999.
4. de Goncourt E, de Goncourt J. uvres Compltes. Vol VII. Paris, France: Honor
Champion; 2013:98.
5. de Chateaubriand FR. Mmoires dOutre-Tombe. Vol I. Paris, France: Galli-
mard, Bibliothque de la Pliade; 1951.
6. Bashkirtseff M. Mon Journal, Date du Lundi 5 Mai 1884. Vol XVI.
7. Sue E. Les Mystres de Paris. ditions Robert Laffont: Paris, France; 1989:298.
8. Dumas A, fils. La Dame aux Camlias. Paris, France: Le Livre de Poche: 1983.
9. Sontag S. Illness as Metaphor. New York, NY: Farrar, Straus and Giroux; 1977.
10. Hugo V. Les Misrables. Vol I. Paris, France: Garnier-Flammarion; 1967.
11. Zola E. Une Page dAmour. Paris, France: Garnier-Flammarion; 1973:320-321.
12. Heller R. Munch. Paris, France: Flammarion; 1991:10.
13. Gefen G. Verdi par Verdi. Paris, France: ditions de lArchipel; 2001:136.
14. Murger H. Scnes de la Vie de Bohme. Paris, France: Gallimard; 1988:39.

DESTINES TRAGIQUES : LES ARTS, LES ARTISTES

ET LA MALADIE ROMANTIQUE DANS LA FRANCE DU XIXE SICLE
Au XIX e
sicle, lpidmie de tuberculose fait des milliers de victimes, illustres ou anonymes, et apparat comme une
maladie mystrieuse dont on ne gurit pas. En France, elle touche de nombreux artistes, comme en tmoignent la
correspondance de Prosper Mrime ou les rcits autobiographiques de Georges Sand et Franois-Ren de Cha-
teaubriand. La maladie devient galement un thme fictionnel majeur dans le roman de lpoque : chez Eugne Sue,
Alexandre Dumas fils ou le romantique Victor Hugo, elle prend un caractre religieux et sabat sur de frles hrones
cherchant expier leurs fautes ; en revanche, chez les ralistes comme les frres Goncourt ou Emile Zola, elle sert
un propos anticlrical. Dans le domaine pictural, peu dartistes reprsentent la maladie et cest Edvard Munch, de pas-
sage Paris en 1885, qui en offre limage la fois la plus explicite et la plus pathtique dans LEnfant Malade. Plus
que la peinture, cest lart lyrique qui fait de la tuberculose un vritable spectacle et cre le paradoxe de la phtisique
chantante : en adaptant les romans franais dAlexandre Dumas et Henry Murger, les compositeurs Verdi et Puccini
donnent naissance La Traviata et La Bohme, deux opras dont le succs ne se dment pas de nos jours. Ainsi,
la tuberculose est un thme artistique qui traverse le roman, la peinture et lopra, et inspire dsormais des adap-
tations cinmatographiques.

Arts, artists, and the Romantic Disease in 19th-century France Percebois MEDICOGRAPHIA, Vol 37, No. 1, 2015 115
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